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

  • 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

No specific immunophenotypic characteristics

Chromosomal Rearrangements (Gene Fusions)

None

Characteristic Chromosomal Aberrations / Patterns

Cytogenetic abnormalities is present about 20% of the cases (see genomic gain/loss/LOH section). Associated with progression and adverse prognosis[4][5].

Genomic Gain/Loss/LOH

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

Gene Mutations (SNV/INDEL)

  • 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 [6].
    • Associated with younger age, increased hemoglobulin and hematocrit levels and lower WBC compated to cases with JAK2 V617F mutations [7]
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]

Epigenomics (Methylation)

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

  • 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[6].

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.

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

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 [7]

  • 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

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.

Other 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. 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)
  6. 6.0 6.1 W, Vainchenker; et al. (2017). "Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms". PMID 28028029.
  7. 7.0 7.1 NCCN guidelines for myefoloproliferative neoplasms https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf (last accessed 8/1/2020)
  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

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