Primary Myelofibrosis



Primary Myelofibrosis


Kaaren K. Reichard, MD





Key Facts


Terminology



  • Definition



    • Clonal stem cell disorder


    • Megakaryocytic and granulocytic proliferation with ultimate fibrosis


Clinical Issues



  • Extramedullary hematopoiesis


  • Microvascular complications


Microscopic Pathology



  • Early phase



    • Variable anemia, thrombocytosis, and granulocytic leukocytosis


    • BM absent/minimal fibrosis


    • BM pleomorphic megakaryocytes


  • Late/fibrotic phase



    • PB leukoerythroblastosis


    • BM marked fibrosis


    • BM osteosclerosis


Ancillary Tests



  • Cytogenetics



    • Common recurring abnormalities: +8, +9, 13q-, 20q


    • Not specific for PMF


  • Molecular genetics



    • JAK2 V617F mutation present in ˜ 50% of patients


    • BCR-ABL1 negative


Top Differential Diagnoses



  • Other classic BCR-ABL1 negative MPNs


  • Chronic myelogenous leukemia, BCR-ABL1 positive


  • Secondary causes of leukoerythroblastosis






The peripheral blood smear demonstrates marked anemia and leukoerythroblastosis image, characteristic features of fibrotic stage primary myelofibrosis.






Marked osteosclerosis, myelofibrosis, & megakaryocytic pleomorphism are hallmark histologic features of primary myelofibrosis. Megakaryocytes range from small to large and are hyperchromatic and clustered image.


TERMINOLOGY


Abbreviations



  • Primary myelofibrosis (PMF)


Synonyms



  • Chronic idiopathic myelofibrosis


  • Agnogenic myeloid metaplasia


  • Myeloid metaplasia with myelofibrosis


Definitions



  • Myeloproliferative neoplasm (MPN)


  • Clonal stem cell disorder


  • Manifests as megakaryocytic and granulocytic proliferation with ultimate fibrosis


  • PMF term should be used in patients without diagnosis of essential thrombocythemia (ET) or polycythemia vera (PV)


ETIOLOGY/PATHOGENESIS


Molecular Pathogenesis



  • JAK2 V617F mutation present in ˜ 50% of patients


  • MPL mutations at codon 515 present in ˜ 10% of patients


  • BCR-ABL1 fusion absent


Fibrosis Hypothesis



  • Secondary proliferation of polyclonal fibroblasts


  • Fibroblasts are stimulated by clonally expanding megakaryocytes via TGF-β


Leukemia Transformation



  • May be JAK2 negative (even if PMF was originally JAK2 positive)


CLINICAL ISSUES


Epidemiology



  • Incidence



    • ∽ 0.2/100,000 in United States


  • Age



    • Median age at diagnosis: 67 years


    • Predominantly adults


  • Gender



    • No significant sex predilection


Site



  • Peripheral blood (PB)


  • Bone marrow (BM)


  • Spleen


  • Liver


Presentation



  • Abdominal fullness


  • Fatigue


  • Splenomegaly


  • Early satiety


  • Left upper quadrant pain


  • Musculoskeletal complaints


  • Fever


  • Night sweats


  • Weight loss


Laboratory Tests



  • Complete blood cell count (CBC)


  • Peripheral blood smear review


  • Bone marrow examination


  • Cytogenetics


  • Molecular genetics (e.g., JAK2)


Treatment



  • Only potential cure is allogeneic stem cell transplantation



    • Toxicity due to myeloablative therapy is prohibitive in many patients



    • Nonmyeloablative regimens exist


  • Drug therapy



    • Targets symptoms


    • Hydroxyurea



      • For leukocytosis, thrombocytosis, and splenomegaly


    • Thalidomide/lenalidomide and steroids



      • For cytopenias, splenomegaly


    • Molecular-targeted therapy against JAK2


  • Splenectomy



    • High-risk procedure


    • Near 10% mortality


Prognosis



  • Median survival: 3.5 to 5 years



    • Worse than other classic MPNs


    • Wide range in survival


  • Prognostic factors



    • Several prognostic scoring systems


    • Variables assessed



      • Age > 65 years


      • Hemoglobin < 10 g/dL


      • Leukocyte count > 25 × 109/L


      • Circulating blasts ≥ 1%


      • Constitutional symptoms


    • Leukemic transformation



      • Poor prognosis


      • ˜ 4-20% of patients


    • Microvascular events



      • Thrombosis


      • Hemorrhage


MICROSCOPIC PATHOLOGY


Peripheral Blood

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Jun 13, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Primary Myelofibrosis

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