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Myeloproliferative neoplasms (MPNs) are associated with dysregulation of tyrosine kinases which leads to abnormal downstream signaling of pathways and increased cellular proliferation. The presence of the BCR-ABL1 mutation characterizes chronic myelogenous leukemia. For BCR- ABL1-negative MPNs, new molecular markers have implications for further classifying and diagnosing MPNs.
Content in tables below based on Chaligné R et al, 2007; Guglielmelli P et al, 2009; Pardanani AD et al, 2006; Schmidt AE et al, 2012; Vainchenker W et al, 2011; Vakil E et al, 2011.
Myeloproliferative neoplasms (MPN) are a group of slow-growing blood cancers, including chronic myelogenous leukemia (CML). MPNs present with clonal proliferation of abnormal hematopoietic cells that involve bone marrow and peripheral blood.
| 2008 WHO Classification of Myeloid Neoplasms and Acute Leukemia |
|---|
Myeloproliferative neoplasms (MPN)
|
| Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFA, PDGFB, or FGFR1 |
Myelodysplastic/myeloproliferative neoplasms
|
| Myelodysplastic syndromes |
| Acute myeloid leukemia (AML) and related precursor neoplasms |
| Acute leukemias of ambiguous lineage |
| 1Considered classic MPN 2Provisional listing; subject to change |
Myeloproliferative neoplasms are extremely rare in children.
Tests generally appear in the order most useful for common clinical situations
| Test name: Erythropoietin |
| ARUP #: 0050227 |
| Methodology: Quantitative Chemiluminescent Immunoassay |
| Use: Initial test for MPN Use to identify or exclude polycythemia vera (PV) - minor criteria |
| Test name: JAK2 Gene, V617F Mutation, Qualitative |
| ARUP #: 0051245 |
| Methodology: Polymerase Chain Reaction |
| Use: First-line test in the workup of unexplained erythrocytosis or thrombocytosis after exclusion of secondary causes Aids in the workup of classical BCR-ABL1 negative myeloproliferative neoplasms (PV, essential thrombocythemia [ET], primary myelofibrosis [PMF]) Clinical sensitivity - 90-95% in PV, ~50% in ET and PMF |
| Limitations: JAK2 exon 12 mutations will not be detected Limit of detection - 1/400 cells Results are not diagnostic of any single MPN Negative JAK2 V617F result does not rule out the presence of a JAK2 c.1849G>T (V617F) mutation or the possible diagnosis of PV, ET, or PMF Mutation must exist within the granulocyte population to be detected |
| Follow-up: Bone marrow biopsy Can confirm result with JAK2 (V617F) mutation, quantitation testing |
| Test name: Myeloproliferative Neoplasms Reflex Panel |
| ARUP #: 2007418 |
| Methodology: Polymerase Chain Reaction/Pyrosequencing |
| Use: Preferred panel in the workup of unexplained erythrocytosis or thrombocytosis after exclusion of secondary causes Aids in the workup of classical BCR-ABL1 negative myeloproliferative neoplasms (PV, ET, PMF) If JAK2 V617F is not detected, JAK2 exon 12 mutation analysis is added If JAK2 exon 12 mutation is not detected, MPL codon 515 mutation detection is added Clinical sensitivity - 90-95% in PV, ~50% in ET and PMF |
| Limitations: Results are not diagnostic of any single MPN Negative JAK2 V617F result does not rule out the presence of a JAK2 c.1849G>T (V617F) mutation or the possible diagnosis of PV, ET, or PMF |
| Follow-up: Bone marrow biopsy Can confirm result with JAK2 (V617F) mutation, quantitation testing |
| Test name: JAK2 Gene, V617F Mutation, Quantitation |
| ARUP #: 0040168 |
| Methodology: Polymerase Chain Reaction |
| Use: Quantitates JAK2 V617F allele frequency in enriched granulocytes from peripheral whole blood to provide an estimate of the fraction of clonal (JAK2 V617F positive) granulopoiesis Clinical sensitivity - 90-95% in PV, ~50% in ET and PMF |
| Limitations: JAK2 exon 12 mutations are not detected Limit of detection is 0.2% |
| Follow-up: Bone marrow biopsy |
| Test name: JAK2 Exon 12 Mutation Analysis by PCR |
| ARUP #: 2002357 |
| Methodology: Polymerase Chain Reaction |
| Use: Due to the rarity of this mutation, this test should be limited to individuals suspected of polycythemia vera with confirmed erythrocytosis, negative JAK2 V617F studies, and a confirmed low erythropoietin level |
| Limitations: Limit of detection - 1% mutant alleles in wild-type alleles |
| Test name: MPL codon 515 Mutation Detection by Pyrosequencing, Quantitative |
| ARUP #: 2005545 |
| Methodology: Polymerase Chain Reaction/Quantitative Pyrosequencing |
| Use: Due to the rarity of this mutation, this test should be limited to individuals suspected of PV with confirmed MPN, negative JAK2 V617F studies, and a confirmed low erythropoietin level |
| Test name: Eosinophilia Panel by FISH |
| ARUP #: 2002378 |
| Methodology: Fluorescence in situ Hybridization |
| Use: Aids in diagnosis and classification of hematopoietic neoplasms presenting with prominent eosinophilia Probes included - PDGFRA, PDGFRB, FGFR1, and CBFB |
| Limitations: Does not detect rearrangements associated with chronic myelogenous leukemia Chromosome alterations outside the regions complementary to these FISH probes will not be detected |
| Test name: Myeloproliferative Disorders Panel by FISH |
| ARUP #: 2002360 |
| Methodology: Fluorescence in situ Hybridization |
| Use: Limited role in the work-up of classical myeloproliferative neoplasms in the setting of an otherwise optimal cytogenetic study Aids in exclusion of cryptic BCR-ABL1 rearrangement in chronic myelogenous leukemia and in the exclusion of a PDGFRA abnormality in cases of neoplastic eosinophilia Probes included - BCR/ABL, PDGFRA, PDGFRB, and FGFR1 |
| Limitations: Chromosome alterations outside the regions complementary to these FISH probes will not be detected |
| Test name: Chromosome Analysis, Bone Marrow |
| ARUP #: 2002292 |
| Methodology: Giemsa Band |
| Use: Detect chromosome abnormalities in bone marrow aspirate consistent with an MPN 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 FISH, Interphase |
| ARUP #: 2002298 |
| Methodology: Fluorescence in situ Hybridization |
| Use: Monitor disease and identify specific abnormalities consistent with an MPN Specific FISH probes must be requested and for this indication include PDGFA, PDGFB, +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 syndromes and AML and are therefore not sufficient for diagnosis but are consistent with the suspected diagnosis (exception is PDGFA and PDGFB, which are specific for MPNs) |
| Follow-up: Repeat testing as clinically indicated to monitor disease progression |
| Test name: CD117 (c-Kit) by Immunohistochemistry |
| ARUP #: 2003806 |
| Methodology: Immunohistochemistry |
| Use: Aid in histologic diagnosis of MPN Stained and returned to client pathologist; consultation available if needed |
| Test name: CD25 by Immunohistochemistry |
| ARUP #: 2003544 |
| Methodology: Immunohistochemistry |
| Use: Aid in histologic diagnosis of MPN Stained and returned to client pathologist; consultation available if needed |
| Test name: Oxygen Dissociation (P50) by Hemoximetry |
| ARUP #: 2002984 |
| Methodology: Spectrophotometry/Clark Electrode |
| Use: Use when JAK2 testing negative and PV present |
| Test name: von Hippel-Lindau (VHL) Sequencing |
| ARUP #: 2002970 |
| Methodology: Polymerase Chain Reaction/Sequencing |
| Use: Use when JAK2 testing negative and PV present |
| Limitations: Large deletions and duplications, deep intronic mutations, and regulatory region mutations are not detected Rare diagnostic errors may occur due to primer-site mutations PV due to causes other than VHL gene mutations will not be detected |
| Test name: CBC with Platelet Count and Automated Differential |
| ARUP #: 0040003 |
| Methodology: Automated Cell Count/Differential |
| Comments: Initial screen for MPN |