Overview of Myeloproliferative Neoplasms



Overview of Myeloproliferative Neoplasms


Kathryn Foucar, MD








The reciprocal translocation between chromosomes 9 and 22 results in the creation of the BCR-ABL1 chimeric fusion gene. The fusion gene has constitutive tyrosine kinase activity and activates many downstream pathways.






Mutations in the JAK2 gene result in constitutive activation with phosphorylation in the absence of ligand binding to the surface membrane receptor. Consequently, there is dysregulated proliferation of hematopoietic cells.


TERMINOLOGY


Abbreviations



  • Myeloproliferative neoplasms (MPN)


Synonyms



  • Chronic myeloproliferative disorders (CMPD)


Definitions



  • Clonal hematopoietic (HP) neoplasm characterized by bone marrow hypercellularity and intact maturation with effective hematopoieses resulting in elevations of ≥ 1 HP lineages in blood



    • Myeloblasts not substantially increased and dysplasia is not significant in chronic phase of MPN


    • Molecular genetic abnormalities are common in MPN and define some subtypes


    • Mutations in tyrosine kinase genes in most MPNs


    • About 10% of MPN cases are unclassifiable


  • WHO 2008 classification of MPN



    • Chronic myelogenous leukemia (CML) BCR-ABL1(+)


    • Polycythemia vera (PV)


    • Primary myelofibrosis (PMF)


    • Essential thrombocythemia (ET)


    • Chronic neutrophilic leukemia (CNL)


    • Chronic eosinophilic leukemia, not otherwise specified (CEL, NOS)


    • Mastocytosis


    • MPN, unclassifiable (MPN-U)



      • Cases do not fulfill criteria for other MPN


ETIOLOGY/PATHOGENESIS


Mutations in Tyrosine Kinase Genes



  • Present in virtually all types of MPN


  • Acquired mutations in tyrosine kinase genes result in constitutive activation


  • BCR-ABL1 fusion gene



    • Defines CML


    • Responsible for dysregulated overproduction of neutrophils, basophils, and variable other HP cells


  • JAK2 V617F mutation



    • Detected in almost all cases of PV (alternate JAK2 mutation in remainder)


    • Detected in about 1/2 of ET and PMF cases


    • Occasionally detected in other myeloid neoplasms


  • MPL W151 L/K mutation



    • Detected in many PMF and some ET cases


  • KIT D816V mutation



    • Common in mastocytosis


CLINICAL IMPLICATIONS


Epidemiology



  • Incidence



    • Rates for MPN subtypes range from rare case reports of CNL to 1-2 cases per 100,000 for CML & ET


  • Age



    • MPNs predominate in middle-aged to elderly


    • Rare presentations in children (e.g., CML)


    • Localized extramedullary (cutaneous) forms of mastocytosis predominate in children


  • Gender



    • No striking gender predilection


  • Ethnicity



    • No striking ethnic predilections


Presentation



  • Most MPNs exhibit indolent type of presentation with gradual onset of symptomatology


  • Many distinctive & more dramatic manifestations in mastocytosis secondary to granule release



    • Flushing, urticaria, gastrointestinal symptoms


  • Splenomegaly is a hallmark of many MPNs



    • CML, PV, PMF



Laboratory Tests



  • Complete blood count (CBC) with differential provides many clues to MPN and specific MPN subtypes



    • Marked nontoxic neutrophilia, left shift to blasts, and basophilia in CML


    • Erythrocytosis in PV


    • Leukocytosis, leukoerythroblastic picture, and teardrop-shaped RBCs in PMF


    • Thrombocytosis in ET


    • Marked eosinophilia in CEL, NOS


  • Many other laboratory tests utilized to exclude differential diagnostic considerations and assess cell turnover, iron stores, and erythropoietin levels


Natural History



  • Most well-delineated for CML, PV, PMF, and ET


  • ET often very indolent with survival times similar to age-matched controls


  • PV characterized by long stable phase with eventual progression to myelofibrosis (> 10-year survival); substantial risk of thrombosis


  • PMF shows variable survival times: Range of 3-7 years


  • Prior to era of tyrosine kinase inhibitor therapy, CML patients had median survival < 5 years and inevitable accelerated/blast phase


Treatment



  • Tyrosine kinase inhibitor therapy has resulted in markedly prolonged survival in CML



    • Dramatic reductions in incidence of disease progression


  • Application of tyrosine kinase inhibitors in JAK2 mutation-mediated neoplasms in progress


MICROSCOPIC FINDINGS


Blood



  • Key general features include cytosis(es), lack of dysplasia, blasts < 2%, and basophilia


  • Other specific features of individual MPNs



    • Teardrop-shaped erythrocytes in PMF


    • Marked erythrocytosis in PV


    • Marked eosinophilia in CEL


    • Toxic neutrophilia in CNL


Bone Marrow



  • General features



    • Hypercellularity


    • Increased megakaryocytes


    • Intact maturation


    • Lack of dysplasia in stable phase (aside from megakaryocytes)


    • Blasts < 2% in stable phase


  • Distinctive MPN subtype-specific features



    • Small, hypolobated megakaryocytes in CML


    • Markedly hyperlobated megakaryocytes in ET


    • Prominent intrasinusoidal megakaryocytes in PMF


    • Osteosclerosis in PMF and some mastocytoses


    • Fibrosis in PMF and some mastocytoses


    • Normocellularity in some ET


    • Marked eosinophilia in CEL, some mastocytoses


    • Associated non-mast cell hematologic disorders in systemic mastocytosis


ANCILLARY TESTS


Flow Cytometric Immunophenotyping



  • Relatively limited utility in chronic phase MPN



    • Valuable for blast lineage assessment and enumeration in progressive MPNs


    • Valuable in detecting aberrant CD2 and CD25 on neoplastic mast cells


Cytogenetics/FISH/Molecular Genetic Testing



  • Essential in diagnosis of most MPN subtypes


  • Essential for exclusionary reasons in CNL, CEL, NOS

Jun 13, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Overview of Myeloproliferative Neoplasms
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