13-26: Primary Myelofibrosis

ESSENTIALS OF DIAGNOSIS

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. Myelofibrosis can also occur as a secondary process following the other myeloproliferative disorders (eg, polycythemia vera, essential thrombocytosis). It is believed that fibrosis occurs in response to increased secretion of platelet-derived growth factor (PDGF) and possibly other cytokines. In response to bone marrow fibrosis, extramedullary hematopoiesis takes place in the liver, spleen, and lymph nodes. In these sites, mesenchymal cells responsible for fetal hematopoiesis can be reactivated. According to the 2016 WHO classification, “prefibrotic” primary myelofibrosis is distinguished from “overtly fibrotic” primary myelofibrosis; the former might mimic essential thrombocytosis in its presentation, and it is prognostically relevant to distinguish the two.

CLINICAL FINDINGS

A. Symptoms and Signs

Primary myelofibrosis develops in adults over age 50 years and is usually insidious in onset. Patients most commonly present with fatigue due to anemia or abdominal fullness related to splenomegaly. Uncommon presentations include bleeding and bone pain. On examination, splenomegaly is almost invariably present and is commonly massive. The liver is enlarged in more than 50% of cases.

Later in the course of the disease, progressive bone marrow failure takes place as it becomes increasingly more fibrotic. Progressive thrombocytopenia leads to bleeding. The spleen continues to enlarge, which leads to early satiety. Painful episodes of splenic infarction may occur. The patient becomes cachectic and may experience severe bone pain, especially in the upper legs. Hematopoiesis in the liver leads to portal hypertension with ascites and esophageal varices, and occasionally myelopoiesis in the epidural space causes transverse myelitis.

B. Laboratory Findings

Patients are almost invariably anemic at presentation. The white blood count is variable—either low, normal, or elevated—and may be increased to 50,000/mcL (50 × 10⁹/L). The platelet count is variable. The peripheral blood smear is dramatic, with significant poikilocytosis and numerous teardrop forms in the RBC line (eFigure 13–21). Nucleated RBCs 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.