Polycythaemia vera

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Haematolymphoid Tumours (5th ed.)

editHAEM5 Conversion Notes
This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Polycythemia Vera (PV).

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Primary Author(s)*

Gokce A. Toruner, MD, PhD

UT MD Anderson Cancer Center

Cancer Category / Type

Myeloproliferative neoplasms

Cancer Sub-Classification / Subtype

Polycythemia Vera

Definition / Description of Disease

  • Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm (MPN).
  • Increased red blood cell (RBC) production independent of normal regulation of erythropoiesis.
  • Proliferation of other myeloid cells such as granulocytes and megakaryocytes are also frequently observed (panmyelosis).
  • Very high majority of PV patients have JAK2 V617F or JAK2 exon 12 mutations.
  • Phases of PV
    • Polycythemic phase: Early phase characterized by increased hemoglobulin and hematocrit levels and increased RBC mass.
    • Post polycythemic myelofibrosis: Later phase associated bone marrow fibrosis, ineffective hematopoiesis (and cytopenias) and extramedullary hematopoiesis.[1]

Synonyms / Terminology

  • Polycythemia rubra vera
  • Proliferative polycythemia
  • Chronic erythema
  • Maladie de Vaquez

Epidemiology / Prevalence

  • Incidence rate: 1.8/100,000 in the US.
  • Slight male predominance.
  • Median age of diagnosis: 60 years, but it can occur any age.[2]

Clinical Features

Put your text here and fill in the table (Instruction: Can include references in the table)

Signs and Symptoms EXAMPLE Asymptomatic (incidental finding on complete blood counts)

EXAMPLE B-symptoms (weight loss, fever, night sweats)

EXAMPLE Fatigue

EXAMPLE Lymphadenopathy (uncommon)

Laboratory Findings EXAMPLE Cytopenias

EXAMPLE Lymphocytosis (low level)


editv4:Clinical Features
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  • Insidious onset  of disease and PV is often discovered incidentally due to increased hemoglobin and hematocrit levels in a routine CBC
  • Non-specific symptoms due to hypertension and vascular issues resulting from increased viscosity of the blood
  • Frequent complaints: Headache, dizziness, vertigo, tinnitus, visual disturbances, pruritus, erythromelalgia
  • Frequent physical examination findings: Splenomegaly, facial plethora
  • About 20% of the cases have documented complications of arterial and venous thrombosis such as myocardial ischemia, cerebrovascular events, deep venous thrombosis, and hepatic portal vein thrombosis.
  • May evolve into myelofibrosis, MDS or post PV blast phase (formerly known as acute leukemia)[1][3]

Sites of Involvement

  • Bone marrow is the major affected site.
  • Splenic and hepatic extramedullary hematopoiesis can be observed in later stages.
  • Any organ can be damaged due to vascular involvement.[1]

Morphologic Features

Polycythemic phase

  • Hypercellularity (notable in subcortical marrow space)
  • Panmyelosis (with marked erythroid and megakaryocytic predominance)
  • Pleomorphic megakaryocytes
  • Decreased often absent iron deposits

Post polycythemic myelofibrosis phase

  • Grade 2-3 BM fibrosis
  • Decreased erythropoiesis (anemia) and granulopoiesis
  • Manifestation of myeloid metaplasia and extramedullary hematopoiesis: Leukoeryhroblastosis, teardrop RBC, splenomegaly[1]

Immunophenotype

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Finding Marker
Positive (universal) EXAMPLE CD1
Positive (subset) EXAMPLE CD2
Negative (universal) EXAMPLE CD3
Negative (subset) EXAMPLE CD4


editv4:Immunophenotype
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No specific immunophenotypic characteristics

Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE t(9;22)(q34;q11.2) EXAMPLE 3'ABL1 / 5'BCR EXAMPLE der(22) EXAMPLE 20% (COSMIC)

EXAMPLE 30% (add reference)

Yes No Yes 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).


editv4:Chromosomal Rearrangements (Gene Fusions)
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None


editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).
Please incorporate this section into the relevant tables found in:
  • Chromosomal Rearrangements (Gene Fusions)
  • Individual Region Genomic Gain/Loss/LOH
  • Characteristic Chromosomal Patterns
  • Gene Mutations (SNV/INDEL)

Diagnosis[1]

  • Major criteria
    • Hemoglobin >16.5 g/dL in men or > 16 g/dL in women; or hematocrit >49% in men or > 48% in women or increased red blood cell mass
    • Bone marrow tri-lineage proliferation with Pleomorphic mature megakaryocytes.
    • Presence of JAK2 V617F mutation or JAK2 exon 12 mutations.
  • Minor criterion:

·        Subnormal serum erythropoietin level 

For the diagnosis either all major criteria or first two major criteria and minor criterion should be fulfilled.

Prognosis[4]

  • Adverse factors for leukemic transformation
    • Advanced age
    • Leukocytosis
    • Abnormal karyotype (occur in progressive stages)
    • AXL1, SRF2, IDH1, IDH2, RUNX1 mutations.
  • Adverse prognostic factors for thrombosis
    • Advanced age
    • History of thrombosis

Therapeutic implications [5]

  • Low risk (Age <60 years and no history of thrombosis)
    • Phlebotomy to maintain hematocrit below 45%
    • Low dose-aspirin
  • High risk
    • In addition to phlebotomy and aspirin, cytoreductive therapy (hydroxyurea of peginterferon alfa-2a.)
    • For inadequate or loss of response with cytoreductive threapy: ruxolitinib or clinical trials

Individual Region Genomic Gain / Loss / LOH

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Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE

7

EXAMPLE Loss EXAMPLE

chr7:1- 159,335,973 [hg38]

EXAMPLE

chr7

Yes Yes 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 reference).

EXAMPLE

8

EXAMPLE Gain EXAMPLE

chr8:1-145,138,636 [hg38]

EXAMPLE

chr8

No No No EXAMPLE

Common recurrent secondary finding for t(8;21) (add reference).

editv4:Genomic Gain/Loss/LOH
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Frequent cytogenetic abnormalities are listed below[1].

Chromosome Number Gain/Loss/Amp/LOH Region
1 Gain 1q
8 Gain +8
9 Gain +9
20 Loss 20q

Characteristic Chromosomal Patterns

Put your text here (EXAMPLE PATTERNS: 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)

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE

Co-deletion of 1p and 18q

Yes No No EXAMPLE:

See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns
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Cytogenetic abnormalities is present about 20% of the cases (see genomic gain/loss/LOH section). Associated with progression and adverse prognosis[4][6].

Gene Mutations (SNV / INDEL)

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Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) Prevalence (COSMIC / TCGA / Other) Concomitant Mutations Mutually Exclusive Mutations Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE: TP53; Variable LOF mutations

EXAMPLE:

EGFR; Exon 20 mutations

EXAMPLE: BRAF; Activating mutations

EXAMPLE: TSG EXAMPLE: 20% (COSMIC)

EXAMPLE: 30% (add Reference)

EXAMPLE: IDH1 R123H EXAMPLE: EGFR amplification EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).


Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) 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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  • JAK2 V617F mutations
    • Highly frequent, but not diagnostic for PV, as more than half of Essential Throbocythemia and Primary Myelofibrosis have JAK2 V617F.
    • This mutation is located in the pseudokinase domain of the JAK2 protein
  • JAK2 exon 12 mutations
    • Located in the so called linked region (amino acids 536- 547) between the SRC2 homology (SH2) and pseudokinase domains.
    • Most of these mutations are in frame indels [7].
    • Associated with younger age, increased hemoglobulin and hematocrit levels and lower WBC compated to cases with JAK2 V617F mutations [5]
Gene Mutation Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence (COSMIC/TCGA/Other)
JAK2 V617F Oncogene GOF; Driver 95-97%
JAK2 Exon 12 mutations Oncogene GOF; Driver 3%

Other Mutations

Most frequent mutations other than JAK2 in PV are TET2 and ASXL1 [8][9].

Type Gene/Region/Other
Concomitant Mutations TET2, ASXL1, SH2B3, CEBPA, ZRSR2,S3FB1,CSF3R,KITSRSF2,IDH2,DNMT3A,SUZ12.SETB1,RUNX1.CBL,TP53,FLT3 [8][9]

Epigenomic Alterations

Methylation of promoter regions has not been documented, but mutations of genes important in epigenetic regulation are observed[8][9]

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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  • JAK2 is physically bound to homodimeric receptors: EPOR, MPL and G-CSFR and act as the catalytic part of these receptors upon the binding of the cytokine to the receptor.
  • JAK2 V617F mutation results in non-cytokine dependent constitutive phosphorylation and activation of the down-stream STAT molecules and Pl3K and MAPK pathways[7].

Genetic Diagnostic Testing Methods

  • Complete blood count
  • Bone marrow aspiration and biopsy with trichrome reticulin stain
  • NGS panels including JAK2 gene analysis
  • Chromosome analysis and FISH
  • Serum erythropoietin levels.

Familial Forms

  • Geographical clustering in Pennsylvania [10]  and Quebec [11]were observed
  • JAK2 46/1 haplotype has been suggested for genetic predisposition[12]
  • A whole exome study on a multi-generation family from Finland suggest several candidate SNPs[13]
  • As of July 2020, a known family with an unequivocal high penetrance mutation has not been documented.

Additional Information

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Links

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References

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  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Thiele J, Kvasnicka HM, Orazi A, Tefferi A, Birgegard G, Barbui T (2017). Polycythemia Vera, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4thedition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Editors. IARC Press: Lyon, France, p39-43
  2. ↑ Rm, Shallis; et al. (2020). "Epidemiology of the classical myeloproliferative neoplasms: The four corners of an expansive and complex map". PMID 32517877 Check |pmid= value (help).
  3. ↑ Tefferi A. Clinical manifestations and diagnosis of polycythemia vera https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polycythemia-vera (last accessed 8/1/2020)
  4. ↑ 4.0 4.1 A, Tefferi; et al. (2019). "Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management". PMID 30281843.
  5. ↑ 5.0 5.1 NCCN guidelines for myefoloproliferative neoplasms https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf (last accessed 8/1/2020)
  6. ↑ G, Tang; et al. (2017). "Characteristics and clinical significance of cytogenetic abnormalities in polycythemia vera". doi:10.3324/haematol.2017.165795. PMC 5685217. PMID 28473622.CS1 maint: PMC format (link)
  7. ↑ 7.0 7.1 W, Vainchenker; et al. (2017). "Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms". PMID 28028029.
  8. ↑ 8.0 8.1 8.2 A, Tefferi; et al. (2016). "Targeted deep sequencing in polycythemia vera and essential thrombocythemia". doi:10.1182/bloodadvances.2016000216. PMC 5744051. PMID 29296692.CS1 maint: PMC format (link)
  9. ↑ 9.0 9.1 9.2 A, Tefferi; et al. (2020). "Mutation-enhanced international prognostic systems for essential thrombocythaemia and polycythaemia vera". PMID 31945802.
  10. ↑ V, Seaman; et al. (2009). "Use of molecular testing to identify a cluster of patients with polycythemia vera in eastern Pennsylvania". PMID 19190168.
  11. ↑ M, Le; et al. (2019). "Identification of significant geographic clustering of polycythemia vera cases in Montreal, Canada". PMID 31381139.
  12. ↑ D, Olcaydu; et al. (2009). "A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms". PMID 19287385.
  13. ↑ Eam, Hirvonen; et al. (2017). "Whole-exome sequencing identifies novel candidate predisposition genes for familial polycythemia vera". doi:10.1186/s40246-017-0102-x. PMC 5397753. PMID 28427458.CS1 maint: PMC format (link)

Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome. *Citation of this Page: “Polycythaemia vera”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/13/2023, https://ccga.io/index.php/HAEM5:Polycythaemia_vera.

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