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Oncologist. 1996;1(4):284-287.

Physician Education: Myelodysplastic Syndrome.

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Division of Human Environment, The Center for South East Asian Studies, Kyoto University, Kyoto, Japan.



Myelodysplastic syndrome (MDS) is a disease of the blood whose etiology is unclear. There is little that can be done therapeutically, and the prognosis for patients with this disease is poor. The main hematologic finding is anemia, but MDS responds poorly to the various kinds of drugs used to treat anemia, and in the past it was called refractory anemia. Moreover, 25% to 40% of MDS patients develop acute leukemia, so MDS has also been referred to as preleukemia or a preleukemic condition. When blood diseases are classified as either erythrocytic or leukocytic, it is often unclear into which category MDS falls. Although MDS sometimes occurs in young adults and children, it most often appears in older patients. Diagnosis is confirmed in laboratory tests by a reduction in peripheral blood cells, an abundance of cells in the bone marrow (cellular marrow), abnormal cellular morphology, and chromosomal abnormalities. In primary cases there is no history of underlying disease or administration of drugs that is toxic to the marrow. The course of the disease is chronic but irreversible, and in a high percentage of cases it either develops into acute leukemia or the patient succumbs to infection or hemorrhage (death due to bone marrow failure). In general, all blood cells arise from a single type of pluripotent hematopoietic stem cell in the marrow. In MDS, the hematopoietic stem cells acquire mutations and cannot produce sufficient numbers of mature blood cells (Fig. 1). In aplastic anemia the hematopoietic stem cells are also abnormal, and blood cell production in the marrow generally declines. In MDS, however, there are sufficient numbers of blood cells of each lineage along the path from hematopoietic stem cell to mature blood cell, but the cells do not completely mature and differentiate. Because of this deficiency in the differentiation process, the cells die in the marrow without maturing and differentiating (ineffective hematopoiesis). Furthermore, blood cells that escape death in the bone marrow and are released into the peripheral blood have both morphological and functional abnormalities compared with normal blood cells. In other words, MDS is an abnormality at the hematopoietic stem cell level, and it is characterized by the presence of clonal blood cells that are abnormal both in quality (morphology, function, differentiation) and quantity (cytopenia) [1]. Because these abnormalities are found in multiple blood cell lineages, they are believed to be clonal abnormalities that originate in the pluripotent hematopoietic stem cells. The reason why the stem cells become abnormal is still unclear. However, MDS can arise following treatment with antineoplastic agents such as alkylating agents or radiation treatments (therapy-related MDS), and it has been proposed that MDS is caused by cumulative DNA damage in stem cells from mutagenic substances such as antitumor drugs [2].


Screening for MDS should begin with the fact that there is chronic, progressive cytopenia, the marrow is normal or hyperplastic, and there is no underlying disease (such as disseminated intravascular coagulation [DIC], portal hypertension, collagen disorder, etc.) that could otherwise cause these conditions (Table 1). MDS is most likely to occur in middle-aged and elderly patients, but because it can also occur in the young, age is not a determining factor for diagnosis. Diagnosis is verified by ineffective hematopoiesis and blood cells with morphological abnormalities in the marrow and peripheral blood. Although there are, for example, ferrokinetic studies for erythroid cells, etc., it is impossible to make an accurate evaluation of ineffective hematopoiesis based only on abnormal laboratory test results. Therefore, if chronic cytopenia and cellular marrow are both present, then abnormal morphology of blood cells becomes the deciding factor in diagnosis. Typical morphological abnormalities in MDS include megaloblasts (photo 1), dissociated maturation of the nucleus and cytoplasm (photo 2), abnormal multinucleated erythroblasts with three or more nuclei (photo 1), and ringed sideroblasts (photo 3) in the erythrocytic lineage; hypersegmented (photo 4) or hyposegmented neutrophils (pseudo Pelger-Hu√ęt nuclear anomaly, photo 5), reduced or missing granules (photos 4 and 5), and peroxidase-negative neutrophils in the granulocytic lineage; and micromegakaryocytes (photo 6), megakaryocytes with multiple, isolated disc-shaped nuclei (photo 7) and giant platelets (photo 8) in the megakaryocytic lineage. However, these morphological abnormalities are not specific to MDS, and they are also seen in pernicious anemia, acute myelocytic leukemia, etc. Therefore, a diagnosis of MDS must exclude these other diseases with which we are already familiar. Once MDS is confirmed, then the type of MDS is determined in accordance with FAB classification [1] (Fig. 2). Differential diagnosis applies to all cases presenting with cytopenia. Various types of anemia such as aplastic anemia, hemolytic anemia, secondary anemia, etc., blood disorders such as idiopathic thrombocytopenic purpura, chronic neutropenia, etc., as well as collagen diseases, portal hypertension, DIC, etc., can all be differentiated from MDS based on their characteristic symptoms and laboratory test results. However, atypical forms of MDS [3, 4] also occur, such as hypoplastic marrow MDS, MDS with minimal dysplasia, amegakaryocytic MDS, etc. Meticulous microscopic examination of blood cell morphology and careful observation of the clinical course are essential, in addition to bone marrow biopsy, chromosomal studies of marrow cells, blood cell clonality analysis, etc.


APOPTOSIS: One biological characteristic of MDS is the presence of blood cells of abnormal clones derived from abnormal hematopoietic stem cells. These abnormal clones demonstrate ineffective hematopoiesis, which is reflected in the contradictory phenomena of normal or hyperplastic bone marrow concurrent with cytopenia in the peripheral blood. This is a result of premature cell death in the bone marrow that accompanies the abnormal blood cell differentiation found in MDS. Therefore, it has been proposed that it is very likely this early cell death takes the form of apoptosis, and, little by little, experimental results supporting this view have been published [5-7]. The development of MDS into acute leukemia is thought to be due to the survival of immature cells (blast cells) that have escaped apoptosis and have acquired the ability to proliferate [6]. Antileukemic drugs act by inducing apoptosis in leukocytes, and it is likely that acute leukemia from MDS is intractable because it has managed to bypass the mechanism of apoptosis. Research is now focused on the detection of excessive apoptosis in vivo in MDS patients and the relationship between apoptosis and the development of MDS.


Chromosomal analysis of bone marrow cells is effective as an everyday laboratory test to verify clonality, but it lacks sensitivity. The FISH method is useful for determining clonality at the level of individual blood cells, but cannot be used in patients with no chromosomal abnormalities. DNA polymorphism of enzymes mapped on the X chromosome can only be used in females, but interesting research is being conducted on the clonality of lymphocytes and the possible survival of normal hematopoietic clones.


Unstable clones with functional deficiencies are produced by abnormal stem cells. From the standpoint of chromosomal research, it is believed that MDS occurs not from a single type of stem cell damage, but from an accumulation of multiple and random stem cell damage. MDS is a prime candidate for research on the onset of human leukemia, and when we combine what we know about MDS with its development into leukemia, we can understand the development of MDS from the standpoint of apoptosis, genetic abnormalities, chromosomal abnormalities and progression of cloning.


Many risk factors for MDS have been proposed, and it has been confirmed internationally that the four major risk factors are the blast cell ratio in the bone marrow, advanced age, chromosomal abnormalities, and thrombocytopenia.

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