Prognostic implications of bone marrow features in chronic myelogenous leukaemia.
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Biomarkers, Tumor↗
Biomedical subjects
J Thiele
Publications and source records attributed to J Thiele.
Macrophages in normal human bone marrow and in chronic myeloproliferative disorders: an immunohistochemical and morphometric study by a new monoclonal antibody (PG-M1) on trephine biopsies.
An immunohistochemical and morphometric study was performed on routinely processed trephine biopsies of the bone marrow in 30 normal individuals and in 90 patients with various subtypes of chronic myeloproliferative disorder. Using a new monoclonal antibody (PG-M1) directed against a formalin-resistant epitope on macrophages and by employment of the Prussian blue reaction, quantitation of this cell population was feasible. Morphometric analysis revealed that the number of iron-laden macrophages represented only a fraction of the total number of histiocytic reticular cells. As could be expected, in polycythaemia rubra vera, no haemosiderin deposits were detectable, but the content of macrophages slightly exceeded that of the normal bone marrow. In chronic myeloid leukaemia 9 of 30 patients showed a significant increase in PG-M1-positive reticular cell elements. These were consistent with pseudo-Gaucher cells, sea-blue histiocytes and intermediate cell types. Primary (idiopathic) myelofibrosis-osteomyelosclerosis was characterized by a significant increase in macrophages (25 of 30 patients). Involvement of macrophages in the complex mechanisms generating bone marrow fibrosis and angiogenesis and in bone remodelling (osteosclerosis) may be responsible for this finding.
Adipose Tissue↗
Atypical micromegakaryocytes, promegakaryoblasts and megakaryoblasts: a critical evaluation by immunohistochemistry, cytochemistry and morphometry of bone marrow trephines in chronic myeloid leukemia and myelodysplastic syndromes.
A morphometric analysis of bone marrow trephine biopsies has been performed to study the frequency and planimetric characteristics of so-called atypical micromegakaryocytes in chronic myeloid leukemia (CML) and myelodysplastic syndromes (MDS). In addition, an attempt was made to discriminate this particular cell population from small immature elements of megakaryocytopoiesis, such as promegakaryoblasts and megakaryoblasts. The staining reactions employed included periodic acid-Schiff (PAS), alpha-naphthyl acetate esterase (ANAE) and immunohistochemistry with a monoclonal antibody against platelet glycoprotein IIIa (Y2/51-CD61). Comparison of the various staining reactions applied to the different megakaryocytic elements together with morphometric measurements resulted in a clearcut identification of promegakaryoblasts. These were defined as the earliest immature and exclusively CD61-positive precursors. Atypical micromegakaryocytes were characterized by their dysplastic features and strong ANAE reactivity in addition to their positive CD61 staining. When stringent diagnostic criteria (diameter ranging between 10 to 15 microns, mean size about 12 microns) were applied, this abnormal cell population comprised less than 10% of total megakaryocytopoiesis in CML and MDS. It may be assumed that dysmegakaryocytic features in the latter disorders are partially generated by small to medium-sized megakaryocytes (diameter less than 30 microns). In conclusion, the relative frequency of promegakaryoblasts in the normal bone marrow (range 6-8%) is confirmed by evaluation of the immunohistochemical and cytochemical staining methods (CD61 and ANAE). Furthermore, the ANAE reaction facilitates the recognition of atypical micromegakaryocytes as well as small megakaryocytes. Thus cytochemistry provides a better insight into alterations of these cell lineages in various pathological conditions.
Adult↗
Megakaryocytopoiesis in bone marrow biopsies of patients with acquired immunodeficiency syndrome (AIDS). An immunohistochemical and morphometric evaluation with special emphasis on myelodysplastic features and precursor cells.
In 25 patients (22 males, 3 females--median age 39 years) with AIDS (CDC stages IV A-D) and no preceding myelotoxic therapy, morphometry and immunohistochemistry (CD 61-Y 2/51) was performed on trephine biopsies of the bone marrow to evaluate the megakaryocytic lineage. In comparison with megakaryocytes in the myelodysplastic syndromes (MDS) significant differences were evident. In AIDS this cell population revealed a size distribution within the normal range (control group) and no predominance of micromegakaryocytes characteristic for MDS. Furthermore, by determination of the form factors more irregular shapes of cell and nuclear perimeters could be shown. Finally, a not-evaluated number of precursors (promegakaryoblasts) was calculable. Particularly in those patients (n = 15) with AIDS-related severe thrombocytopenia the missing increase in the relative amount of promegakaryoblasts was conspicuous. This result was strikingly different from findings in idiopathic (autoimmune) thrombocytopenia and suggested an impairment of progenitor cell proliferation and differentiation in the acquired immunodeficiency syndrome. In conclusion, morphometry in combination with immunohistochemistry failed to establish characteristic myelodysplastic aspects of the megakaryocytic lineage in AIDS. For this reason, bone marrow lesions in this disorder should be properly termed HIV-myelopathy and not myelodysplasia.
Acquired Immunodeficiency Syndrome↗
Macrophages (phagocytic-histiocytic reticular cells) in reactive-inflammatory lesions of the bone marrow and in myelodysplastic syndromes (MDS). An immunohistochemical and morphometric study by use of a new monoclonal antibody (PG-M1).
An immunohistochemical and morphometric study was performed on trephine biopsies of the bone marrow in 52 patients (28 males/24 females; age 68 years) with various subtypes of myelodysplastic syndromes (MDS) to determine the number of macrophages (phagocytic-histiocytic reticular cells). Quantifications included the haemosiderin-storing subpopulation (Prussian-blue reaction) of this lineage as well as the iron-free compartment. The latter was identified by a new monoclonal antibody (PG-M1) which is specifically directed against histiocytic reticular cells. Bone marrow specimens of individuals without haematological disorders and those showing reactive lesions served as controls. In comparison with the normal bone marrow and inflammatory changes (i.e. rheumatoid arthritis) 23 of the 52 patients with MDS revealed a significant increase in macrophages. This increase encompassed not only the iron-laden subpopulation but also the total number of phagocytic reticular cells. Accumulation of macrophages in MDS was speculated to be due to a premature and enforced degradation of dysplastic cell elements leading to phagocytosis of haemosiderin and debris material. Moreover, cells of the monocyte-macrophage system could be involved in the complex pathomechanism of fibrillogenesis, since in a considerable percentage of patients with MDS, an increase in reticulin (argyrophilic) fibres was noticeable. Our finding of an expansion of the macrophage compartment in about half of the patients with MDS is in keeping with results of cell culture studies on colony formation of granulocyte-macrophage precursors (CFU-GM).
Adult↗
[The Sellink CT method].
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Barium Sulfate↗
Bone marrow involvement in non-Hodgkin's lymphoma: increased diagnostic sensitivity by combination of immunocytology, cytomorphology and trephine histology.
Diagnostic results from cytomorphology and immunocytology of aspirated bone marrow (BM) were compared with the findings from standard trephine histology of 100 adult patients with non-leukaemic non-Hodgkin's lymphomas (NHL) in a retrospective study. Immunocytological investigations were performed by the immunoenzymatic APAAP-technique on BM smears monoclonal antibodies against CD19, Cd3, CD10 or TdT antigens and determination of positive cells in relation to total BM leucocytes. Corresponding results were obtained for trephine histology and for the combination of cytomorphology and immunocytology in 93/100 cases. Four cases with BM involvement by trephine histology were missed by the combination of immunocytology and cytomorphology. In turn, three cases negative by trephine histology, were found to be positive by the combination of immunocytology and cytomorphology. Immunocytochemistry considerably increased the number of true positive detected BM-infiltrations by cytomorphology in low grade B-cell lymphoma from 58% to 97%. For the diagnosis of BM involvement in high-grade NHL cytomorphology of the aspirate was of equal sensitivity to the biopsy and was always confirmed by immunocytology. The high diagnostic sensitivity of immunocytology was mainly due to high B-cell counts in BM involved by B-cell lymphoma (means = 38%, s = 23) in contrast to low B-cell counts in BM not involved by NHL (means = 4.5%, s = 3.8). We conclude from our data that immunocytology in addition to standard cytomorphology improves diagnostic sensitivity in the detection of BM involvement by NHL.
Adolescent↗
Vascular architecture and collagen type IV in primary myelofibrosis and polycythaemia vera: an immunomorphometric study on trephine biopsies of the bone marrow.
Using a monoclonal antibody against collagen type IV, an immunohistochemical and morphometric study was performed on trephine biopsies of the bone marrow to determine the vascular architecture of the myeloid stroma as well as the occurrence of subendothelial collagen type IV deposits. In comparison with a control group (20 patients), we investigated specimens from 20 patients with polycythaemia vera (P. vera) and 40 patients showing primary (idiopathic) osteomyelofibrosis/-sclerosis (OMF). Morphometric analysis disclosed a significant increase in the number of sinusoids and also in the extent of collagen type IV deposits in the latter disorder. Sinusoids of P. vera showed only a dilatation of their lumina corresponding with enlarged areas of sectioned vascular profiles. Contrary to this finding, in OMF sinusoidal distension was accompanied by an excessive deviation from a circular profile and prominent intravascular haematopoiesis. Furthermore, there was a significant formation of basement membrane collagen (collagen type IV). All these features were far less pronounced in early hypercellular stages of OMF than in the late fibro-osteosclerotic subtypes. Our morphometric findings confirm haemodynamic studies on advanced stages of OMF which revealed an increased vascularity. Moreover, these results are in keeping with the assumption that angiogenesis in the evolution of the fibroosteosclerotic marrow process is mediated by certain growth factors. The increase in collagen type IV formation is thought to be generated by the pronounced endothelial cell proliferation in the course of neovascularization.
Aged↗
Splenic megakaryocytopoiesis in primary (idiopathic) osteomyelofibrosis. An immunohistological and morphometric study with comparison of corresponding bone marrow features.
An immunohistochemical and morphometric study has been performed on splenic tissue of 10 patients with primary (idiopathic) osteomyelofibrosis (OMF) to determine characteristic features of megakaryocytopoiesis in myeloid metaplasia. Using the periodic acid-Schiff reaction (PAS) and particularly the monoclonal antibody CD61 (Y2/51), all elements of this cell lineage including precursors could be identified. In comparison with bone marrow specimens from our file material (40 patients with OMF, 15 control cases) which were processed in a similar way, megakaryocytes in the spleen revealed significant differences. These differences included smaller cell sizes, a disturbed nuclear-cytoplasmic ratio, and a conspicuous increase in the relative frequency of promegakaryoblasts. In conclusion, extramedullary megakaryocytopoiesis in OMF did not only show more pronounced abnormalities of differentiation, but also a higher degree of immaturity. Our finding of a significant accumulation of megakaryocytic precursors in the spleen as opposed to the bone marrow, corroborates the so-called filtration theory which has been introduced to explain the evolution of splenic myeloid metaplasia in OMF.
Aged↗
Chronic myelogenous leukemia: recent developments in prognostic evaluation and chemotherapy. The German CML Study Group.
Recent developments in CML research are illustrated by the results of one large randomized multicenter study carried out by the German CML Study Group. From July 1983 to January 1991, a total of 703 CML patients were recruited; 624 patients were randomized to compare hydroxyurea and interferon alpha (IFN) with busulfan. The median survival of Ph+ patients by now is 3.95 years, that of Ph- patients 1.1 years. Some difference in survival is recognizable between the treatment arms, but this is not yet significant. Fewer adverse effects are being observed in the hydroxyurea group. Ph-negative patients tend to have lower white blood cell and platelet counts. Patients (164) were randomized to receive IFN. In 50 patients (30%) IFN had to be terminated because of adverse effects, therapy resistance, or other reasons. Reduction of the Ph-chromosome was observed in 20% of evaluable patients. In 3 patients complete cytogenetic remissions were observed. Clinically relevant neutralizing antibodies were detected in 9 cases. Prospectively evaluated age, organomegaly related symptoms, Karnofsky index, extramedullary manifestations, erythroblasts, and percent of circulating blasts proved to be of prognostic significance. A prognostic score (score 1) was determined and compared to Sokal's score. It is expected that the study results will allow statements as to the advantages or disadvantages of the use of busulfan, hydroxyurea and IFN in the treatment of CML as well as to the reliability of prognostic markers.
Bone Marrow Transplantation↗
Megakaryocytopoiesis in haematological disorders: diagnostic features of bone marrow biopsies. An overview.
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Biopsy↗
Dysmegakaryopoiesis in myelodysplastic syndromes (MDS): an immunomorphometric study of bone marrow trephine biopsy specimens.
An immunohistochemical and morphometric analysis was performed on trephine biopsy specimens of the bone marrow in 40 patients (23 men and 17 women, mean age 62 years) with different subtypes of myelodysplastic syndromes (MDS) to determine dysmegakaryopoiesis, but particularly precursor cells--that is, pro- and megakaryoblasts. In 31 of the 40 patients the numbers of megakaryocytes were increased which was associated with a predominance of smaller cell forms (micromegakaryocytes). Compared with periodic acid Schiff, immunostaining with a formalin resistant monoclonal antibody against glycoprotein IIIa (Y2/51(CD61) showed a clinically important proportion of immature elements. These could be designated pro- and megakaryoblasts by taking morphometric measurements on smears and bone marrow sections. There was a relevant increase in the number of promegakaryoblasts in 32 patients, consistent with uncontrolled expansion of the precursor pool. Seventeen repeated bone marrow biopsy specimens taken after chemotherapy largely showed a decrease in the numbers of megakaryocytes including the precursor cell population. Moreover, morphometric evaluation disclosed that micromegakaryocytes in MDS differ significantly from those in chronic myeloid leukaemia (CML) due to distinctive nuclear features and a disturbed nuclear:cytoplasmic ratio. These changes generate a more pleomorphic or atypical appearance of this cell population in MDS, compared with micromegakaryocytes in CML. It is concluded that the disproportionate increase in megakaryocyte precursors and the grossly abnormal aspects of micromegakaryocytes in MDS are characteristics of the severe defect involving haematopoiesis in this disorder.
Adult↗
[Immunohistochemistry and morphometry of bone marrow in acquired immunodeficiency syndrome with special emphasis on megakaryopoiesis and macrophages].
An immunomorphometric study was performed on formalin-fixed and paraffin-embedded bone marrow biopsies in 20 patients with AIDS (18 males, 2 females-stage IV A-D). In comparison with a control group megakaryocytes (CD61-Y2/51) revealed not only a significant hyperplasia, but remarkably irregular shapes of cells and nuclei, together with a disturbance of the nuclear-cytoplasmic ratio. No predominance of micromegakaryocytes as in myelodysplastic syndromes was observable. Contrasting idiopathic (immune)-thrombocytopenia, HIV-infected patients with a pronounced depression of the platelet count did not show a significant elevation of the number of promegakaryoblasts. This feature is in keeping with findings of a severe impairment of progenitor cell proliferation and differentiation in AIDS. There was a pronounced increase in the macrophage population (PG-M1). This alteration may be related to inflammatory lesions accompanying this disorder as well as to an enforced and premature destruction of hematopoietic cell elements in the myeloid stroma.
Acquired Immunodeficiency Syndrome↗
Interactions between megakaryocytes and sinus wall. An ultrastructural study on bone marrow tissue in primary (essential) thrombocythemia.
An ultrastructural study was performed on bone marrow tissue in primary (essential) thrombocythemia to evaluate possible interactions between megakaryocytes and sinusoids. In addition to a preferential localization of megakaryocytes in the subendothelial space, two different kinds of cytoplasmic processes could be discriminated penetrating the sinus wall. Serial sections disclosed that megakaryocytes developed multiple pseudopod-like plump projections derived from their peripheral zone and devoid of organelles. It is tempting to speculate that these ameboid features could serve as anchors to keep the cell in a subendothelial position and to monitor changes occurring in circulation. The second type of cytoplasmic processes reaching into the vascular lumen consisted of tentacle-like elongated protrusions rich in organelles, apparently originating from the intermediate zone. These projections were thought to present either the beginning of megakaryocytes egress into circulation or putative platelets. Frequently, there was an intrasinusoidal localization of megakaryocytes which revealed numerous so-called platelet territories and apparently an enforced platelet shedding. Generally, these features are comparable with aspects obtained from animal studies, following excessively stimulated megakaryo- and thrombocytopoiesis by application of anti-platelet serum.
Bone Marrow↗
Follow-up study on bone marrow reticulin fibrosis in AML.
Planimetric analysis of argyrophilic (reticulin) fibers of the bone marrow was performed on 17 patients (7 males, 10 females, median age 52 years) with acute myeloid leukemia (AML). Trephine biopsies were investigated at presentation and during the course of chemotherapy. Density of reticulin was determined by examining the total marrow area as well as the hematopoietic tissue. In about half of the patients with FAB-subtypes M4, M5 an increased amount of fibers was recognizable on admission in comparison with age-matched controls. Two to five bone marrow biopsies (total 81) of each patient were obtained at intervals ranging mostly between three and seven weeks after cytotoxic treatment. The following results could be demonstrated: in several patients with a normal or elevated fiber count at onset, partial and complete remission was characterized by an increase in reticulin in the regenerative hematopoietic tissue. On the other hand, a relapse was most frequently heralded by a reduction of the formerly increased amount of fibers. Because of the inverse relationship between the density of argyrophilic fibers and the amount of fat cells, these findings were observable only by considering the hematopoietic tissue and not the total marrow area, as has been done in previous studies. For this reason a significant decrease in reticulin fibers in the areas of regenerative hematopoiesis may be suggestive of an impending relapse of AML.
Adult↗
Megakaryocytopoiesis in idiopathic thrombocytopenic purpura: a morphometric and immunohistochemical study on bone marrow biopsies with special emphasis on precursor cells.
A morphometric and immunohistochemical study was performed on trephine biopsies of the bone marrow in patients showing idiopathic thrombocytopenic purpura (ITP) and reactive thrombocytosis (RTH). Features of megakaryocytopoiesis were determined not only by using the periodic acid Schiff reaction (PAS), but also by immunostaining with the monoclonal antibody Y2/51, detecting a formalin-resistant epitope of glycoprotein IIIa (CD61). An increased number of megakaryocytes was observed in both ITP and in RTH as compared with a control group. Immunostaining revealed a predominance of small immature elements of this cell lineage, particularly in cases of ITP. Following previous experimental cell culture studies on megakaryocyte precursors and features derived from corresponding smear preparations, we characterized promegakaryoblasts immunomorphometrically. According to these calculations, ITP, as opposed to RTH, features a disproportionate expansion of the megakaryocyte precursor pool.
Antibodies, Monoclonal↗
Ultrastructure of bone marrow tissue in so-called primary (idiopathic) myelofibrosis-osteomyelosclerosis (agnogenic myeloid metaplasia). II. The myeloid stroma (hematopoietic microenvironment).
An ultrastructural study was performed on bone marrow tissue in 8 patients revealing early and late stages of so-called primary (idiopathic) myelofibrosis - osteomyelosclerosis (agnogenic myeloid metaplasia) to evaluate the constituents of the hematopoietic microenvironment (myeloid stroma). A survey of the stroma cells disclosed an overall increase, particularly in so-called undifferentiated (primitive - pluripotent), but also in transitional (fibroblastic) reticular cells and myofibroblasts. The most primitive reticular cells were characterized by their stellate aspect with elongated slender cytoplasmic processes traversing the interstitial space, and by the scarcity of organelles. The transition into a fibroblast was preceded by the appearance of branching cisternal structures of the rough endoplasmic reticulum, extensively developed Golgi fields and an abundance in mitochondria. Frequently, so-called myofibroblasts were encountered displaying bundles of filaments along the subplasmalemmal region. Extracellularly fibrillar material with an irregular cross-banding as well as microfibrils could be observed. The many vascular structures (sinusoids and capillaries) exhibited a multilayered basement membrane-like material including many fibrils and adventitial cells (pericytes, smooth muscle and transitional reticular cells) with numerous cytoplasmic processes. Undifferentiated and transitional reticular cells as well as myofibroblasts seem to form an integral part of the hematopoietic microenvironment in OMF and are assumed to play an important role for the evolution of the disease-specific myelofibrosis in this disorder.
Bone Marrow↗
Ultrastructure of bone marrow tissue in so-called primary (idiopathic) myelofibrosis-osteomyelosclerosis (agnogenic myeloid metaplasia). I. Abnormalities of megakaryopoiesis and thrombocytes.
An electron microscopic study was conducted with the aim to analyze abnormalities of the megakaryopoiesis in bone marrow tissue of patients suffering from so-called primary (idiopathic) myelofibrosis-osteomyelosclerosis. In comparison with control specimens and in confirmation of light microscopical findings, a pronounced pleomorphism of the megakaryocytic cell line could be observed consisting of giant forms, micromegakaryocytes and naked (pyknotic) nuclei. Further atypias were expressed by a dissociation of nuclear-cytoplasmic maturation. These included particularly the amount of dense granules, and the development of the demarcation membrane system as well as the occurrence of emperipolesis (i.e. internalization of hematopoietic cells) already in immature or megakaryoblastic elements. In these specimens there was a striking variety in the appearance of dense granules of the alpha or bull's eye type revealing frequent elongated roll- and dumbbell-like shapes and a doubling of the nucleoids. Thrombocytes showed giant forms with either hypertrophy of the open canalicular system or abundance of dense granules and beta-glycogen accumulation. Remarkable was a focal sponge-like proliferation of the open canalicular system in many of the large platelets and giant and fused granules of the alpha and osmiophilic type. The abnormalities disclosed in megakaryo- and thrombocytes may have certain functional implications, i.e. to hemorrhage and thrombosis which are often encountered out of proportion to the platelet counts in this disorder. Moreover, those anomalies indicate a disorganization of megakaryopoiesis which may contribute to the abnormal release of factors (platelet-derived growth factor and factor 4) predominantly involved in the process of myelofibrosis.
Blood Platelets↗