View source for HAEM4Backup:Polycythemia Vera (PV)

==Primary Author(s)*==

Gokce A. Toruner, MD, PhD

UT MD Anderson Cancer Center

__TOC__

==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.<ref name=":0">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, 4<sup>th</sup>edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Editors. IARC Press: Lyon, France, p39-43</ref>

==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.<ref>{{Cite journal|last=Rm|first=Shallis|last2=R|first2=Wang|last3=A|first3=Davidoff|last4=X|first4=Ma|last5=Na|first5=Podoltsev|last6=Am|first6=Zeidan|date=2020|title=Epidemiology of the classical myeloproliferative neoplasms: The four corners of an expansive and complex map|url=https://pubmed.ncbi.nlm.nih.gov/32517877/|language=en|pmid=32517877}}</ref>

==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)<ref name=":0" /><ref>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)</ref>

==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.<ref name=":0" />

==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<ref name=":0" />

==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<ref name=":1">{{Cite journal|last=A|first=Tefferi|last2=T|first2=Barbui|date=2019|title=Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management|url=https://pubmed.ncbi.nlm.nih.gov/30281843/|language=en|pmid=30281843}}</ref><ref>{{Cite journal|last=G|first=Tang|last2=Je|first2=Hidalgo Lopez|last3=Sa|first3=Wang|last4=S|first4=Hu|last5=J|first5=Ma|last6=S|first6=Pierce|last7=W|first7=Zuo|last8=Aa|first8=Carballo-Zarate|last9=Cc|first9=Yin|date=2017|title=Characteristics and clinical significance of cytogenetic abnormalities in polycythemia vera|url=https://pubmed.ncbi.nlm.nih.gov/28473622/|language=en|doi=10.3324/haematol.2017.165795|pmc=PMC5685217|pmid=28473622}}</ref>.

==Genomic Gain/Loss/LOH==

Frequent cytogenetic abnormalities are listed below<ref name=":0" />.

{| class="wikitable sortable"
|-
!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

*''JAK''2 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 <ref name=":2">{{Cite journal|last=W|first=Vainchenker|last2=R|first2=Kralovics|date=2017|title=Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/28028029/|language=en|pmid=28028029}}</ref>.
**Associated with younger age, increased hemoglobulin and hematocrit levels and lower WBC compated to cases with JAK2 V617F mutations <ref name=":3">NCCN guidelines for myefoloproliferative neoplasms https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf (last accessed 8/1/2020)</ref>

{| class="wikitable sortable"
|-
!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'' <ref name=":4">{{Cite journal|last=A|first=Tefferi|last2=Tl|first2=Lasho|last3=P|first3=Guglielmelli|last4=Cm|first4=Finke|last5=G|first5=Rotunno|last6=Y|first6=Elala|last7=A|first7=Pacilli|last8=Ca|first8=Hanson|last9=A|first9=Pancrazzi|date=2016|title=Targeted deep sequencing in polycythemia vera and essential thrombocythemia|url=https://pubmed.ncbi.nlm.nih.gov/29296692/|language=en|doi=10.1182/bloodadvances.2016000216|pmc=PMC5744051|pmid=29296692}}</ref><ref name=":5">{{Cite journal|last=A|first=Tefferi|last2=P|first2=Guglielmelli|last3=Tl|first3=Lasho|last4=G|first4=Coltro|last5=Cm|first5=Finke|last6=Gg|first6=Loscocco|last7=B|first7=Sordi|last8=N|first8=Szuber|last9=G|first9=Rotunno|date=2020|title=Mutation-enhanced international prognostic systems for essential thrombocythaemia and polycythaemia vera|url=https://pubmed.ncbi.nlm.nih.gov/31945802/|language=en|pmid=31945802}}</ref>.
{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
|Concomitant Mutations||''TET2, ASXL1, SH2B3, CEBPA, ZRSR2,S3FB1,CSF3R,KITSRSF2,IDH2,DNMT3A,SUZ12.SETB1,RUNX1.CBL,TP53,FLT3'' <ref name=":4" /><ref name=":5" />
|}

==Epigenomics (Methylation)==

Methylation of promoter regions has not been documented, but mutations of genes important in epigenetic regulation are observed<ref name=":4" /><ref name=":5" />

==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.
*J''AK2'' V617F mutation results in non-cytokine dependent constitutive phosphorylation and activation of the down-stream STAT molecules and Pl3K and MAPK pathways<ref name=":2" />.

==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)==

''<u>Diagnosis</u>''<ref name=":0" />

*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.

''<u>Prognosis</u>''<ref name=":1" />

*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

''<u>Therapeutic implications</u>'' <ref name=":3" />

*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 <ref>{{Cite journal|last=V|first=Seaman|last2=A|first2=Jumaan|last3=E|first3=Yanni|last4=B|first4=Lewis|last5=J|first5=Neyer|last6=P|first6=Roda|last7=M|first7=Xu|last8=R|first8=Hoffman|date=2009|title=Use of molecular testing to identify a cluster of patients with polycythemia vera in eastern Pennsylvania|url=https://pubmed.ncbi.nlm.nih.gov/19190168/|language=en|pmid=19190168}}</ref>  and Quebec  <ref>{{Cite journal|last=M|first=Le|last2=Fm|first2=Ghazawi|last3=E|first3=Rahme|last4=A|first4=Alakel|last5=E|first5=Netchiporouk|last6=E|first6=Savin|last7=A|first7=Zubarev|last8=Sj|first8=Glassman|last9=D|first9=Sasseville|date=2019|title=Identification of significant geographic clustering of polycythemia vera cases in Montreal, Canada|url=https://pubmed.ncbi.nlm.nih.gov/31381139/|language=en|pmid=31381139}}</ref>were observed
*JAK2 46/1 haplotype has been suggested for genetic predisposition<ref>{{Cite journal|last=D|first=Olcaydu|last2=A|first2=Harutyunyan|last3=R|first3=Jäger|last4=T|first4=Berg|last5=B|first5=Gisslinger|last6=I|first6=Pabinger|last7=H|first7=Gisslinger|last8=R|first8=Kralovics|date=2009|title=A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/19287385/|language=en|pmid=19287385}}</ref>
*A whole exome study on a multi-generation family from Finland suggest several candidate SNPs<ref>{{Cite journal|last=Eam|first=Hirvonen|last2=E|first2=Pitkänen|last3=K|first3=Hemminki|last4=La|first4=Aaltonen|last5=O|first5=Kilpivaara|date=2017|title=Whole-exome sequencing identifies novel candidate predisposition genes for familial polycythemia vera|url=https://pubmed.ncbi.nlm.nih.gov/28427458/|language=en|doi=10.1186/s40246-017-0102-x|pmc=PMC5397753|pmid=28427458}}</ref>
*As of July 2020, a known family with an unequivocal high penetrance mutation has not been documented.

==Other Information==

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==Notes==
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