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Minimal diagnostic criteria for the myelodysplastic syndrome in clinical practice
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
6
Introduction
criteria; (1) prominent dysplastic features in at least two haematopoietic cell lines in the absence of other conditions, known to cause marrow dysplasia; (2) evidence of an acquired clonal chromosomal abnormality or (3) subsequent evolution to refractory anaemia with excess of blasts or AML [12]. In the absence of any of these criteria, patients should not be considered having MDS. Many months of follow-up may be necessary to establish the correct diagnosis. If clinicians do not use minimal diagnostic criteria, MDS m a y b e considered a common denominator for all unexplained cytopenias and bone marrows, which are difficult to interpret. There are good reasons to be very strict in what is considered MDS: (1) It is difficult to interpret data of studies on MDS if the patient group is ill-defined. Data about median survival, natural course, causes of death and percentage of long-term survivors will become less relevant. (2) Patients who do not fulfil minimal diagnostic criteria for MDS should not be given the same grim prognosis as true MDS cases. Moreover, by attaching a diagnosis to a patient, clinicians might be less inclined to further search for another possible diagnosis. (3) Therapeutic trials with chemotherapy and inducers of differentiation will be hampered by inclusion of cases that are not true MDS. Moreover, in non-MDS patients these approaches may be dangerous. It is hoped that further diagnostic tools, such as refinement in chromosome and oncogene studies and DNA analysis will enable us to demonstrate more definitely whether a patient has MDS or not. Until then, we will have to proceed with our imperfect tools to diagnose early stage MDS and rather be too strict than too inclusive. REFERENCES 1. Tricot G. (1986) Evolution of the myelodysplastic syndromes. Br. J. Haemat. 63, 609--614.
2. Bagby G. C. Jr (1986) The concept of preleukemia: clinical and laboratory studies. CRC Crit. Rev. Oncol./ Hemat. 4, 203--220. 3. Raskind W. H., Tirumaly N., Jacobson R., etal. (1984) Evidence for a multistep pathogenesis of a myelodysplastic syndrome. Blood 62, 1318-1323. 4. Prchal J. T., Trockmorton D. W., Carrol A. J., et al. (1978) A common progenitor for myeloid and lymphoid cells. Nature 274, 590-591. 5. Lawrence J., Broudy V. C., Magenis R. E., et al. (1987) Cytogenetic evidence for involvement of B lymphocytes in acquired idiopathic sideroblastic anemias. Blood 70, 1003-1005. 6. Janssen W. G., Buschle M., Layton M., et al. (1989) Clonal analysis of myelodysplastic syndromes: evidence of multipotent stem cell origin. Blood 73, 248254. 7. Bennett J. M., Catovsky D., Daniel M. T., etal. (1982) Proposals for the classification of the myelodysplastic syndromes. Br. J. Haemat. 51, 189-199. 8. Bennett J. M. (1986) Classification of the myelodysplastic syndromes. Clinics Haemat. 15, 909-923. 9. Linman J. W. & Bagby G. C. (1978) The preleukemic syndrome (hemopoietic dysplasia). Cancer 42, 854864. 10. Todd W. M. & Pierre R. V. Preleukemia: a long term prospective study of 326 patients. Blood 4 (Suppl. 1), 184a. 11. Gattermann N., Aul C. & Schneider W. (1990) Two types of acquired idiopathic sideroblastic anaemia (AISA). Br. J. Haemat. 74, 45-52. 12. 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, 19-32.
GUIDO J. TRICOT Division of Hematology/Oncology Department of Medicine Indiana University Medical Center Indianapolis, Indiana, U.S.A.
MINIMAL DIAGNOSTIC CRITERIA FOR THE MYELODYSPLASTIC SYNDROME (MDS) IN CLINICAL PRACTICE DIAGNOSTIC criteria for primary MDS (pMDS) are obtained by correlation of clinical, cytologic, histologic, cytogenetic and immunologic findings. BASIC INVESTIGATIONS Clinical data
They include (1) a meticulous history to establish or rule out (a) the presence of conditions that may be
associated with myelodysplasia, such as nutritional deficiencies or a tumour with or without metastases, current therapy with, or use of drugs, infections (e.g. bacterial, viral), and (b) to elicit information concerning a possible congenital anomaly in young people or previous exposure to potentially cytotoxic agents in older (and younger) individuals. (2) A thorough physical examination supplemented by imaging and other techniques as indicated [1-5].
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
6
Introduction
criteria; (1) prominent dysplastic features in at least two haematopoietic cell lines in the absence of other conditions, known to cause marrow dysplasia; (2) evidence of an acquired clonal chromosomal abnormality or (3) subsequent evolution to refractory anaemia with excess of blasts or AML [12]. In the absence of any of these criteria, patients should not be considered having MDS. Many months of follow-up may be necessary to establish the correct diagnosis. If clinicians do not use minimal diagnostic criteria, MDS m a y b e considered a common denominator for all unexplained cytopenias and bone marrows, which are difficult to interpret. There are good reasons to be very strict in what is considered MDS: (1) It is difficult to interpret data of studies on MDS if the patient group is ill-defined. Data about median survival, natural course, causes of death and percentage of long-term survivors will become less relevant. (2) Patients who do not fulfil minimal diagnostic criteria for MDS should not be given the same grim prognosis as true MDS cases. Moreover, by attaching a diagnosis to a patient, clinicians might be less inclined to further search for another possible diagnosis. (3) Therapeutic trials with chemotherapy and inducers of differentiation will be hampered by inclusion of cases that are not true MDS. Moreover, in non-MDS patients these approaches may be dangerous. It is hoped that further diagnostic tools, such as refinement in chromosome and oncogene studies and DNA analysis will enable us to demonstrate more definitely whether a patient has MDS or not. Until then, we will have to proceed with our imperfect tools to diagnose early stage MDS and rather be too strict than too inclusive. REFERENCES 1. Tricot G. (1986) Evolution of the myelodysplastic syndromes. Br. J. Haemat. 63, 609--614.
2. Bagby G. C. Jr (1986) The concept of preleukemia: clinical and laboratory studies. CRC Crit. Rev. Oncol./ Hemat. 4, 203--220. 3. Raskind W. H., Tirumaly N., Jacobson R., etal. (1984) Evidence for a multistep pathogenesis of a myelodysplastic syndrome. Blood 62, 1318-1323. 4. Prchal J. T., Trockmorton D. W., Carrol A. J., et al. (1978) A common progenitor for myeloid and lymphoid cells. Nature 274, 590-591. 5. Lawrence J., Broudy V. C., Magenis R. E., et al. (1987) Cytogenetic evidence for involvement of B lymphocytes in acquired idiopathic sideroblastic anemias. Blood 70, 1003-1005. 6. Janssen W. G., Buschle M., Layton M., et al. (1989) Clonal analysis of myelodysplastic syndromes: evidence of multipotent stem cell origin. Blood 73, 248254. 7. Bennett J. M., Catovsky D., Daniel M. T., etal. (1982) Proposals for the classification of the myelodysplastic syndromes. Br. J. Haemat. 51, 189-199. 8. Bennett J. M. (1986) Classification of the myelodysplastic syndromes. Clinics Haemat. 15, 909-923. 9. Linman J. W. & Bagby G. C. (1978) The preleukemic syndrome (hemopoietic dysplasia). Cancer 42, 854864. 10. Todd W. M. & Pierre R. V. Preleukemia: a long term prospective study of 326 patients. Blood 4 (Suppl. 1), 184a. 11. Gattermann N., Aul C. & Schneider W. (1990) Two types of acquired idiopathic sideroblastic anaemia (AISA). Br. J. Haemat. 74, 45-52. 12. 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, 19-32.
GUIDO J. TRICOT Division of Hematology/Oncology Department of Medicine Indiana University Medical Center Indianapolis, Indiana, U.S.A.
MINIMAL DIAGNOSTIC CRITERIA FOR THE MYELODYSPLASTIC SYNDROME (MDS) IN CLINICAL PRACTICE DIAGNOSTIC criteria for primary MDS (pMDS) are obtained by correlation of clinical, cytologic, histologic, cytogenetic and immunologic findings. BASIC INVESTIGATIONS Clinical data
They include (1) a meticulous history to establish or rule out (a) the presence of conditions that may be
associated with myelodysplasia, such as nutritional deficiencies or a tumour with or without metastases, current therapy with, or use of drugs, infections (e.g. bacterial, viral), and (b) to elicit information concerning a possible congenital anomaly in young people or previous exposure to potentially cytotoxic agents in older (and younger) individuals. (2) A thorough physical examination supplemented by imaging and other techniques as indicated [1-5].