Plasma cell neoplasms with associated paraneoplastic syndrome

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:POEMS Syndrome.

Other relevent pages include: HAEM4:TEMPI Syndrome

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(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

Sohini Anand, MBBS

Tharanga Niroshini Senaratne, PhD

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	B-cell lymphoid proliferations and lymphomas
Family	Plasma cell neoplasms and other diseases with paraproteins
Type	Plasma cell neoplasms
Subtype(s)	Plasma cell neoplasms with associated paraneoplastic syndrome

WHO Essential and Desirable Genetic Diagnostic Criteria

(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)

WHO Essential Criteria (Genetics)*
WHO Desirable Criteria (Genetics)*
Other Classification

*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.

Related Terminology

(Instructions: The table will have the related terminology from the WHO autocompleted.)

Acceptable
Not Recommended

Gene Rearrangements

Put your text here and fill in the table (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: ABL1	EXAMPLE: BCR::ABL1	EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.	EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: Common (CML)	EXAMPLE: D, P, T	EXAMPLE: Yes (WHO, NCCN)	EXAMPLE: The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).
EXAMPLE: CIC	EXAMPLE: CIC::DUX4	EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5.	EXAMPLE: t(4;19)(q25;q13)	EXAMPLE: Common (CIC-rearranged sarcoma)	EXAMPLE: D		EXAMPLE: DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
EXAMPLE: ALK	EXAMPLE: ELM4::ALK Other fusion partners include KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1	EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18.	EXAMPLE: N/A	EXAMPLE: Rare (Lung adenocarcinoma)	EXAMPLE: T		EXAMPLE: Both balanced and unbalanced forms are observed by FISH (add references).
EXAMPLE: ABL1	EXAMPLE: N/A	EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.	EXAMPLE: N/A	EXAMPLE: Recurrent (IDH-wildtype Glioblastoma)	EXAMPLE: D, P, T

editv4:Chromosomal Rearrangements (Gene Fusions)

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editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

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• Chromosomal Rearrangements (Gene Fusions)
• Individual Region Genomic Gain/Loss/LOH
• Characteristic Chromosomal Patterns
• Gene Mutations (SNV/INDEL)

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

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.

RADIATION THERAPY:

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.

MONITORING OF RESPONSE FOLLOWING THERAPY

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

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Individual Region Genomic Gain/Loss/LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)

Chr #	Gain, Loss, Amp, LOH	Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]	Relevant Gene(s)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7	EXAMPLE: Unknown	EXAMPLE: D, P	EXAMPLE: No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8	EXAMPLE: Unknown	EXAMPLE: D, P		EXAMPLE: Common recurrent secondary finding for t(8;21) (add references).
EXAMPLE: 17	EXAMPLE: Amp	EXAMPLE: 17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]	EXAMPLE: ERBB2	EXAMPLE: D, P, T		EXAMPLE: Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.

editv4:Genomic Gain/Loss/LOH

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A study conducted at Peking Union Medical college Hospital from November 2011 to June 2012 showed the following chromosomal abnormalities associated with POEMS syndrome.. 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

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Characteristic Chromosomal or Other Global Mutational Patterns

Put your text here and fill in the table (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Chromosomal Pattern	Molecular Pathogenesis	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: Co-deletion of 1p and 18q	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).	EXAMPLE: Common (Oligodendroglioma)	EXAMPLE: D, P
EXAMPLE: Microsatellite instability - hypermutated		EXAMPLE: Common (Endometrial carcinoma)	EXAMPLE: P, T

editv4:Characteristic Chromosomal Aberrations / Patterns

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Gene Mutations (SNV/INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Gene	Genetic Alteration	Tumor Suppressor Gene, Oncogene, Other	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE:EGFR	EXAMPLE: Exon 18-21 activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (lung cancer)	EXAMPLE: T	EXAMPLE: Yes (NCCN)	EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
EXAMPLE: TP53; Variable LOF mutations	EXAMPLE: Variable LOF mutations	EXAMPLE: Tumor Supressor Gene	EXAMPLE: Common (breast cancer)	EXAMPLE: P		EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations	EXAMPLE: Activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (melanoma)	EXAMPLE: T

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)

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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. HAEM4: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.

PROPERTIES OF GENES INVOLVED IN POEMS SYNDROME

Somatic genes mutations	%	Type of mutations	20 MUTATIONS	LOCATION
KLHL6	20	MISSENSE MUTATION	R559Q L71R A91D L258P	BTB BACK kelch1
LTB	15	MISSENSE MUTATION SPLICE-SITE MUTATION	Q51E T56R 163-1 G>C	TNF
EHD1	10	MISSENSE MUTATION SPLICE-SITE MUTATION	G70D 71_75 del 404+2 T>A	Dynamin N EFhand4
EML4	10	MISSENSE MUTATION	S68N D243N	HELP
HEPHL1	10	MISSENSE MUTATION	A270V V526I	cu oxidase 2/3
PCDH10	10	MISSENSE MUTATION	S464C V565M L782R L397L	Pkinase
HIPK1	10	MISSENSE MUTATION	N530S I682V	cadherine2/c2

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.

SOMATIC MUTATIONS OF FOLLOWING GENES CAN LEAD TO DEVELOPMENT OF NEUROPATHY IN POEMS SYNDROME

GENE	CHROMOSOME LOCATION	LOCATION	AA changes	Stability (Kcal/mol)
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

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Epigenomic Alterations

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.

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations	EXAMPLE: Histone modification, chromatin remodeling	EXAMPLE: Abnormal gene expression program

editv4:Genes and Main Pathways Involved

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PATHOGENESIS OF POEMS SYNDROME

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.

• 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.
• λ Immunoglobulins

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Genetic 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.

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.

Familial Forms

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Additional Information

PROGNOSIS

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

GOOD PROGNOSIS

• Response to radiotherapy
• Absence of clubbing and effusions.

POOR PROGNOSIS

• 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.

DIFFRENTIAL DIAGNOSES

• 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.
• 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.

• 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%. 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)
• 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.

Links

HAEM4:Plasma Cell Neoplasms with Associated Paraneoplastic Syndrome

References

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Notes

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*Citation of this Page: “Plasma cell neoplasms with associated paraneoplastic syndrome”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/11/2025, https://ccga.io/index.php/HAEM5:Plasma_cell_neoplasms_with_associated_paraneoplastic_syndrome.