Introduction
MINIMAL DIAGNOSTIC CRITERIA FOR THE MYELODYSPLASTIC S Y N D R O M E CLINICAL suspicion of a myelodysplastic syndrome (MDS) should be aroused when a patient is found to have a persistent but unexplainable abnormality in the peripheral blood. Such abnormalities may range from clinically insignificant findings detected on a routine blood count [1], to marked single or multiple cytopenias. They may include macrocytosis, anaemia, neutropenia, thrombocytopenia, or abnormal red cell, leucocyte or platelet morphology. Persistence implies a duration of 4-6 months and inexplicable implies a lack of response to vitamin B12, folic acid and Pyridoxine therapy or the presence of non-haematological causes of macrocytosis or cytopenia such as liver disease, renal failure, drug therapy, chronic alcoholism, autoimmune disease and hypersplenism. Once the above criteria have been met several steps should be taken to confirm the diagnosis. It is mandatory to perform a careful morphological examination of a bone marrow aspirate and to karyotype bone marrow cells. Studies of peripheral blood progenitor cell growth [2, 3] and studies of clonality based on X-chromosome inactivation in blood or marrow [4, 5] are valuable. If cytopenia or macrocytosis is accompanied by clear morphological evidence of dysplasia in one or more cell lines [6], then the diagnosis is confirmed. We would consider one or more of the following as fulfilling this criterion: (1) Micromegakaryocytes, or megakaryocytes with multiple separate nuclei. (2) Agranular myeloblasts, or myeloblasts with Auer rods accounting for 5-30% of 400 nucleated cells counted. (3) Hypogranular neutrophils. (4) Dyserythropoiesis. (5) Ring sideroblasts. We would also consider the presence of a clonal karyotypic abnormality [7] as confirming the diagnosis, though this was present in only 33% of our patients at the time of diagnosis. When dysplasia is minimal or seems insufficient to account for the abnormality in the blood, Table 1 illustrates how abnormal progenitor growth, or evidence of X-linked monoclonality provides positive evidence for MDS. However, given that equivocal findings are more likely to represent very early stages of disease, careful follow-up and sequential studies are often the best way of reaching the correct diagnosis, since disease progression will put the diagnosis beyond doubt. We would commend the
TABLE 1.
POSITIVE DIAGNOSTIC FEATURES IN DIAGNOSIS IN CARDIFF PATIENTS
MDS
AT
CFU-GM BFU-E Karyotype Clonality* Abnormal
45%
79%
33%
90%
*Females only. TABLE2. DIAGNOSTICGROUPSIN MDS Diagnostic group 1. Uncertain/ possibly early M D S
2. Probable MDS
3. M D S confirmed
Features Minimaldysplasia Normal cytogenetics Normal progenitor growth Minimaldysplasia with normal cytogenetics but abnormal progenitors Overt dysplasia or
Action Review every six months for evidence of deterioration in the blood Careful frequent review with yearly marrow examination Treat as clinically indicated
Clonal cytogenetic abnormality or
X-linked monoclonality or
Absent progenitor cells in the peripheral blood All groups have a persistent unexplained abnormality in the peripheral blood. diagnostic groups in Table 2 as a useful practical approach to establishing the diagnosis. REFERENCES 1. Bowen D. & Jacobs A. (1989) Primary acquired sideroblastic erythropoiesis in non-anaemic and minimally anaemic subjects. J. clin. Pathol. 42, 56--58. 2. Chui D. H. K. & Clarke B. J. (1982) Abnormal erythroid progenitor cells in human preleukaemia. Blood 60, 362-367. 3. Tennant G. B. & Jacobs A. (1989) Effect of 5637conditioned medium on peripheral blood granulocytemacrophage progenitors in normal subjects and patients with the myelodysplastic syndrome. Leukemia Res. 13, 385-389. 4. Jansen J. W. G., Buschle M., Layton M., et al. (1989) Clonal analysis of myelodysplastic syndromes, evidence of multipotential stem cell origin. Blood 73, 248-254.
Introduction 5. Tefferi A., Thibodeau S.N. & Soldberg L.A. Jr (1990) Clonal studies in the myelodysplastic syndrome using X-linked restriction fragment length polymorphism. Blood 75, 1770-1773. 6. Bennett J. M., Catovsky D., Danier M. T., et al. (1982) Proposal for the classification of the myelodysplastic syndromes. Br. J. Haemat. 51, 189-199. 7. Geddes A. D., Bowen D. J. & Jacobs A. (1990) Clonal karyotype abnormalities and clinical progress in the
5 myelodysplastic syndromes. Br. J. Haemat. 76, 194202. D. J. CULLIGAN A. JACOBS Department of Haematology University of Wales College of Medicine Cardiff, U.K.
MINIMAL DIAGNOSTIC CRITERIA FOR THE MYELODYSPLASTIC SYNDROME IN CLINICAL PRACTICE THE term, the myelodysplastic syndromes (MDS) is now reserved for clonal malignant haematologic disorders, characterised by cytopenia in the peripheral blood, while the bone marrow is usually normo- or hypercellular and shows clear signs of dysplasia. With time, MDS patients tend to have increasing cytopenia and are at high risk of evolution to overt leukaemia. MDS are malignant neoplasms. The term 'preleukaemia' might imply a premalignant condition, but the neoplastic clone already exists fully expanded and dominates the bone marrow in the myelodysplastic phase [1, 2]. There is now mounting evidence that MDS results from neoplastic transformation at the level of the pluripotent stem cell, with involvement not only of the haematopoietic, but also of the lymphoid progenitor cells. G-6PD studies, cytogenetics and oncogene analysis have confirmed the clonality and involvement of the lymphoid cells, certainly B cells, but probably also T cells in the MDS ]3-6]. In contrast to the paucity of meaningful clues obtained by history and physical examination, the haematologic alterations in peripheral blood and bone marrow of MDS patients are quite uniform and constant. A detailed description of these alterations has been provided by the French-American-British (FAB) cooperative group [7] and by Bennett [8]. It should be stressed, however, that each of the blood and bone marrow findings separately are essentially non-diagnostic. The most specific finding in bone marrow aspirates is the increase in per cent of blast cells. Excess of blasts are only found in some of the MDS patients and again are not pathognomic. It can be found in other conditions, such as early diagnosed acute myeloid leukaemia (AML), early relapse and recovery after intensive chemotherapy. Although it is easy to make the diagnosis of MDS in typical cases, it is sometimes difficult to delineate MDS from AML on the one hand and from disorders associated with
marrow dysplasia, due to nutritional deficiencies, side effects of drugs, intoxications, metabolic disturbances, chronic inflammation or non-haematopoietic malignancies on the other hand. The diagnosis in the early stages of the disease is always based on the exclusion of the above-mentioned disorders. Minimal haematologic criteria for MDS have never been defined by the FAB cooperative group. In contrast, Linman and Bagby have formulated minimal requirements for the diagnosis of the preleukaemia syndrome (haemopoietic dysplasia) [9]. Their diagnostic criteria were based on a retrospective study. Even using these precisely-defined criteria, Todd et al. made the very important observation that 31 (10%) of 326 patients meeting the criteria for the preleukaemic syndrome recovered to a normal haematologic status and another 15 (5%) progressed to typical agnogenic myeloid metaplasia [10]. On a morphologic basis, two subtypes of refractory anaemia with sideroblasts can be distinguished: pure sideroblastic anaemia, which is confined to dyserythropoiesis and sideroblastic anaemia with dysplastic features of granulopoiesis and/or megakaryoporesis [11]. In a follow-up study of 94 patients, a striking difference in survival and risk of leukaemia transformation was observed. The five-year cumulative chance of survival was 69% in pure sideroblastic anaemia, compared to only 19% in those with additional dysplastic features. The cumulative risk of leukaemic transformation was 1.9% and 48% respectively. Pure sideroblastic anaemia in all likelihood is not a myelodysplastic syndrome in the sense of a clonal haematologic malignancy and unless evidence of clonality, based on cytogenetics or G-6PD is present, it should not be considered MDS. Because no minimal diagnostic criteria for patients with refractory anaemia, refractory anaemia with sideroblasts and chronic myelomonocytic leukaemia are available, we have only included those cytopenic patients in our studies who met one of the following
MINIMAL DIAGNOSTIC CRITERIA FOR THE MYELODYSPLASTIC S Y N D R O M E CLINICAL suspicion of a myelodysplastic syndrome (MDS) should be aroused when a patient is found to have a persistent but unexplainable abnormality in the peripheral blood. Such abnormalities may range from clinically insignificant findings detected on a routine blood count [1], to marked single or multiple cytopenias. They may include macrocytosis, anaemia, neutropenia, thrombocytopenia, or abnormal red cell, leucocyte or platelet morphology. Persistence implies a duration of 4-6 months and inexplicable implies a lack of response to vitamin B12, folic acid and Pyridoxine therapy or the presence of non-haematological causes of macrocytosis or cytopenia such as liver disease, renal failure, drug therapy, chronic alcoholism, autoimmune disease and hypersplenism. Once the above criteria have been met several steps should be taken to confirm the diagnosis. It is mandatory to perform a careful morphological examination of a bone marrow aspirate and to karyotype bone marrow cells. Studies of peripheral blood progenitor cell growth [2, 3] and studies of clonality based on X-chromosome inactivation in blood or marrow [4, 5] are valuable. If cytopenia or macrocytosis is accompanied by clear morphological evidence of dysplasia in one or more cell lines [6], then the diagnosis is confirmed. We would consider one or more of the following as fulfilling this criterion: (1) Micromegakaryocytes, or megakaryocytes with multiple separate nuclei. (2) Agranular myeloblasts, or myeloblasts with Auer rods accounting for 5-30% of 400 nucleated cells counted. (3) Hypogranular neutrophils. (4) Dyserythropoiesis. (5) Ring sideroblasts. We would also consider the presence of a clonal karyotypic abnormality [7] as confirming the diagnosis, though this was present in only 33% of our patients at the time of diagnosis. When dysplasia is minimal or seems insufficient to account for the abnormality in the blood, Table 1 illustrates how abnormal progenitor growth, or evidence of X-linked monoclonality provides positive evidence for MDS. However, given that equivocal findings are more likely to represent very early stages of disease, careful follow-up and sequential studies are often the best way of reaching the correct diagnosis, since disease progression will put the diagnosis beyond doubt. We would commend the
TABLE 1.
POSITIVE DIAGNOSTIC FEATURES IN DIAGNOSIS IN CARDIFF PATIENTS
MDS
AT
CFU-GM BFU-E Karyotype Clonality* Abnormal
45%
79%
33%
90%
*Females only. TABLE2. DIAGNOSTICGROUPSIN MDS Diagnostic group 1. Uncertain/ possibly early M D S
2. Probable MDS
3. M D S confirmed
Features Minimaldysplasia Normal cytogenetics Normal progenitor growth Minimaldysplasia with normal cytogenetics but abnormal progenitors Overt dysplasia or
Action Review every six months for evidence of deterioration in the blood Careful frequent review with yearly marrow examination Treat as clinically indicated
Clonal cytogenetic abnormality or
X-linked monoclonality or
Absent progenitor cells in the peripheral blood All groups have a persistent unexplained abnormality in the peripheral blood. diagnostic groups in Table 2 as a useful practical approach to establishing the diagnosis. REFERENCES 1. Bowen D. & Jacobs A. (1989) Primary acquired sideroblastic erythropoiesis in non-anaemic and minimally anaemic subjects. J. clin. Pathol. 42, 56--58. 2. Chui D. H. K. & Clarke B. J. (1982) Abnormal erythroid progenitor cells in human preleukaemia. Blood 60, 362-367. 3. Tennant G. B. & Jacobs A. (1989) Effect of 5637conditioned medium on peripheral blood granulocytemacrophage progenitors in normal subjects and patients with the myelodysplastic syndrome. Leukemia Res. 13, 385-389. 4. Jansen J. W. G., Buschle M., Layton M., et al. (1989) Clonal analysis of myelodysplastic syndromes, evidence of multipotential stem cell origin. Blood 73, 248-254.
Introduction 5. Tefferi A., Thibodeau S.N. & Soldberg L.A. Jr (1990) Clonal studies in the myelodysplastic syndrome using X-linked restriction fragment length polymorphism. Blood 75, 1770-1773. 6. Bennett J. M., Catovsky D., Danier M. T., et al. (1982) Proposal for the classification of the myelodysplastic syndromes. Br. J. Haemat. 51, 189-199. 7. Geddes A. D., Bowen D. J. & Jacobs A. (1990) Clonal karyotype abnormalities and clinical progress in the
5 myelodysplastic syndromes. Br. J. Haemat. 76, 194202. D. J. CULLIGAN A. JACOBS Department of Haematology University of Wales College of Medicine Cardiff, U.K.
MINIMAL DIAGNOSTIC CRITERIA FOR THE MYELODYSPLASTIC SYNDROME IN CLINICAL PRACTICE THE term, the myelodysplastic syndromes (MDS) is now reserved for clonal malignant haematologic disorders, characterised by cytopenia in the peripheral blood, while the bone marrow is usually normo- or hypercellular and shows clear signs of dysplasia. With time, MDS patients tend to have increasing cytopenia and are at high risk of evolution to overt leukaemia. MDS are malignant neoplasms. The term 'preleukaemia' might imply a premalignant condition, but the neoplastic clone already exists fully expanded and dominates the bone marrow in the myelodysplastic phase [1, 2]. There is now mounting evidence that MDS results from neoplastic transformation at the level of the pluripotent stem cell, with involvement not only of the haematopoietic, but also of the lymphoid progenitor cells. G-6PD studies, cytogenetics and oncogene analysis have confirmed the clonality and involvement of the lymphoid cells, certainly B cells, but probably also T cells in the MDS ]3-6]. In contrast to the paucity of meaningful clues obtained by history and physical examination, the haematologic alterations in peripheral blood and bone marrow of MDS patients are quite uniform and constant. A detailed description of these alterations has been provided by the French-American-British (FAB) cooperative group [7] and by Bennett [8]. It should be stressed, however, that each of the blood and bone marrow findings separately are essentially non-diagnostic. The most specific finding in bone marrow aspirates is the increase in per cent of blast cells. Excess of blasts are only found in some of the MDS patients and again are not pathognomic. It can be found in other conditions, such as early diagnosed acute myeloid leukaemia (AML), early relapse and recovery after intensive chemotherapy. Although it is easy to make the diagnosis of MDS in typical cases, it is sometimes difficult to delineate MDS from AML on the one hand and from disorders associated with
marrow dysplasia, due to nutritional deficiencies, side effects of drugs, intoxications, metabolic disturbances, chronic inflammation or non-haematopoietic malignancies on the other hand. The diagnosis in the early stages of the disease is always based on the exclusion of the above-mentioned disorders. Minimal haematologic criteria for MDS have never been defined by the FAB cooperative group. In contrast, Linman and Bagby have formulated minimal requirements for the diagnosis of the preleukaemia syndrome (haemopoietic dysplasia) [9]. Their diagnostic criteria were based on a retrospective study. Even using these precisely-defined criteria, Todd et al. made the very important observation that 31 (10%) of 326 patients meeting the criteria for the preleukaemic syndrome recovered to a normal haematologic status and another 15 (5%) progressed to typical agnogenic myeloid metaplasia [10]. On a morphologic basis, two subtypes of refractory anaemia with sideroblasts can be distinguished: pure sideroblastic anaemia, which is confined to dyserythropoiesis and sideroblastic anaemia with dysplastic features of granulopoiesis and/or megakaryoporesis [11]. In a follow-up study of 94 patients, a striking difference in survival and risk of leukaemia transformation was observed. The five-year cumulative chance of survival was 69% in pure sideroblastic anaemia, compared to only 19% in those with additional dysplastic features. The cumulative risk of leukaemic transformation was 1.9% and 48% respectively. Pure sideroblastic anaemia in all likelihood is not a myelodysplastic syndrome in the sense of a clonal haematologic malignancy and unless evidence of clonality, based on cytogenetics or G-6PD is present, it should not be considered MDS. Because no minimal diagnostic criteria for patients with refractory anaemia, refractory anaemia with sideroblasts and chronic myelomonocytic leukaemia are available, we have only included those cytopenic patients in our studies who met one of the following
