Quantitative changes include granulocytopenia and/or absolute monocytosis, with monocyte counts above 1.0 x 109/1. Dysplastic changes in neutrophilic granulocytes, i.e. nuclear abnormalities and cytoplasmatic hypogranulation, can be estimated by the percentage of pelgeroid polymorphs (ppp), and the use of a granulation scoring system (G-score), respectively .
states or toxic exposures. MDS should also be separated from myeloproliferative disorders and de novo acute myeloid leukaemia. Even though most cases of MDS are diagnosed during its chronic anaemic phase, it is evident that many patients pass this stage unnoticed and are diagnosed only when presenting with an acute myeloid leukaemia. In these cases the identification of bone marrow tri-lineage dysplasia  or peripheral blood polymorph dysplasia  could suggest a diagnosis of MDS.
Thrombocytopenia, particularly in the presence of large abnormal platelets with balloon-like features . SPECIAL INVESTIGATIONS Cytogenetics
Identification of an abnormal chromosomal clone in the bone marrow is a significant finding in MDS, especially if chromosomes Nos. 5, 7, and 11 are involved. Complex clones with multiple chromosomal aberrations would indicate imminent transformation to acute myeloid leukaemia. Bone marrow in vitro colony growth
Abnormal in vitro growth of haematopoietic stem cells is a characteristic of MDS, best documented for the granulocyte-macrophage lineage (CFU-GM), but also found within erythroid and megakaryocytic lineages. However, normal growth patterns or cytogenetics, do not rule out a diagnosis of MDS.
REFERENCES 1. Bennett J. M., Catovsky D., Daniel M. T., Flandrin G., Galton D. A. G., Gralnick H. R. & Sultan C. (1982) Proposals for the classification of myelodysplastic syndromes. Br. J. Haemat. 51, 189. 2. Tricot G., Vlietinck R., Boogaerts M. A., et al. (1985) Prognostic factors in the myelodysplastic syndromes: importance of initial data on peripheral blood counts, bone marrow cytology, trephine biopsy and chromosomal analysis. Br. J. Haemat. 60,..10. 3. Hast R., Nilsson I., Widell S. & Ost/~. (1989) Diagnostic significance of dysplastic features of peripheral blood polymorphs in myelodysplastic syndromes. Leukemia Res. 13, 173-i78. 4. Widell S. & Hast R. (1987) Balioon-platelets in myelodysplastic syndrome a feature of dysmegakaryopoiesis? Leukemia Res. 11,747-752. 5. Brito-Babapulle F., Catovsky D. & Galton D. A. G. (1987) Clinical and laboratory features of de novo acute myeloid leukemia with trilineage myelodysplasia. Br. J. Haemat. 66, 445-450. 6. Hast R. & Widell S. (1991) Dysplastic peripheral blood polymorphs link acute myeloblastic leukemia in elderly to the myelodysplastic syndromes. (Submitted for publication.) ROBERT HAST
DIFFERENTIAL DIAGNOSIS Differential diagnoses that should be eliminated include hereditary or reversible causes of bone marrow dysmaturation, like vitamin or mineral deficiencies, immunological disorders, haemolytic
MYELODYSPLASTIC TrIE possibility to establish a reliable diagnosis of MDS is increasingly important because MDS is a prevalent disease. In most cases it is a slowly progressing disease and therefore, in clinical practice, one finds patients with the entire spectrum of findings from those giving only a vague suspicion of MDS to a classical full-blown picture of MDS. Diagnoses require criteria sensitive enough to include the majority of patients suffering from a
PER BERNELL Division of Hematology Department of Medicine Danderyd Hospital and Karolinska Institute Stockholm, Sweden
SYNDROME certain disease, but also specific enough to exclude patients suffering from other diseases with similar features. A high degree of sensitivity usually results in a rather low degree of specificity and vice versa. It is difficult to find the ideal balance between sensitivity and specificity for the diagnosis of MDS and especially concerning the differential diagnosis against some intimately related disorders, i.e. aplastic anaemia, paroxysmal nocturnal haemoglobinuria,
myeloproliferative disorders with or without fibrosis, and acute myeloid leukaemia. We believe that the diagnosis of MDS should be based on clinical, morphological, functional and cytogenetical findings. It is important to exclude cases in which the cytopenia is caused by nutritional deficiency or by chronic inflammatory diseases (including AIDS) and also by use or abuse of substances with toxic effects on the bone marrow which can produce alterations similar to those found in MDS. We also believe that one should exclude cases with Auer rods, Philadelphia chromosomes and of course cases fulfilling generally accepted criteria for AML. Furthermore it seems questionable whether cases with unilinear erythrocytopoietic dysplasia in the form of ring sideroblasts without any involvement of other lineages should be included.
Clinical findings Most patients developing MDS are elderly. In younger patients efforts should be made to rule out other causes of cytopenia. Most patients have pancytopenia or at least bicytopenia and most patients show a slow clinical progression.
Morphological findings The FAB proposal  pointed out the most important morphological features of MDS. We, however, disagree with the FAB group concerning Auer rods. We consider all cases with unequivocal finding of Auer rods as cases of AML even though other criteria for AML may not be fulfilled and even though dysplasia may appear in different lineages. A study of bone marrow histology is mandatory. A plastic embedded trephine biopsy is the best basis but a clot section is frequently satisfactory. Most patients have a hypercellular bone marrow with stainable iron. Of special interest is the finding of 'abnormal localisation of immature precursor cells' (ALIP) according to Tricot's definition . The finding of ALIPs has been shown to have prognostic implications but is also of diagnostic value. This interpretation can however only be made on semi-thin sections from plastic-embedded trephine biopsies. Immunophenotypic studies may also be of help as, in some patients, an abnormal biphenotypic expression of certain antigens indicates a pathological clone.
Cytogenetic findings Cytogenetic techniques can show a pathological clone. Cases with a Philadelphia chromosome should be excluded.
Functional tests A reduced number of CFU-c is found in most patients.
MINIMAL DIAGNOSTIC CRITERIA Based on the above given comments the following criteria are proposed: (1) Exclusion criteria: - n u t r i t i o n a l anaemia or simple chronic anaemia secondary to tumour or inflammatory disease. - recent exposure to agents toxic to the bone marrow. - AML with a diagnosis either based on the finding of > = 30% blast cells in the bone marrow or > = 50% blast cells + promyelocytes/promonocytes or an unequivocal finding of Auer rods. - finding of a Philadelphia chromosome. unilinear erythrocytopoietic dysplasia with mitochondrial ring sideroblasts with isolated anaemia. (2) Inclusion criteria: - slowly progressing cytopenia not caused by any of the findings mentioned as exclusion criteria. hypercellular bone marrow with stainable iron. dysplasia in at least one lineage according to the criteria proposed by the FAB group. (3) Contributory but not obligatory findings: - old age. > 14% intermediate (ferritin) sideroblasts. cytogenetical aberrations. - i m m u n o p h e n o t y p i c pathological findings, especially aberrant biphenotypic antigen expression. - reduced number of CFU-c. CONCLUSION Despite these criteria there will be difficulties in the differential diagnosis in cases with a hypoplastic bone marrow with dysplastic features reflected by the fact that an increasing number of reports have appeared concerning cases of aplastic anaemia developing into MDS. Due to the fact that the FAB group included chronic myelomonocytic leukaemia (CMML) in the MDS group cytogenetic investigation should be made in all cases of suspected CMML to exclude the presence of a Philadelphia chromosome. In cases of myelofibrosis the interpretation of myelodysplasia is very difficult because of the cyto-
Introduction logical distortion of cells that may be due to the fibrosis itself. To summarise we believe that there are still two main problems in differential diagnosis, i.e. aplastic anaemia and myeloproliferative disorders with or without fibrosis. In cases with these differential diagnostic difficulties it is frequently possible to wait and observe the clinical development.
(1982) Proposals for the classification of the myelodysplastic syndromes. The French-American-British Cooperative Group. Br. J. Haemat. 51, 189-199. 2. Tricot G., De Wolf-Peeters C., Hendrick B. & Verwilghen R. L. (1984) Bone marrow histology in myelodysplastic syndromes. Br. J. Haemat. 57, 423430.
,~KE (~)ST REFERENCES 1. Bennett J. M., Catovsky D., Daniel M. T., Flandrin G., Galton D. A. G., Gralnick H. R. & Sultan C.
PETER REIZENSTEIN Divisions of Hematopathology and Hematology Karolinska Hospital and Institute Stockholm, Sweden