Idiopathic Primary Osteo-myelofibrosis: A Clinico-Pathological Study on 208 Patients with Special Emphasis on Evolution of Disease Features, Differentiation from Essential Thrombocythemia and Variables of Prognostic Impact

Abstract

A retrospective clinico-pathological study was performed on 208 consecutively recruited patients (94 males, 114 females, median age 67 years) with idiopathic (primary) osteo-/ myelofibrosis (IMF). According to bone marrow histology (cellularity) as well as extent (semiquantitative grading) and quality (reticulin/collagen) of myelofibrosis, stages of the disease process were determined. At closure of this study (observation time 65 months) 133 patients were dead and 75 alive and median survival was 56 months. The wide spectrum of clinical signs and symptoms and laboratory data on admission was reflected by a corresponding variety of histological features. Significant differences of hematological values could be calculated between patients with or without early reticulin fibrosis (fiber scores 0 and 1) and advanced fibro-osteosclerotic stages (fiber scores 2 and 3). Evolution of disease features was elicited by longitudinal follow-up studies and sequential bone marrow biopsies. Morphometric assessment of fiber density in patients without preceding chemotherapy revealed an unpredictable and varying progression of myelofibrosis associated with alterations of certain laboratory parameters (hemoglobin level, spleensize, thrombocytosis). Differentiation from essential (primary) thrombocythemia (ET) was required in 25 patients who fulfilled the postulated diagnostic criteria. In fact, this group was consistent with hypercellular, early stages of IMF without relevant reticulin fibrosis and an excessively raised platelet count (> or = 1000 x 10(9)/1). Discrimination was only feasible by regarding histology carefully, particularly abnormalities of megakaryopoiesis and follow-up data. Parameters of predictive value indicating a significant loss in life expectancy in comparison with a sex- and age-adjusted normal population included: age (> or = 60 years), hemoglobin levels (< or = 10 g/dl), thrombocyte count (< or = 600 x 10(9)/1) and the presence of myeloblasts and promyelocytes. Statistical analysis disclosed that in the so-called early stages of IMF without relevant myelofibrosis, findings indicative for extramedullary hemopoiesis or generalization of the disease process exerted an unfavourable influence on survival.

Follow‐up examinations including sequential bone marrow biopsies in essential thrombocythemia (ET): A retrospective clinicopathological study of 120 patients

“…A number of relevant evaluations reported an incidence of up to 54% [15][16][17]23]. This result fits well with our findings that by following the PVSG criteria [3] many patients with (initial-early) IMF and accompanying thrombocytosis were regarded as ET [30]. Moreover, there is only scant knowledge about follow-up examinations, because clinical studies very rarely included repeatedly performed BM trephines for the proper assessment of fibrosis.…”

“…About onehalf of this cohort revealed an unfavorable prognosis and consisted of patients that showed an increased cellularity including myeloid precursors and a higher content of reticulin fibers with trapped "dysplastic" megakaryocytes in their BM [23]. Regarding these data, our findings are in keeping with the assumption that a considerable number of patients with the putative clinical diagnosis of ET should be correctly placed into this category of early IMF [7,30]. The obvious difficulty to distinguish ET from initial IMF is further documented by the enormous range of frequency concerning the presence of reticulin fibrosis in larger series of patients.…”

“…As has been demonstrated in this observational clinicopathological study, repeatedly performed BM trephines lend further support to the fact that only a fraction (about 35%) of the total series was compatible with (true) ET. Considering these findings and previous clinical [11,32,33] and morphological data [6,7,13,30,34,39,40] as well as cell culture studies [41][42][43], the WHO criteria [12] should be slightly modified by defining a lower limit of the platelet count. Finally, when comparing the diagnostic implications of histopathology with that of colony assays, one has to keep in mind that cell culture studies are burdensome and time-consuming and that interpretations are limited to an experienced observer in this speciality.…”

Acute leukemia and myelodysplasia in patients with a Philadelphia chromosome negative chronic myeloproliferative disorder treated with hydroxyurea alone or with hydroxyurea after busulphan

“…Some patients with "ET" may transform to myelofibrosis. In recent years it has been shown that some of these patients actually have a diagnosis of IMF from the very beginning, this prefibrotic phase of IMF being only distinguished from ET by the highly characteristic bone marrow findings [48]. Our patients with ET who had developed AML had been observed for several years with a diagnosis of ET.…”

Life expectancy and prognostic factors in the classic BCR/ABL-negative myeloproliferative disorders

“…7,37 Bone marrow histologic findings did not have prognostic relevance in most studies. 12,38,39 A pattern of red cell aplasia in a cellular bone marrow has been associated with a more unfavourable outcome. 7 A correlation has recently been reported between PMF prognosis and angiogenesis.…”