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Myelodysplastische Syndrome (MDS) umfassen ein Spektrum klonaler hamatopoetischer Stammzellerkrankungen, die nach den Kriterien der 2008 revidierten Klassifikation der WHO eingeordnet werden. Eine Weiterentwicklung ist zu erwarten. Das klinische Krankheitsbild ist durch ungeklarte periphere Zytopenien gekennzeichnet, die zu Anamie, Blutungsereignissen und vermehrter Infektanfalligkeit fuhren. Das meist hyper-, selten hypozellulare, gelegentlich auch fibrosierte Knochenmark zeigt Dysplasien in ≥ 10% der Zellen zumindest einer oder aber mehrerer hamatopoetischer Zellreihen. Diese Veranderungen sowie eine gesteigerte Apoptoserate, Stammzellseneszenz und eine immunologische Dysregulation fuhren zu einer ineffektiven Hamatopoese. Die diagnostische Aufarbeitung sollte komplementare hamatologische, morphologische und zytogenetische/molekulare Parameter berucksichtigen. Das Methodenspektrum umfasst zytologische Untersuchungen von Blut und Knochenmark, Zytogenetik, Fluoreszenz-in-situ-Hybridisierung (FISH), Beckenkammtrepanate, Immunphanotypisierung und Evaluation molekularer Marker durch etablierte und neue Techniken. Mutationen, die Wachstumsfaktorrezeptoren, Regulatoren von Zellzyklus und Apoptose, intrazellulare Signalwege, Transkriptionsfaktoren, epigenetische Regulationsmechanismen und das Splicosom betreffen, sind an der MDS-Pathogenese und -Progression beteiligt.

Myeloproliferative neoplasms (MPNs) and related chronic disorders constitute a subgroup of myeloid malignancies which are defined according to clinical, morphological and molecular features by the actual World Health Organization classification of tumors of the haematopietic system. Screening procedures for a BCR-ABL fusion gene, JAK2, thrombopoietin receptor and KIT mutations are formally included in the diagnostic approach. Myelodysplastic/MPN overlap syndromes include rare entities such as refractory anemia with ringed sideroblasts characterized by a high proportion of JAK2V617F mutated cases. The paradigm of targeted treatment of chronic myeloid leukemia with imatinib has now been extended to eosinophilia-associated myeloid neoplasms with PDGFRA, PDGFRB or FGFR1 gene mutations. Pegylated interferon-alpha has convincingly been proved to reduce the JAK2 allele burden. JAK2 inhibitor drugs are currently being tested in clinical trials. The development of pathogenesis-targeted diagnostic and therapeutic approaches to the various MPNs will continue in the future.

Imatinib (STI571, Gleevec/Glivec) and other small-molecule tyrosine kinase inhibitors are highly effective in the treatment of chronic myeloid leukemia (CML), gastrointestinal stromal tumors and, for example, eosinophilia-associated chronic myeloproliferative disorders. This molecularly targeted approach disrupts abnormal tyrosine kinase dependent signalling pathways, thus providing a preferred treatment option for selected neoplastic disorders with activating mutations of Abelson-, Abl-related-, Kit-, and platelet-derived growth factor receptor A and B genes. Loss of response to imatinib may be due to an acquired resistance of emerging mutant tumor cell clones. Therapy is generally well tolerated. However, toxicities including edema, skin rashes, fatigue, nausea and myelosuppression have been reported. Philadelphia/Bcr-Abl-negative clonal chromosomal abnormalities may develop. Bone marrow trephines obtained from CML patients in complete remission with prolonged pancytopenia secondary to imatinib generally show marrow hypoplasia. Morphological features may be in keeping with either aplastic anemia or myelodysplasia developing in Philadelphia-negative hematopoiesis. Single or multilineage myelodysplasia may be accompanied by an excess of blasts and rarely evolves into acute leukemia in CML patients. Severe adverse hematological effects of imatinib are extremely rare. Current questions involve the molecular mechanisms of hematological side effects of tyrosine kinase inhibitors with special regard to the emergence of distinct aberrant clones.

Ziel dieser Studie war, den Effekt von Interferon (IFN), Hydroxyurea (HU) und des Tyrosinkinasehemmers Imatinib (STI571) auf die Angiogenese abzuklaren. Es wurden Knochenmarkbiopsien von 104 Patienten mit Philadelphia-Chromosom-positiver chronischer myeloischer Leukamie (CML) und Biopsien von 138 Patienten vor und nach allogener Knochenmarktransplantation (KMT) untersucht. Die CD34-Farbung und die morphometrische Analyse zeigten bei Diagnose eine im Vergleich zur Kontrollgruppe erhohte Anzahl von Gefasanomalien. Eine Beziehung zwischen Mikrogefasen und Fasergehalt war sowohl in den Erstbiopsien als auch in den Entnahmen nach Therapie erkennbar. Monotherapien mit Imatinib und HU bewirkten signifikante Verringerungen der Mikrogefasdichte und der retikularen Fasern im Gegensatz zu den Veranderungen nach IFN-Behandlung oder einer Kombinationstherapie von IFN und HU. Numerische und strukturelle Anomalien der Mikrogefase waren noch mehrere Monate nach KMT nachweisbar und sind Ausdruck der Stromaveranderungen nach myeloablativer Therapie. Die wechselseitigen Beziehungen zwischen Mikrogefasdichte und Myelofibrose werden von Veranderungen der Megakaryopoese begleitet, die als Ursprung verschiedener Mediatoren in das komplexe funktionelle Netzwerk der Fibrillogenese und Neoangiogenese eingebunden ist.

Granulozytare Sarkome (sog. Chlorome) sind seltene extramedullare Tumore bzw. tumorartige Proliferate myeloischer Vorlauferzellen, die de novo einer akuten Leukamie vorausgehen oder auch in zeitlichem Zusammenhang mit der Erstmanifestation oder dem Rezidiv einer AML auftreten konnen. Selten sind diese Tumore Ausdruck eines Blastenschubs einer chronischen myeloproliferativen Erkrankung, z.B. einer chronischen myeloischen Leukamie. Differentialdiagnostische Schwierigkeiten konnen insbesondere dann entstehen, wenn sich das Chlorom, wie im vorgestellten Fall eines 58jahrigen Mannes, primar im spinalen epiduralen Raum mit Kompression des Ruckenmarks manifestiert.

An immunohistochemical and morphometric study was performed on bone marrow biopsies in 604 patients with chronic myelogenous leukemia (CML) to compare morphological and clinical features and to evaluate effects of interferon (IFN) and chemotherapy. Following morphometry significant correlations were calculated between number of CD61(+) megakaryocytes, including their precursors with fiber density. This finding is in line with the close functional relationship between megakaryopoiesis and fibroblasts regarding the complex pathomechanism of myelofibrosis. The latter was observed in about 28% of patients already at diagnosis. In a similar way, the frequency of CD68(+) macrophages was correlated with the amount of Ret40f(+) nucleated erythroid precursors, implicating an involvement of this cell lineage in iron turnover, hemoglobin synthesis, and degradation of the expelled nuclei from normoblasts. The (alpha-D-galactosyl residue-expressing) Pseudo-Gaucher cells were detectable in 30% of pretreatment specimens. Moreover, significant associations were calculable between reduction in erythropoiesis or increase in fibers with clinical features such as hemoglobin level, percentages of myelo- and erythroblasts in the peripheral blood, and spleen size. These variables are in keeping with more advanced stages of CML. Based on our morphometric evaluations, a classification into three different histological subgroups: granulocytic, megakaryocytic, and myelofibrotic was carried out. This simplified staging system was correlated with corresponding sets of hematological data. Sequential biopsies in 173 patients with monotherapy by IFN, hydroxyurea (HU), or busulfan (BU) revealed a fibrogenic effect of IFN in contrast to a fiber-reducing property of HU. The dynamics of myelofibrosis and changes of major cell lineages during treatment were readily demonstrable by calculating corresponding indices. These included the ratios between quantitative differences of corresponding variables at repeated examinations and time. Thus, in patients with complete hematological remission following IFN administration, regeneration of erythropoiesis was found to be accompanied by an increase in the total number of CD68(+) macrophages, including activated subpopulations. Histological subgroups showed a transition from a (nonfibrotic) granulocytic and megakaryocyte pattern to the myelofibrotic subtype in about 40% of patients. This change was opposed to a numerical reduction in the myelofibrotic subtype which occurred in 17 patients (36%), but predominantly in those under HU therapy. In conclusion, the striking heterogeneity of bone marrow features in CML warrants a careful morphological evaluation of trephine biopsies and appropriate means of processing to achieve relevant correlations with clinical data and, thus, allows a more elaborate insight into the dynamics of the disease process.

Myelodysplastic syndromes (MDS) are a heterogenous group of clonal stem cell disorders which generally occur in older adults but may also affect children. Primary MDS should be distinguished from secondary MDS associated with antineoplastic or immunosuppressive therapy (t-MDS), exposure to toxic compounds, or genetic disorders. The establishment of a neoplastic clone is reflected by dysplastic features and impaired function which may affect all three hematopoietic cell lineages. The ineffective hematopoiesis which causes bone marrow failure is accompanied by peripheral blood cytopenia and is considered to result from increased apoptosis, at least in the less advanced MDS stages. The elucidation of the molecular pathogenesis of MDS has provided evidence that chromosomal abnormalities are present in about 50% of patients with primary MDS. They include numerical aberrations such as monosomy 5 or 7, trisomy 8, loss of the Y-chromosome and structural abnormalities such as deletion of the long arm of chromosome 5 (5q-syndrome), 7, or 8. Based on the percentage of blasts ( 15% ringed sideroblasts for marrows with 1x10(9)/l). However, a modification of this classification will be proposed by the World Health Organization, with the intention of lowering the threshold for the diagnosis of AML from 30% to 20% blast cells. In patients presenting with cytopenias suggesting impaired hematopoiesis, the initial diagnosis depends mainly on the cytological evaluation of bone marrow and blood smears and the histological findings of trephine bone marrow biopsy. In a retrospective analysis we evaluated the occurrence of the distinct FAB-categories as percentage of the total number of MDS cases diagnosed at the Institute of Pathology of the University of Freiburg. A total of 63% fullfilled the criteria of RA/RARS, 17% of RAEB, 14% of RAEB-t, and 6% of CMML. A fibrotic variant of MDS was observed in 7.67% of all cases, ranging from 2.34% in RA up to 15. 42-15.84% in the categories which did not show significant differences with regard to myelofibrosis. The histologic evaluation of a trephine bone marrow biopsy is of critical importance for the evaluation of fibrotic or hypocellular MDS since these patterns are not reflected by the cytological examination. The combined cytological and histological diagnosis of bone marrow and peripheral blood is a reliable tool for the initial diagnosis of MDS. In addition, cytogenetic and molecular analysis should be performed. Presently, the risk of leukemic transformation is evaluated using the International Prognostic Scoring System for MDS, which is the sum of the scores of bone marrow blasts, karyotypes and cytopenia. In the context of clinical trials therapeutic modalities should be considerd according to the age and the general performance state and the prognostic scores of individual patients.