Tatsuki Matsuo

Diagnostic significance of detecting pseudo‐Pelger‐Huet anomalies and micro‐megakaryocytes in myelodysplastic syndrome

To investigate the kind of morphological dysplastic changes important in the diagnosis of myelodysplastic syndrome (MDS), we examined 50 patients with MDS and 86 control subjects. Micromegakaryocytes and pseudo‐Pelger‐Huët anomalies were detected in 46 patients (92%) with MDS, and were also found in the differentiated types of acute myeloid leukaemia and chronic myeloid leukaemia, but not in other haematological disorders, or healthy subjects. We believe that evaluation of these changes would be helpful in diagnosing MDS.

Risk of Myelodysplastic Syndromes in People Exposed to Ionizing Radiation: A Retrospective Cohort Study of Nagasaki Atomic Bomb Survivors

PURPOSE The risk of myelodysplastic syndromes (MDS) has not been fully investigated among people exposed to ionizing radiation. We investigate MDS risk and radiation dose-response in Japanese atomic bomb survivors. PATIENTS AND METHODS We conducted a retrospective cohort study by using two databases of Nagasaki atomic bomb survivors: 64,026 people with known exposure distance in the database of Nagasaki University Atomic-Bomb Disease Institute (ABDI) and 22,245 people with estimated radiation dose in the Radiation Effects Research Foundation Life Span Study (LSS). Patients with MDS diagnosed from 1985 to 2004 were identified by record linkage between the cohorts and the Nagasaki Prefecture Cancer Registry. Cox and Poisson regression models were used to estimate relationships between exposure distance or dose and MDS risk. RESULTS There were 151 patients with MDS in the ABDI cohort and 47 patients with MDS in the LSS cohort. MDS rate increased inversely with exposure distance, with an excess relative risk (ERR) decay per km of 1.2 (95% CI, 0.4 to 3.0; P < .001) for ABDI. MDS risk also showed a significant linear response to exposure dose level (P < .001) with an ERR per Gy of 4.3 (95% CI, 1.6 to 9.5; P < .001). After adjustment for sex, attained age, and birth year, the MDS risk was significantly greater in those exposed when young. CONCLUSION A significant linear radiation dose-response for MDS exists in atomic bomb survivors 40 to 60 years after radiation exposure. Clinicians should perform careful long-term follow-up of irradiated people to detect MDS as early as possible.

Poor response to intensive chemotherapy in de novo acute myeloid leukaemia with trilineage myelodysplasia

Summary. The findings of morphologically dysplastic features in haemopoietic cells in de novo acute myeloid leukaemia (AML) has been named AML with trilineage myelodysplasia (AML/TMDS). We analysed the clinical data, karyotypes, and treatment outcomes of 230 de novo AML patients treated with the Japan Adult Leukaemia Study Group AML‐87 protocol. 40 (17%) patients had AML/TMDS. Platelet count was significantly higher (F=0·006) and bone marrow blasts were fewer (P=0·01) in the AML/TMDS group than in the AML without TMDS. Abnormal karyotype was shown in 12/30 patients (40%) analysed.

Dysmegakaryocytopoiesis in acute leukaemias: its predominance in myelomonocytic (M4) leukaemia and implication for poor response to chemotherapy

Megakaryocytopoiesis was morphologically investigated in 129 adults with de novo acute leukaemia. Three types were identified: type I (84 cases), no detectable megakaryocytes; type II (32 cases), quantitatively preserved megakaryocytes with normal morphology; type III (13 cases): quantitatively preserved megakaryocytes but with distinct dysplastic changes such as micromegakaryocytes and megakaryocytes with multiple small separated nuclei. Type III was found in M1 (one out of 21 cases), M2 (one out of 20 cases), M4 (eight out of 24 cases), M6 (two out of four cases) and hypoplastic leukaemia (one out of 13 cases). M3 cases were all classified into type I. Most of acute lymphoid leukaemia cases (21 cases) belonged to type II. Among AML cases, the complete remission (CR) rate by intensive chemotherapy with daunorubicin and cytosine arabinoside was significantly lower in type III (11%) than in types I (87%) and II (71%). Among M4 cases, CR rates in type III (14%) was also significantly lower than those in type I (75%) and II (100%). Thus, the present study indicates the importance of recognizing dysmegakaryocytopoiesis in AML for clariflcation of the heterogeneous biology or pathophysiology of acute leukaemias and formulation of an appropriate therapeutic strategy.

Cytogenetic evidence for partially committed myeloid progenitor cell origin of chronic myelomonocytic leukaemia and juvenile chronic myeloid leukaemia: both granuloctye-macrophage precursors and erythroid precursors carry identical marker chromosome

Summary. We used a micromethod for cytogenetic analysis from single haematopoietic colonies to study two adults with chronic myelomonocytic leukaemia (CMML) and a boy with juvenile chronic myeloid leukaemia (JCML) carrying distinct chromosome abnormalities, 7q—, der(21), and trisomy 21. We wanted to know if both granulocyte‐macrophage (GM) and erythroid precursors are involved in the abnormal clone. In all three patients, their chromosome abnormality was seen in almost all metaphases obtained from GM‐colonies and erythroid bursts. Peripheral blood leucocytes stimulated with phytohaemagglutinin exhibited only normal karyotypes. Clones of B‐cell produced by Epstein‐Barr virus had only normal karyotypes in the CMML patients. These findings indicate that CMML and JCML are clonal haemopathies that originate in a partially committed myeloid progenitor cell.

The percentage of myeloperoxidase-positive blast cells is a strong independent prognostic factor in acute myeloid leukemia, even in the patients with normal karyotype.

To examine whether the percentage of myeloperoxidase (MPO)-positive blast cells is useful as a prognostic factor for acute myeloid leukemia (AML), cytochemical analysis of MPO was performed in 491 patients who were registered to the Japan Adult Leukemia Study Group-AML92 study. Patients were divided into two using the percentage of MPO-positive blast (high [⩾50%] and low (<50%)). Complete remission rates were 85.4% in the former and 64.1% in the latter (P=0.001). The overall survival (OS) and the disease-free survival (DFS) were significantly better in the high MPO group (48.3 vs 18.7% for OS, and 36.3 vs 20.1% for DFS, P<0.001, respectively). Multivariate analysis showed that both karyotype and the percentage of MPO-positive blast cells were equally important prognostic factors. The high MPO group still showed a better survival even when restricted to the intermediate chromosomal risk group or the patients with normal karyotype (P<0.001). The OS of patients with normal karyotype in the high MPO group was almost equal with that of the favorable chromosomal risk group. The percentage of MPO-positive blast cells is a simple and highly significant prognostic factor for AML patients, and especially useful to stratify patients with normal karyotype.

Cytogenetic heterogeneity of acute myeloid leukaemia (AML) with trilineage dysplasia: Japan Adult Leukaemia Study Group-AML 92 study

Summary. Acute myeloid leukaemia (AML) with trilineage dysplasia (AML/TLD) is de novo AML recognized by the morphological dysplasia of three mature cell lines in the presence of leukaemic blasts. We studied the karyotypes of AML/TLD of patients with de novo AML, except for those with the French–American–British classification M3, who were enrolled onto the Japan Adult Leukaemia Study Group (JALSG)‐AML 92 trial. Morphological and cytogenetic analyses were performed in 559 patients and TLD phenotype was found in 155 patients (27·7%). The 511 patients with informative morphological and cytogenetic data were classified into three groups according to karyotype: favourable, intermediate and adverse risk groups (92, 375 and 44 patients respectively). Normal karyotype was the most frequent as a total, and among both the non‐TLD and TLD patients (164 patients 45·3% and 78 patients 52·7% respectively). All but one patient with AML/TLD was classified into the intermediate or adverse cytogenetic risk group. TLD phenotype was associated with lower remission rate and shorter overall survival but it did not influence disease‐free survival. Although we did not find any specific cytogenetic abnormalities for AML/TLD, the rarity of favourable karyotypes among TLD patients indicates the biological difference between AML/TLD and AML/non‐TLD.

A unique case of t(15;17) acute promyelocytic leukaemia (M3) developing into acute myeloblastic leukaemia (M1) with t(7;21) at relapse

Summary. This report describes a case of t(15;17) acute promyelcytic leukaemia (APL, FAB subtype M3) with dysgranulopoiesis at diagnosis in a patient who developed myelodysplasia (MDS) and then a second phenotype of t(7;21) acute myeloblastic leukaemia (AML, FAB subtype M1) at the time of relapse. To our knowledge, there is no report of a second phenotype of AML occurring after complete remission (CR) of APL. Furthermore, this is the first report of chromosomal abnormality t(7;21) in a case of AML. Several hypotheses for this unusual course of APL are discussed.

Diagnostic criteria for hypocellular acute leukemia: A clinical entity distinct from overt acute leukemia and myelodysplastic syndrome

In order to establish diagnostic criteria for hypocellular acute leukemia (HL), we have reviewed 32 cases selected on the basis of hypothetical 40% or less cellularity, by focusing on morphology, immunophenotype, karyotype and response to low dose Ara-C (LDAC) regimen and compared them with 40 cases of myelodysplastic syndrome (MDS) and 66 cases of overt acute myeloid leukemia (AML). The onset age ranged from 44 to 75 years (median 67 years). Bone marrow (BM) cellularity ranged from 12.4 to 39.8% (mean 29.8%) in HL, being significantly lower than in MDS (mean 80.7%) or AML (mean 86.4%) (P < 0.001). All reviewed cases characteristically showed smoldering clinical course, bi- or pancytopenia with rare leukemic blasts in the peripheral blood (PB), proliferation of type I leukemic blasts in the BM and markedly reduced background hematopoietic cells with some dysplastic changes in 12/32 cases (37.50/6). Blast percentage (blast %) in the BM ranged from 38.2 to 93.7% (mean 57.3%) in all nucleated cells (ANC). Although a considerable number of cases had blasts with negative or very low myeloperoxidase activity, immunophenotyping revealed that the leukemic blasts in HL had only myeloid markers. Karyotyping revealed non-random chromosome abnormalities in 30% of cases analyzed, which were considerably different from those seen in MDS. With LDAC regimen, a significantly higher CR rate (13/20 cases: 65.0%) was gained in HL than in RAEB/RAEB-t (0%) and overt AML in the elderly cases (27.3%) (P < 0.05). In CR, most cases showed recovery to normocellular BM with an apparent normalization of PB parameters. However, 12 CR cases relapsed 4-12 months later; most of which again showed hypocellular BM. These results indicate that HL is a distinct subtype of AML characterized by slow but distinct proliferation of immature myeloid blasts and by unique hematological features distinct from MDS or overt AML in the elderly. We propose the following diagnostic criteria: (1) pancytopenia with rare appearance of blasts in PB; (2) less than 40% BM hypocellularity; (3) more than 30% blasts in BM-ANC; and (4) myeloid phenotypes of leukemic blasts by MPO staining and/or immunophenotyping.

Relationship between monoclonal gammopathy of undetermined significance and radiation exposure in Nagasaki atomic bomb survivors

Radiation exposure is a possible predisposing factor for monoclonal gammopathy of undetermined significance (MGUS), but the association has been uncertain. We investigated the relationship between radiation exposure and MGUS prevalence by using data from the M-protein screening for Nagasaki atomic bomb survivors between 1988 and 2004. Radiation exposure was assessed by exposure distance from the hypocenter and exposure radiation dose. We computed prevalence ratios (PRs) and the 95% confidence intervals (CIs) adjusting for exposure age and sex. A total of 1082 cases of MGUS were identified from 52 525 participants. MGUS prevalence was significantly higher in people exposed at distance within 1.5 km than beyond 3.0 km (PR, 1.4; 95% CI, 1.1-1.9) among those exposed at age 20 years or younger, but it was not found among those exposed at age 20 years or older. MGUS prevalence was also significantly higher in people exposed to more than 0.1 Gy than those exposed to less than 0.01 Gy (PR, 1.7; 95% CI, 1.0-2.8) among those exposed at age 20 years or younger. Thus, people exposed at younger age exhibited a significantly high risk of MGUS when exposed to a high radiation dose. There was no clear association between radiation exposure and the malignant progression of MGUS. Further detailed analysis is needed.