Polycythemia Vera (PV)
Gokce A. Toruner, MD, PhD
UT MD Anderson Cancer Center
Cancer Sub-Classification / Subtype
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.
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.
- 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)
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.
- 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
No specific immunophenotypic characteristics
Chromosomal Rearrangements (Gene Fusions)
Characteristic Chromosomal Aberrations / Patterns
Frequent cytogenetic abnormalities are listed below.
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 .
- Associated with younger age, increased hemoglobulin and hematocrit levels and lower WBC compated to cases with JAK2 V617F mutations 
|Gene||Mutation||Oncogene/Tumor Suppressor/Other||Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)||Prevalence (COSMIC/TCGA/Other)|
|JAK2||Exon 12 mutations||Oncogene||GOF; Driver||3%|
|Concomitant Mutations||TET2, ASXL1, SH2B3, CEBPA, ZRSR2,S3FB1,CSF3R,KITSRSF2,IDH2,DNMT3A,SUZ12.SETB1,RUNX1.CBL,TP53,FLT3 |
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.
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)
- 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.
- Adverse factors for leukemic transformation
- Advanced age
- Abnormal karyotype (occur in progressive stages)
- AXL1, SRF2, IDH1, IDH2, RUNX1 mutations.
- Adverse prognostic factors for thrombosis
- Advanced age
- History of thrombosis
Therapeutic implications 
- 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
- Geographical clustering in Pennsylvania  and Quebec were observed
- JAK2 46/1 haplotype has been suggested for genetic predisposition
- A whole exome study on a multi-generation family from Finland suggest several candidate SNPs
- As of July 2020, a known family with an unequivocal high penetrance mutation has not been documented.
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- NCCN guidelines for myefoloproliferative neoplasms https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf (last accessed 8/1/2020)
- 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)
- A, Tefferi; et al. (2020). "Mutation-enhanced international prognostic systems for essential thrombocythaemia and polycythaemia vera". PMID 31945802.
- V, Seaman; et al. (2009). "Use of molecular testing to identify a cluster of patients with polycythemia vera in eastern Pennsylvania". PMID 19190168.
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- 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)
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