HAEM5:Polycythaemia vera

Haematolymphoid Tumours (5th ed.)

editHAEM5 Conversion Notes

This page was converted to the new template on 2023-11-30. The original page can be found at HAEM4:Polycythemia Vera (PV).

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.

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.

Clinical Features

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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)

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.

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

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

• 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

• 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

• 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.

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.

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 .
  • 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	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 .

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

Epigenomic Alterations

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

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.

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  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.

Additional Information

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Links

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References

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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 11/30/2023, https://ccga.io/index.php/HAEM5:Polycythaemia_vera.