Chapter 48: Primary Myelofibrosis

DEFINITION

• Primary myelofibrosis is a chronic myeloid neoplasm that originates in mutations in a multipotential hematopoietic cell, possibly the lymphohematopoietic stem cell. The disease is characterized by (1) anemia; (2) splenomegaly; (3) increased CD34+ cells, immature granulocytes, erythroid precursors, and teardrop-shaped red cells in the blood; (4) increased dysmorphic megakaryocytes, the cytokines from which induce marrow fibrosis; and (5) osteosclerosis.

• The designation (name) for this clonal neoplasm has been problematic throughout the years. The decision to call it primary myelofibrosis is a failure to understand its pathobiology. There are no tumors of connective tissue fibers. The disease is principally a profound, neoplastic expression of exaggerated and profoundly disordered hematopoiesis, with disordered megakaryocytopoiesis being the most prominent and consistent finding and the basis for the fibrosis characteristic of the disease. The primary abnormality of megakaryocytopoiesis is amplified by the fact that CD34+ cells from patients with this disease, when grown in culture, generate 24-fold the clonal megakaryocytes as the number of megakaryocytes generated by normal CD34+ cells. Thus, this disease most closely conforms to chronic megakaryocytic leukemia, using the standard convention of naming a myeloid neoplasm by its dominant morphologic expression (eg, monocytic leukemia, erythroid leukemia).

EPIDEMIOLOGY

• Onset is characteristically after age 50 years.

• Median age at diagnosis is approximately 70 years.

• Adult males and females are affected equally.

• Incidence is approximately 1 case per 100,000 in persons of European descent.

• Rarely, myelofibrosis is preceded by extended high-dose ionizing radiation.

PATHOGENESIS

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

• Mutations may exist in blood cells of patients. Approximately 50% have JAK2 V617F, 35% CALR, and 5% MPL mutations; approximately 10% do not have one of these mutations (triple-negative primary myelofibrosis).

• Frequently, other somatic mutations may be found in patients’ blood cells, including TET2, ASXL1, DNMT3A, EZH2, IDH1, TP53, and CBL.

• Constitutive mobilization and circulation of CD34+ cells occur 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 reticulin 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 (eg, 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 ...