the peripheral blood and < 10% in the bone marrow aspirate); also note auer rods may be seen in mature neutrophils in aml with translocation t(8;21) dimorphic granules (basophilic and eosinophilic granules) within eosinophils erythroid series: binucleated erythroid precursors and karyorrhexis erythroid nuclear budding erythroid nuclear strings or internuclear bridging (also seen in congenital dyserythropoietic anemias) loss of e-cadherin in normoblasts is a sign of aberrancy. pas (globular in vacuoles or diffuse cytoplasmic staining) within erythroid precursors in the bone marrow aspirate (has no bearing on paraffin-fixed bone-marrow biopsy). note: one can see pas vacuolar positivity in l1 and l2 blasts (fab classification; the l1 and l2 nomenclature is not used in the who classification) ringed sideroblasts (10 or more iron granules encircling one-third or more of the nucleus) seen on perls' prussian blue iron stain (>15% ringed sideroblasts when counted among red cell precursors for refractory anemia with ring sideroblasts) megakaryocytic series (can be the most subjective): hyposegmented nuclear features in platelet producing megakaryocytes (lack of lobation) hypersegmented (osteoclastic appearing) megakaryocytes ballooning of the platelets (seen with interference contrast microscopy) other stains can help in special cases (pas and naphthol asd chloroacetate esterase positivity) in eosinophils is a marker of abnormality seen in chronic eosinophilic leukemia and is a sign of aberrancy. on the bone-marrow biopsy, high-grade dysplasia (raeb-i and raeb-ii) may show atypical localization of immature precursors, which are islands of immature precursors cells (myeloblasts and promyelocytes) localized to the center of the intertrabecular space rather than adjacent to the trabeculae or surrounding arterioles. this morphology can be difficult to differentiate from treated leukemia and recovering immature normal marrow elements. also, topographic alteration of the nucleated erythroid cells can be seen in early myelodysplasia (ra and rars), where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placed erythroid islands. differential diagnosis myelodysplasia is a diagnosis of exclusion and must be made after proper determination of iron stores, vitamin deficiencies, and nutrient deficiencies are ruled out. also, congenital diseases such as congenital dyserythropoietic anemia (cda i through iv) have been recognized, pearson's syndrome (sideroblastic anemia), jordans anomaly – vacuolization in all cell lines may be seen in chanarin-dorfman syndrome, aminolevulinic acid enzyme deficiency and other more esoteric enzyme deficiencies are known to give a pseudomyelodysplastic picture in one of the cell lines; however, all three cell lines are never morphologically dysplastic in these entities with the exception of chloramphenicol, arsenic toxicity, and other poisons. all of these conditions are characterized by abnormalities in the production of one or more of the cellular components of blood (red cells, white cells other than lymphocytes, and platelets or their progenitor cells, megakaryocytes). world health organization in the late 1990s, a group of pathologists and clinicians working under the world health organization (who) modified this classification, introducing several new disease categories and eliminating others. in 2008, the who developed a new classification scheme that is based more on genetic findings, but morphology of the cells in the peripheral blood, bone marrow aspirate, and bone marrow biopsy are still the screening tests used to decide which classification is best and which cytogenetic aberrations may be related. the list of dysplastic syndromes under the new who system includes: myelodysplastic syndrome description refractory cytopenia with unilineage dysplasia refractory anemia, refractory neutropenia, and refractory thrombocytopenia. refractory anemia with ringed sideroblasts (rars) thrombocytosis (rars-t) (provisional entity) which is in essence a myelodysplastic/myeloproliferative disorder and usually has a jak2 mutation (janus kinase) – new who classification 2008 refractory cytopenia with multilineage dysplasia (rcmd) includes the subset refractory cytopenia with multilineage dysplasia and ring sideroblasts (rcmd-rs). rcmd includes patients with pathological changes not restricted to red cells (i.e., prominent white cell precursor and platelet precursor (megakaryocyte) dysplasia. refractory anemia with excess blasts i and ii raeb was divided into raeb-i (5–9% blasts) and raeb-ii (10–19%) blasts, which has a poorer prognosis than raeb-i. auer rods may be seen in raeb-ii which may be difficult to distinguish from acute myeloid leukemia. 5q- syndrome typically seen in older women with normal or high platelet counts and isolated deletions of the long arm of chromosome 5 in bone marrow cells, was added to the classification. myelodysplasia unclassifiable seen in those cases of megakaryocyte dysplasia with fibrosis and others. refractory cytopenia of childhood (dysplasia in childhood) – note : not all physicians concur with this reclassification, because the underlying pathology of this disease is not well understood. myelodysplastic syndrome unclassified the who has proposed a criterion for diagnosis and classification of mds that may apply to most cases. however, occasional cases are difficult to classify into defined categories because of one or more unusual features: rare cases with less than 5% blast will present with auer rods. these cases usually have the features of ramd. occasionally, cases of mds present with isolated neutropenia or thrombocytopenia without anemia and with dysplastic changes confined to the single lineage. the terms refractory neutropenia and refractory thrombocytopenia have sometimes been used to describe these cases. a diagnosis of mds in patients with neutropenia or thrombocytopenia without anemia should be made with caution. patients with ra or raeb occasionally present with leukocytosis or thrombocytosis instead of the usual cytopenia. management the goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to aml. the ipss scoring system can help triage patients for more aggressive treatment (i.e. bone marrow transplant) as well as help determine the best timing of this therapy. supportive care with blood products and hematopoietic growth factors (e.g. erythropoietin) is the mainstay of therapy. the regulatory environment for the use of erythropoietins is evolving, according to a recent us medicare national coverage determination. however, no comment on the use of hematopoietic growth factors for mds was made in that document. agents have been approved by the u.s. food and drug administration (fda) for the treatment of mds: 5-azacytidine: 21-month median survival decitabine: complete response rate reported as high as 43%. a phase i study has shown efficacy in aml when decitabine is combined with valproic acid. lenalidomide: effective in reducing red blood cell transfusion requirement in patients with the chromosome 5q deletion subtype of mds decitabine/cedazuridine (inqovi) is a fixed-dosed combination medication for the treatment of adults with myelodysplastic syndromes (mds) and chronic myelomonocytic leukemia (cmml). chemotherapy with the hypomethylating agents 5-azacytidine and decitabine has been shown to decrease blood transfusion requirements and to retard the progression of mds to aml. lenalidomide was approved by the fda in december 2005 only for use in the 5q- syndrome. in the united states, treatment of mds with lenalidomide costs about $9,200 per month. the chemotherapy may be supported by other drugs like all-trans retinoic acid (atra), however the evidence of benefit is not clear. hla-matched allogeneic stem cell transplantation, particularly in younger (i.e. less than 40 years of age) and more severely affected patients, offers the potential for curative therapy. the success of bone marrow transplantation has been found to correlate with severity of mds as determined by the ipss score, with patients having a more favorable ipss score tend to have a more favorable outcome with transplantation. iron levels iron overload can develop in mds as a result of the rbc transfusions, which are a major part of the supportive care for anemic mds patients. although the specific therapies patients receive may alleviate the rbc transfusion need in some cases, many mds patients may not respond to these treatments, thus may develop secondary hemochromatosis due to iron overload from repeated rbc transfusions. patients requiring relatively large numbers of rbc transfusions can experience the adverse effect of chronic iron overload on their liver, heart, and endocrine functions. for patients requiring many rbc transfusions, serum ferritin levels, number of rbc transfusions received, and associated organ dysfunction (heart, liver, and pancreas) should be monitored to determine iron levels. monitoring serum ferritin may also be useful, aiming to decrease ferritin levels to < 1000 µg/l.currently, two iron chelators are available in the us, deferoxamine for intravenous use and deferasirox for oral use. these options now provide potentially useful drugs for treating the iron overload problem. a third chelating agent is available in europe, deferiprone, for oral use, but is not available in the us. clinical trials in mds patients are ongoing, with iron chelating agents to address the question of whether iron chelation alters the natural history of patients with mds who are transfusion dependent. reversal of some of the consequences of iron overload in mds by iron chelation therapy has been shown. both the mds foundation and the national comprehensive cancer network mds guidelines panel have recommended that chelation therapy be considered to decrease iron overload in selected mds patients. evidence also suggests a potential value exists to iron chelation in patients who will undergo a stem-cell transplant. although deferasirox is generally well tolerated (other than episodes of gastrointestinal distress and kidney dysfunction in some patients), recently a safety warning by the fda and novartis was added to deferasirox treatment guidelines. following postmarketing use of deferasirox, rare cases of acute kidney failure or liver failure occurred, some resulting in death. due to this, patients should be closely monitored on deferasirox therapy prior to the start of therapy and regularly thereafter. prognosis the outlook in mds is variable, with about 30% of patients progressing to refractory aml. the median survival time varies from years to months, depending on type. stem-cell transplantation offers possible cure, with survival rates of 50% at 3 years, although older patients do poorly. indicators of a good prognosis: younger age; normal or moderately reduced neutrophil or platelet counts; low blast counts in the bone marrow (< 20%) and no blasts in the blood; no auer rods; ringed sideroblasts; normal or mixed karyotypes without complex chromosome abnormalities; and in vitro marrow culture with a nonleukemic growth pattern indicators of a poor prognosis: advanced age; severe neutropenia or thrombocytopenia; high blast count in the bone marrow (20–29%) or blasts in the blood; auer rods; absence of ringed sideroblasts; abnormal localization or immature granulocyte precursors in bone marrow section; completely or mostly abnormal karyotypes, or complex marrow chromosome abnormalities and in vitro bone marrow culture with a leukemic growth pattern karyotype prognostic factors: good: normal, -y, del(5q), del(20q) intermediate or variable: +8, other single or double anomalies poor: complex (>3 chromosomal aberrations); chromosome 7 anomalies the ipss is the most commonly used tool in mds to predict long-term outcome. cytogenetic abnormalities can be detected by conventional cytogenetics, a fish panel for mds, or virtual karyotype. the best prognosis is seen with ra and rars, where some nontransplant patients live more than a decade (typical is on the order of three to five years, although long-term remission is possible if a bone-marrow transplant is successful). the worst outlook is with raeb-t, where the mean life expectancy is less than one year. about one-quarter of patients develop overt leukemia. the others die of complications of low blood count or unrelated diseases. the international prognostic scoring system is another tool for determining the prognosis of mds, published in blood in 1997. this system takes into account the percentage of blasts in the marrow, cytogenetics, and number of cytopenias. genetic markers although not yet formally incorporated in the generally accepted classification systems, molecular profiling of myelodysplastic syndrome genomes has increased the understanding of prognostic molecular factors for this disease. for example, in low-risk mds, idh1 and idh2 mutations are associated with significantly worsened survival. epidemiology the exact number of people with mds is not known because it can go undiagnosed and no tracking of the syndrome is mandated. some estimates are on the order of 10,000 to 20,000 new cases each year in the united states alone. the number of new cases each year is probably increasing as the average age of the population increases, and some authors propose that the number of new cases in those over 70 may be as high as 15 per 100,000 per year. the typical age at diagnosis of mds is between 60 and 75 years; a few people are younger than 50, and diagnoses are rare in children. males are slightly more commonly affected than females. history since the early 20th century, some people with acute myelogenous leukemia were begun to be recognized to have