Bailey.Glen: Created page with "==Primary Author(s)*== Gokce A. Toruner, MD, PhD UT MD Anderson Cancer Center TOC ==Cancer Category/Type== Myeloproliferative neoplasms ==Cancer Sub-Classification /..."

2023-11-03T17:27:42Z

Created page with "==Primary Author(s)*== Gokce A. Toruner, MD, PhD UT MD Anderson Cancer Center __TOC__ ==Cancer Category/Type== Myeloproliferative neoplasms ==Cancer Sub-Classification /..."

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==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, 4thedition. 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)==

''Diagnosis''<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.

''Prognosis''<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

''Therapeutic implications'' <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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HAEM4Backup:Polycythemia Vera (PV) - Revision history

Bailey.Glen: Created page with "==Primary Author(s)*== Gokce A. Toruner, MD, PhD UT MD Anderson Cancer Center __TOC__ ==Cancer Category/Type== Myeloproliferative neoplasms ==Cancer Sub-Classification /..."

Bailey.Glen: Created page with "==Primary Author(s)*== Gokce A. Toruner, MD, PhD UT MD Anderson Cancer Center TOC ==Cancer Category/Type== Myeloproliferative neoplasms ==Cancer Sub-Classification /..."