myelodysplastic syndrome myelodysplastic syndrome a myelodysplastic syndrome (mds) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. early on, no symptoms typically are seen. later, symptoms may include feeling tired, shortness of breath, bleeding disorders, anemia, or frequent infections. some types may develop into acute myeloid leukemia. myelodysplastic syndromeother namespreleukemia, myelodysplasiablood smear from a person with myelodysplastic syndrome. a hypogranular neutrophil with a pseudo-pelger-huet nucleus is shown. there are also abnormally shaped red blood cells, in part related to removal of the spleen.specialtyhematology, oncologysymptomsnone, feeling tired, shortness of breath, easy bleeding, frequent infectionsusual onset~ 70 years oldrisk factorsprevious chemotherapy, radiation therapy, certain chemicals such as tobacco smoke, pesticides, and benzene, exposure to mercury or leaddiagnostic methodblood test, bone marrow biopsytreatmentsupportive care, medications, stem cell transplantationmedicationlenalidomide, antithymocyte globulin, azacitidineprognosistypical survival time 2.5 years risk factors include previous chemotherapy or radiation therapy, exposure to certain chemicals such as tobacco smoke, pesticides, and benzene, and exposure to heavy metals such as mercury or lead. problems with blood cell formation result in some combination of low red blood cell, platelet, and white blood cell counts. some types of mds cause an increase in the production of immature blood cells (called blasts), in the bone marrow or blood. the different types of mds are identified based on the specific characteristics of the changes in the blood cells and bone marrow. treatments may include supportive care, drug therapy, and hematopoietic stem cell transplantation. supportive care may include blood transfusions, medications to increase the making of red blood cells, and antibiotics. drug therapy may include the medications lenalidomide, antithymocyte globulin, and azacitidine. some people can be cured by chemotherapy followed by a stem-cell transplant from a donor. about seven per 100,000 people are affected by mds; about four per 100,000 people newly acquire the condition each year. the typical age of onset is 70 years. the prognosis depends on the type of cells affected, the number of blasts in the bone marrow or blood, and the changes present in the chromosomes of the affected cells. the average survival time following diagnosis is 2.5 years. mds was first recognized in the early 1900s; it came to be called myelodysplastic syndrome in 1976. signs and symptoms enlarged spleen due to myelodysplastic syndrome; ct scan coronal section, spleen in red, left kidney in green signs and symptoms are nonspecific and generally related to the blood cytopenias: anemia (low rbc count or reduced hemoglobin) – chronic tiredness, shortness of breath, chilled sensation, sometimes chest pain neutropenia (low neutrophil count) – increased susceptibility to infection thrombocytopenia (low platelet count) – increased susceptibility to bleeding and ecchymosis (bruising), as well as subcutaneous hemorrhaging resulting in purpura or petechiae many individuals are asymptomatic, and blood cytopenia or other problems are identified as a part of a routine blood count: neutropenia, anemia, and thrombocytopenia splenomegaly or rarely hepatomegaly abnormal granules in cells, abnormal nuclear shape and size chromosome abnormality, including chromosomal translocations and abnormal chromosome number although some risk exists for developing acute myelogenous leukemia, about 50% of deaths occur as a result of bleeding or infection. however, leukemia that occurs as a result of myelodysplasia is notoriously resistant to treatment. anemia dominates the early course. most symptomatic patients complain of the gradual onset of fatigue and weakness, dyspnea, and pallor, but at least half the patients are asymptomatic and their mds is discovered only incidentally on routine blood counts. previous chemotherapy or radiation exposure is an important factor in the person's medical history. fever, weight loss and splenomegaly should point to a myelodysplastic/myeloproliferative neoplasm (mds/mpn) rather than pure myelodysplastic process. cause some people have a history of exposure to chemotherapy (especially alkylating agents such as melphalan, cyclophosphamide, busulfan, and chlorambucil) or radiation (therapeutic or accidental), or both (e.g., at the time of stem cell transplantation for another disease). workers in some industries with heavy exposure to hydrocarbons such as the petroleum industry have a slightly higher risk of contracting the disease than the general population. xylene and benzene exposures have been associated with myelodysplasia. vietnam veterans exposed to agent orange are at risk of developing mds. a link may exist between the development of mds "in atomic-bomb survivors 40 to 60 years after radiation exposure" (in this case, referring to people who were in close proximity to the dropping of the atomic bombs in hiroshima and nagasaki during world war ii). children with down syndrome are susceptible to mds, and a family history may indicate a hereditary form of sideroblastic anemia or fanconi anemia. pathophysiology mds most often develops without an identifiable cause. risk factors include exposure to an agent known to cause dna damage, such as radiation, benzene, and certain chemotherapies; other risk factors have been inconsistently reported. proving a connection between a suspected exposure and the development of mds can be difficult, but the presence of genetic abnormalities may provide some supportive information. secondary mds can occur as a late toxicity of cancer therapy (therapy associated mds, t-mds). mds after exposure to radiation or alkylating agents such as busulfan, nitrosourea, or procarbazine, typically occurs 3–7 years after exposure and frequently demonstrates loss of chromosome 5 or 7. mds after exposure to dna topoisomerase ii inhibitors occurs after a shorter latency of only 1–3 years and can have a 11q23 translocation. other pre-existing bone-marrow disorders such as acquired aplastic anemia following immunosuppressive treatment and fanconi anemia can evolve into mds. mds is thought to arise from mutations in the multipotent bone-marrow stem cell, but the specific defects responsible for these diseases remain poorly understood. differentiation of blood precursor cells is impaired, and a significant increase in levels of apoptotic cell death occurs in bone-marrow cells. clonal expansion of the abnormal cells results in the production of cells that have lost the ability to differentiate. if the overall percentage of bone-marrow myeloblasts rises over a particular cutoff (20% for who and 30% for fab), then transformation to acute myelogenous leukemia (aml) is said to have occurred. the progression of mds to aml is a good example of the multistep theory of carcinogenesis in which a series of mutations occurs in an initially normal cell and transforms it into a cancer cell. although recognition of leukemic transformation was historically important (see history), a significant proportion of the morbidity and mortality attributable to mds results not from transformation to aml, but rather from the cytopenias seen in all mds patients. while anemia is the most common cytopenia in mds patients, given the ready availability of blood transfusion, mds patients rarely experience injury from severe anemia. the two most serious complications in mds patients resulting from their cytopenias are bleeding (due to lack of platelets) or infection (due to lack of white blood cells). long-term transfusion of packed red blood cells leads to iron overload. genetics the recognition of epigenetic changes in dna structure in mds has explained the success of two (namely the hypomethylating agents 5-azacytidine and decitabine) of three (the third is lenalidomide) commercially available medications approved by the u.s. food and drug administration to treat mds. proper dna methylation is critical in the regulation of proliferation genes, and the loss of dna methylation control can lead to uncontrolled cell growth and cytopenias. the recently approved dna methyltransferase inhibitors take advantage of this mechanism by creating a more orderly dna methylation profile in the hematopoietic stem cell nucleus, thereby restoring normal blood counts and retarding the progression of mds to acute leukemia. some authors have proposed that the loss of mitochondrial function over time leads to the accumulation of dna mutations in hematopoietic stem cells, and this accounts for the increased incidence of mds in older patients. researchers point to the accumulation of mitochondrial iron deposits in the ringed sideroblast as evidence of mitochondrial dysfunction in mds. 5q- syndrome since at least 1974, the deletion in the long arm of chromosome 5 has been known to be associated with dysplastic abnormalities of hematopoietic stem cells. by 2005, lenalidomide, a chemotherapy drug, was recognized to be effective in mds patients with the 5q- syndrome, and in december 2005, the us fda approved the drug for this indication. patients with isolated 5q-, low ipss risk, and transfusion dependence respond best to lenalidomide. typically, prognosis for these patients is favorable, with a 63-month median survival. lenalidomide has dual action, by lowering the malignant clone number in patients with 5q-, and by inducing better differentiation of healthy erythroid cells, as seen in patients without 5q deletion. splicing factor mutations mutations in splicing factors have been found in 40–80% of cases with myelodysplastic syndrome, particularly in those with ringed sideroblasts. idh1 and idh2 mutations mutations in the genes encoding for isocitrate dehydrogenase 1 and 2 (idh1 and idh2) occur in 10–20% of patients with myelodysplastic syndrome, and confer a worsened prognosis in low-risk mds. because the incidence of idh1/2 mutations increases as the disease malignancy increases, these findings together suggest that idh1/2 mutations are important drivers of progression of mds to a more malignant disease state. gata2 deficiency gata2 deficiency is a group of disorders caused by a defect, familial, or sporadic inactivating mutations, in one of the two gata2 genes. these autosomal dominant mutations cause a reduction in the cellular levels of the gene's product, gata2. the gata2 protein is a transcription factor critical for the embryonic development, maintenance, and functionality of blood-forming, lymph-forming, and other tissue-forming stem cells. in consequence of these mutations, cellular levels of gata2 are low and individuals develop over time hematological, immunological, lymphatic, or other presentations. prominent among these presentations is mds that often progresses to acute myelocytic leukemia, or less commonly, chronic myelomonocytic leukemia. transient myeloproliferative disease transient myeloproliferative disease is the abnormal proliferation of a clone of noncancerous megakaryoblasts in the liver and bone marrow. the disease is restricted to individuals with down syndrome or genetic changes similar to those in down syndrome, develops during pregnancy or shortly after birth, and resolves within 3 months, or in about 10% of cases, progresses to acute megakaryoblastic leukemia. diagnosis the elimination of other causes of cytopenias, along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome, so differentiating mds from anemia, thrombocytopenia, and leukopenia is important. a typical diagnostic investigation includes: full blood count and examination of blood film: the blood film morphology can provide clues about hemolytic anemia, clumping of the platelets leading to spurious thrombocytopenia, or leukemia. blood tests to eliminate other common causes of cytopenias such as lupus, hepatitis, b12, folate, or other vitamin deficiencies, kidney failure or heart failure, hiv, hemolytic anemia, monoclonal gammopathy: age-appropriate cancer screening should be considered for all anemic patients. bone marrow examination by a hematopathologist: this is required to establish the diagnosis since all hematopathologists consider dysplastic marrow the key feature of myelodysplasia. cytogenetics or chromosomal studies: this is ideally performed on the bone marrow aspirate. conventional cytogenetics require a fresh specimen since live cells are induced to enter metaphase to allow chromosomes to be seen. interphase fluorescence in situ hybridization testing, usually ordered together with conventional cytogenetic testing, offers rapid detection of several chromosome abnormalities associated with mds, including del 5q, −7, +8, and del 20q. virtual karyotyping can be done for mds, which uses computational tools to construct the karyogram from disrupted dna. virtual karyotyping does not require cell culture and has a dramatically higher resolution than conventional cytogenetics, but cannot detect balanced translocations. flow cytometry is helpful to identify blasts, abnormal myeloid maturation, and establish the presence of any lymphoproliferative disorder in the marrow. testing for copper deficiency should not be overlooked, as it can morphologically resemble mds in bone-marrow biopsies. the features generally used to define an mds are blood cytopenias, ineffective hematopoiesis, dyserythropoiesis, dysgranulopoiesis, dysmegakaropoiesis, and increased myeloblasts. dysplasia can affect all three lineages seen in the bone marrow. the best way to diagnose dysplasia is by morphology and special stains (pas) used on the bone marrow aspirate and peripheral blood smear. dysplasia in the myeloid series is defined by: granulocytic series: hypersegmented neutrophils (also seen in vit b12/folate deficiency) hyposegmented neutrophils (pseudo pelger-huet) hypogranular neutrophils or pseudo chediak-higashi (large azurophilic granules) auer rods – automatically raeb ii (if blast count < 5% in