An analysis of clinical, haematological, histological and cytogenetic data was performed in 85 consecutive patients with myelodysplastic syndromes (MDS). The criteria for diagnosis of refractory anaemia (RA), acquired idiopathic sideroblastic anaemia (AISA) and chronic myelomonocytic leukaemia (CMML) were clearly defined, since the inclusion criteria provided by the FAB co-operative group are imprecise. None of these patients has received chemotherapy during the follow-up period. The median survival of the whole group was only 15 months, with less than 10% of the patients surviving after 5 years. Fifteen patients (17.6%) were still alive at time of analysis, 31 (36.5%) have developed acute myeloid leukaemia (AML) and only one of them is still alive; 30 (35.3%) died of infectious and/or haemorrhagic complications. Patients who developed AML had a shorter survival (median survival time 9.5 versus 15 months) but this difference was not significant (P = 0.10). Factors with prognostic value are in order of significance: abnormal localized immature myeloid precursors (= ALIP) in the trephine biopsy, circulating myeloblasts, excess of blasts in the bone marrow smears, age, FAB classification and granulocyte count. In comparison to refractory anaemia with excess of blasts (RAEB), CMML and RAEB in transformation (RAEBt), patients with RA and AISA had a lower incidence of evolution to AML (11% versus 56%), but a higher mortality rate from infections and/or bleeding (59.2% versus 29%). ALIP negative cases were only found among patients with RA and AISA, whereas ALIP positivity was observed in all cases of RAEB and RAEBt, in 10/11 patients with CMML and in almost half the cases of RA and AISA. In RA and AISA patients survival was significantly different between ALIP positive and ALIP negative cases (P = 0.009). Among MDS patients, ALIP negative cases developed significantly less AML than ALIP positive cases (5% versus 44%), but a similar percentage of mortality from infectious and/or haemorrhagic complications was seen in both groups (33% versus 36.5%). Chromosomal analysis proved to be of no significant prognostic value, although a trend for shorter survival was observed in patients with complex karyotype anomalies or without mitoses. Because of their prolonged survival, antileukaemic chemotherapy is contra-indicated in ALIP negative patients (median survival 50 months). Nevertheless they only constitute a minor subgroup of MDS cases. Prognosis in ALIP positive patients is poor (median survival 12.5 months); in these patients therapeutic trials with cytostatic drugs or with inducers of differentiation of myeloid precursor cells seem to be justified.

Late erythroblasts and reticulocytes from bone marrow of male Wistar rats were studied by electron-microscopic stereology. Late erythroblasts with morphological signs of nuclear extrusion (EN + erythroblasts) and late erythroblasts without these signs (EN-erythroblasts) were analysed separately. The volumes of mitochondria, autophagosomes, autophagocytosed mitochondria, autophagocytosed cytoplasm and degraded material inside autophagosomes were calculated per unit volume of cytoplasm. The results demonstrate that (1) the volume density of mitochondria in the cytoplasm decreases by 34% during maturation from (EN-)- to (EN +)-erythroblasts (P less than 0.001) and by 60% during differentiation from (EN +)-erythroblasts to reticulocytes (P less than 0.001), (2) a fivefold increase in the volume density of autophagosomes in the cytoplasm is noted during maturation from (EN-)- to (EN +)-erythroblasts (P less than 0.01), whereas the value of this parameter remains essentially unchanged during the subsequent differentiation to reticulocytes, (3) no mitochondria are found inside autophagosomes of (EN-)-erythroblasts, whereas mitochondria occupy 26% and 35%, respectively, of the autophagosomal volume in (EN +)-erythroblasts and in reticulocytes. Our results show that autophagocytosis of mitochondria starts at the moment of nuclear extrusion and continues in the bone marrow reticulocytes.

Serial morphological and cytogenetic investigations were performed in 46 patients with the myelodysplastic syndrome (MDS). Twenty-one patients (45.5%) progressed to AML (greater than 30% blasts in bone marrow smears). Based on sequential determinations of percentages of bone marrow blasts, three patterns of evolution were observed in MDS. Patients with evolution pattern A (48%) had an apparently stable disease with minimal or no increase in bone marrow blasts. Exceptionally they developed new or additional chromosomal anomalies during the course of their disease. Cases in this group, who showed no abnormal localization of immature myeloid precursors (ALIP) at time of diagnosis experienced prolonged survival (median: 43 months), while ALIP positive patients had shorter survival times (median: 14 months), with high probability of early death from infections and/or bleeding problems. Patients with evolution pattern B (28%) initially had a morphologically stable disease, comparable to cases with evolution pattern A, but showed an abrupt shift from MDS to AML. Most of these patients (82%) were ALIP positive and a substantial proportion (46%) showed karyotype anomalies at diagnosis. The abrupt shift to AML in these patients was frequently (61.5%) associated with additional cytogenetic anomalies. Patients with evolution pattern C (24%) showed a gradual increase in bone marrow blasts. The majority of these cases (8/11) ultimately developed acute myeloid leukaemia (gradual progression to AML), whereas some patients (3/11) died from infections and/or haemorrhagic complications before they had reached the level of clinical AML. All of these patients were ALIP positive at diagnosis and no additional cytogenetic alterations occurred during evolution. Acquisition of new karyotypic anomalies during the course of MDS was almost invariably associated with abrupt shift to AML. From this retrospective study we conclude that evolution in MDS shows two important aspects, which seem to be preponderant in determining the course and outcome of the disease: one is the proliferative capacity and resulting growth advantage of the neoplastic clone over normal haematopoiesis, as measured by increasing percentages of bone marrow blasts in sequential aspirates; the other one is instability of the clone. Unstable clones have a high propensity to further intraclonal changes; they are expressed morphologically by the abrupt increase in bone marrow blasts and cytogenetically by the acquisition of new or additional karyotype anomalies.(ABSTRACT TRUNCATED AT 400 WORDS)

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