Evolution of Myelofibrosis in Chronic Idiopathic Myelofibrosis as Evidenced in Sequential Bone Marrow Biopsy Specimens

Abstract

Although the new World Health Organization (WHO) classification acknowledges "prefibrotic" phases, progression of myelofibrosis in chronic idiopathic myelofibrosis (cIMF) is controversial because there are only a few studies about sequential biopsy specimens, and they yield conflicting results. The conflicting results might be due to a mixture of different degrees of myelofibrosis and therapy regimens within the respective groups studied. To prove this hypothesis, we studied sequential bone marrow biopsy specimens from patients with cIMF and compared 3 groups with different degrees of myelofibrosis at initial diagnosis with a group of patients with primarily unfibrosed disease who met the WHO criteria for prefibrotic cIMF. Patients receiving chemotherapy were considered separately from patients without treatment. Our results favor a steady progression of myelofibrosis unrelated to therapy modalities, whereas confusing literature data can be explained: fibrosis may remain static or lessen, especially in more advanced stages of cIMF.

Prodromal myeloproliferative neoplasms: The 2008 WHO classification

“…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]. Additionally, scrutinized evaluations of follow-up studies including BM examinations were in keeping with a stepwise evolution of the disease process starting with a prefibrotic precursor stage and progressing over many years into overt MMM [103,106,107,109,110,[112][113][114]. Concerning the dynamics of disease process in PMF, the former gold standard for the diagnosis of MMM [6,22,23,89,115,116] or agnogenic myeloid metaplasia (AMM) should be avoided, because these criteria include only the advanced or overt stages of a wide spectrum of clinical and morphological disease manifestations [102].…”

“…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]. Additionally, scrutinized evaluations of follow-up studies including BM examinations were in keeping with a stepwise evolution of the disease process starting with a prefibrotic precursor stage and progressing over many years into overt MMM [103,106,107,109,110,[112][113][114].…”

“…It has been estimated that between 40% and 50% of patients present with a prefibrotic or early reticulin fibrotic stage of PMF [98,99,109,110], although these figures are significantly biased by considering reference centers. The presence of the JAK2V617F mutation in precursor stages of PMF does not exert a specific diagnostic impact, because it may be found in about 50% of patients [11,91].…”

“…A remarkable point is that progression of prodromal PMF into MMM/AMM [6,22,115,116] is not triggered by the JAK2V617F mutation status, but by a number of relevant target genes that are involved in matrix modeling and regulation of fibrillogenesis [119]. Clinical data in these prodromal stages of PMF are usually characterized by only minimal abnormalities as borderline to slight anemia, minimal splenomegaly, a very low or missing peripheral blast count but often a conspicuous thrombocytosis [93,98,102,103,106,107,[109][110][111]120] as shown in Table III.…”

Megakaryocytic expression of miRNA 10a, 17-5p, 20a and 126 in Philadelphia chromosome-negative myeloproliferative neoplasm

“…Cases were diagnosed from 2001-2006 according to histomorphology and clinical data. Myelofibrosis was classified according to presence and extent of fibre deposition, osteosclerosis, and intrasinusoidal haematopoiesis, as described [16]. In all control cases under investigation, biopsies were taken for exclusion of neoplastic BM infiltration and showed normal or mild hyperplastic non-leukaemic haematopoiesis.…”