Refractory cytopenia with multilineage dysplasia (RCMD) is one of the more common myelodysplastic syndromes (MDSs). MDSs are clonal disorders of myeloid stem cells. These syndromes are characterized by ineffective hematopoiesis manifested in morphologic dysplasia of hematopoietic precursors, 1 or more peripheral blood cytopenias, and a propensity to progress to acute myeloid leukemia (AML). 
Myelodysplastic syndromes (MDSs) include the following:
Refractory cytopenia with multilineage dysplasia
Refractory anemia with multilineage dysplasia
Refractory anemia and neutropenia with multilineage dysplasia
Refractory anemia and thrombocytopenia with multilineage dysplasia
Refractory pancytopenia with multilineage dysplasia
Refractory neutropenia with multilineage dysplasia
Refractory neutropenia and thrombocytopenia with multilineage dysplasia
Refractory thrombocytopenia with multilineage dysplasia
Refractory cytopenia with multilineage dysplasia (RCMD) is defined by the World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues  as a type of myelodysplastic syndrome (MDS) with 1 or more cytopenias and dysplastic changes in 2 or more of the myeloid lineages (erythroid, granulocytic, or megakaryocytic). 
Cytopenias are defined as a hemoglobin level of less than 10g/dL, an absolute neutrophil count of less than 1,800/μL (see the Absolute Neutrophil Count calculator), and a platelet count of less than 100,000/μL. A diagnosis of RCMD requires that dysplastic features be present in more than 10% of cells from 2 or more lineages. There are less than 1% blasts in the peripheral blood and less than 5% blasts in the bone marrow. Auer rods are absent.
Cases in which there are findings of RCMD in conjunction with a history of cytotoxic chemotherapy and/or radiation therapy are better classified as therapy-related MDS (t-MDS).
Myelodysplastic syndrome (MDS) is an uncommon disorder; the incidence of MDS is increased in elderly patients.  Approximately 10-15,000 new cases of MDS are diagnosed each year in the United States; the large majority occurs in patients older than age 60 years.
The incidence of MDS has been reported to be between 22 and 45 cases per 100,000 people older than age 70 years. In a review, refractory cytopenia with multilineage dysplasia (RCMD) and RCMD with ring sideroblasts accounted for 39% of 1095 MDS cases;  however, the precise incidence of RCMD is not known.
As noted, patients with refractory cytopenia with multilineage dysplasia (RCMD) tend to be elderly. Most patients are asymptomatic at presentation, and RCMD is detected incidentally. However, some patients present with fatigue, easy bruising, or susceptibility to infection related to anemia, thrombocytopenia, or neutropenia, respectively. Laboratory findings include 1 or more cytopenias, as defined earlier.
Other potential etiologies for cytopenias, including nutritional deficiencies, the effects of medications (particularly chemotherapeutic agents) or toxins, infection, immunologic processes, or sequestration, must be excluded before a diagnosis of myelodysplastic syndrome (MDS) is considered. If cytopenias are persistent and other causes are excluded, a bone marrow biopsy and aspiration are performed, usually with submission of material for cytogenetic and/or flow cytometric analysis.
Morphologically abnormal cells may be seen in the peripheral blood or bone marrow. The morphologic findings characteristic of dysplasia vary depending on the lineage. A diagnosis of refractory cytopenia with multilineage dysplasia (RCMD) requires that more than 10% of cells be present in 2 or more cell lineages. This is often best appreciated on bone marrow aspirate smears; peripheral blood and biopsy sections may offer additional information.
Morphologic findings of granulocytic dysplasia include abnormal nuclear segmentation, particularly with hypolobated nuclei, including pseudo–Pelger-Huet anomaly with bilobed nuclei in which the nuclear lobes are connected by a fine filament of chromatin. Hypersegmented nuclei may also be a dysplastic finding, although this feature is less common. Other forms of granulocytic dysplasia include abnormalities of the cytoplasmic granularity. In some cases, the dysplastic neutrophils are hypogranular and the cytoplasm takes on a pale blue tinge (water-clear cytoplasm). (See the image below.)
In other cases, there is an increase in large, coarse, azurophilic granules (pseudo–Chediak-Higashi granules). Auer rods may also be a sign of dysplasia in the granulocyte lineage; however, the presence of Auer rods excludes a diagnosis of RCMD. Their presence indicates a more aggressive form of disease.
Erythroid dysplasia may present as nuclear or cytoplasmic abnormalities. Common forms of dyserythropoiesis include multinucleation with internuclear bridges, nuclear blebs or nuclear buds, and nuclear fragmentation (karyorrhexis). Megaloblastoid change, in which there is asynchrony between cytoplasmic hemoglobinization and nuclear maturation, may be present; the nuclear chromatin appears more immature than is appropriate for the degree of hemoglobinization. (See the images below.)
Dysplastic findings in the cytoplasm include vacuolization and periodic acid-Schiff positivity. The presence of ring sideroblasts is another abnormal cytoplasmic finding that may be demonstrated with a stain for iron. (See the image below.)
In the megakaryocyte lineage, dysplasia is recognized by the presence of small forms with nonlobated or hypolobated nuclei, as well as micromegakaryocytes. Dysplastic megakaryocytes may exhibit multiple discrete nuclei, a finding that has been described as “pawn ball megakaryocytes” because of the resemblance to the signs that are sometimes used to indicate pawnshops. (See the images below.)
Morphologic findings of dysplasia may also be identified in histologic sections of the bone marrow biopsy or clot section. The cellularity of the bone marrow is usually normal or increased in myelodysplastic syndrome (MDS), although a form of hypoplastic MDS has been recognized. The presence of clusters of immature myeloid elements away from bone trabeculae or blood vessels (so-called abnormal localization of immature precursors) may also be noted, particularly in cases of refractory anemia with excess blasts.
It is important to note that the described morphologic changes are not sufficient for making a diagnosis of myelodysplasia. Rather, for a diagnosis of myelodysplasia, the findings must be seen in the appropriate clinical setting, and persistent cytopenia(s) must be present; in addition, other causes of morphologic “dysplasia” must be absent. 
A study by Kazama et al found results that suggest that peroxiredoxin 2, a member of the peroxiredoxin family that regulates reactive oxygen species, may perform an important function in the pathogenesis of RCMD. 
Immunophenotypic Features and Methods
Myelodysplastic syndrome (MDS) has largely been diagnosed on the basis of morphologic and clinical features; in some cases, the diagnosis is supported by abnormal cytogenetic findings. The use of immunohistochemical analysis and flow cytometry in the diagnosis of MDS is an area of active investigation. Some tests have proved useful in establishing the diagnosis of MDS.
Immunohistochemical analysis of bone marrow biopsy and clot sections has centered on the identification of immature myeloid precursors, or blasts, especially with the use of antibodies to the progenitor cell antigen CD34. It is important to note that CD34 is not expressed in all populations of myeloid blasts. Its expression is also not limited to myeloid blasts; CD34 is expressed in vascular endothelium, as well as in some immature B-cell precursors (hematogones).
Other markers (eg, monocytic markers) have been shown to have limited utility in establishing the diagnosis of MDS. However, immunohistochemical markers may help to delineate the distribution and proportions of erythroid (glycophorin, hemoglobin), megakaryocytic (CD61), monocytic (CD68, CD14), and myeloid (myeloperoxidase) elements in the bone marrow. 
Immunophenotyping by flow cytometry is being used with increasing frequency in the evaluation of MDS. In flow cytometry, the proportion of myeloid blasts may be readily assessed. In addition to simply enumerating blasts, aberrant patterns of antigen expression can help to separate regenerative blast populations from abnormal blast populations. For instance, expression of CD7 (a T-cell–associated antigen) and CD56 (a natural killer [NK]-cell – associated antigen) by myeloid blasts is considered aberrant because it is not seen in normal blast populations. Other findings that may be of value in the diagnosis of myelodysplasia include abnormal patterns of antigen expression in maturing myeloid and monocytic cells and decreased numbers of immature B-cell precursors. 
Molecular/Genetic Features and Methods
The precise molecular mechanisms of myelodysplastic syndrome (MDS) are not fully understood. However, in many MDS cases, there is an increase in apoptosis among bone marrow precursors, which accounts for the ineffective hematopoiesis.
Cytogenetic abnormalities are relatively common in refractory cytopenia with multilineage dysplasia (RCMD); abnormal karyotypes are identified in up to 50% of cases.  The more-frequently encountered abnormalities include deletions of the long arm of chromosomes 5 or 7, monosomy of chromosomes 5 or 7, deletions of chromosome 20, additional copies of chromosome 8, loss of chromosome Y, and some structural rearrangements or a complex karyotype with multiple abnormalities.
The cytogenetic findings have been shown to have prognostic significance and have been classified into "good," "intermediate," and "poor" subgroups. The cytogenetic findings in the good prognosis group include normal cytogenetic findings, loss of chromosome Y (-Y), and isolated deletions of chromosomes 5 (del(5q)) or 20 (del(20q)).
The poor prognosis group of findings includes complex cytogenetic abnormalities (3 or more cytogenetic abnormalities) and abnormalities of chromosome 7. The intermediate prognosis group includes other cytogenetic abnormalities.
Fluorescence in situ hybridization (FISH) may be used to assess interphase cells for common cytogenetic abnormalities, particularly in cases in which there are insufficient metaphase cells for routine cytogenetic analysis. FISH may also be of value in the follow-up of known abnormalities.
Prognosis and Predictive Factors
Different variables have been assessed for their usefulness in determining the prognosis of patients with various types of myelodysplastic syndrome (MDS), such as refractory anemia, refractory cytopenia with multilineage dysplasia (RCMD), and refractory anemia with excess blasts (RAEB). [10, 11]
The International Prognostic Scoring System (IPSS), first described in 1997,  allows cases to be stratified on the basis of the percentage of blasts in the bone marrow, the karyotype, and the number of cytopenias (see the Myelodysplastic Syndrome International Prognostic Scoring System calculator). On the basis of the combination of these findings, cases are divided into 4 risk groups: low, intermediate-1, intermediate-2, and high. These groups were found to have significant differences in overall survival and risk of progression to acute myeloid leukemia.
This prognostic system has been used widely since its inception, although it may be less predictive in cases classified in accordance with the World Health Organization (WHO) classification system than it is with MDS cases stratified using the French-American-British (FAB) categories. (The WHO classification eliminates the FAB category of RAEB in transformation [RAEB-t] by including those cases among the acute myeloid leukemias.)
Consideration of lactate dehydrogenase (LDH) levels may add to the value of the IPSS; in one study, the degree of elevation of the LDH level was used to further divide the 4 prognostic groups defined in the IPSS.  There is some debate over whether a proposed WHO Prognostic Scoring System (WPSS), which includes the WHO classification of MDS, cytogenetic findings, and red blood cell transfusion dependency, would be a better predictor of outcome than the IPSS. 
Results from a study by Chu et al indicated that in patients with MDS, especially those with RCMD, the flow cytometric scoring system (FCSS) can also aid in determining prognosis.