Chronic Myeloproliferative Disease

Polycythemia, or erythrocytosis, is an increase in the blood concentration of red cells, which usually correlates with an increase in the hemoglobin concentration

•       Classification

–      Relative

–      Absolute

•       Relative polycythemia

–      Hemoconcentration caused by a decrease in plasma volume

–      Results  from any cause of dehydration

•        Water deprivation

•        Prolonged vomiting

•       Diarrhea

•       Excessive use of diuretics

•       Absolute polycythemia

–      Increase in the total red cell mass

–      Primary: increase in red cell mass results from an autonomous proliferation of the myeloid stem cells. Normal or low erythropoietin levels.

•        Secondary: Red cell progenitors proliferate in response to an increase in erythropoietin

•       Pathophysiologic Classification of Polycythemia

•       Relative

–      Reduced plasma volume (hemoconcentration)

•       Water deprivation

•        Prolonged vomiting

•       Diarrhea

•       Excessive use of diuretics

•       Absolute

–      Primary: Polycythemia vera

–      Absolute

–      Secondary

•       Lung disease

•       High-altitude living

•        Cyanotic heart disease

•        Erythropoietin-secreting tumors (e.g., renal cell carcinoma, hepatoma, cerebellar hemangioblastoma)

Polycythemia Vera

•       Clonal, neoplastic proliferation of myeloid progenitors (erythroid, granulocytic, and megakaryocytic)

•        Panmyelosis

•       Clinical signs and symptoms are related to the absolute increase in red cell mass

•       Polycythemia Vera

•       Low levels of erythropoietin in the serum

•       Mutation in JAK2, a tyrosine kinase that acts in the signaling pathways downstream of the erythropoietin receptor and other growth factor receptors à erythropoietic receptor hypersensitive to erythropoietin

Morphology

•       Increase in viscosity

•       Congestion of all tissues and organs

•       Liver is enlarged and frequently contains foci of extramedullary hematopoiesis

•       Spleen enlarged

•       As a result of the increased viscosity and vascular stasis, thromboses and infarctions are common, particularly in the heart, spleen, and kidneys

•       Morphology

•       Hemorrhages in gastrointestinal tract, oropharynx, or brain due to excessive distention of blood vessels and abnormal platelet function

•       Platelets produced from the neoplastic clone are often dysfunctional à thrombosis, abnormal bleeding

•        Peripheral blood shows increased basophils

•       Bone marrow is hypercellular due to the hyperplasia of erythroid, myeloid, and megakaryocytic forms

•        Disease may progresses to myelofibrosis, where the marrow space is largely replaced by fibroblasts and collagen.

Diagnosis

•        Red cell counts range from 6 to 10 million per microliter

•        Hematocrit : 60%

•        Granulocyte count can be as high as 50,000 cells/mm³

•        Platelet count is often greater than 400,000 cells/mm³

•       Basophil count is also frequently elevated

•        Platelets are functionally abnormal, and giant forms and megakaryocyte fragments are seen in the blood

Myelofibrosis

•       Idiopathic myelofibrosis

•       Secondary myelofibrosis

–      Metastatic carcinoma in bone marrow

–      Hodgkin lymphoma involving marrow

–      Chronic myeloid leukemia

–      AML – M7

–      Systemic lulus erythematosus

•       Myeloid Metaplasia with Primary Myelofibrosis

•       Chronic myeloproliferative disorder with marrow fibrosis

•       Extramedullary hematopoiesis which is disordered and inefficient

•       Moderate-to-severe anemia and thrombocytopenia

•       Platelet-derived growth factor and transforming growth factor β released from neoplastic megakaryocytesà proliferation of marrow fibroblasts

•       JAK2 mutation

Morphology

•       Extramedullary hematopoiesis in spleen à normoblasts, granulocyte precursors, and megakaryocytes

•       Massive splenomegaly à subcapsular infarcts are often present

•       Hepatomegaly

•       Foci of extramedullary hematopoiesis in liver and lymph node

•       Morphology

•        Bone marrow is hypocellular and diffusely fibrotic

•        However, early in the course the marrow can be hypercellular, with equal representation of the three major cell lines

•       Megakaryocytes are often prominent and are usually dysplastic in both early and late disease

Clinical Course

•       Begin with a blood picture suggestive of PCV or CML à progress to marrow fibrosis by the time it comes to clinical attention

•       The peripheral blood smear appears markedly abnormal

–      Red cell: poikilocytes, teardrop cells,  Nucleated erythroid precursors

–       Immature white cells (myelocytes and metamyelocytes) are seen

–      Basophils are sometimes increased

–      The presence of nucleated red cell precursors and immature white cells is referred to as leukoerythrocytosis/leukoerythroblastic blood picture

–       Platelets are often abnormal in size and shape and defective in function

–       In some cases the clinical and blood picture resembles CML, but the Ph chromosome is absent

•       High rate of cell turnover à  hyperuricemia and gout

•       Infections

•        Thrombotic and hemorrhagic episodes

•        Splenic infarctions are common

•        In 5% to 15% of individuals there is eventually a blast crisis resembling AML

•       Median survival time is 4 to 5 years.