Diagnosis, pathogenesis and treatment of the myeloproliferative disorders essential thrombocythemia, polycythemia vera and essential megakaryocytic granulocytic metaplasia and myelofibrosis

According to strict clinical, hematological and morphological criteria, the Philadelphia (Ph) chromosome negative chronic myeloproliferative disorders essential thrombocythemia (ET), polycythemia vera (PV), and agnogenic myel oid (megakaryocytic/granulocytic) metaplasia (AMM) or idiopathic myelofibro sis (IMF) are three distinct disease entities with regard to clinical manif estations, natural history and outcome in terms of life expectancy. As clon ality studies have clearly demonstrated that fibroblast proliferation in AM M, as well as in many other conditions such as advanced stages of Ph+-essen tial thrombocythemia, Ph+-granulocytic leukemia, and Ph--polycythemia vera, is polyclonal indicating that myelofibrosis is secondary to the megakaryoc ytic granulocytic metaplasia in these various conditions, AMM is illogicall y labeled as IMF. As abnormal megakaryocytic granulocytic metaplasia is the essential feature preceding the early prefibrotic stage of AMM, the term e ssential megakaryocytic granulocytic metaplasia (EMGM) can readily be used to characterize this condition more appropriately at the biological level. Clinical, hematological and morphological characteristics, in particular me gakaryocytopoiesis and bone marrow cellularity, reveal diagnostic features, which enable a clear-cut distinction between ET, PV and EMGM or classical IMF. The characteristic increase and clustering of enlarged megakaryocytes with mature cytoplasm and multilobulated nuclei and their tendency to clust er in a normal or only slightly increased cellular bone marrow represent th e hallmark of ET. The characteristic increase and clustering of enlarged ma ture and pleiomorphic megakaryocytes with multilobulated nuclei and prolife ration of erythropoiesis in a moderate to marked hypercellular bone marrow with hyperplasia of dilated sinuses are the specific diagnostic features of untreated PV; EMGM, including the early prefibrotic stages as well as the various myelofibrotic stages of classical IMF appear to be a distinct neopl astic dual proliferation of abnormal megakaryopoiesis and granulopoiesis. T he histopathology of the bone marrow in prefibrotic EMGM and in classical I MF is dominated by atypical, enlarged and immature megakaryocytes with clou d-like immature nuclei, which are not seen in ET and PV at diagnosis and du ring follow-up. Myelofibrosis in ET, PV and EMGM is graded into: no reticul in fibrosis (MFO), early reticulin fibrosis (MF1), advanced reticulin scler osis with minor or moderate collagen fibrosis (MF2) and advanced collagen f ibrosis with osteosclerosis (MF3). Myelofibrosis is not a feature of ET at diagnosis and during long-term follow-up. Myelofibrosis may be present in a minority of PV-patients at diagnosis and usually becomes apparent during long-term follow-up in the majority of PV-p atients. Myelofibrosis secondary to the abnormal megakaryocytic and granulo cytic myeloproliferation constitutes a prominent feature in the majority of EMGM/IMF at time of diagnosis and usually progresses more or less rapidly during the natural history of the disease. Life expectancy is normal in ET, normal during the Ist ten years and compro mised during the 2nd ten years follow-up in PV, but significantly shortened in the prefibrotic stage of EMGM as well as in the various myelosclerotic stages of classical IMF. First line treatment options in prospective randomized clinical trials of n ewly diagnosed MPD-patients are control of platelet function with low-dose aspirin versus reduction of platelet count with anagrelide, interferon or h ydroxyurea in ET; control of platelet and erythrocyte counts by interferon alone versus bloodletting plus hydroxyurea on indication in PV; interferon versus no treatment in the early stages of EMGM; a wait and see strategy in the fibrotic stages of EMGM or classical IMF with favorable prognostic fac tors, and bone marrow transplantation in classical IMF with poor prognostic factors at presentation or during short-term follow-up. (C) 1999 Elsevier Science BN. All rights reserved.