Thebonemarrowishypercellularowingtoincreasednumbersoferythroid,myeloid,andmegakaryocyticforms.Inaddition,somedegreeofmarrowfibrosisispresentin10%ofpatientsatthetimeofdiagnosis.Inasubsetofpatients,thisprogressestoaspentphasewherethemarrowislargelyreplacedbyfibroblastsandcollagen.
Polycythemia vera appears insidiously, usually in late middle age. Patients are plethoric and often somewhat cyanotic. Histamine released from the neoplastic basophils may contribute to pruritus and also may account for the increased incidence of peptic ulceration. Other complaints are referable to the thrombotic and hemorrhagic tendencies and to hypertension. Headache, dizziness, gastrointestinal symptoms, hematemesis, and melena are common. Because of the high rate of cell turnover, symptomatic gout is seen in 5% to 10% of cases.
The diagnosis usually is made in the laboratory. Red cell counts range from 6 to 10 million/µL, and the hematocrit is often 60% or greater. The granulocyte count can be as high as 50,000 cells/µL, and the platelet count is often more than 400,000/µL. Basophilia is common. The platelets are functionally abnormal in most cases, and giant platelets and megakaryocyte fragments are often seen in the blood. About 30% of patients develop thrombotic complications, usually affecting the brain or heart. Hepatic vein thrombosis giving rise to Budd-Chiari syndrome (Chapter 15) is an uncommon but grave complication. Minor hemorrhages (e.g., epistaxis and bleeding from gums) are common and life-threatening hemorrhages that occur in 5% to 10% of patients. In those receiving no treatment, death occurs from vascular complications within months; however, the median survival is increased to about 10 years by lowering the red cell count to near normal through repeated phlebotomy.
Unfortunately, prolonged survival has shown a propensity for polycythemia vera to evolve to a “spent phase” resembling primary myelofibrosis. After an average interval of 10 years, 15% to 20% of cases undergo such a transformation. Owing to the extensive marrow fibrosis, hematopoiesis shifts to the spleen, which enlarges markedly. Inhibitors that target JAK2 have been approved for treatment of the spent phase of polycythemia vera and lead to some improvement in most patients. Transformation to a “blast crisis” identical to AML also occurs, but much less frequently than in CML.
The hallmark of primary myelofibrosis is the development ofobliterativemarrowfibrosis,whichreducesbonemarrow hematopoiesis and leads to cytopenias and extensive extramedullary hematopoiesis. Histologically, the appearance is identical to the spent phase that occurs occasionally late in the course of other myeloproliferative disorders. This similarity also extends to the underlying pathogenesis.
JAK-STAT signaling seems to be the underlying driver in almost all cases. Thus, JAK2 mutations are present in 50% to 60% of cases and activating mutations in MPL, the thrombopoietin receptor, are seen in an additional 1% to 5% of cases. Most of the remaining cases have other mutations, which also are hypothesized to stimulate increased JAK-STAT signaling. Why JAK2 mutations are associated with polycythemia vera in some patients and primary myelofibrosis in others is not understood; differences in the cell of origin and the genetic backgrounds that give rise to these two disorders are suspected.