1.Laboratoire d Hématologie, Hôpital Necker-Enfants Malades, Paris, France
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.
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.
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.
Classification of myelodysplasic syndromes 1999
Atlas Genet Cytogenet Oncol Haematol. 2002-05-01
Online version: http://atlasgeneticsoncology.org/haematological/1239/classifmdsid1239