Chapter 48: Primary Myelofibrosis

DEFINITION

• Primary myelofibrosis is a chronic clonal myeloid disorder that originates in mutations in a multipotential hematopoietic cell. The disease is characterized by (a) anemia, (b) splenomegaly, (c) increased CD34+ cells, immature granulocytes, erythroid precursors, and teardrop-shaped red cells in the blood, (d) marrow fibrosis and increased dysmorphic megakaryocytes, and (e) osteosclerosis.

EPIDEMIOLOGY

• Onset characteristically after age 50 years.

• Median age at diagnosis approximately 68 years.

• Adult males and females affected equally.

• Incidence about 1.0 case per 100,000 in persons of European descent.

PATHOGENESIS

• Origin in the neoplastic transformation of a multipotential hematopoietic cell.

• In approximately 50 percent of cases, the hematopoietic cells (blood cell lineages) contain the mutation JAK2 V617F.

• In approximately 10 percent of cases, the hematopoietic cells contain a mutation in the MPL gene, which encodes the thrombopoietin receptor.

• Constitutive mobilization and circulation of CD34+ cells as a result of epigenetic methylation of the CXCR4 promoter, leading to decreased expression of CXCR4 on CD34+ cells and their enhanced migration from marrow to blood.

• CD34+ cells in this disorder generate about 24-fold the megakaryocytes in culture than do CD34+ cells from normal persons.

Fibroplasia

• Reticulin fibers (type III collagen), as detected by silver staining, are increased in the marrow in most patients. Fibrosis may progress to thick collagen bands (type I collagen) identified with the trichrome stain.

• Increased plasma concentrations of procollagen III amino-terminal peptide, prolylhydroxylase, and fibronectin are present.

• The extent of fibrosis is correlated with the prevalence of dysmorphic megakaryocytes and release of fibroblast growth factors from the megakaryocyte α granules (e.g., platelet-derived growth factor, basic fibroblast growth factor, epidermal growth factor, transforming growth factor-β, and others).

• The fibroblastic proliferation in the marrow is a reaction to the cytokines released by an increased density of dysmorphic megakaryocytes, not an intrinsic part of the clonal expansion of hematopoietic cells.

• Thicker bands of collagen fibrosis (type I collagen) may develop as the marrow fibrosis advances.

CLINICAL FEATURES

• The median age at diagnosis is approximately 68 years, but the disorder may occur at any age.

• The sex incidence is equal in adults, but twice as many females as males in young children.

• Rarely, myelofibrosis is preceded by extended exposure to benzene or very high-dose ionizing radiation.

• Approximately 25 percent of patients are asymptomatic at time of diagnosis.

• Fatigue, weakness, shortness of breath, palpitations, weight loss, night sweats, and bone pain are common presenting symptoms.

• Wasting, peripheral edema, or bone tenderness may occur.

• Left upper-quadrant fullness, pain or dragging sensation, left shoulder pain, and early satiety may result from splenic enlargement and/or infarction.

• Splenomegaly is present in virtually all patients at the time of diagnosis and is massive in one-third of cases.

• Hepatomegaly is present in two-thirds of patients.

• Neutrophilic dermatosis (Sweet syndrome) may be present.