The Incidence of Myelofibrosis in Essential Thrombocythaemia, Polycythaemia vera and Chronic Idiopathic Myelofibrosis: A Retrospective Evaluation of Sequential Bone Marrow Biopsies

Abstract

The incidence of myelofibrosis (MF) among the three major Philadelphia chromosome-negative chronic myeloproliferative disorders, i.e. essential thrombocythaemia (ET), polycythaemia vera (PV) and chronic idiopathic myelofibrosis (CIMF), is not well documented since the diagnostic criteria have recently been redefined by the WHO. Therefore we performed a retrospective analysis of follow-up biopsies of 275 patients with ET, PV and CIMF according to the WHO classification of chronic myeloproliferative disorders. In the diagnostic bone marrow biopsies, MF was observed in 57 of the 136 CIMF patients (42%), 4 of the 73 PV patients (5%) and none of the 66 patients with ET. Within a median observation time of 2.9 years, 34 of the 79 patients with CIMF (43%), 13 of the 69 patients with PV (19%) and 1 of the 66 patients with ET (1.5%) – each initially without MF – developed MF regardless of myelosuppressive therapy.

Prodromal myeloproliferative neoplasms: The 2008 WHO classification

“…Eleven of 226 patients regarded as ET with an increased fiber score (Grades 2) at onset developed overt MF, contrasting none of 135 patients with a normal fiber content (Grades 1) [124]. This finding is generally in line with follow-up examinations including BM biopsies in patients with PMF versus ET [109,110,114,127]. In context with this negative attitude regarding the reproducibility of morphological features, i.e., a clear-cut differentiation between ET and early stage PMF, the results of the UK-PT 1 trial [27] have to be discussed.…”

“…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].…”

“…Histopathology of BM biopsy samples in prodromal PMF reveals a hypercellularity by a prominent neutrophil granulocytic and megakaryocytic proliferation often associated with a concomitant reduction of nucleated red cell precursors [62,102,103,109,110,[112][113][114] in the absence or only minor reticulin MF (Fig. 2A).…”

“…It has to be realized that reproducibility of histological features endorsed by the WHO persists to be a critical issue. However, several groups confirmed their ability to discriminate between the thrombocythemic manifestations of early stage PMF versus ET [96,97,99,100,114]. On the other hand, in a blinded study among three hematologists/pathologists partially using BM specimens from the UK-PT 1 trial [27], the reproducibility and validity of distinguishing so-called true ET according to the WHO classification [1,2] from prefibrotic PMF [122] was questioned.…”

“…This finding has also been shown in several retrospective and observational studies. Therefore, myelofibrotic transformation in ET is a very rare event in the first 5 years of follow-up provided the diagnostic guidelines of the WHO were applied [98,99,114,126,127].…”