Myeloproliferative Diseases

Clinical Background

Chronic myeloproliferative disorders are clonal proliferation disorders of hematopoietic cells and have been renamed myeloproliferative diseases (MPD).

Classification of MPD:

Classical MPDs
- Chronic myelogenous leukemia (CML)
- Polycythemia vera (PV)
- Essential thrombocythemia (ET)
- Primary myelofibrosis (PMF)
Other often included MPDs
- Chronic eosinophilic leukemia
- Hypereosinophilic syndrome
- Mast cell disease
- Myeloproliferative neoplasm, unclassified

Polycythemia vera (polycythemia rubra vera, PV)

Erythroid dominant trilineage proliferation of hematopoietic precursor cells
Epidemiology
- Incidence - 2.8/100,000 per year
- Age - peak age is 50-70 years
- Gender - slightly higher incidence in males
Clinical Presentation
- Insidious onset
- Thrombotic complications
  - Deep vein thrombosis (DVT)
  - Stroke
  - Myocardial infarction
  - Budd-Chiari syndrome
  - Mesenteric ischemia
- Bleeding complications
  - Epistaxis
  - Oral mucosal hemorrhage
  - Gastrointestinal hemorrhage
  - Ecchymoses
- Hyperviscosity syndrome less common
  - Hypertension
  - Headache
  - Dizziness
  - Visual disturbances
  - Claudication
- Erythromelalgia
  - Redness and burning of palms and plantar areas of feet
  - At times progressing to necrosis of digits
- Gouty arthritis
- Pruritus
- Hepatosplenomegaly
- Transformation to myelofibrosis (spent phase) short survival
- Transformation to acute leukemia (always fatal unless allogeneic marrow transplantation

Essential thrombocythemia (hemorrhagic thrombocythemia/thrombocytosis, primary thrombocythemia)

Thrombocytosis and abnormal megakaryocyte proliferation with clonal proliferation of pluripotent stem cells
Epidemiology
- Age - peak 50-60 years old, secondary peak 20-30 years old mainly females
- Incidence - 1.5/100,000 per year
- Sex - male to female ratio is 1 to 1, except in secondary age peak; where male to female ratio is 2 to 1
Clinical Presentation
- Arterial thrombosis
  - Brain
  - Cardiac
  - Extremities
- Venous thrombosis
  - Lower extremity DVT
  - Portal and hepatic vein thrombosis
  - Pulmonary emboli
- Many patients are asymptomatic and do not require therapy
- Transformation to myelofibrosis (spent phase) short survival <10%
- Transformation to acute leukemia (always fatal unless allogeneic marrow transplantation <5%)
Treatment
- Few therapeutic options

Primary myelofibrosis (agnogenic myeloid metaplasia, myelosclerosis with myeloid metaplasia, idiopathic myelofibrosis)

Clonal stem cell deficit characterized by panmyelosis with intact maturation, progressive bone marrow fibrosis, splenomegaly and multiorgan extramedullary hematopoiesis
Epidemiology
- Age - mean age 67 years old
- Incidence - 0.3-1.5/100,000 per year
- Gender - equal incidence in males and females
Clinical Presentation
- May be a secondary process in polycythemia vera and essential shortest survival of all MPDs
- Some with insidious onset, other rapidly progressing
Acute leukemic transformation common
Symptoms
- Hypercatabolic state - fever, weight loss, night sweats
- Blood abnormality - fatigue, dyspnea secondary to anemia, petechia secondary to thrombocytopenia
- Gout
- Splenomegaly (90% of patients)
- Hepatomegaly (50% of patients)

See Also

Acute Myelogenous Leukemia - AML

Chronic Myelogenous Leukemia - CML

Leukemia Lymphoma Phenotyping

Diagnosis

Polycythemia vera (polycythemia rubra vera, PV)

Diagnosis
- 2008 WHO diagnostic criteria - both major and 1 minor or the first major criterion and 2 minor must be met
- Major criteria
  - Hgb>18.5 g/dL (men), >16.5 g/dL (women) or Hgb or Hct >99th percentile of reference or elevated red cell mass >25% above mean predicted or Hgb>17g/dL (men), Hgb>15 g/dL (women) if associated with sustained increase greater than or equal to 2g/dL not attributed to correction of iron deficiency anemia
  - Presence of JAK2V617F (90-95%) or JAK2 exon 12 mutations (5-10%)
- Minor criteria
  - Bone marrow trilineage proliferation
  - Subnormal serum EPO level
  - Endogenous erythroid colony growth

Essential thrombocythemia (hemorrhagic thrombocythemia/thrombocytosis, primary thrombocythemia)

Diagnosis
- WHO criteria 2008 (all 4 must be present)
  - Sustained elevation of platelets greater than or equal to 450 x 10^9/L
    - Defined as at least 2 measurements 2 months apart
  - Megakaryocyte proliferation with little or no granulocyte/erythrocyte proliferation
  - Does not meet WHO criteria for CML, PV, PMF, myelodysplastic syndrome or other myeloid neoplasm
  - Demonstration of JAK2V617F (50%) or cMPL mutations (MPLW515L and MPLW515K) or no evidence of reactive thrombocytosis
- Must exclude other causes of thrombocytosis
  - Reactive
    - Anemias
      - Iron deficiency
      - Hemolytic
      - Acute blood loss
  - Post splenectomy
  - Inflammatory disorders
- Bone marrow biopsy
  - Normal to hypercellular with increased megakaryocytes
  - Stainable iron
  - Normal red cell blood mass
  - No significant collagen or reticulin fibrosis

Primary myelofibrosis (agnogenic myeloid metaplasia, myelosclerosis with myeloid metaplasia, idiopathic myelofibrosis)

Diagnosis
- WHO 2008 criteria (3 major and 2 minor must be met)
  - Major criteria
    - Megakaryocyte proliferation and atypia accompanied by reticulin or collagen fibrosis or, in the absence of reticulin fibrosis, megakaryocyte changes must be accompanied by increased marrow cellularity
    - Not meeting WHO criteria for CML, PV, MDS or other myeloid neoplasm
    - JAK2V617F present or similar mutation or no evidence of reactive fibrosis
  - Minor criteria
    - Leukoerythroblastosis
    - Increased serum LDH
    - Anemia
    - Splenomegaly
- Molecular testing
  - Chromosomal abnormalities common (50% of patients)

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: CBC with Platelet Count & Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count with Flow Cell Differential

Use:

Initial screening for myeloproliferative diseases

Test name: Chromosome Analysis, Bone Marrow

ARUP #: 0097605

Methodology: Giemsa-Band Analysis

Use:

Detect chromosome abnormalities in bone marrow aspirate consistent with a myeloproliferative neoplasm. Can also aid in distinguishing this class of hematologic disorders from CML

Follow-up:

Repeat testing as clinically indicated to monitor disease progression

Test name: Chromosome Analysis, FISH-Interphase

ARUP #: 0092615

Methodology: Fluorescence in situ Hybridization

Use:

Monitor disease and identify specific abnormalities consistent with an MPD

Specific FISH probes must be requested and for this indication include +8, +9, 20q deletion, monosomy 7/7q deletion, 5q deletion, and 13q deletion

Limitations:

Limit of detection is probe dependent and around 2-5% in interphase nuclei

Many of these abnormalities can also be detected in myelodysplastic disorders and AML and therefore are not sufficient for diagnosis but rather consistent with the suspected diagnosis

Follow-up:

Repeat testing as clinically indicated to monitor disease progression

Test name: JAK2 Gene, V617F Mutation, Quantitation

ARUP #: 0040168

Methodology: Polymerase Chain Reaction

Use:

Identifies whether patient is heterozygous or homozygous for the mutation

Analytical sensitivity - 99% accurate

Clinical sensitivity - >90% in polycythemia vera patients, 50% in essential thrombocythemia patients, 50% in idiopathic myelofibrosis patients

Absolute amount of JAK2V617F mutation correlates with risk of thrombosis, marrow fibrosis and survival

Limitations:

Limit of detection is .1%
Test is not intended to be used as the sole means for clinical diagnosis or patient management decisions

Follow-up:

Bone marrow biopsy

May be useful during clinical trial treatment situations in patients who were previously positive

Test name: JAK2 Gene, V617F Mutation, Qualitative

ARUP #: 0051245

Methodology: Polymerase Chain Reaction

Use:

Identify the non-chronic myelogenous leukemia subgroup of myeloproliferative disorders

Limitations:

Not diagnostic of any myeloproliferative disorder

A negative result does not rule out the presence of a JAK2 c.1849G>T (V61F) mutation nor the possibility of diagnosis of PV, ET or PMF

The mutation has been correlated to disease state in >80% PV and 50% PMF and ET patients

The limit of quantification for this assay is approximately 1/400 cells harboring the mutation

The mutation must exist within the granulocyte population to be detected

Follow-up:

Bone marrow biopsy

Can confirm result with JAK2 gene, V617F mutation, quantitation testing

Test name: Erythropoietin

ARUP #: 0050227

Methodology: Chemiluminescent Immunoassay

Use:

Use to identify or exclude PV (minor criteria)

References

Guidelines

Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2007;:[Epub ahead of print].

General References

Ahmed A, Chang CC. Chronic idiopathic myelofibrosis: clinicopathologic features, pathogenesis, and prognosis. Arch Pathol Lab Med. 2006;130(8):1133-1143.

Cao M, Olsen RJ, Zu Y. Polycythemia vera: new clinicopathologic perspectives. Arch Pathol Lab Med. 2006;130(8):1126-1132.

Chang CC. BCR/ABL-negative chronic myeloproliferative disorders: JAK2 mutation and beyond. Arch Pathol Lab Med. 2006;130(8):1123-1125.

Mesa RA. Practical management of classical myeloproliferative disorder patients: a clinician's guide. Future Oncol. 2006;2(4):515-524.

Sanchez S, Ewton A. Essential thrombocythemia: a review of diagnostic and pathologic features. Arch Pathol Lab Med. 2006;130(8):1144-1150.

Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, Futreal PA, Erber WN, McMullin MF, Harrison CN, Warren AJ, Gilliland DG, Lodish HF, Green AR. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356(5):459-468.

Steensma DP. JAK2 V617F in myeloid disorders: molecular diagnostic techniques and their clinical utility: a paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology. J Mol Diagn. 2006;8(4):397-411.

Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA, Barosi G, Verstovsek S, Birgegard G, Mesa R, Reilly JT, Gisslinger H, Vannucchi AM, Cervantes F, Finazzi G, Hoffman R, Gilliland DG, Bloomfield CD, Vardiman JW. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood. 2007;110(4):1092-1097.

References from the ARUP Institute for Clinical and Experimental Pathology Research®

Agarwal N, Mojica-Henshaw MP, Simmons ED, Hussey D, Ou CN, Prchal JT. Familial polycythemia caused by a novel mutation in the beta globin gene: essential role of P50 in evaluation of familial polycythemia. Int J Med Sci. 2007;4(4):232-236.

Bruchova H, Yoon D, Agarwal AM, Mendell J, Prchal JT. Regulated expression of microRNAs in normal and polycythemia vera erythropoiesis. Exp Hematol. 2007;35(11):1657-1667.

Chen G, Prchal JT. Polycythemia vera and its molecular basis: an update. Best Pract Res Clin Haematol. 2006;19(3):387-397.

Chen GL, Liu E, Naidoo K, Popat U, Coetzer TL, Prchal JT. Idiopathic myelofibrosis without dacryocytes. Haematologica. 2006;91(6 Suppl):ECR29.

Gaikwad A, Nussenzveig R, Liu E, Gottshalk S, Chang K, Prchal JT. In vitro expansion of erythroid progenitors from polycythemia vera patients leads to decrease in JAK2 V617F allele. Exp Hematol. 2007;35(4):587-595.

Gaikwad A, Prchal JT. Study of two tyrosine kinase inhibitors on growth and signal transduction in polycythemia vera. Exp Hematol. 2007;35(11):1647-1656.

Hsieh PP, Olsen RJ, O'Malley DP, Konoplev SN, Hussong JW, Dunphy CH, Perkins SL, Cheng L, Lin P, Chang CC. The role of Janus Kinase 2 V617F mutation in extramedullary hematopoiesis of the spleen in neoplastic myeloid disorders. Mod Pathol. 2007;20(9):929-935.

Nussenzveig RH, Swierczek SI, Jelinek J, Gaikwad A, Liu E, Verstovsek S, Prchal JF, Prchal JT. Polycythemia vera is not initiated by JAK2V617F mutation. Exp Hematol. 2007;35(1):32-38.

Percy MJ, Sanchez M, Swierczek S, McMullin MF, Mojica-Henshaw MP, Muckenthaler MU, Prchal JT, Hentze MW. Is congenital secondary erythrocytosis/polycythemia caused by activating mutations within the HIF-2 alpha iron-responsive element?. Blood. 2007;110(7):2776-2777.

Popat U, Frost A, Liu E, Guan Y, Durette A, Reddy V, Prchal JT. High levels of circulating CD34 cells, dacrocytes, clonal hematopoiesis, and JAK2 mutation differentiate myelofibrosis with myeloid metaplasia from secondary myelofibrosis associated with pulmonary hypertension. Blood. 2006;107(9):3486-3488.

Reading NS, Lim MS, Elenitoba-Johnson KS. Detection of acquired Janus kinase 2 V617F mutation in myeloproliferative disorders by fluorescence melting curve analysis. Mol Diagn Ther. 2006;10(5):311-317.

Xiong Z, Liu E, Yan Y, Silver RT, Yang F, Chen IH, Chen Y, Verstovsek S, Wang H, Prchal J, Yang XF. An unconventional antigen translated by a novel internal ribosome entry site elicits antitumor humoral immune reactions. J Immunol. 2006;177(7):4907-4916.

Xiong Z, Yan Y, Liu E, Silver RT, Verstovsek S, Yang F, Wang H, Prchal J, Yang XF. Novel tumor antigens elicit anti-tumor humoral immune reactions in a subset of patients with polycythemia vera. Clin Immunol. 2007;122(3):279-287.

Medical Reviewers

Bahler, David W., M.D., Ph.D. Medical Director, Hematologic Flow Cytometry, and Acting Medical Director, Molecular Hematopathology at ARUP Laboratories; Associate Professor, Pathology, University of Utah

Lamb, Allen N., Ph.D. Medical Director, Cytogenetics, ARUP Laboratories; Associate Professor, Department of Pathology, University of Utah

Lyon, Elaine, Ph.D. Medical Director, Molecular Genetics at ARUP Laboratories; Associate Professor, Pathology, University of Utah

Prchal, Josef T., M.D. Medical Director, Hematology at ARUP Laboratories; Professor, Hematology, Pathology and Genetics, University of Utah

Reading, N. Scott , Ph.D. Scientist II, Special Genetics at ARUP Laboratories

South, Sarah T. , Ph.D. Medical Director, Cytogenetics at ARUP Laboratories; Assistant Medical Director, CGH Microarray Laboratory, and Assistant Professor, Department of Pediatrics, University of Utah

Comprehensive Review: March 2008
Last Update: May 2008