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Idiopathic myelofibrosis (IMF) is generally characterized by bone marrow (BM) fibrosis, anemia, splenomegaly and a leuko-erythroblastic blood picture. Although, histopathology is in keeping with the assumption of a stepwise evolution of the disease, little hematological data are available for patients with prefibrotic and early stages of disease. Therefore a clinicopathological study was performed that included firstly an exploratory sample of 68 patients with minor supportive therapy in whom BM biopsies during follow-up (41 +/- 32 months) revealed an evolution of a prefibrotic or very early fibrotic lesion into overt IMF. The validation sample consisted of 556 patients with pretreatment marrow specimens on admission. Diagnostic features and BM lesions were identical compared with the patients of the exploratory sample at their first examination. BM biopsies were processed by routine stainings including silver impregnation (reticulin fibers) and frequently also by immunohistochemistry to identify megakaryocytes and erythroid precursor cells more properly. Apart from minor hemorrhage and peripheral thrombosis patients with early stage IMF presented with non-specific symptoms including varying degrees of leukocytosis (51%), anemia (38%), a platelet count exceeding 600 x 10(9)/l (86%), splenomegaly (15%) and increase in leukocyte alkaline phosphatase (LAP) (24%) and serum lactate dehydrogenase (LDH) (20%). BM histology confirmed a moderate increase in hematopoiesis with a mixed granulocytic and megakaryocytic myeloproliferation, a reduction of erythroid precursors and significant megakaryocytic abnormalities. In keeping with the first BM examination of the exploratory sample no or only a borderline to slight increase in reticulin fibers was detectable, however, in 68 of 134 patients follow-up biopsies revealed a transition into overt IMF (intervals about three years). Median survival of this cohort with early-stage IMF was 129 months thus contrasting manifest IMF with an usually more unfavorable prognosis. Recognition of early stage IMF certainly alters the generally applied diagnostic criteria of this disorder. Regarding patients with associated thrombocytosis, differentiation from essential thrombocythemia is recommended. Moreover, characterization of early stage IMF probably exerts an impact on survival and may influence the decision to perform a BM transplantation.

A multicenter, immunohistochemical and morphometric study was performed on diagnostic pretreatment bone marrow biopsies in 614 adult patients with Ph1+ chronic myeloid leukemia (CML) to compare histological features with clinical findings. For identification of megakaryopoiesis we used the monoclonal antibody CD61 and additionally the PAS reaction to determine the subfraction of atypical micromegakaryocytes and precursors. Labelling of erythroid precursors was carried out by a monoclonal antibody directed against glycophorin C. In order to selectively stain macrophages and their activated subset we applied CD68 and the GSA-I lectin. Density of argyrophilic fibers (reticulin plus collagen) was measured following Gomori's silver impregnation method. In accordance with laboratory data morphological variables revealed a comparable amount of congruence in the various groups of CML patients derived from different sources. In about 26% of patients early (reticulin) to advanced (collagen) fibrosis was detectable. Significant correlations were calculated between the extent of myelofibrosis with splenomegaly, anemia and increasing numbers of erythroblasts and myeloblasts in the peripheral blood count. These features were assumed to indicate more advanced stages of the disease process with ensuing transition into myeloid metaplasia and consequently were associated with an unfavorable prognosis. Significant relationships were revealed between the number of CD61+ megakaryocytes and more important, also their precursor fraction with the degree of fibrosis. This result extends previous experimental findings regarding the impact of immature elements of this cell lineage for the generation of myelofibrosis. The significant association of erythroid precursors with the number of mature (resident) macrophages including their activated GSA-I subset may shed some light on their functional involvement in iron turnover and hemoglobin synthesis. A modified histological classification of predominant bone marrow features is introduced. This simplified synthesis staging system (Cologne Classification) is not only associated with certain sets of laboratory data, but also with different survival patterns.

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.

The prognostic significance of disease features at the time of diagnosis was examined in 113 patients (75 males/38 females, median age 49 years) with chronic myeloid leukemia (CML) using multivariate regression analysis. In the course of this study we tested the validity of the prognostic model described by Sokal and coworkers(3), the predictive value of histopathological variables, and determined the disease-specific loss in life expectancy. The median survival time was 35 months in our patients. By using Cox's proportional hazards model for covariate analysis of censored survival data(26)'(32) two prognostic models were derived. The first consisted of the following parameters-age, presence of pseudo-Gaucher cells in the marrow, spleen size and the product of myeloblasts and normoblasts in the peripheral blood. The second model included age, the presence of myelofibrosis, the number of megakaryocytes in the bone marrow and the liver size. Both models provided a risk status that showed an excellent predictive relationship to relative survival rates and life expectancy. Application of the Sokal model(3) to our subpopulation of CML patients failed to reveal a significant segregation of the intermediate group from the other risk groups, even when assessing the disease-specific loss in life expectancy. Our results suggest that an amendment of the generally accepted model for prognostic evaluation of survival in CML should be made by inclusion of histological variables and the determination of relative survival rates.