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ABSTRACT: Der klinische Verlauf der chronischen myeloproliferativen Erkrankungen ist sehr variabel. Bei der essentiellen Thrombozythämie
und Polycythaemia vera stehen vaskuläre Komplikationen im Vordergrund, während die primäre Myelofibrose meist durch Zytopenie
und ein hohes Risiko der Transformation in eine sekundäre akute Leukämie gekennzeichnet ist. Die Entdeckung der Mutation V617F
im Gen der Januskinase 2 (JAK2) im Jahr 2005 hat die Diagnostik der chronischen myeloproliferativen Erkrankungen in vielen
Fällen vereinfacht und zur Revision der WHO-Diagnosekriterien geführt. Der Beitrag bietet einen Überblick über den aktuellen
Stand bei Diagnostik und Therapie von essentieller Thrombozythämie, Polycythaemia vera und primärer Myelofibrose.
best practice onkologie 04/2012; 3(2):24-32.
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ABSTRACT: Scant knowledge exists concerning lineage-restricted mixed chimerism (mCh) after allogeneic peripheral blood stem cell transplantation (PSCT) in patients with chronic idiopathic myelofibrosis (CIMF). Following a sex-mismatched PSCT, a combined immunopheno- and genotyping by fluorescence in-situ hybridization (FISH) was performed on sequential bone marrow (BM) biopsies at standardized intervals. Results were compared with PCR analysis of corresponding peripheral blood samples in five patients. According to FISH, pretransplant specimens revealed a gender congruence of more than 99%, while in the first three months the total BM exhibited a persistent fraction of host cells (30% to 40%) with a tendency to decline after about one year. It is noteworthy that the majority of endothelial cells maintained a recipient origin, whereas CD34+ progenitors and especially CD61+ megakaryocytes exhibited only very few host-derived cells. In keeping with the prevalence of donor cells in the hematopoietic compartment, PCR analysis of peripheral blood cells displayed a non-significant degree of mCh. In conclusion, according to FISH and PCR analysis, successful PSCT in CIMF results in an almost complete chimeric (donor-derived) state of the hematopoietic cell population. The non-transplantable stromal compartment includes the vascular endothelium with a predominance of recipient cells. The minimal mCh of this population implies probably a donor-derived origin (endothelial progenitor cells).
Histology and histopathology 05/2007; 22(4):365-72. · 2.48 Impact Factor
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ABSTRACT: In chronic myeloproliferative disorders, presenting or evolving myelofibrosis (MF) is associated with significant morbidity and mortality. A systematically conducted evaluation of previous studies and data from our own material reveals a strikingly expressed heterogeneity of findings. Assessment of MF should be performed by a recently established semiquantitative scoring system regarding quantity and quality (reticulin versus collagen). It is important to differentiate between a fiber increase in bone marrow specimens and the clinical diagnosis that is explicitly based on extramedullary hematopoiesis (myeloid metaplasia). For this reason, prodromal stages of (reticulin) fibrosis are overlooked by the clinicians. Up to 30% of patients with chronic myelogenous leukemia show a minimal to advanced MF that is significantly associated not only with corresponding clinical parameters but more importantly with prognosis. In polycythemia vera about 20% of patients may display some degree of reticulin fibrosis at diagnosis, depending on stage of the disease. Transformation into (collagen) MF after more than 10 years is accompanied by clinical signs of myeloid metaplasia (spent phase). Essential thrombocythemia (ET) is characterised by the absence of increased reticulin at onset and an insignificant progression into MF, provided diagnosis is performed by the WHO criteria. Discrimination of prefibrotic and early stages of chronic idiopathic myelofibrosis (CIMF) from ET is relevant, especially concerning the rate and time usually required for the development of MF with myeloid metaplasia (full-blown CIMF). In conclusion, more elaborate evaluations including standardized grading of MF is warranted by regarding bone marrow biopsy specimens in association with clinical parameters including follow-up examinations.
Histology and histopathology 01/2007; 21(12):1367-78. · 2.48 Impact Factor
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ABSTRACT: Controversy continues to exist regarding not only the exact definition and grading of myelofibrosis (MF), but also whether, and to what extent, this feature may be correlated with clinical findings. A retrospective study was performed involving 865 bone marrow (BM) biopsies together with the clinical records from patients with chronic idiopathic myelofibrosis (CIMF). Diagnosis was established according to the World Health Organization criteria, and assessment of MF followed a consensus scoring system that included four grades (MF-0 to MF-3). Histopathological and clinical evaluations were carried out in an independent fashion. Prefibrotic and early CIMF (MF-0/-1) were presented by 565 patients showing borderline to mild anemia and no or slight splenomegaly, but frequently, thrombocytosis exceeding 500x10(9)/l was shown. In 300 patients, manifest reticulin and collagen fibrosis (MF-2/-3) were characterized by marked anemia, gross splenomegaly, peripheral blasts, and normal to decreased platelet and leukocyte counts. The latter cohort was consistent with findings generally in keeping with MF with myeloid metaplasia. Regarding the stepwise evolution of disease, sequential BM examinations showed that in 103 patients, prefibrotic and early CIMF transformed into advanced stages accompanied by correspondingly developing clinical and histomorphological features. Survival analysis (univariate calculation) revealed a significantly more favorable prognosis in prefibrotic vs advanced stages of CIMF. On the other hand, higher classes of MF also exerted a higher clinical risk profile (Lille score). In conclusion, the dynamics of the disease process in CIMF are characterized by evolving MF in the BM and closely associated changes of relevant hematological findings.
Annals of Hematology 05/2006; 85(4):226-32. · 2.62 Impact Factor
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ABSTRACT: Malignant Hodgkin's lymphoma (HL) has become a curable disease through the increasing intensity of the treatment strategies applied. These regimens are aggressive, including radiotherapy and chemotherapy leading to the possibility of secondary malignancies. The German Hodgkin Lymphoma Study Group considered three cohorts including 5,411 patients with all stages of HL. In 127 patients a secondary solid tumor was diagnosed (cumulative risk 2%, median follow-up 72 months), with bronchial carcinomas (23.6%) and colorectal adenocarcinomas (20.5%) being the most frequent neoplasms. Secondary acute myeloid leukemia was found in 36 patients, another ten developed myeloid dysplasia (cumulative risk 1%, median follow-up 55 months). A total of 52 patients revealed a non-Hodgkin's lymphoma (NHL; cumulative risk 0.9%, median follow-up 46 months). The overall incidence of secondary malignancies was 3.9% in patients who had been treated successfully for their HL with radio- and/or chemotherapy.A secondary NHL can be particularly difficult to be distinguished from the preceding HL. Therefore, in case of a suspected relapse, a complete histopathological work-up must be performed.
Der Pathologe 03/2006; 27(1):47-52. · 0.67 Impact Factor
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ABSTRACT: In many haematological conditions the only curative option is stem cell (SCT) or bone marrow (BM) transplantation. Little information exists about BM morphology following non-ablative engraftment. During the pretransplantation period and depending on the kind of pretreatment, there may be hypoplasia, residual disease and varying degrees of fibrosis. In the post-transplantation period, after 1–3 weeks of transfusion-dependent pancytopenia, the first signs of successful engraftment are indicated by the recurrence of neutrophils, monocytes and erythrocytes in the peripheral blood. In the BM there is slow regeneration of erythropoiesis, followed by the other lineages of haematopoiesis and increase in reticulin fibres or even a resolution of fibrosis. Diagnostic problems arise when neoplastic lympho- or haematopoiesis are maintained following transplantation. Moreover, there may be a significant graft versus tumour response reaction or an already relapsing disease needing aggressive treatment. On the other hand, a conspicuous dyshaematopoiesis should not be mistaken as representing a myelodysplastic syndrome. The presence of granulomas being treatment-related or a manifestation of intercurrent granulomatous disease has to be considered. More advanced knowledge of the histological features of regenerating BM will certainly aid the recognition of relapsing disease and is needed for the adequate reporting of post-transplant alterations associated with a successful or failing engraftment.
Histopathology 02/2006; 48(4):329 - 342. · 3.08 Impact Factor
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ABSTRACT: Repeatedly performed bone marrow biopsies were studied in 30 patients with chronic idiopathic myelofibrosis (CIMF) by fluorescence in situ hybridization to detect and quantify trisomy 8 anomaly during the evolution of disease. For the establishment of threshold values we used negative and positive control specimens. At least 500 cells were evaluated in each specimen and only nuclei with three distinctive signals were regarded as positive. According to the controls, 27 patients revealed false-positive signals ranging from 0 to 1.2% (0.88 +/- 1.12). On the other hand, 3 patients showed an incidence of more than 6.5% (up to 10.1%) in the initial prefibrotic as well as advanced fibro-osteosclerotic stages of CIMF. In conclusion, trisomy 8 has been demonstrated already in the prodromal stages of CIMF and therefore is not limited to classical fibro-osteosclerotic manifestations.
Acta Haematologica 02/2006; 115(1-2):97-101. · 1.35 Impact Factor
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ABSTRACT: Histopathology of bone marrow (BM) biopsies plays a crucial role in the interdisciplinary approach to diagnosis and classification of chronic myeloproliferative disorders (CMPDs). Based on careful clinicopathologic studies, BM features are critical determinants that help to predict overall prognosis, to detect complications such as progression to myelofibrosis and blast crisis, and to assess therapy-related changes. A systematic evaluation of BM histopathology allows an objective identification of cases of (true) essential thrombocythemia (ET) and their separation from (false) ET, which often is the prodromal stage of chronic idiopathic myelofibrosis (CIMF). By follow-up examinations that include BM biopsies, the progression of the disease process is unveiled, which is especially important for patients with initial (early) polycythemia vera and prefibrotic CIMF that may require a different therapeutic approach than the full-blown stages. In conclusion, BM biopsy should be considered as major diagnostic tool for evaluation and follow-up of patients enrolled in prospective studies.
Bailliè re s Best Practice and Research in Clinical Haematology 02/2006; 19(3):413-37. · 2.64 Impact Factor
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ABSTRACT: A comparative immunohistochemical and morphometric study was performed on megakaryocytes in 20 patients presenting with initial-early stage chronic idiopathic myelofibrosis and accompanying thrombocythemia to elucidate histological features developing after hydroxyurea (HU) versus anagrelide (ANA) therapy. Representative pre-and posttreatment bone marrow biopsies were involved including the monoclonal antibody CD61 for the identification of precursor and mature stages of megakaryopoiesis. An elaborate morphometric evaluation was in keeping with a left-shifting showing a more frequent occurrence of promegakaryoblasts and microforms in both therapy groups. However, contrasting ANA, HU generated defects of differentiation consistent with significant dysplastic changes. In conclusion, concern about a possible leukemogenic capacity following long-term HU therapy is supported by our findings.
Histology and histopathology 11/2005; 20(4):1071-6. · 2.48 Impact Factor
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J Thiele, H M Kvasnicka,
H Dietrich,
G Stein,
M Hann,
A Kaminski,
N Rathjen,
K A Metz,
D W Beelen,
M Ditschkowski,
A Zander,
N Kroeger
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ABSTRACT: Scant knowledge exists about the dynamics of fibro-osteosclerotic bone marrow (BM) lesions and regeneration of hematopoiesis following allogeneic peripheral stem cell transplantation (SCT) in chronic idiopathic myelofibrosis. Therefore, an immunohistochemical and morphometric study was performed on BM biopsies in 20 patients before and at standardized intervals (days 30 through 384) following SCT. In responding patients, a total regression of the pretransplant increased fibrosis was completed in the posttransplant period after about six months, while the extent of osteosclerosis did not change significantly during observation time. The quantity of CD61+ megakaryocytes including precursors was strikingly variable after SCT and, by using planimetric methods, atypical microforms exhibiting a dysplastic aspect could be demonstrated. These anomalies may be responsible for posttransplant thrombocytopenia. CD34+ progenitor cells were increased before transplantation, however, their number declined rapidly to normal values in responding patients. Nucleated erythroid precursors revealed a decreased amount before and after SCT accounting for anemia. Large clusters of this cell lineage indicated an initial hematopoietic reconstitution comparable with the expansion of the neutrophil granulopoiesis. Proliferative activity and apoptosis showed an increase until one year after SCT that implied a still regenerating hematopoiesis in keeping with an enhanced cell turnover.
Histology and histopathology 08/2005; 20(3):879-89. · 2.48 Impact Factor
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J Thiele, H M Kvasnicka,
A Schmitt-Graeff,
S Kriener,
K Engels,
P Staib,
E S Ollig,
C Keller,
S Fokkema,
M Griesshammer,
C F Waller,
O G Ottmann,
M L Hansmann
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ABSTRACT: To carry out an immunohistochemical study on bone marrow (BM) biopsy specimens in 75 patients with chronic myelogenous leukaemia (CML) on long-term STI571 therapy.
Sequential BM specimens taken at intervals of 21 +/- 6 months were investigated by enzyme- and immunohistochemistry including proliferating cell nuclear antigen and apoptosis. Evaluation was performed either by semiquantitative scoring or by morphometry (CD61+ megakaryopoiesis). In 41 patients with chronic phase CML, treatment resulted in a significant decrease in cellularity and neutrophil granulopoiesis contrasting with an accumulation of erythroid precursor cells. Morphometry showed a reduction of abnormal micromegakaryocytes consistent with normalization. Regression of myelofibrosis was identified in eight of 15 patients, whereas progression occurred in 17 patients; mostly in those with acceleration and blastic crisis. The increased post-treatment incidence of reactive lymphoid nodules was remarkable. Myeloblasts, CD34+ progenitors and immature myelomonocytic cells initially decreased, but recurred in 14 patients who later developed a relapse. STI571 exerted an inhibitory effect on cell proliferation associated with enhanced apoptosis in responding patients.
Long-term treatment with STI571 exerts pronounced changes on BM histopathology that not only involve haematopoiesis and stromal constituents, but also proliferation and apoptosis.
Histopathology 06/2005; 46(5):540-50. · 3.08 Impact Factor
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ABSTRACT: Standardized bone marrow (BM) features determined by semiquantitative scoring are valuable tools for the recognition and easily reproducible interpretation of histological patterns in hematopathology. This procedure may help to characterize various disease entities, but especially to differentiate chronic myeloproliferative disorders (MPDs) with increased platelet counts from reactive thrombocytosis (RTh). A clear-cut separation of these conditions continues to present a major problem in hematology. Therefore MPDs are a most suitable model to test the diagnostic relevance of this procedure. By regarding the literature and based on archive material that involved BM biopsies of 319 patients, a semiquantitative grading of histological parameters was performed. Standardized features were applied for a stepwise discriminant analysis to establish different sets of variables exerting a diagnostic impact. A distinction into five histological patterns was achieved that showed a correctly predicted group membership of about 94 %. These were consistent with the clinicopathological diagnosis of polycythemia vera, essential thrombocythemia (ET), prefibrotic or early fibrotic chronic idiopathic myelofibrosis (CIMF) and finally RTh. Variables of discriminating potency according to their ranking included megakaryopoiesis (maturation defects, nuclear lobulation, naked and bulbous nuclei, small and giant size), reticulin fibers, erythro- and granulopoiesis (left shifting and quantity) and cellularity. These findings are in keeping with the assumption that characteristic patterns of BM histopathology can be assigned to different subtypes of MDPs mimicking ET. Discrimination between ET and especially early stage CIMF with thrombocythemia is warranted because of significant implications concerning therapeutic strategies, follow-up examinations and survival. Regarding these results, a schematic procedure is proposed to be used for daily routine diagnosis concerning the discrimination of MPDs.
Histology and histopathology 05/2005; 20(2):633-44. · 2.48 Impact Factor
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ABSTRACT: The criteria of the Polycythemia Vera Study Group (PVSG), although acknowledged as the gold standard to establish the diagnosis of polycythemia vera (PV), do not regard bone marrow (BM) histopathology. Arguments include the existence of sufficient objective markers of disease and the lack of independently performed morphological studies or standardized criteria. The aim of this review is to evaluate morphological characteristics of erythrocytosis and to determine whether distinctive patterns of histopathology exist. A review of the pertinent literature and evaluation of 334 patients from our files with a borderline to marked increase in hemoglobin was performed. In extension to former descriptions of BM features by the PVSG, a tri-lineage myeloproliferation (panmyelosis) with a pleomorphous appearance of megakaryopoiesis revealed that, besides increase in size, there was a lack of gross cytological anomalies. Differentiation from secondary polycythemia (SP) was accomplished by regarding these features and the conspicuously expressed stromal changes (plasmacytosis, eosinophils, cell debris and iron deposits). In about 96% of this cohort a clear-cut separation from SP was achieved, even in the initial (latent) stages. When accompanied by an elevated platelet count, these precursor stages may clinically mimick essential thrombocythemia because they are not recognized by the conventional criteria. Advanced stages (spent phases) of PV were consistent with an increased left-shifted granulocytic proliferation, accompanied by reduction of erythroid precursors and progressive myelofibrosis (post-polycythemic myeloid metaplasia). Finally, an increase in dysplastic changes and immaturity signalled a transition into blastic crisis. In conclusion, PV is characterized by a distinctive pattern of histopathology that has been gained in an independent and blind fashion and therefore, dissolves arguments about failing specificity.
Histology and histopathology 02/2005; 20(1):317-28. · 2.48 Impact Factor
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J Thiele, H M Kvasnicka,
E Varus,
S Kriener,
K Engels,
P Staib,
E S Ollig,
M Griesshammer,
C F Waller,
H Pfeifer,
A Schmitt-Gräff
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ABSTRACT: In chronic myeloid leukemia following therapy with Imatinib (STI571) hematologic and cytogenetic response is associated with conspicuous changes of bone marrow morphology. However, it is not known to which extent these alterations are accompanied by a loss of the bcr/abl translocation. To study regression of the leukemic cell population we recruited 14 patients lacking pretreatment. Therapy resulted in a reduction of CD61(+) megakaryopoiesis. Dwarf megakaryocytes characteristic for this disorder were replaced by large, normally appearing cells of this lineage. Morphometric analysis confirmed the significant decrease in the number of micromegakaryocytes and yielded planimetric parameters in keeping with normalization. Moreover, a fluorescence in-situ hybridization study in five patients of this cohort revealed that before therapy 70% of all myeloid cells exhibited the bcr/abl gene. Regarding megakaryopoiesis about 65% of the micromegakaryocytes displayed positive signals. Following treatment these bcr/abl(+) cell populations decreased significantly while the emerging large megakaryocytes lacked a proper labeling. Because cytogenetic response and reduction of atypical micromegakaryocytes are linked, this feature may be useful to monitor therapeutic efficacy.
Der Pathologe 12/2004; 25(6):428-35. · 0.67 Impact Factor
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ABSTRACT: Preliminary data are available about bone marrow (BM) changes in patients with chronic myeloid leukemia (CML) who received the molecularly targeted and highly effective tyrosine kinase inhibitor Imatinib mesylate (STI571). This review is focused on a systematic assessment of BM features detectable at different stages of CML (stable, accelerated, blastic) following long-term (more than 10 months) treatment. By applying enzyme- and immunohistochemistry including monoclonal antibodies visualizing proliferating cell nuclear antigen (PCNA) and apoptosis (anti-apostatin), a more elaborate insight into alterations affecting hematopoiesis and the stroma compartment was gained. In patients with stable-phase CML therapy resulted in a significant reduction in cellularity, neutrophil granulopoiesis and number of megakaryocytes, accompanied by a retrieval of erythroid precursors. In patients with Imatinib as the only treatment morphometric analysis of CD61+ megakaryopoiesis was in keeping with a significant decrease in maturation defects implying a lesser amount of atypical micromegakaryocytes almost consistent with normalization. Moreover, a reduction of the initially enhanced (CD34+) microvessel density was detectable associated with a decrease in luminal distension. Regression of marked to moderate myelofibrosis was recognizable in about 70% of patients especially in the accelerated and blastic phases. The amount of myeloblasts, CD34+ progenitor cells and lysozyme-expressing immature myelomonocytic cells declined with treatment, but recurred in about 19% of patients that developed a leukemic relapse after 21+/-6 months of therapy. Data on proliferative activity and apoptosis in general supported in vitro findings concerning the inhibitory effect of this agent on growth associated with a tendency for stimulated apoptosis, at least in responding patients.
Histology and histopathology 11/2004; 19(4):1277-88. · 2.48 Impact Factor
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ABSTRACT: Until now little information is available about bone marrow (BM) angiogenesis in chronic myeloproliferative disorders (CMPDs). Amongst the various immunohistochemical markers for endothelial cells CD34 and CD105 have proven to be most reliable since they exhibit no relevant co-staining. Determination of vascularity has to include pathophysiological aspects of perfusion. Therefore, quantification of the microvascular density (MVD) by the so-called hot spot method has to be improved by parameters that characterize blood flow more properly like microvessel area (luminal distension), shape (form factor), tortuosity, and branching (maximal vessel length). In comparison to the normal BM chronic myeloid leukemia (CML) revealed a significant increase in MVD which was functionally associated with elevated levels of angiogenic cytokines. Structure of vessels was significantly altered by showing an enhanced irregularity of shape and tortuosity and increase in fibers was conspicuously accompanied by a higher degree of MVD. Contrasting the group of patients with Imatinib (STI571) therapy interferon failed to reduce the number of vessels. Following bone marrow transplantation a significant enhancement of the MVD was found in the early post-transplant period, but after about 6 months normalization occurred. Anomalies of microvascular architecture were easily demonstrable by three-dimensional reconstruction and consisted of a complex branching network of irregular shaped sinuses. Chronic idiopathic myelofibrosis displayed a significant increase in the MVD only in the advanced fibrosclerotic stages. This feature was accompanied by an enhanced luminal distension and tortuosity, thus contrasting the prefibrotic and early fibrotic phases of this disorder. Similar to CML a relationship between evolving myelofibrosis and change in vascular architecture was encountered. This feature may present a possible target for future anti-angiogenic therapy. In essential thrombocythemia there is only a mild increase in MVD detectable while in polycythemia vera besides an enlarged number, a luminal dilation due to the densely packed erythrocytes is recognizable. In conclusion, contrasting the usually applied quantification technique more elaborate morphometrical methods are warranted to obtain a better insight into the vascular architecture of the BM. In CMPDs angiogenesis is significantly associated with the evolution of myelofibrosis and may be altered by therapeutic regimens probably due to changes in cytokine release.
Histology and histopathology 11/2004; 19(4):1245-60. · 2.48 Impact Factor
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J. Thiele, H. M. Kvasnicka,
E. Varus,
S. Kriener,
K. Engels,
P. Staib,
E. S. Ollig,
M. Griesshammer,
C. F. Waller,
H. Pfeifer,
A. Schmitt-Gräff
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ABSTRACT: Bei der CML kommt es nach Therapie mit Imatinib (STI571) zu auffallenden Vernderungen der Knochenmarkmorphologie. Bisher ist nicht bekannt, in welchem Ausma diese mit einem Verlust der bcr/abl-Translokation einhergehen. Um die therapiebedingte Regression der leukmischen Zellpopulation abzuklren, wurden 14 Patienten ausgewhlt, die keinerlei Vorbehandlung aufwiesen.Ein wesentlicher Therapieeffekt war eine Reduktion der CD61+-Megakaryozytenzahl. Die Mikroformen, die diese Erkrankung charakterisieren, wurden durch groe, normal erscheinende Zellen ersetzt. Eine morphometrische Analyse besttigte die signifikante Regression der atypischen Mikromegakaryozyten und erbrachte planimetrische Messwerte, die mit einer Normalisierung vereinbar waren. Eine Fluoreszenz-in-situ-Hybridisierung erfolgte bei 5Patienten dieser Serie, die vor Therapiebeginn das bcr/abl-Gen in 70% aller myeloischen Zellen zeigten. Dabei lie auch die Megakaryopoiese in etwa 65% der Mikromegakaryozyten entsprechende positive Signale erkennen. Nach Behandlung kam es zu einer deutlichen Reduzierung dieser bcr/abl+-Zellpopulationen, whrend die auftretenden groen Megakaryozyten kein entsprechendes Markergen hatten.Da zytogenetisches Ansprechen und Reduktion der Mikromegakaryozyten miteinander gekoppelt sind, kann dieses als Merkmal zum Abschtzen des Therapieerfolges benutzt werden.In chronic myeloid leukemia following therapy with Imatinib (STI571) hematologic and cytogenetic response is associated with conspicuous changes of bone marrow morphology. However, it is not known to which extent these alterations are accompanied by a loss of the bcr/abl translocation. To study regression of the leukemic cell population we recruited 14 patients lacking pretreatment. Therapy resulted in a reduction of CD61+ megakaryopoiesis. Dwarf megakaryocytes characteristic for this disorder were replaced by large, normally appearing cells of this lineage. Morphometric analysis confirmed the significant decrease in the number of micromegakaryocytes and yielded planimetric parameters in keeping with normalization. Moreover, a fluorescence in-situ hybridization study in five patients of this cohort revealed that before therapy 70% of all myeloid cells exhibited the bcr/abl gene. Regarding megakaryopoiesis about 65% of the micromegakaryocytes displayed positive signals. Following treatment these bcr/abl+ cell populations decreased significantly while the emerging large megakaryocytes lacked a proper labeling. Because cytogenetic response and reduction of atypical micromegakaryocytes are linked, this feature may be useful to monitor therapeutic efficacy.
Der Pathologe 10/2004; 25(6):428-436. · 0.67 Impact Factor
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ABSTRACT: Controversy continues whether acute panmyelosis with myelofibrosis (APMF) exists as a well-defined clinicopathological entity. Following exclusion of overt acute myeloid leukemia (AML), especially the megakaryoblastic subtype, a retrospective study was performed on 46 patients with clinical and morphological features suggesting the diagnosis of APMF. All patients had a bone marrow (BM) biopsy performed at onset, and 13 had follow-up examinations. Enzyme histochemical and immunohistochemical techniques were applied and BM features evaluated by a semiquantitative scoring system. Clinical findings consisted of pancytopenia associated with a left-shifted differential count of the peripheral blood (less than 5% blasts) and no or minor splenomegaly. During follow-up (median survival 9 months) 35 patients developed severe BM insufficiency and 10 transformed into overt AML. Although myelofibrosis was a characteristic finding, other BM features proved to be heterogeneous. Cellularity was reduced in 13 and increased in 25 specimens. Most prominent was a left-shifted, often macrocytic erythropoiesis and a maturation defect of the neutrophil series. In 15 patients an increase (less than 20%) in CD34+ progenitors, immature myelomonocytic cells, and megakaryoblasts was noted. Abnormalities of megakaryocytes (atypical microforms, clustering, dysplasia) were regularly present. The stroma showed an inflammatory reaction (perivascular plasmacytosis, lymphoid nodules, many macrophages, iron deposits) in about 50% of the samples. Sequential BM biopsies revealed an accumulation of lysozyme-expressing myelomonocytic and CD34+ progenitor cells suggesting an increase in blasts. In conclusion, APMF may not be a distinct entity, but includes hyperfibrotic myelodysplastic syndromes (MDS) either primary or secondary, a rare form of initial AML with fibrosis, and even cases of toxic myelopathy.
Annals of Hematology 09/2004; 83(8):513-21. · 2.62 Impact Factor
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ABSTRACT: To elucidate the effect of first-line treatment with interferon (IFN), hydroxyurea (HU) and the tyrosine kinase inhibitor imatinib (STI571) on angiogenesis, we studied bone marrow (BM) biopsies in 104 patients with chronic myelogenous leukemia (CML) and 138 patients before and after allogeneic BM transplantation (BMT). After immunostaining (CD34) and morphometric analysis in comparison with a control group, CML specimens showed an increased vascularity and conspicuous morphological abnormalities of microvessels. A close relationship between microvessels and fiber density was detectable in initial biopsies and also in repeatedly performed examinations following therapy. Monotherapy by imatinib and HU generated a significant reduction of microvessels and reticulin fibers in contrast to changes after IFN administration or combination regimens of IFN and HU. A persistence of numerical and structural anomalies of vasculature was observable even several months after BMT. These anomalies shed some light on disturbances of the stroma compartment after myeloablative therapy. The relationship between BM vascularity and fibers is probably dependent on concomitant changes of megakaryopoiesis as the source of various mediators involved in the development of myelofibrosis and neo-angiogenesis acting within a complex functional network.
Der Pathologe 04/2004; 25(2):127-34. · 0.67 Impact Factor
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ABSTRACT: Ziel dieser Studie war, den Effekt von Interferon (IFN), Hydroxyurea (HU) und des Tyrosinkinasehemmers Imatinib (STI571) auf die Angiogenese abzuklren. Es wurden Knochenmarkbiopsien von 104Patienten mit Philadelphia-Chromosom-positiver chronischer myeloischer Leukmie (CML) und Biopsien von 138Patienten vor und nach allogener Knochenmarktransplantation (KMT) untersucht. Die CD34-Frbung und die morphometrische Analyse zeigten bei Diagnose eine im Vergleich zur Kontrollgruppe erhhte Anzahl von Gefanomalien. Eine Beziehung zwischen Mikrogefen und Fasergehalt war sowohl in den Erstbiopsien als auch in den Entnahmen nach Therapie erkennbar. Monotherapien mit Imatinib und HU bewirkten signifikante Verringerungen der Mikrogefdichte und der retikulren Fasern im Gegensatz zu den Vernderungen nach IFN-Behandlung oder einer Kombinationstherapie von IFN und HU. Numerische und strukturelle Anomalien der Mikrogefe waren noch mehrere Monate nach KMT nachweisbar und sind Ausdruck der Stromavernderungen nach myeloablativer Therapie. Die wechselseitigen Beziehungen zwischen Mikrogefdichte und Myelofibrose werden von Vernderungen der Megakaryopoese begleitet, die als Ursprung verschiedener Mediatoren in das komplexe funktionelle Netzwerk der Fibrillogenese und Neoangiogenese eingebunden ist.To elucidate the effect of first-line treatment with interferon (IFN), hydroxyurea (HU) and the tyrosine kinase inhibitor imatinib (STI571) on angiogenesis, we studied bone marrow (BM) biopsies in 104 patients with chronic myelogenous leukemia (CML) and 138 patients before and after allogeneic BM transplantation (BMT). After immunostaining (CD34) and morphometric analysis in comparison with a control group, CML specimens showed an increased vascularity and conspicuous morphological abnormalities of microvessels. A close relationship between microvessels and fiber density was detectable in initial biopsies and also in repeatedly performed examinations following therapy. Monotherapy by imatinib and HU generated a significant reduction of microvessels and reticulin fibers in contrast to changes after IFN administration or combination regimens of IFN and HU. A persistence of numerical and structural anomalies of vasculature was observable even several months after BMT. These anomalies shed some light on disturbances of the stroma compartment after myeloablative therapy. The relationship between BM vascularity and fibers is probably dependent on concomitant changes of megakaryopoiesis as the source of various mediators involved in the development of myelofibrosis and neo-angiogenesis acting within a complex functional network.
Der Pathologe 02/2004; 25(2):127-134. · 0.67 Impact Factor
