Classification of myelodysplasic syndromes 1999

2002-05-01   Georges Flandrin 

1.Laboratoire d Hématologie, Hôpital Necker-Enfants Malades, Paris, France

Clinics and Pathology


Refractory anemia (RA)


Refractory anemia demonstrates less than 5% bone marrow blast cells. RA should be included in a more general group of myelodysplastic syndromes without excess blasts. The typical presentation is anemia but the first hematological manifestation could be thrombocytopenia alone, or more rarely neutropenia alone (refractory cytopenia). Since refractory cytopenias (RC) are heterogeneous with regard to their morphology, clinical features and survival, it has been proposed to separate RC patients in two categories: RC with multilineage dyspalsia (mRC), a distinct subset with an unfavorable clinical outcome and RC with minimal dysplasia (RC). , Splitting RAEB into two classes: RAEB I and RAEB II. It has been recommended to separate RAEB patients in two groups: RAEB I with < 10 % blasts in the bone marrow and/or 1 to 5% blast cells in the peripheral blood. RAEB II with 10-20 % in the bone marrow and/or 5% to 20% blast cells in the peripheral blood.


Refractory anemia with excess of blasts (RAEB)


The RAEB category remain unchanged and as previously described include MDS patient having more than 5 and less than 20% bone marrow blasts. Suppressing the RAEB-T category. This subclass was identical to RAEB except for a higher percentage blasts: between 20 and 30% in the bone marrow and/or more than 5% in the peripheral blood. Most of these patients have been recognized to have an AML M2 outcome. For that reason, it has been suggested that patients with more than 20% of blast cells in the peripheral blood or bone marrow may be considered as acute myeloid leukemia M2. Presence of Auer rods that was an indication for RAEBT is no more taken into consideration for the classification.


Refractory anemia with ringed sideroblasts (RARS).


Restricting the definition of RARS. Ineffective erythropoiesis, dysplastic erythroid precursors and progressive anemia characterize RARS. The FAB has defined RARS as <15% sideroblasts. Some confusion has arisen in using this point. It has been shown that patients with increased sideroblasts and other myelodysplastic features have a more severe course than those without additional dysplasia. The "pure" RARS (without dysplasia) is characterized by a very low risk of progression to leukemia and has usually a high percentage of bone marrow erythroblasts and ringed sideroblasts. An increase in ring sideroblasts in other MDS/MPS with dysplasia should be mentioned as an additional factor but is not crucial for classification.


Chronic myelomonocytic leukemia (CMML)


The arbitrary definition of the FAB CMML subtype has led to some controversy. The minimal monocyte count for CMML was set at 1 x 109/l. Many subsequent studies have recognized the heterogeneity that exists within the subgroup of CMML. Some patients present with a modest monocytosis and leukocytosis (MDS/CMML) and others have an extreme leukocytosis and extramedullary hematopoiesis characterized by splenomegaly, serous effusions or skin infiltration (MPS/CMML). Whether dysplastic and proliferative CMML represent different phases of a single disease or are distinct entities remains unclear. Disparate results have been obtained concerning median survival between these two subtypes. The WHO classification recommends putting CMML into a new category between Myelodysplastic and Myelproliferative syndromes (MDS/MPS). The WHO classification recommends keeping only the CMML patients with myeloproliferative features defined as having > 1x109/l monocytes in the peripheral blood. The WHO classification recommand to classify CMML in a separate group (SMD/SMP) having both criteria of MDS and MPS.


Atypical Chronic Myeloid Leukemia (a-CML)


This new definition,(SMD/SMP), simplifies the distinction between CMML and another MPS category, atypical chronic myeloid leukemia which may have an increased monocytic count in addition to significant increase in circulating immature granulocytes; a-CML is usually characterized by more obvious myelodysplastic changes. Whether CMML and a-CML are separate disorders or part of a spectrum of MPS with various dysplastic features remains unclear. The WHO classification recommand to classify a-CML into the SMD/SMP group. Amongst patients that are presenting as MDS or MPS (depending on their WBC count), a peculiar morphological syndrome is the " abnormal chromatin clumping syndrome" (ACCS). This subtype is only based on morphologic features and is characterized by abnormal chromatin clumping of the granulocytic lineage. No precise correlation has been yet demonstrated with chromosomal changes in the few cases described in the literature the clinical outcome is poor.


"Unclassified" MDS


Other distinct MDS subgroups, such as hypocellular MDS and MDS with myelofibrosis have been recognized. Some cases of MDS with abnormal eosinophilia and MDS associated with abnormal mast cell have been described.


Cytogenetic classification.

The myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by cytopenia and bone marrow dysplasia. This is resulting from proliferation, differentiation and apoptotic processes of hematopoietic precursors with frequent evolution to acute myeloid leukemia (AML). Anemia, neutropenia or thrombocytopenia, separated or in combination, despite a hyper or normo-cellular bone marrow, define MDS. The concept of myelodysplastic syndromes has evolved gradually from the description of a group of anemias previously described as "refractory anemias".

MDS is a somewhat heterogeneous group of patients with regard to clinical presentation, laboratory findings and prognosis. Methods for evaluating the potential clinical outcome have been developed by taking into account the hematological presentation (degree of cytopenia, classification in subgroup based on the percentage of bone marrow blast cells), bone marrow karyotype and some clinical parameters, mainly age.

Primary and secondary MDS are defined by taking into account the prior patients history: previous treatments with chemotherapy, radiotherapy or professional exposure to toxic substances are defining secondary MDS (sMDS) or "primary" MDS. Cytogenetically, a difference between the two groups is the complexity of abnormal karyotypes since single chromosome aberrations are typical for primary MDS, while multiple changes are more frequently seen in secondary disorders. Some drugs may have specific targets such as: hydroxurea for 17p, topoisomerases inhibitors for 11q23 and 21q22. The genetic changes in the malignant cells of MDS result mainly in the loss of genetic material, including probable tumor suppressor genes.

Primary MDS

  • MDS IN ELDERLY PATIENTS: MDS is primarily a disease of the elderly. The median age of patients varies from about 60 years to 75 years. Patients below the age of 50 years are less frequent and their number varies greatly among different series in the literature. MDS sub-types, as defined by the FAB-working group, have prognostic significance in the elderly, in whom survival and incidence of AML progression are more favorable in lower stages of the disease (lower blast cell count). MDS characteristically responds poorly to AML chemotherapy, with prolonged cytopenias and poor remission rates. Less than 50% of MDS cases have cytogenetic abnormalities at presentation; this frequency increases with progression and includes gain or loss of major segments of chromosomes ( -5/del(5q), -7/del(7q), +8, +9, +11, del(11q), del(12p), del(17p), -18, +19, del(20q), +21).
  • CHILDHOOD MDS: MDS appears to be uncommon in children but it is characterized by a higher rate of progression to overt acute leukemia. Their classification has been the subject of controversy. If some cases of childhood MDS are similar to adult MDS, others have a more "myeloproliferative" presentation with prominent hepato-splenomegaly, leucocytosis, monocytosis, frequent skin involvement, and presence of immature cells in the peripheral blood. These cases have been referred to chronic myelomonocytic leukemia (CMML) or juvenile chronic myelogenous leukemia ( JCML). This feature is primarily observed in infancy and early childhood.
    THE CRITERIA FOR DIAGNOSIS: The diagnosis of MDS is mainly morphological and based on the presence of dysplastic features in the peripheral blood and bone marrow. The French-American-British (FAB) Cooperative Group has proposed (1982) a classification based on easily obtainable laboratory information; despite its effectiveness for classifying MDS, omission of biological parameters such as marrow cytogenetics and the degree of cytopenia makes necessary a reappraisal of certain novel aspects of the diagnosis and prognosis.

    Secondary MDS (sMDS)
    Cases of MDS related to chemotherapy and radiotherapy (sMDS) are increasingly being recognized as long-term complications of cancer therapy. This entity is not clearly different from sAML (sAML frequently evolves from a preceeding myelodysplastic phase. The bone marrow blast cell cut-off of 20% that distinguishes sAML from sMDS, often depends on the hematological follow-up of at-risk groups of patients who have received chemotherapy and/or radiotherapy. If early bone marrow examination is performed, MDS may be diagnosed but AML could be diagnosed too if bone marrow examination is delayed until the blast cells appeared in the peripheral blood. sMDS/AML after chemotherapy is diagnosed after lymphoma therapy with a percentage of relative risk ranging from 2.2 to 3.3 at 15 years. For both sMDS and sAML the most frequently involved drugs include alkykating agents, epipodophyllotoxins and anthracyclins. The majority of sMDS/AML are morphologically characterized by multilineage myeloid dysplasia; the great majority have chromosome abnormalities, the most common being the loss of genetic material of either part or all of chromosome 7 and/or 5 (7q/-7, /5q-, -5). sMDS has a rapid course and a short survival.

    Morphological classification
    Historical background and basis for the practical classification
    The diagnosis of MDS is often made unexpectedly after a routine blood count. There are no specific symptoms other than those related to progressive bone marrow failure.
    PERIPHERAL BLOOD: Patients are commonly anemic with normal or low reticulocyte counts. Anemia is usually normocytic or macrocytic. In cases with severe dyserythropoiesis in the bone marrow, the peripheral blood may show poikilocytosis and anisocytosis. The neutrophil count is variable and may be low. Neutrophil granulations may be reduced or not visible on MGG stained smears. Thrombocytopenia is common in MDS but the platelet count may be normal.
    BONE MARROW: In the bone marrow, different degrees of morphological and functional abnormalities of erythroid (DysE), megakaryocytic (DysM) and granulocytic (DysG) lineages are a hallmark of the disease. In the granulocytic lineage, hypogranular cells may be associated with other abnormalities such as persistent cytoplasmic basophilia and vacuolisation; abnormal nuclear feature are common, such as hyposegmented forms (pseudo Pelegre-Huet) or binucleated cells. Abnormal eosinophils, basophils and mast cells are rarely seen. Cytochemical abnormalities include reduced myeloperoxidase or inappropriately increase in alpha-napthtyl esterase activity. Megacaryocytic dysplastic features are particularly frequent in MDS and include megakaryocyte hypoploidy (micromegakaryocytes) and multinucleated megakaryocytes or large monolobed cells.

    WHO Reassessment of MDS morphological classification
    The FAB cooperative group initially proposed (1982) morphological criteria to distinguish between MDS and AML on the basis of the arbitrary bone marrow blast count and divided MDS into five subtypes: Refractory anemia (RA), RA with excess of blasts (RAEB), RA with excess of blasts in Transformation (RAEBT), RA with ringed sideroblasts (RARS), Chronic myelomonocytic leukemia (CMML). This subdivision is mainly based on the percentage of blasts in the peripheral blood and bone marrow (RA to RAEBT) but, also, on the absolute peripheral blood monocyte count (CMML) and the percentage of ring sideroblasts (RARS).
    Readjustment of this FAB classification has recently been undertaken in order to resolve some ambiguities (WHO Classification). RAEB T is suppressed as category and is included with AML M2.CHROMOSOMAL ABNORMALITIES IN PRIMARY MDS: Myelodysplastic syndromes are typical cytogenetic models of the leukemogenesis process: the clonal population progresses through a chronic phase that can last for years, to frank leukemia. Chromosome abnormalities should be taken in consideration in addition to specific hematological abnormalities in order to define new MDS syndromes. Most investigators working on MDS integrate morphology and cytogenetics in diagnosis and classification. In (primary) MDS, non-random chromosomal aberrations contribute to characterized distinct clinico-pathological entities in which cytogenetic findings correlate with morphological features or with the clinical course of the disease. In primary MDS, around 50% of karyotypes are abnormal, depending on the patient series and on the techniques used. Cytogenetic studies have focused on chromosomal deletions as the most typical changes in MDS. Molecular genetics allow narrowing of the loss of genomic regions and are useful to discover cryptic deletions. It is obvious that some cases of MDS will need multi-color FISH to identify complex chromosomal rearrangements.

    PATTERNS OF CHROMOSOMAL ABNORMALITIES IN SECONDARY MDS (sMDS): The incidence of chromosomal abnormalities is higher in sMDS (more than 85%) than in the corresponding de novo diseases (about 50%). The ploidy is different in secondary MDS and primary MDS: hypoploidy is clearly more frequent in secondary MDS. Several numerical and/or structural chromosomal abnormalities are frequently associated with sMDS: among the most common, there is the association of abnormalities of chromosomes 5 and 7 (-5 or 5q- and -7 or 7q-).

    KARYOTYPIC/MORPHOLOGIC CORRELATION IN MDS: Attempts to correlate cytogenetic changes with the morphological subtypes of MDS as defined by the initial FAB criteria have not been successful. However, some molecular changes and karyotypic aberrations are more or less correlated with a specific cytological presentation, mainly in primary MDS. The major chromosomal anomalies are the following: del(5)q, monosomy 7, del(20)(q), trisomy 8 and less frequently +6, +13, +21, t(5;12)(q33;p13), other 12p changes, t(3;5)(q25;q34), inv(3)(q21q26), rearrangements involving 1q, 11q23, 17p-/-17 and X.

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    Basis of classification in conformity with WHO recommandations.

    The classification of acute myeloid leukemia (AML) and myelodysplasic syndromes (MDS) includes clinical data (previous history, age) and biologic characteristics (morphology, cytochemistry, immunophenotype, cytogenetic and molecular biology). The separation of homogeneous classes allows us to distinguish pronostic parameters and to identify groups of patients sensitive to drugs or to specific treatment. Recurrent cytogenetic abnormalities are strong prognostic indicators in AML and MDS. Molecular studies of structural chromosomal changes have enabled the cloning of genes located at chromosomal breakpoints and have helped to characterize the proteins involved in leukemogenesis. Morphologic studies remain important because of a strong correlation with cytogenetic and molecular abnormalities.


    Georges Flandrin

    Classification of myelodysplasic syndromes 1999

    Atlas Genet Cytogenet Oncol Haematol. 2002-05-01

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