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Myelofibrosis
is a chronic, usually idiopathic disease characterized by bone marrow
fibrosis, splenomegaly, and anemia with immature and teardrop-shaped
RBCs. Diagnosis requires bone marrow examination and exclusion of
other conditions that can cause secondary myelofibrosis. Treatment
is usually supportive.
Etiology
and Pathophysiology
Myelofibrosis is excessive marrow fibrosis and loss of hematopoietic cells, with subsequent marked increase in extramedullary hematopoiesis (primarily in the liver and spleen, which enlarge significantly). It is usually a primary disorder probably resulting from neoplastic transformation of multipotent marrow stem cells; these stem cells stimulate the marrow fibroblast (which is not part of the neoplastic transformation), to secrete excessive collagen. Myelofibrosis also may occur secondary to a number of hematologic, malignant, or infectious conditions (see Table 3: Myeloproliferative Disorders: Conditions Associated with Myelofibrosis ). Myelofibrosis may complicate chronic myelocytic leukemia and occurs in 15 to 30% of patients with polycythemia vera if they survive long enough. Large numbers of immature RBCs and granulocytes are released into the circulation (leukoerythroblastosis); they may release excess LDH into the bloodstream. Marrow failure eventually occurs, with consequent anemia and thrombocytopenia. Malignant or acute myelofibrosis, an unusual variant, has a more rapidly progressive downhill course; this may actually be a true megakaryocytic leukemia.
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Table 3
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Conditions
Associated with Myelofibrosis
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Condition
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Examples
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Malignant diseases
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Leukemias, polycythemia vera, multiple myeloma, Hodgkin lymphoma (Hodgkin's disease), non-Hodgkin lymphoma, cancer with marrow metastases
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Infections
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TB, osteomyelitis
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Toxins
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X- or γ-radiation, benzene, thorium dioxide
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Autoimmune disorders (rarely)
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SLE
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The peak incidence of idiopathic myelofibrosis is between 50 and 70 yr.
Symptoms,
Signs, and Diagnosis
Early stages may be asymptomatic. Splenomegaly, or, in later stages, general malaise, weight loss, fever, or splenic infarction, may occur. Hepatomegaly occurs in 50% of patients. Lymphadenopathy may occur but is not typical. Rapidly progressive acute leukemia develops in about 10% of patients.
Idiopathic myelofibrosis should be suspected in patients with splenomegaly, splenic infarction, anemia, or unexplained elevations in LDH. If the disease is suspected, CBC should be obtained and peripheral blood morphology and bone marrow should be examined, including cytogenetic testing. Other disorders associated with myelofibrosis (eg, chronic infections, granulomatous disorders, metastatic cancer, hairy cell leukemia, autoimmune disorders) should be excluded, usually by bone marrow examination when clinical suspicion and laboratory evaluation warrant it.
Blood cell morphology is variable. Anemia is usual and generally increases over time. RBCs are normochromic-normocytic with mild poikilocytosis, reticulocytosis, and polychromatophilia. Nucleated RBCs may be in peripheral blood. In advanced cases, RBCs are severely misshapen and teardrop-shaped; this appearance is sufficiently abnormal to suggest the diagnosis.
WBC counts are usually increased but are highly variable. Neutrophils are usually immature, and myeloblasts may be present, even in the absence of acute leukemia. Platelet counts initially may be high, normal, or decreased; however, thrombocytopenia tends to supervene as the disease progresses. Levels of progenitor cells in the peripheral blood, as measured by CD34+ enumeration, may increase.
Bone marrow aspiration is usually dry. Because demonstration of marrow fibrosis is required and fibrosis may not be uniformly distributed, biopsy should be repeated at a different site if the first biopsy is nondiagnostic.
Prognosis
and Treatment
The median survival is 5 yr from onset, although initial diagnosis may be delayed. Constitutional symptoms, anemia, or some cytogenetic abnormalities suggest a poor prognosis; with anemia and some cytogenetic abnormalities, median survival is as low as 2 yr. No treatment reverses or controls the underlying process. Instead, therapy is directed at symptoms and complications.
Androgens, splenectomy, chemotherapy, and splenic radiation therapy have sometimes been used for palliation. For patients with low erythropoietin (EPO) levels relative to the degree of anemia, EPO 40,000 units sc once/wk may increase Hct sufficiently; otherwise, RBC transfusion may be necessary. For younger patients with advanced disease, allogeneic marrow transplantation should be considered.
Last full review/revision November 2005
Content last modified November 2005
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