Myelofibrosis, Primary

Key Features

Essentials of Diagnosis

• Striking splenomegaly

• Teardrop poikilocytosis on peripheral smear

• Leukoerythroblastic blood picture; giant abnormal platelets

• Initially, hypercellular bone marrow, then hypocellular bone marrow with reticulin or collagen fibrosis

General Considerations

• Primary myelofibrosis is a myeloproliferative disorder characterized by clonal hematopoiesis that is often but not always accompanied by JAK2, CALR or MPL mutations, bone marrow fibrosis, anemia, splenomegaly, and a leukoerythroblastic peripheral blood picture with teardrop poikilocytosis

• A myeloproliferative disorder, also known as myelofibrosis with myeloid metaplasia, agnogenic myeloid metaplasia, and idiopathic myelofibrosis

• Can also occur as a secondary process following other myeloproliferative disorders (see Polycythemia Vera and Essential Thrombocytosis)

• It is believed that bone marrow fibrosis occurs in response to increased secretion of platelet-derived growth factor (PDGF) and possibly other cytokines

• In response to the bone marrow fibrosis, extramedullary hematopoiesis takes place in the liver, spleen, and lymph nodes

• Abnormalities of JAK2 and MPL are involved in the pathogenesis

Clinical Findings

Symptoms and Signs

• Onset is usually insidious

• Develops in adults over age 50 years

• Most common presentations

  • Fatigue due to anemia

  • Abdominal fullness related to splenomegaly

• Uncommon presentations

  • Bleeding

  • Bone pain

• Splenomegaly

  • Almost invariably present

  • Commonly massive

• Liver is enlarged in > 50% of cases

• Later in the course of the disease

  • Splenomegaly may result in early satiety

  • Splenic infarction may occur

  • Progressive bone marrow failure takes place as it becomes increasingly more fibrotic

  • Progressive thrombocytopenia leads to bleeding

  • Patient becomes cachectic and may experience severe bone pain, especially in the upper legs

  • Hematopoiesis in the liver leads to portal hypertension with ascites, esophageal varices, and occasionally transverse myelitis caused by myelopoiesis in the epidural space

Differential Diagnosis

• Severe infection, inflammation, or infiltrative bone marrow processes

• Metastatic carcinoma, Hodgkin lymphoma, and hairy cell leukemia

• Chronic myeloid leukemia (CML)

• Polycythemia vera

• Essential thrombocytosis

Diagnosis

Laboratory Findings

• Anemia

• White blood count

  • Variable—either low, normal, or elevated

  • May be increased to 50,000/mcL

• Platelet count is variable

• Peripheral blood smear is dramatic, with significant poikilocytosis and numerous teardrop forms in the red cell line

• Nucleated red blood cells are present and the myeloid series is shifted, with immature forms including a small percentage of promyelocytes or myeloblasts

• Platelet morphology may be bizarre, and giant degranulated platelet forms (megakaryocyte fragments) may be seen

• The triad of teardrop poikilocytosis, leukoerythroblastic blood, and giant abnormal platelets is highly suggestive of myelofibrosis

• Bone marrow usually cannot be aspirated (dry tap), though early in the course of the disease it is hypercellular, with a marked increase in megakaryocytes

• Fibrosis at this stage is detected by a silver stain demonstrating increased reticulin fibers; later, marrow biopsy reveals ...