Myelofibrosis

Etiology

Myelofibrosis is a chronic myeloproliferative disorder characterized by bone marrow fibrosis and the development of extramedullary hematopoiesis. Myelofibrosis can occur as a primary disease entity (also termed idiopathic myelofibrosis or agnogenic myeloid metaplasia ) or can occur secondary to diffuse bony metastatic disease, infections (e.g., tuberculosis and fungal infections), sarcoidosis, myeloma, and lymphoma. The etiology of primary myelofibrosis is unknown, but an increased incidence of this disease is seen after exposure to radiation and to bone marrow toxins, such as benzene and toluene. Primary myelofibrosis occurs as a result of a clonal proliferation of myeloid cells with variable maturity and hematopoietic efficiency.

The marrow fibrosis that occurs is a reactive process of nonclonal fibroblasts, mediated by cytokines, such as platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-β, shed from clonally expanded megakaryocytes. A variety of genetic factors have been implicated in the development of primary myelofibrosis, including the JAK2 tyrosine kinase mutation that has been described in a variety of myeloproliferative disorders.

Prevalence and Epidemiology

Primary myelofibrosis is a rare disorder with reported incidence figures that range from 0.5 to 1.5 in 100,000. The male-to-female ratio has been reported as 1.2 to 1.6 : 1. The median age at diagnosis is 60 years, with rare cases reported in young adults and children. Cases of primary myelofibrosis in children often have a more indolent course than those in adults.

Clinical Presentation

Myelofibrosis is typically insidious in onset, and many patients are asymptomatic at the time of diagnosis. The most common presenting symptoms are fatigue due to anemia or abdominal fullness related to splenomegaly (a site of extramedullary hematopoiesis). Less common presenting symptoms include bleeding, bone pain, primary hypertension, and variceal bleeding.

On examination, there is splenomegaly in virtually all patients, which can be massive. Hepatomegaly is seen in 50% of patients, and lymphadenopathy is seen in 10%. As the disease progresses, the associated anemia becomes more severe and may require repeated transfusions. Splenic infarction can occur, leading to episodes of abdominal pain. Extramedullary hematopoiesis in the epidural space can lead to cord compression late in the course of the disease.

Pathophysiology

Myelofibrosis is characterized by the replacement of normal marrow with fibrous material (reticulin and collagen) and by the presence of extramedullary hematopoiesis. The fibrotic changes that occur in bone are due to a process of nonclonal fibroblasts, mediated by cytokines that are shed from clonal megakaryocytes. The major cytokines implicated are PDGF and TGF-β. PDGF stimulates fibroblasts to proliferate and secrete collagen, whereas TGF-β enhances the secretion of extracellular matrix proteins. The degree of bone marrow cellularity seen is variable and depends on the degree of fibrosis present. In acute cases, the bones may appear osteopenic on radiographs with marrow infiltration seen on scintigraphy and MRI. As the disease progresses, the marrow becomes hypocellular and fibrotic. In more chronic cases, bone marrow fibrosis is then seen as areas of osteosclerosis on radiographs and as areas of T1 and T2 hypointensity on MRI.

Almost all cases of myelofibrosis have splenomegaly, and splenic histology shows extramedullary hematopoiesis. Foci of extramedullary hematopoiesis can also be seen in the liver, kidneys, lymph nodes, adrenal glands, lungs, and the epidural space. At these sites, mesenchymal cells responsible for fetal hematopoiesis can be activated. The mechanisms responsible for extramedullary hematopoiesis are not fully understood. Sites of extramedullary hematopoiesis may enlarge significantly after splenectomy.

Imaging Techniques