To evaluate the prognostic significance of clinical as well as histological disease features at the time of diagnosis, an immunohistochemical and morphometric study was performed on bone marrow trephine biopsies in 130 patients with Ph(1+)-CML. For identification of all cell elements of the megakaryocytopoiesis we used the monoclonal antibody CD61 (Y2/51) and for the macrophages, the recently characterized antibody PG-M1. Density of argyrophilic fibers was determined per fat cell-free marrow area. Based on a multivariate analysis-derived risk model, the reproducibility of the prognostic score described by Sokal and co-workers was tested, particularly with regard to histological variables. Additionally, we calculated the disease-specific loss in life expectancy. Our prognostic model (Cox model) consisted of the variables: age, spleen size, peripheral erythro-normoblasts, pseudo-Gaucher cells, and fiber density. To assess the validity of this new CML score, a receiver-operating curve (ROC) of sensitivity and specificity was constructed. The improved prognostic efficiency of this newly developed risk model in predicting death within 3 years after diagnosis of CML was demonstrated in comparison with generally accepted staging systems. Immunohistochemistry revealed that not the total number of macrophages, but only the subfraction of pseudo-Gaucher cells exerted a significant impact on survival. Furthermore, it was feasible to calculate the number of atypical micromegakaryocytes and pro- and megakaryoblasts. This abnormal and immature cell population showed a significant correlation with fiber density and prognosis. Finally, the practical value of the Hannover classification was tested. This histological classification enabled a discrimination between two groups with different survival patterns, i.e., granulocyte and/or megakaryocyte-rich subtypes versus subtypes with increase in reticulin and collagen fibers.
There is general agreement on the fact that bone marrow macrophages present a non-proliferating cell population. Using a sequential double-immunostaining technique, a morphometric analysis was performed on routinely processed bone marrow biopsies derived from 70 patients. The purpose of this study was, firstly, to determine the frequency of bone marrow macrophages in a variety of lesions and, secondly, to elucidate whether there is any proliferative activity detectable by immunohistochemical markers. Bone marrow pathology included reactive myelitis (RM), secondary aplastic anaemia (AP), AIDS-related myelopathy, primary (idiopathic) osteomyelofibrosis (OMF) and myelodysplastic syndromes (MDS). The monoclonal antibody PG-M1 which recognizes a formalin-resistant epitope on macrophages and PC10 raised against proliferating cell nuclear antigen (PCNA) were employed. For comparison with the PCNA-labelling index, the newly developed monoclonal antibody Ki-S1, which is associated with cell proliferation, was applied. In comparison with normal bone marrow, morphometric evaluation revealed a significant increase in macrophages in MDS, OMF, RM and especially in HIV-infected patients. Moreover, a positive immunostaining of single macrophages with PC10 was noted very infrequently. This rather inconspicuous PCNA labelling increased in AIDS. By contrast, Ki-S1 expression was found in none of the other pathologies studied. The prevalence of the macrophage population in certain disorders may have a multifactorial origin, such as inflammatory changes like intercurrent infections in AIDS and enhanced cell turnover in MDS as well as involvement of the complex pathomechanisms generating bone marrow fibrosis. In keeping with previous studies, the insignificant PCNA expression of macrophages should not be related to cell proliferation, but to unscheduled DNA strand repair which may be generated in the course of viral infection in AIDS.
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