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Essential Thrombocythemia

Definition

  • Chronic myeloproliferative neoplasm involving primarily the megakaryocytic lineage

Diagnostic Criteria

  • All of the following are required
    • Must not meet criteria for CML, PMF, PV, MDS or other myeloid neoplasm (see Differential Diagnosis)
      • Always check for BCR-ABL1
        • Rare p230 isoform of CML can present with thrombocytosis
      • MDS syndromes with thrombocytosis such as RARS-T and 5q- can have JAK5V617F mutations
    • Sustained platelet elevation ≥450 x 103/μL
    • Bone marrow biopsy with megakaryocytic hyperplasia
      • Enlarged, mature megakaryocytes
      • No significant hyperplasia or left shift of granulocytic or erythroid lineages
    • JAK2V617F (present in about 50%) or other clonal marker
  • Peripheral blood thrombocytosis
    • Markedly elevated platelets with giant platelets
    • Normal or mildly elevated WBC
    • RBC normal or show effects due to hemorrhage
      • May be hypochromic/microcytic
      • No increase in hemoglobin or hematocrit to polycythemia range when iron replete
      • No significant teardrop population
    • No granulocyte dysplasia
  • Bone marrow shows megakaryocytic hyperplasia
    • Overall normocellular or moderately hypercellular
    • Megakaryocytes dispersed or loosely clustered throughout the marrow
    • Large to giant mature megakaryocytes
      • Abundant cytoplasm
      • Deeply lobulated nuclei (staghorn-like)
        • Not hyperchromatic and clustered (as in cellular phase primary myelofibrosis)
        • Not monolobated or multinucleated (as in MDS)
    • Minimal fibrosis (MF-0 or 1 in European Consensus System, Thiele 2005)
      • No dense reticulin fibrosis or collagen fibrosis
    • Typically no erythroid or granulocytic hyperplasia
      • Secondary erythroid hyperplasia may ocurr post hemorrhage
    • No erythroid dysplasia or ring sideroblasts
    • No granulocytic dysplasia or increased blasts
  • Rare progression to post-ET marrow fibrosis
    • Approximately 2%

Dita Gratzinger MD PhD
Tracy I George MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting: 10/23/11

Supplemental Studies

  • 40-50% JAK2V617F mutations
    • 1% MPL W515K/L
  • Cytogenetic abnormalities in 5-10% of cases
    • +8, +9q, del(20q)
  • Absence of Ph’ or BCR-ABL1
    • Rare p230 isoform can present with thrombocytosis

Disorder Molecular or Cytogenetic Alteration Test Used
Chronic myelogenous leukemia BCR-ABL1 CG, PCR
Polycythemia vera JAK2 V617F, JAK2 exon 12 PCR
Essential thrombocythemia JAK2 V617F, MPL W515K/L PCR
Primary myelofibrosis JAK2 V617F, MPL W515K/L PCR
Hematolymphoid neoplasms with FIP1L1-PDGFRA FIP1L1-PDGFRA CG, FISH with CH1C2 probe
Hematolymphoid neoplasms with eosinophilia ETV6-PDGFRB. various involving FGFR1 CG
Chronic eosinophilic leukemia NOS none specific, may have clonal CG abnormalities CG
Mastocytosis KIT D816V CG, PCR on BM, not PB
Acute myelogenous leukemia, even if <20% blasts inv or t(16)(p13.1q22); CBFB-MYH11 FISH
PCR = polymerase chain reaction, CG = conventional cytogenetics, FISH = fluorescent in situ hybridization

Differential Diagnosis

Secondary Thrombocythemia

  • Splenectomy
  • Inflammatory conditions
    • Infection
    • Connective tissue diseases
  • Neoplasms
    • Metastatic
    • Lymphoproliferative disorders
  • Iron deficiency
Hematolymphoid Disorders with Thrombocytosis
  CML PV PMF, Cellular Phase ET RARS-T 5q-
Tyrosine kinase ABL p230 variant* JAK2 JAK2 or MPL 50% JAK2 or MPL 50% JAK2 50% JAK2 or MPL 10%
Blood ↑PMN, basophils, platelets Normo or hypochromatic anemia, may have ↑basophils, platelets Anemia, leukocytosis, ↑or nl platelets ↑platelets, often abnormal Dimorphic RBC, ↑platelets Macrocytic anemia, ↑or nl platelets
Marrow ↑↑Myeloids, ↑dwarf megas Panmyelosis, ±erythroid hyperplasia, atypical megas Panmyelosis, atypical tightly clustered megas ↑↑Megas Erythroid dysplasia, ring sideroblasts, ↑megas Erythroid hypoplasia, ↑small megas
Marrow Fibrosis Varies ↑ in spent phase ↑↑ in fibrotic phase Minimal Varies Minimal
Splenomegaly ++ ++ +++ ± ± Absent
Clinical/Other B symptoms Hypertension, thrombosis, pruritus, ↓EPO B symptoms, bleeding, gout Thrombosis, hemorrhage Anemia Anemia
EPO = erythropoietin, * rare p230 BCR-ABL1 isoform can present with thrombocytosis and /or neutrophilia

 

Essential Thrombocythemia vs Cellular Phase Primary Myelofibrosis vs CML
  Essential Thrombocythemia Cellular Phase Primary Myelofibrosis CML with p230
Cellularity Normal to moderately hypercellular Markedly hypercellular (cellular phase) Markedly hypercellular
Megas - Distribution Dispersed or loose clusters Tight clusters, touching each other Dispersed or loose clusters
Megas - Size Large and giant Pleomorphic Variable, may have dwarf forms
Megas - Nuclei Lobulated Bulbous, hyperchromatic Hypolobated
Megas - Cytoplasm Mature Variable, may have naked nuclei Mature
Granulopoietic Hyperplasia Infrequent, mild Moderate to marked in cellular phase Marked
Splenomegaly Infrequent Frequent Rare
JAK2V617I Allele burden <50% Allele burden >50%  
Megas = megakaryocytes

Common Myeloproliferative Neoplasms - Overview
  CML PV PMF ET
Tyrosine kinase ABL JAK2 JAK2 or MPL JAK2 or MPL
Blood ↑WBC with IG, basophils Normo or hypochromatic anemia, may have ↑platelets & basophils Leukoerythroblastic with teardrops ↑Platelets, often abnormal
Marrow ↑↑Myeloids Panmyelosis, ± erythroid hyperplasia, atypical megas Panmyelosis, atypical megas ↑↑Megas
Marrow fibrosis Varies ↑In spent phase ↑↑In fibrotic phase Minimal
Splenomegaly ++ ++ +++ ±
Clinical Presentation /Other B symptoms Hypertension, thrombosis, pruritus,↓EPO B symptoms, bleeding, gout Thrombosis, hemorrhage
CML = chronic myeloid leukemia; PV = polycythemia vera; PMF = primary myelofibrosis; ET = essential thrombocythemia; IG = immature granulocytes; Megas = megakaryocytes; EPO = erythropoietin

 

Common Myeloproliferative Neoplasms - Peripheral Blood
  CML PV Cellular Phase PMF ET
RBC Normal or ↓ Normal, ↑ or ↓, may be hypochromatic or polychromatic ↓, teardrop cells Normal or ↓ (iron deficient anemia)
WBC ↑, left shifted, basophilia, eosinophilia, rarely monocytosis Normal or ↑, +/- basophils, (leukoerythroblastic ini fibrotic stage) ↑granulocytes if leukoerythroblastic Normal
Platelets Normal or ↑ Normal or ↑ Normal or ↑ ↑ (>450 x103/μL)
CML = chronic myeloid leukemia; PV = polycythemia vera; PMF = primary myelofibrosis; ET = essential thrombocythemia

Clinical

  • Complications of thromboembolism and secondary hemorrhage
  • <5% transformation to AML/MDS
    • Probably secondary to cytotoxic therapy
  • Median survival 10-15 years
  • Post-ET fibrosis is rare

Classification / Lists

WHO 2008 Classification of Myeloid Neoplasms

Myeloproliferative Neoplasms (MPN)

Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1

Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN)

Myelodysplastic Syndromes (MDS)

Therapy Related Myeloid Neoplasms

 

Bibliography

  • Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours 2008
  • Anastasi J. The myeloproliferative neoplasms: insights into molecular pathogenesis and changes in WHO classification and criteria for diagnosis. Hematol Oncol Clin North Am. 2009 Aug;23(4):693-708.
  • George TI, Arber DA. Pathology of the myeloproliferative diseases. Hematol Oncol Clin North Am. 2003 Oct;17(5):110
    Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2008 Jan;22(1):14-22.
  • Wadleigh M, Tefferi A. Classification and diagnosis of myeloproliferative neoplasms according to the 2008 World Health Organization criteria. Int J Hematol. 2010 Mar;91(2):174-9. 1-27.
  • Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999 Apr 29;340(17):1330-40.
  • Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A,  Cazzola M, Skoda RC. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005 Apr 28;352(17):1779-90.
  • Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR; Cancer Genome Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005 Mar 19-25;365(9464):1054-61. Erratum in: Lancet. 2005 Jul 9-15;366(9480):122.
  • James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C, Garçon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005 Apr 28;434(7037):1144-8.
  • Thiele J, Kvasnicka HM, Schmitt-Graeff A, Zankovich R, Diehl V. Follow-up examinations including sequential bone marrow biopsies in essential thrombocythemia (ET): a retrospective clinicopathological study of 120 patients.  Am J Hematol. 2002 Aug;70(4):283-91.
  • Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, Kutok J, Clark J, Galinsky I, Griffin JD, Cross NC, Tefferi A, Malone J, Alam R, Schrier SL, Schmid J, Rose M, Vandenberghe P, Verhoef G, Boogaerts M, Wlodarska I, Kantarjian H, Marynen P, Coutre SE, Stone R, Gilliland DG. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003 Mar 27;348(13):1201-14.
  • Gotlib J, Cools J, Malone JM 3rd, Schrier SL, Gilliland DG, Coutré SE. The
    FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management. Blood. 2004 Apr 15;103(8):2879-91.
  • Finazzi G, Carobbio A, Thiele J, Passamonti F, Rumi E, Ruggeri M, Rodeghiero F, Randi ML, Bertozzi I, Vannucchi AM, Antonioli E, Gisslinger H, Buxhofer-Ausch V, Gangat N, Rambaldi A, Tefferi A, Barbui T. Incidence and risk factors for bleeding in 1104 patients with essential thrombocythemia or prefibrotic myelofibrosis diagnosed according to the 2008 WHO criteria. Leukemia. 2011 Sep 16. doi: 10.1038/leu.2011.258.
  • Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 2005 Aug;90(8):1128-32.
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