Agnogenic Myeloid Metaplasia Ammmyelofibrosis With Myeloid Metaplasia

AMM (also known as idiopathic MMM), is characterized initially by a hypercellular bone marrow, extramedullary hematopoiesis, splenomegaly, and a leukoerythroblastic peripheral blood picture. The disease can be defined as the causally unknown (agno-genic) proliferation of hematopoietic cells (myeloid cells) in organs or tissues that are not usually involved in blood cell formation (metaplasia). Extramedullary hematopoiesis is a term meaning that this blood cell formation occurs outside the medullary or bone marrow cavity. Leukoerythroblastic anemia means that WBCs and RBCs of varying degrees of immaturity are seen in the peripheral blood.

AMM occurs primarily in older patients. Nearly two thirds of the cases occur between the ages of 50 and 70, about equally in men and in women. Symptoms and signs depend upon the stage of disease when the patient is first encountered. Most often, symptoms are related to anemia and/or an enlarged spleen. Otosclerosis, which can be a presenting symptom in advanced cases, causes deafness in about 10% of patients.

Symptoms and signs depend upon the stage of disease when the patient is first seen. Classically, the spleen is enlarged, the degree depending upon the severity and/or duration of the disease. About a fourth of the patients are asymptomatic and seek medical attention solely because an enlarged spleen is found on routine physical examination, or because of an abnormal peripheral blood smear. Those patients who become symptomatic suffer from fatigue, symptoms related to an enlarged spleen, gout due to elevated uric acid levels, and constitutional symptoms such as weight loss, night sweats, fatigue, and peripheral edema. The latter represent advanced symptoms. Pressure of a large spleen on the stomach may lead to delayed gastric emptying and early satiety.21 Myeloid metaplasia may occur in unusual sites, such as the pulmonary, gastrointestinal, and central nervous systems. Although extramedullary hematopoiesis occurs frequently in the lymph nodes, it rarely accounts for significant nodal enlargement.

Splenomegaly may be found only on radiographic or sonographic examination when it cannot be appreciated clinically.

The hemoglobin ranges between 9 and 13 g/dL. The WBC count is elevated in about half of the patients, normal in one third, and low in the remainder. Examination of the peripheral blood smear discloses a shift toward granulocytic immaturity, including a few myeloblasts and promyelocytes. Significant changes in the RBCs include variation in size and shape and teardrop-shaped forms (though teardrop forms are not specific for AMM). Large fragments and clumps of megakaryocytes and large platelets may be seen. Nucleated RBCs are noted in advanced cases. The platelet count may be increased, normal, or low, depending upon the stage of disease.

The bone marrow aspirate in almost every patient yields a "dry tap," even when the marrow biopsy is highly cellular. Recently, a prefibrotic stage of AMM without splenomegaly has been defined, with the diagnosis based on bone marrow findings (see below). Thus, unless a marrow examination is performed when the patient is initially seen, the clinical diagnosis may be confused with ET. A bone marrow biopsy shows panhypercellularity in the early stages of the disease and, most strikingly, increased numbers of morphologically atypical megakaryocytes appearing in clusters.18 22 These changes occur when there is little fibrosis, and have been labeled "the prefibrotic state."22 Previously, such patients had been incorrectly thought to have ET.22 Often the nuclear segmentation with hypolobulation of the megakaryocytes gives rise to a bulbous or open nuclear appearance. Megakaryocytes in AMM are more atypical than those in other subtypes of MPDs, and consequently present the major discriminating diagnostic hallmark. As the disease progresses, there is a striking increase in retic-ulin and collagen fibrosis. In advanced stages, overt collagen and fibrous osteosclerosis is noted. Special silver stains demonstrate an increase in the amount of reticulin fibers even before the classic increase in collagen tissue occurs.

Obviously, the true morphologic diagnosis of myeloid metaplasia (or equivalently, extramedullary hematopoiesis) rests upon the demonstration of this process in the spleen and/or the liver; however, rarely are the risks justified to make the diagnosis by biopsy of either of these organs.

As the disease progresses, the spleen gradually enlarges, as may the liver. Anemia becomes more severe and is complicated both by iron deficiency owing to bleeding from esophageal varices and by relative folic acid deficiency. The high portal blood flow due to the enlarged spleen may cause "forward liver failure," portal hypertension, and ascites. Thrombosis of the hepatic vein and development of the Budd-Chiari syndrome have been recognized. Eventually, the spleen may occupy the entire abdomen. Ascites may develop.

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