Clinical and Pathological Criteria for the Diagnosis of Essential Thrombocythemia, Polycythemia Vera, and Idiopathic Myelofibrosis (Agnogenic Myeloid Metaplasia)

Abstract

A set of clinical and pathological criteria for the diagnosis and staging of Philadelphia chromosome-negative myeloproliferative disorders (Ph(1-)-MPDs) is presented by including bone marrow histopathology as a significant tool to identify the early, manifest, and advanced stages of essential thrombocythemia (ET), polycythemia vera (PV), and idiopathic myelofibrosis/agnogenic myeloid metaplasia (IMF/AMM). This combined approach provides a pathognomonic clue to each of the different subtypes of Ph(1-)-MPDs and further enables recognition of the various steps in the evolution of the myeloproliferative process Increase and clustering of giant to large megakaryocytes with mature cytoplasm and multilobulated staghorn-like nuclei in a normal or only slightly increased cellular bone marrow represent major hallmarks of ET. Loose assemblies of small to giant pleiomorphic megakaryocytes containing deeply lobulated nuclei together with a proliferation of erythro- and granulopoiesis (panmyelosis) are the specific lesions of PV. The initial prefibrotic and the overt and more advanced myelofibrotic stages of IMF/AMM show a pronounced proliferation of an abnormal megakaryo- and granulopoiesis dominated by clustered atypical medium-sized to giant megakaryocytes with cloud-like, bulbous, and often hyperchromatic nuclei, which are not seen in allied subtypes of MPDs including chronic myeloid leukemia (Ph(1+)-CML) and myelodysplastic syndromes (MDS). The presented clinical and pathological criteria modify the Polycythemia Vera Study Group (PVSG) proposals for the Ph(1-)-MPDs by including bone marrow histopathology and are in keeping with features outlined in the new World Health Organization classification. The latter allows the differentiation of true ET from reactive thrombocytosis and from thrombocythemias as an eventually presenting finding in PV, IMF/AMM, MDS, and Ph(1+)-CML. Moreover, these diagnostic guidelines are able to separate latent and early PV from secondary erythrocytosis and to detect the prefibrotic and early stages of IMF/AMM. Myelofibrosis is not a feature of ET and is rarely observed in PV at time of diagnosis, but it becomes apparent during long-term follow-up and constitutes a prominent lesion during the course of IMF/ AMM. Life expectancy is almost normal in ET and is also not significantly altered during the first, but compromised during the second, decade of follow-up in PV. On the other hand, survival is substantially shortened in IMF/AMM, even for patients with thrombocythemia as a frequent finding of prefibrotic and early stage IMF/AMM.

Prodromal myeloproliferative neoplasms: The 2008 WHO classification

“…These findings concern a number of patients with presumptive ET in whom relevant complications (i.e., hemorrhage, vascular events) have been described [31][32][33]89,90]. These patients presented with a persistent platelet count much lower than the threshold value ( 600 3 10 9 /l) required to meet the diagnostic criteria of the PVSG [5,7,21].…”

“…Clinicians are aware that in large series a striking variability in the hematological findings of patients may be observed at the time of first presentation [90,[102][103][104][105][106][107][108]. Wide ranges of clinical parameters on first sight were paralleled by corresponding BM features that may very initially present a hypercellular BM without or only slight reticulin MF [102,104,106,[109][110][111].…”

Bone Marrow Features and Natural History of BCR/ABL-Positive Thrombocythemia and Chronic Myeloid Leukemia Compared to BCR/ABLNegative Thrombocythemia in Essential Thrombocythemia and Polycythemia Vera

“…Michiels et al and the German pathologists Georgii and Thiele recognized that small mono-or bi-nucleated megakaryocytes are diagnostic for the Ph-positive diseases ET and CML. In contrast, large megakaryocytes with hyper-lobulated nuclei are pathognomonic for Ph-negative essential thrombocythemia (Figures 1 and 2) [13][14][15][16][17][18][19][20][21][22][23][24]. The Hannover Bone Marrow Classification of CML and MPD regarded myelofibrosis (MF) as a reactive secondary feature of myeloproliferative disease.…”

“…Secondary MF in ET, PV and CMGM is classified as reticulin fibrosis (RF) grade 0 and 1 (=MF 0), RF grade 2 (=MF 1), RF 3 with minor collagen fibrosis (=MF 2) and advanced reticulin-collagen fibrosis (RCF) with or without osteosclerosis (=MF 3) [17,18]. In the Hannover Bone Marrow Classification the megakaryocytes in BRC/ABL-positive thrombocythemia and CML are small containing uni-or bi-lobulated nuclei (Figures 1 and 2) but large and mature with hyperlobulated nuclei in ET [16][17][18][19][20][21][22][23][24][25][26]. The megakaryocytes in trilinear PV are of medium size to large (pleomorphic) with hyperploid nuclei.…”

“…Prefibrotic CMGM is dominated by primary megakaryocyticgranulocytic myeloproliferation (PMGM) and increase of clustered atypical dysmorphic megakaryocytes due to increases of cellular and nuclear sizes. In CMGM/PMGM, the nuclei of dysmorphic megakaryocytes are bulky with clumsy lobuli and irregular roundish shaped form (so-called cloud-like nuclei), which are never seen in ET, PV and CML [16][17][18][19][20][21][22][23][24][25][26]. CMGM/PMGM is not preceded or followed by normocellular ET, PV or MDS and can be regarded as the third distinct prefibrotic primary MPD (Table 1) [19][20][21][22][23][24][25][26][27][28][29].…”