The elimination of other causes of cytopenias, along with a dysplastic bone marrow, is required to diagnose a<unk> , so differentiating<unk>  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<unk> , including del 5q, −7, +8, and del 20q. * Virtual karyotyping can be done for<unk> , 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<unk>  in bone-marrow biopsies. The features generally used to define an<unk>  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 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 napthol 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<unk>  (sideroblastic anemia), Jordans anomaly – vacuolization in all cell lines may be seen in Chanarin-Dorfman<unk> , 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). Classification French-American-British (FAB) classification In 1974 and 1975, a group of pathologists from France, the US, and Britain produced the first widely used classification of these diseases. This French-American-British classification was published in 1976, and revised in 1982. It was used by pathologists and clinicians for almost 20 years. Cases were classified into five categories: ICD-O Name Description Refractory anemia (RA) characterized by less than 5% primitive blood cells (myeloblasts) in the bone marrow and pathological abnormalities primarily seen in red cell precursors Refractory anemia with ring sideroblasts (RARS) also characterized by less than 5% myeloblasts in the bone marrow, but distinguished by the presence of 15% or greater of red cell precursors in the marrow being abnormal iron-stuffed cells called "ringed sideroblasts" Refractory anemia with excess blasts (RAEB) characterized by 5–19% myeloblasts in the marrow Refractory anemia with excess blasts in transformation (RAEB-T) characterized by 5–19% myeloblasts in the marrow (>20% blasts is defined as acute myeloid leukemia) Chronic myelomonocytic leukemia (CMML), not to be confused with chronic myelogenous leukemia or CML characterized by less than 20% myeloblasts in the bone marrow and greater than 1*109/L monocytes (a type of white blood cell) circulating in the peripheral blood. (A table comparing these is available from the Cleveland Clinic.) The best prognosis is seen with RA and RARS, where some nontransplant patients live more than a decade (typical is on the order of 3–5 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 1 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<unk> , published in Blood in 1997. This system takes into account the percentage of blasts in the marrow, cytogenetics, and number of cytopenias. 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. Most recently, the WHO has evolved a new classification scheme (2008) 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<unk> s under the new WHO system includes: Old system New system Refractory anemia (RA) Refractory cytopenia with unilineage dysplasia (Refractory anemia, Refractory neutropenia, and Refractory thrombocytopenia) Refractory anemia with ringed sideroblasts (RARS) Refractory anemia with ring sideroblasts (RARS)Refractory anemia with ring sideroblasts – thrombocytosis (RARS-t) (provisional entity) which is in essence a<unk> /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 (RAEB) Refractory anemias 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. Refractory anemia with excess blasts in transformation (RAEB-T) This category was eliminated; such patients are now considered to have acute leukemia. 5q-<unk> , 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. Chronic myelomonocytic leukemia (CMML) CMML was removed from the<unk> s and put in a new category of<unk> -myeloproliferative overlap<unk> s. Myelodysplasia unclassifiable (seen in those cases of megakaryocyte dysplasia with fibrosis and others) Refractory cytopenia of childhood (dysplasia in childhood) – New in WHO classification 2008 Note : not all physicians concur with this reclassification, because the underlying pathology of this disease is not well understood.<unk>  unclassified The WHO has proposed a criterion for diagnosis and classification of<unk>  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<unk>  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<unk>  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.
Myelodysplastic syndrome
Primary myelofibrosis
Acute myeloid leukemia
Myeloid leukemia
Autoimmune neutropenia
Mixed-phenotype acute leukemia
Childhood leukemia
B-cell leukemia