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Clinical manifestations and diagnosis of the myelodysplastic syndromes
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Clinical manifestations and diagnosis of the myelodysplastic syndromes
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Literature review current through: Nov 2017. | This topic last updated: Sep 25, 2017.

INTRODUCTION — The myelodysplastic syndromes (MDS) comprise a heterogeneous group of malignant hematopoietic stem cell disorders characterized by dysplastic and ineffective blood cell production and a variable risk of transformation to acute leukemia.

Patients with MDS have varying reductions in the production of red blood cells, platelets, and mature granulocytes that may also exhibit functional (ie, qualitative) defects; these abnormalities often result in anemia, bleeding, and increased risk of infection.

The pathogenesis, epidemiology, clinical manifestations, pathologic features, and diagnosis of MDS will be reviewed here. The cytogenetics, prognosis, and treatment of this syndrome are discussed separately. (See "Prognosis of the myelodysplastic syndromes in adults" and "Overview of the treatment of myelodysplastic syndromes" and "Therapy-related myeloid neoplasms: Acute myeloid leukemia and myelodysplastic syndrome" and "Cytogenetics and molecular genetics of myelodysplastic syndromes".)

PATHOGENESIS — The pathogenesis of MDS is incompletely understood but, like other cancers, involves the stepwise acquisition of oncogenic mutations that may arise de novo or after exposure to certain forms of chemotherapy (eg, alkylating agents), environmental toxins (eg, benzene), or radiation (eg, therapeutic or accidental). MDS that develops after treatment with chemotherapy may also develop from the selection of pre-existent chemotherapy-resistant clones (eg, those with mutations of TP53) [1].

MDS is a clonal process that is thought to develop from a single transformed hematopoietic progenitor cell [2-4]. Studies suggest that the cell of origin has acquired multiple mutations resulting in dysplasia and ineffective hematopoiesis [5]. Up to 10 percent of asymptomatic adults >70 years old have clonal hematopoiesis of indeterminant potential (CHIP) associated with an MDS-associated mutation [6,7]. CHIP may be a common precursor of MDS (akin to monoclonal gammopathy of uncertain significance), but further studies are needed to determine its natural history. Patients with CHIP are at significantly increased risk of dying of cardiovascular disease, for reasons that are incompletely understood [8,9]. (See 'Clonal hematopoiesis of indeterminant potential' below and "Idiopathic cytopenias of undetermined significance (ICUS), clonal hematopoiesis of indeterminate potential (CHIP), and clonal cytopenias of undetermined significance (CCUS)".)

Together with cytogenetic testing, targeted DNA sequencing is increasingly being used to evaluate patients with MDS and has revealed that a large majority (>90 percent) of cases are associated with one or more driver mutations. Among the most commonly mutated genes are DNMT3A, TET2, ASXL1, TP53, RUNX1, and genes that are components of the 3' RNA splicing machinery (eg, SF3B1, U2AF1, SRSF2, and ZRSR2) [10-15]. In particular, somatic mutations in the SF3B1 gene that encodes components of the RNA splicing machinery occurs in 60 to 80 percent of the subtype MDS with ring sideroblasts (previously called refractory anemia with ring sideroblasts) and in a high fraction of MDS/MPN with ring sideroblasts and thrombocytosis (previously RARS-T) [10,16-22]. (See "Cytogenetics and molecular genetics of myelodysplastic syndromes", section on 'Gene mutations'.)

SF3B1 knockout mice develop ring sideroblasts, proving that this mutation leads to abnormal mitochondrial iron handling. SF3B1 mutant erythroblasts have coarser mitochondrial iron deposits than ring sideroblasts in MDS associated with wild type versions of the gene [19]. In contrast to the favorable prognosis of MDS with ring sideroblasts, mutation of another splicing factor mutation (SRSF2), which occurs in approximately 15 percent of MDS patients without ring sideroblasts, appears to carry a negative prognostic impact [23]. Patient-derived cells rarely have more than one mutation in a gene encoding a splicing factor, suggesting cells can tolerate haploinsufficiency but not biallelic loss.

Haploinsufficiency of ribosomal proteins, particularly RPS14, has been linked to the anemia seen in MDS cases with deletion of the long arm of chromosome 5 (5q-) [24]. Other factors that may be important in MDS pathophysiology include congenital or acquired telomerase dysfunction and aberrant or absent expression of microRNA species [25-27].

MDS genomes are characterized by global DNA hypomethylation with concomitant hypermethylation of gene-promoter regions relative to normal controls. These hypermethylated genes are not expressed (ie, they are silenced). As such, DNA methylation provides an epigenetic mechanism for controlling gene expression. While the underlying mechanism of altered-DNA methylation in MDS genomes is unclear, it is notable that several of the most frequently mutated genes encode regulators of DNA methylation. Specifically, DNMT3A encodes DNA methyltransferase 3, which carries out de novo DNA methylation, whereas TET2 (ten-eleven translocation) encodes an enzyme that is involved in DNA demethylation. Mutations in IDH1 and IDH2 (isocitrate dehydrogenase-1 and -2, respectively) create a neomorphic enzyme activity that leads to production of 2-hydroxyglutarate, an oncometabolite that inhibits the activity of several enzymes that regulate the epigenome, including TET2 [28-34]. IDH and TET2 mutations rarely co-occur, implying a similar pathophysiological effect. The role of DNA methylation in the pathobiology of MDS is also supported by studies that have demonstrated disease response to hypomethylating agents, although whether such responses are on the basis of expression of silenced anticancer genes or antimetabolite-induced cytotoxicity is controversial. (See "Treatment of intermediate, low, or very low risk myelodysplastic syndromes", section on 'Azacitidine' and "Treatment of intermediate, low, or very low risk myelodysplastic syndromes", section on 'Decitabine'.)

Other mutations affect genes that regulate normal hematopoiesis. Among these are mutations in RUNX1, a gene encoding a transcription factor that regulates normal hematolymphoid development. Alteration of RUNX1 function in mouse models deranges hematopoietic stem cell homeostasis and induces the development of MDS-like abnormalities [35].

Factors extrinsic to hematopoietic cells, such as stromal abnormalities [36] and T cell dysregulation [37], either intrinsic or promoted by immune evasion of the MDS stem cell, may also contribute to the pathobiology of MDS [38]. Studies showing that some cases of MDS respond to treatment with immunosuppressive agents (eg, cyclosporine, antithymocyte globulin) suggest that abnormalities of the immune system may be responsible for the myelosuppression and/or marrow hypocellularity, especially in younger subjects with lower risk disease, low platelet count, and who carry the HLA-DR15 allele [39,40]. (See 'Aplastic anemia' below and "Treatment of intermediate, low, or very low risk myelodysplastic syndromes", section on 'Immunosuppressive therapy'.)

EPIDEMIOLOGY — The precise incidence of de novo MDS is not known; conservative estimates from cancer databases suggest that there are approximately 10,000 cases diagnosed annually in the United States [41-43]. One series, for example, reported a crude annual incidence rate of 4.1 per 100,000 [42]. A similar incidence rate has been reported in the United Kingdom and Ireland [44,45]. In comparison, lower incidence rates of 0.27 per 100,000 have been reported in Eastern Europe, perhaps related to patterns of hospital use [44]. The actual incidence of MDS is likely higher than that predicted by cancer databases since the nonspecific symptoms may evade detection in early stages of the disease and suspected cases may not undergo definitive testing (ie, bone marrow biopsy) due to comorbidities [46-48]. Investigations that have analyzed reimbursement claims have estimated the incidence in the United States to be 30,000 to 40,000 new cases per year [47,49].

MDS occurs most commonly in older adults, with a median age at diagnosis in most series of ≥65 years and a male predominance [41,45,50-59]. Onset of the disease earlier than age 50 is unusual [60,61], with the exception of treatment-induced MDS [58,62], but rare cases of MDS have been reported in children at a median age of six years [63-65]. The risk of developing MDS increases with age. In one study, the annual incidence per 100,000 was estimated to be 0.5, 5.3, 15, 49, and 89 for individuals <50, 50 to 59, 60 to 69, 70 to 79, and >80 years of age, respectively [66].

MDS has been associated with environmental factors (eg, exposure to chemicals, particularly benzene [67], radiation, tobacco, or chemotherapy drugs), inherited genetic abnormalities (eg, trisomy 21, Fanconi anemia, Bloom syndrome, ataxia telangiectasia), and other benign hematologic diseases (eg, paroxysmal nocturnal hemoglobinuria, congenital neutropenia) (table 1) [68]. Familial MDS, while rare, has been associated with germ line mutations in RUNX1, ANKRD26, CEBPA, DDX41, ETV6, TERC, TERT, SRP72, and GATA2 (table 2). Familial MDS is discussed in more detail separately. (See "Familial acute leukemia and myelodysplastic syndromes".)

Although connective tissue disorders such as relapsing polychondritis, polymyalgia rheumatica, Sjögren's syndrome, inflammatory bowel disease, pyoderma gangrenosum, Behçet's syndrome, and glomerulonephritis have been reported in association with MDS, a causal relationship has not been firmly established [69-74]. Moreover, the demonstration that MDS-associated mutations, such as TET2 mutations, promote inflammation in mouse models by altering the activity of innate immune cells (eg, macrophages) suggests that with certain genotypes, connective tissue disorders may occur secondary to MDS [8,9]. This possibility is supported by the observation that treatment of MDS with hypomethylating agents sometimes ameliorates the autoimmune condition [75]. (See 'Autoimmune abnormalities' below.)

CLINICAL PRESENTATION — Signs and symptoms at presentation of MDS are nonspecific. Many patients are asymptomatic at diagnosis and only come to the physician's attention based upon abnormalities found on routine blood counts (eg, anemia, neutropenia, and thrombocytopenia). Others present with symptoms or complications resulting from a previously unrecognized cytopenia (eg, infection, fatigue).

Anemia is the most common cytopenia and can manifest as fatigue, weakness, exercise intolerance, angina, dizziness, cognitive impairment, or an altered sense of wellbeing [49,52,76,77]. Fatigue is ubiquitous in patients with MDS, and is sometimes out of proportion to the degree of anemia [78]. Less commonly, infection, easy bruising, or bleeding precipitate a hematologic evaluation. Systemic symptoms such as fever and weight loss are uncommon, and generally represent late manifestations of the disease or its attendant complications.

Physical findings in MDS are nonspecific. Sixty percent of patients are pale (reflecting anemia), and 26 percent have petechiae and/or purpura (due to thrombocytopenia) [52]. Hepatomegaly, splenomegaly, and lymphadenopathy are uncommon [79]. Sweet syndrome (neutrophilic dermatosis) may be the presenting symptom.

Infection — Patients with MDS may develop infections related to neutropenia and granulocyte dysfunction (eg, impaired chemotaxis and microbial killing) [80,81]. Bacterial infections predominate, with the skin being the most common site involved. Although fungal, viral, and mycobacterial infections can occur, they are rare in the absence of concurrent administration of immunosuppressive agents. The evaluation and treatment of infections in patients with MDS are discussed in more detail separately. (See "Management of the complications of the myelodysplastic syndromes", section on 'Infection'.)

Abnormalities of adaptive immune system may also be found in patients with MDS, although, in the majority of cases, lymphocytes are not derived from the malignant clone [82]. Lymphopenia, due largely to a reduced number of CD4+ cells, is inversely related to the number of transfusions received [83,84]. However, CD8+ cells are normal or slightly increased [85]. Immunoglobulin production is variably affected, with hypogammaglobulinemia, polyclonal hypergammaglobulinemia, and monoclonal gammopathy reported in 13, 30, and 12 percent of patients, respectively [86,87].

Autoimmune abnormalities — Autoimmune abnormalities, although uncommon, may complicate the course of MDS in up to 25 percent of patients [69-75,88]. In an analysis of the SEER database that compared 2471 patients with MDS with 42,886 controls from the Medicare population, patients with MDS were more likely to demonstrate autoimmune phenomena (23 versus 14 percent) [89]. The most common autoimmune conditions in patients with MDS were chronic rheumatic heart disease (7 percent), rheumatoid arthritis (6 percent), pernicious anemia (6 percent), psoriasis (2 percent), and polymyalgia rheumatica (2 percent). Other autoimmune abnormalities include Sweet syndrome, pericarditis, pleural effusions, skin ulcerations, iritis, myositis, peripheral neuropathy, and pure red cell aplasia. On occasion, patients may present with an acute clinical syndrome characterized by cutaneous vasculitis, fever, arthritis, peripheral edema, and pulmonary infiltrates [69]. (See "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Paraneoplastic disease' and "Acquired pure red cell aplasia in the adult", section on 'Etiology and pathogenesis'.)

Acquired hemoglobin H disease — Acquired hemoglobin H disease (also called acquired alpha thalassemia, alpha thalassemia myelodysplastic syndrome) has been documented in approximately 8 percent of cases of MDS and 2.5 percent of those with various myeloproliferative disorders [90-93], and results in a spectrum of red cell morphologic changes similar to those seen in patients with alpha thalassemia (eg, microcytosis, hypochromia, hemoglobin H-containing red cells) (figure 1 and picture 1) [94]. An acquired somatic mutation of ATRX, an X-linked gene encoding a chromatin-associated protein, has been linked to this entity [90], as have acquired deletions of the alpha globin loci. (See "Molecular genetics of the thalassemic syndromes", section on 'Globin gene anatomy and physiology' and "Clinical manifestations and diagnosis of the thalassemias", section on 'Hemoglobin H disease'.)

Cutaneous manifestations — Skin lesions are uncommon in patients with MDS; two syndromes occur with sufficient frequency to merit description:

Sweet syndrome (acute febrile neutrophilic dermatosis), when complicating the course of MDS, may herald transformation to acute leukemia [95-98]. Paracrine and autocrine elaboration of the cytokines interleukin-6 and granulocyte colony-stimulating factor have been implicated in the pathogenesis of this condition [97]. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)

Myeloid sarcoma (also called granulocytic sarcoma or chloroma) of the skin may be the first sign of transformation to acute leukemia [99-101]. Since myeloid sarcoma is now considered an extra-medullary presentation of acute myeloid leukemia (AML), the approach to treatment of patients with myeloid sarcoma without evidence of AML on bone marrow biopsy is similar to that for patients with overt AML [102]. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Myeloid sarcoma'.)

PATHOLOGIC FEATURES — MDS is characterized by abnormal cell morphology (dysplasia) and quantitative changes in one or more of the blood and bone marrow elements (ie, red cells, granulocytes, platelets).

Complete blood count — Complete blood count with leukocyte differential almost always demonstrates a macrocytic or normocytic anemia; neutropenia and thrombocytopenia are more variable. Pancytopenia (ie, anemia, leukopenia, and thrombocytopenia) is present at the time of diagnosis in up to 50 percent of patients. While isolated anemia is not uncommon, less than 5 percent of patients present with an isolated neutropenia, thrombocytopenia, or monocytosis in the absence of anemia [79].

Anemia – Anemia is almost uniformly present and is generally associated with an inappropriately low reticulocyte response. The mean corpuscular volume (MCV) may be macrocytic (>100 femtoliters) or normal. The red cell distribution width (RDW) is often increased reflecting the presence of increased variability in red cell size, also called anisocytosis. The mean corpuscular hemoglobin concentration (MCHC) is usually normal, reflecting a normal ratio of hemoglobin to cell size.

Leukopenia – Approximately half of patients have a reduced total white blood cell count (ie, leukopenia), usually resulting from absolute neutropenia [58]. Circulating immature neutrophils (myelocytes, promyelocytes, and myeloblasts) may be identified, but blasts constitute fewer than 20 percent of the leukocyte differential.

Thrombocytopenia – Varying degrees of thrombocytopenia are present in roughly 25 percent of patients with MDS [58]. Unlike anemia, isolated thrombocytopenia is not a common early manifestation of MDS [103]. However, a thrombocytopenic presentation with minimal morphologic dysplasia has been described in patients in whom del(20q) was the sole karyotypic abnormality [104]. Such patients may be easily misdiagnosed as having immune thrombocytopenia (ITP). (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Differential diagnosis'.)

Thrombocytosis – Thrombocytosis is less commonly seen in MDS than thrombocytopenia. In one report, of the 388 patients diagnosed with MDS from 1980 to 2006 at a single institution, 31 (8 percent) presented with a high platelet count [105]. Among these patients, there was a low incidence of spontaneous bleeding or thromboembolic events. Thrombocytosis has been described in 5q- syndrome, 3q21q26 syndrome, and in MDS/MPN with ring sideroblasts and thrombocytosis (previously called RARS-T), which is often associated with activating mutations in JAK2 as well as SF3B1 [106]. (See 'MDS/MPN with ring sideroblasts and thrombocytosis' below.)

Peripheral blood smear — The peripheral blood smear usually demonstrates evidence of dysplasia in the red and white blood cell series. Platelets are usually morphologically normal. Less commonly, platelets may be smaller or larger than normal or hypergranular. Megakaryocytic fragments are not seen.

Red blood cells — The following erythroid findings have been noted in the peripheral blood of patients with MDS (table 3):

Red cells are usually normocytic or macrocytic [107,108], although patients with ring sideroblasts may present with a variably sized subpopulation of hypochromic, microcytic red cells [109]. (See "Sideroblastic anemias: Diagnosis and management".)

Ovalomacrocytosis is the best-recognized morphologic abnormality of erythrocytes. In some cases, however, elliptocytes [110,111], teardrops, stomatocytes, or acanthocytes (spur cells) [112] may be seen, reflecting intrinsic alterations in cytoskeletal proteins [111,113].

Basophilic stippling, Howell-Jolly bodies, and megaloblastoid nucleated red cells may also be found in the peripheral smear (picture 2 and picture 3). These peripheral blood findings are associated with dyserythropoietic features in bone marrow precursors, characterized by delayed and dysplastic nuclear and cytoplasmic maturation, erythroid hyperplasia with megaloblastoid features, nuclear budding, multinucleation, karyorrhexis, and cytoplasmic vacuolization [107,114].

Reticulocytosis may be indicative of a superimposed autoimmune hemolytic anemia [115] or may be a marker of delayed reticulocyte maturation, so-called pseudoreticulocytosis [116,117].

White blood cells — Dysplastic neutrophils are commonly found in the peripheral blood smear. These cells may demonstrate increased size, abnormal nuclear lobation, and abnormal granularity (table 3). Monocytes may also demonstrate immature characteristics.

Granulocytes commonly display reduced segmentation, the so-called pseudo-Pelger-Huet (Pelgeroid) abnormality [55], often accompanied by reduced or absent granulation (picture 4 and picture 5) [118,119].

Occasionally, granulocytes have a clumped chromatin pattern in which blocks of chromatin are separated by a void in nuclear material, creating an appearance of nuclear fragmentation associated with loss of segmentation [120,121]. Ring-shaped nuclei and nuclear sticks may be identified [122], particularly in therapy-related MDS. Rarely, a pseudo-Chediak-Higashi anomaly (picture 6) [123] or myelokathexis-like features (picture 7) may be evident [124]. (See "Congenital neutropenia", section on 'Severe congenital neutropenia'.)

Myeloblasts can be identified by their nuclear and cytoplasmic characteristics, which include a high nuclear:cytoplasmic ratio, easily visible nucleoli, fine nuclear chromatin, variable cytoplasmic basophilia, few or no cytoplasmic granules, and absent Golgi zone [125,126]. Auer rods within leukemic blasts (picture 8) are uncommon and if present in a patient with a prior diagnosis of MDS are often a harbinger of transformation to AML [127].

Bone marrow aspirate and biopsy

Bone marrow aspirate — Optimally, the bone marrow aspirate provides material for a 500-cell differential count to determine the percentage of blasts in the marrow; it also allows for a detailed cytologic evaluation of the blasts and other cells. Impaired myeloid maturation is often readily apparent. The percentage of granulocytic precursors is variable, but more often decreased than increased, and a relative maturation arrest may be seen at the myelocyte stage [51]. Maturation of the cytoplasm may progress more rapidly than the nucleus [60].

The myeloid:erythroid ratio is variable, but often decreased. There is a shift towards more immature precursors, but the blast percentage, by definition, is less than 20 percent [128]. Morphologic abnormalities in the erythroid precursors include large size, nuclear multilobation, nuclear budding, and other abnormal forms. The cytoplasm of erythroid progenitors may show vacuolization, coarse or fine periodic acid-Schiff-positive granules, or a "necklace" of iron-laden mitochondria surrounding the nuclei (ie, ring sideroblasts detected with Prussian blue staining) [129,130]. Granulocytic precursors may also demonstrate dysplastic features, such as abnormally large size, abnormal nuclear shape, and increased or decreased cytoplasmic granularity.

Bone marrow biopsy — The bone marrow biopsy gives a general overview of the degree of involvement and specific histologic features associated with the process (eg, fibrosis). Cellularity is usually increased, but may be normal or decreased. Other features include reactive lymphocytosis and mastocytosis, lymphoid aggregates, fibrosis, increased histiocytes, and pseudo-Gaucher histiocytes. In addition, clusters of immature cells may locate centrally in the marrow space rather than along the endosteal surface [129,131]. Special techniques can reveal increased apoptosis in lower risk MDS [132].

The bone marrow is usually hypercellular and features single- or multi-lineage dysplasia (table 3) [131,133-135]. The classic paradox of peripheral pancytopenia despite the presence of a hypercellular bone marrow reflects premature cell loss via intramedullary cell death (apoptosis) [136,137]. Although hypocellularity is uncommon, it is found with greatest frequency in therapy-related MDS and must be distinguished from aplastic anemia [62]. (See 'Aplastic anemia' below.)

Red blood cells – Specific erythroid findings in the bone marrow include (table 3):

Ring sideroblasts containing mitochondria laden with iron may be evident on bone marrow aspirates stained for the presence of iron (picture 9). Ring sideroblasts may also be seen in biopsies, but because the decalcification procedure needed to cut biopsy sections also leaches out iron, the aspirate is preferred when assessing for ring sideroblasts. (See 'MDS with ring sideroblasts' below.)

Internuclear bridging characterized by chromatin threads tethering dissociated nuclei reflects impaired mitosis and may contribute to the addition and deletion of genetic material characteristic of MDS [138].

Although erythroid hyperplasia usually is the predominant finding in the setting of ineffective erythropoiesis, red cell aplasia and/or hypoplasia also rarely occur [139].

Megakaryocytes – Megakaryocytes are usually normal or increased in number, and sometimes occur in clusters. Abnormal megakaryocytes, including micromegakaryocytes, large mononuclear forms, megakaryocytes with multiple dispersed nuclei ("Pawn ball" changes), and hypogranular megakaryocytes are common bone marrow findings (picture 10) [55,140,141]. Nonlobulated or mononuclear megakaryocytes may be identified, particularly in association with the 5q- syndrome. Antibodies to von Willebrand factor, CD41, or CD61 (the latter two both components of the platelet GpIIa/IIIb fibrinogen receptor) may be used to identify these atypical megakaryocytes in biopsy sections [142]. (See 'MDS with isolated del(5q)' below.)

Abnormal localization of immature precursors – Granulopoiesis may be displaced from its normal paratrabecular location to more central marrow spaces [131,143]. This displacement of granulocyte precursors has been termed "abnormal localization of immature precursors," or ALIP [131,143,144].

Fibrosis – Mild to moderate degrees of myelofibrosis are reported in up to 50 percent of patients with MDS, and marked fibrosis is found in 10 to 15 percent [145-148]. While myelofibrosis occurs in all subtypes of MDS, it is most common in therapy-related MDS [62]. Importantly, deposition of mature collagen (detected with a trichrome stain) is uncommon in MDS. Instead, fibrosis takes the form of increases in the number and thickness of reticulin fibers, best detected with a silver impregnation stain [149]. The degree of fibrosis can be graded using European consensus criteria (table 4) [150,151], and, if prominent enough, could lead to a diagnosis of MDS/myeloproliferative disorder overlap. (See 'MDS/MPN syndromes' below.)

Cytochemistry and immunocytochemistry — Cytochemical stains and immunophenotyping studies may demonstrate a decrease or loss of normal myeloid maturation antigens [83], or the presence of antigens not normally expressed [152]. Myeloperoxidase [81] and alkaline phosphatase [107] activities may be diminished in myeloid cells, whereas monocyte-specific esterase may be increased [153].Useful cytochemical methods include:

Iron stains for identification of ring sideroblasts

PAS staining of erythroblasts to assess dyserythropoiesis

Peroxidase or Sudan black B staining to confirm the myeloid lineage of blasts

Nonspecific or double esterase stains to discern abnormal granulocytic and monocytic forms

Immunocytochemistry may be helpful in order to:

Exclude lymphoid origin of primitive blasts

Distinguish erythroid precursors via staining with antibodies specific for glycophorin (CD235a) or transferrin receptor (CD71)

Quantify myeloid blasts and progenitors using antibodies to CD34, CD117, CD13, CD14, and CD33 [154]

Detect dysplastic or immature megakaryocytes via antibodies with specificity for von Willebrand factor [142], factor VIII [155], CD41 [156], CD61, or the HPI-ID monoclonal antibody [157]

Detect lineage infidelity (eg, myeloid lineage cells expressing nonmyeloid antigens) and confirm the presence of bi- or tri-lineage dysplasia [158,159]

Flow cytometry — Morphologic analysis of the peripheral blood and bone marrow for evidence of dysplasia is important in the diagnosis of MDS, but is subjective and has limited reproducibility when dysplastic changes are not overt [160,161]. Automated flow cytometric systems (multiparameter flow cytometry) for scoring dyspoiesis in MDS have been developed [162]. These systems appear to have both diagnostic and prognostic value in patients with MDS [162-168]. Findings on flow cytometry can suggest clonality and the presence of MDS. While flow cytometry findings are not considered diagnostic, they can provide further support for the diagnosis in suspected cases. Flow cytometry should be performed according to the standard methods proposed by the International Flow Cytometry Working Group of the European LeukemiaNet [167,169].

Genetic features — The diagnosis of MDS is made based upon an evaluation of the bone marrow and peripheral smear in the appropriate clinical context. Detection of certain chromosomal abnormalities by routine cytogenetic analysis, reverse transcriptase polymerase chain reaction (RT-PCR), or fluorescent in situ hybridization (FISH) distinguishes between MDS and acute myeloid leukemia (AML) in some cases, aids in the classification of MDS, and is a major factor in determining prognostic risk group and therapy [170]. Some centers use targeted next-generation sequencing panels to aid in the diagnosis of MDS, and it seems likely that this will become a part of the standard work-up of known or suspected MDS patients over the next several years, both for confirming the diagnosis and for determining prognosis [31,171-174]. (See "Overview of the treatment of myelodysplastic syndromes", section on 'Pretreatment evaluation' and "Cytogenetics and molecular genetics of myelodysplastic syndromes".)

Importantly, the following cytogenetic abnormalities, if found, result in the diagnosis of AML, regardless of blast count [128] (see "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Bone marrow infiltration'):

t(8;21)(q22;q22); RUNX1-RUNX1T1 (previously AML1-ETO)

inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11

t(15;17)(q22;q21.1); PML-RARA

Similarly, the presence of one of the following chromosomal abnormalities is presumptive evidence of MDS in patients with otherwise unexplained refractory cytopenia and no morphologic evidence of dysplasia [128]:





del(12p) or t(12p)



t(17p) (unbalanced translocations) or i(17q) (ie, loss of 17p)







In contrast, certain acquired karyotypic changes that lack diagnostic specificity (eg, acquired loss of the Y chromosome, trisomy 8, or loss of the long arm of chromosome 20 [del(20q)]) are not sufficient criteria for a diagnosis of MDS [128].

Whether other methods to detect chromosomal abnormalities such as FISH, flow-FISH, comparative genomic hybridization (CGH), single nucleotide polymorphism array, and loss of heterozygosity (uniparental disomy) are superior prognostically or may be used to direct therapy remains to be determined [175,176]. Further details regarding cytogenetic changes in patients with MDS are presented separately. (See "Cytogenetics and molecular genetics of myelodysplastic syndromes".)

EVALUATION — The diagnosis of MDS should be considered in any patient with unexplained cytopenia(s) or monocytosis. A careful history should elicit details regarding nutritional status, alcohol and drug use, medications, occupational exposure to toxic chemicals, prior treatment with antineoplastic agents or radiotherapy, and risk factors for and/or treatment of human immunodeficiency virus (HIV) infection. Evaluation of the peripheral blood smear and a unilateral bone marrow biopsy and aspirate are key components to the diagnosis of MDS. Conditions that present with features similar to MDS must be ruled out (eg, HIV; vitamin B12, folate, and copper deficiencies; zinc excess). In addition, clinicians may wish to perform some of the tests recommended for the pretreatment evaluation of patients with MDS in concert with the initial evaluation. These are described in more detail separately. (See "Overview of the treatment of myelodysplastic syndromes", section on 'Pretreatment evaluation'.)

Even in the setting of neutropenia, thrombocytopenia, and/or coagulopathy, it is unusual for bleeding or infection to develop at the site of marrow aspiration/biopsy as a complication of the procedure. The preferred biopsy location in adults is the posterior superior iliac crest, although a different site should be used if the patient has received prior irradiation to this area. The sternum is a reasonable alternative site for bone marrow aspiration, but bone marrow biopsy cannot be performed at this site. (See "Bone marrow aspiration and biopsy: Indications and technique", section on 'Choice of aspiration or biopsy site'.)

Occasional patients may have a "dry tap" on aspiration, due to the presence of fibrosis. An adequate bone marrow biopsy with touch preparations should provide sufficient material for diagnostic purposes in situations when the marrow cannot be aspirated. A portion of the biopsy can be submitted in saline or, preferably, culture medium (eg, Roswell Park Memorial Institute culture medium, RPMI) and teased apart in the flow cytometry laboratory in an attempt to isolate a cell suspension for analysis.

Careful inspection of the peripheral blood smear and bone marrow aspirate is necessary to document the requisite dysplastic cytologic features identifiable in any or all of the hematopoietic lineages. The bone marrow biopsy gives a general overview of the degree of involvement and specific histologic features associated with the process (eg, fibrosis), but is suboptimal for assessment of dysplasia. Since the diagnosis relies heavily on morphologic changes, the quality of the smears is of the utmost importance. Slides should be made from freshly obtained specimens; slides made from specimens exposed to anticoagulants for two or more hours are less satisfactory because such treatment may induce cytologic artifacts.

To determine the blast percentage in the peripheral blood, a 200-leukocyte differential is recommended; Buffy coat smears may be necessary in severely cytopenic patients. The percentage of blasts in the marrow should be calculated from a 500-cell differential count performed on the bone marrow aspirate. Blast counts from the aspirate are superior to those calculated from a flow specimen since the latter may be influenced by hemodilution and artifacts produced by specimen preparation (eg, red cell lysis techniques, density gradient centrifugation) and the approach through which different cell populations are selected for gating.

DIAGNOSIS — The diagnosis of MDS is made based upon findings in the peripheral blood and bone marrow as interpreted within the clinical context. Most cases of MDS are diagnosed based upon the presence of the three main features outlined below [128]. While most cases of MDS will have these three features, some will not, as clarified in the caveats presented.

Otherwise unexplained quantitative changes in one or more of the blood and bone marrow elements (ie, red cells, granulocytes, platelets). The values used to define cytopenia are: hemoglobin <10 g/dL (100 g/L); absolute neutrophil count <1.8 x 109/L (<1800/microL); platelets <100 x 109/L (<100,000/microL).

Morphologic evidence of significant dysplasia (ie, ≥10 percent of erythroid precursors, granulocytes, or megakaryocytes) upon visual inspection of the peripheral blood smear, bone marrow aspirate, and bone marrow biopsy in the absence of other causes of dysplasia (table 3). In the absence of morphologic evidence of dysplasia, a presumptive diagnosis of MDS can be made in patients with otherwise unexplained refractory cytopenia in the presence of certain genetic abnormalities. (See 'Genetic features' above.)

Blast forms account for less than 20 percent of the total nucleated cells of the bone marrow aspirate and peripheral blood. Cases with higher blast percentages are considered to be acute myeloid leukemia (AML). In addition, the presence of myeloid sarcoma (extramedullary AML) or certain genetic abnormalities, such as those with t(8;21), inv(16), or t(15;17), are considered diagnostic of AML, irrespective of the blast cell count. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Blast count'.)

Detection of a CHIP-type clonal mutation alone (ie, without the hematologic abnormalities described above) does not constitute a diagnosis of MDS. As an example, detection of such a mutation in an older patient with anemia of chronic disease/inflammation does not meet the criteria for MDS. (See 'Genetic features' above and "Idiopathic cytopenias of undetermined significance (ICUS), clonal hematopoiesis of indeterminate potential (CHIP), and clonal cytopenias of undetermined significance (CCUS)", section on 'Clonal hematopoiesis of indeterminate potential (CHIP)'.)

DIFFERENTIAL DIAGNOSIS — MDS must be distinguished from other entities that may also present with cytopenias and/or dysplasia. The entities considered in a specific case depend largely upon the presenting features. As examples, in cases presenting with cytopenias, circulating blasts, or significant fibrosis, it is important to consider idiopathic cytopenia of undetermined significance, acute myeloid leukemia, and myelofibrosis, respectively, as well as other entities. The following sections describe the most common entities that should be considered.

Idiopathic cytopenia of undetermined significance — The term "idiopathic cytopenia of undetermined significance" (ICUS) is used to classify cases of persistent cytopenia without significant dysplasia, without any of the specific cytogenetic and/or genetic abnormalities considered as presumptive evidence of MDS, and without a potentially related hematologic or nonhematologic disease (table 5). (See "Idiopathic cytopenias of undetermined significance (ICUS), clonal hematopoiesis of indeterminate potential (CHIP), and clonal cytopenias of undetermined significance (CCUS)", section on 'Idiopathic cytopenias of undetermined significance (ICUS)' and 'Genetic features' above.)

Clonal hematopoiesis of indeterminant potential — The term "clonal hematopoiesis of indeterminant potential" (CHIP) has been proposed to classify cases in which blood cells contain somatic mutations of genes known to be recurrently mutated in hematologic malignancies in the absence of other diagnostic criteria for hematologic malignancy (table 5) [177]. The cases should not meet the criteria for MDS, paroxysmal nocturnal hemoglobinuria, monoclonal gammopathy of undetermined significance, or monoclonal B cell lymphocytosis. Persons with CHIP may have normal blood counts, cytopenias unrelated to MDS, or cytopenias that do not meet the criteria for MDS. The related term "clonal cytopenia of undetermined significance" (CCUS) is used for patients with clinically meaningful unexplained cytopenias and a clonal mutation that do not meet the criteria for MDS or another hematologic neoplasm. (See "Idiopathic cytopenias of undetermined significance (ICUS), clonal hematopoiesis of indeterminate potential (CHIP), and clonal cytopenias of undetermined significance (CCUS)", section on 'Clonal hematopoiesis of indeterminate potential (CHIP)'.)

Acute myeloid leukemia — MDS and acute myeloid leukemia (AML) lie along a disease continuum with distinction between the two largely made based upon the blast percentage. In the current World Health Organization (WHO) classification system, blast forms account for at least 20 percent of the total nucleated cells in AML [151,178]. In addition, the presence of myeloid sarcoma or any one of the following genetic abnormalities is considered diagnostic of AML without regard to the blast count:

AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 (previously AML1-ETO)

AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11

APL with t(15;17)(q24.1;q21.1); PML-RARA

It may not be possible to distinguish MDS with excess blasts from early, evolving AML. This distinction can be made reliably only after at least 30 days of observation; in general, the peripheral blood and/or bone marrow blast percentage should continue to rise in evolving AML and remain relatively stable in MDS. (See 'MDS with excess blasts' below and "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

Previously in the French-American-British (FAB) classification system, cases of MDS with Auer rods or with 21 to 30 percent blasts in the bone marrow or ≥5 percent blasts in the blood were classified as refractory anemia with excess blasts in transformation [179]. However, in the WHO classification system AML is defined by greater than 20 percent blasts in the marrow or blood, or any number of blasts with the AML defining cytogenetic aberrations listed above [128,151], despite some evidence of biologic differences between MDS and AML as defined in the FAB classification [180].

MDS/MPN syndromes — MDS is characterized by dysplasia and cytopenias. In contrast, the myelodysplastic/myeloproliferative neoplasms (MDS/MPN) include disorders where both dysplastic and proliferative features coexist [128]. These include:

Chronic myelomonocytic leukemia (CMML) – CMML is characterized by the overproduction of maturing monocytic cells and sometimes dysplastic neutrophils, often accompanied by anemia and/or thrombocytopenia (table 6). This entity was previously considered to be a subtype of MDS, but is currently classified as a MDS/MPN. (See 'Chronic myelomonocytic leukemia' below.)

Atypical chronic myeloid leukemia, BCR-ABL1 negative – Cases are usually characterized by marked neutrophilia with accompanying dysgranulopoiesis (table 7). (See "Clinical manifestations and diagnosis of chronic myeloid leukemia", section on '"Atypical CML"'.)

Juvenile myelomonocytic leukemia – This rare disorder of infancy and early childhood is characterized by hepatosplenomegaly and lymphadenopathy, with or without evidence of dysgranulopoiesis (table 8). (See "Clinical manifestations and diagnosis of chronic myeloid leukemia", section on 'Juvenile myelomonocytic leukemia' and "Juvenile myelomonocytic leukemia".)

MDS/MPN with ring sideroblasts and thrombocytosis (table 9). (See 'MDS/MPN with ring sideroblasts and thrombocytosis' below.)

MDS/MPN, unclassifiable.

Cases with prominent dysplastic and myeloproliferative features should be classified as MDS/MPN rather than MDS. Myeloproliferative features include significant thrombocytosis (eg, platelet count ≥450 x 109/L) associated with megakaryocytic proliferation and leukocytosis (white blood cell count ≥13 x 109/L), with or without prominent splenomegaly.

While not considered a distinct entity, patients with MDS/MPN and isolated isochromosome 17p have a high risk of transformation to AML. Findings on examination of the peripheral blood and bone marrow include leukocytosis, anemia, thrombocytopenia, splenomegaly, micromegakaryocytes, and fibrosis [181].

Chronic myelomonocytic leukemia — Chronic myelomonocytic leukemia (CMML) is a MDS/MPN characterized by the overproduction of maturing monocytic cells and sometimes dysplastic neutrophils, often accompanied by anemia and/or thrombocytopenia (table 6). Borderline or relative elevations in the monocyte count are common in MDS. In contrast, cases of CMML have a peripheral blood monocyte count >1000/microL and often display other proliferative features such as splenomegaly, leukocytosis, and constitutional symptoms (picture 11). While both may display dysplastic features, such features are generally more subtle in CMML compared with MDS and are often identified in <10 percent of mononuclear cells counted. (See "Chronic myelomonocytic leukemia".)

MDS/MPN with ring sideroblasts and thrombocytosis — Some patients with the clinical and morphologic features of MDS with ring sideroblasts also have thrombocytosis [182-184]. These patients demonstrate features of MDS (eg, ring sideroblasts) as well as MPN (eg, megakaryocytes resembling those seen in essential thrombocythemia, thrombocytosis), and have been designated by the WHO as MDS/MPN with ring sideroblasts and thrombocytosis within the category of MDS/MPN [151,185]. (See "Diagnosis and clinical manifestations of essential thrombocythemia".)

The diagnosis of MDS/MPN with ring sideroblasts and thrombocytosis requires all of the following (table 9) [151]:

Anemia associated with erythroid lineage dysplasia with or without multilineage dysplasia, ≥15 percent ring sideroblasts, <1 percent blasts in the peripheral blood, and <5 percent blasts in the bone marrow

Persistent thrombocytosis with platelet count ≥450 x 109/L (≥450,000/microL)

Presence of a SF3B1 mutation or, in the absence of SF3B1 mutation, no history of recent cytotoxic or growth factor therapy that could explain MDS/MPN features

No BCR-ABL1 or PCM1-JAK2 fusion gene; no rearrangement of PDGFRA, PDGFRB, or FGFR1; no (3;3)(q21;q26), inv(3)(q21;q26), or del(5q)

No preceding history of MPN, MDS (except MDS with ring sideroblasts), or other type of MDS/MPN

This diagnosis is strongly supported by the presence of an SF3B1 mutation together with a mutation in JAK2 V617F, CALR, or MPL; however, at least 15 percent ring sideroblasts are required for the diagnosis even if a SF3B1 mutation is detected [151].

The finding of the JAK2 V617F mutation in up to two-thirds of patients with this entity and in only 2 of 89 cases of typical MDS, suggests that it is best considered another JAK2 mutation-associated chronic MPN [186-189]. In one instructive report, three patients with MDS with ring sideroblasts, who initially had low to normal platelet counts, progressed to MDS with ring sideroblasts and thrombocytosis [190]. Two of the three acquired the JAK2 mutation at this time, suggesting that MDS with ring sideroblasts, who initially had low to normal platelet counts, progressed to MDS with ring sideroblasts and thrombocytosis may evolve from MDS with ring sideroblasts through the acquisition of somatic mutations.

Aplastic anemia — Although most patients with MDS have normal or increased bone marrow cellularity, a minority have cellularity that is lower than expected based upon the patient's age (ie, cellularity <30 percent in patients <60 years or <20 percent in patients >60 years), termed hypoplastic MDS [128]. Hypocellularity is found with greatest frequency in therapy-related MDS [62]. Marrow cells in these patients are as a rule morphologically and karyotypically abnormal, features that enable distinction from aplastic anemia (AA). Many patients with both AA and MDS have small populations of glycosylphosphatidyl inositol-anchor deficient cells characteristic of paroxysmal nocturnal hemoglobinuria (PNH), but few patients with MDS alone either develop PNH or display typical PNH clinical manifestations [191]. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)

The presence of a clonal chromosomal abnormality (eg, 5q-, monosomy 7) identifies cases that are likely to follow a course typical of MDS [192]. A diagnosis of MDS is also suggested by an increase in the percentage of CD34-expressing cells in the bone marrow, the presence of ring sideroblasts, and granulocytic or megakaryocytic dysplasia [193]. Expression of the tumor necrosis factor (TNF) receptor on bone marrow stem cells by flow cytometry may discriminate AA from MDS [194] as patients with AA have a markedly greater TNF receptor expression than those with MDS.

The genetic relationship between MDS and AA was explored in a study that performed targeted DNA sequencing     on the peripheral blood cells of 439 adult patients carrying a diagnosis of AA [195]. Clonal hematopoiesis was documented in roughly 50 percent of AA cases, and somatic mutations in driver genes linked to MDS were found in about a third. However, these mutations tended to be present in small subclones and were not generally predictive of progression to myeloid neoplasia. Exceptions were mutations in ASXL1 and DNMT3A, which were more likely to be associated with progression to MDS and AML. Further work is needed to determine the role of DNA sequencing in distinguishing aplastic anemia from hypocellular MDS.

Myelofibrosis — Mild to moderate degrees of bone marrow fibrosis are common in patients with MDS, and a small percentage will display marked fibrosis similar to that seen in patients with primary myelofibrosis (PMF). Patients with hyperfibrotic MDS are often pancytopenic, with trilineage dysplasia and atypical megakaryocytic proliferation [147,148,196]. Most cases of hyperfibrotic MDS can be distinguished from PMF by the absence of splenomegaly (table 10 and table 11). In complicated cases, evaluation for mutations that are characteristic of PMF may be of benefit, namely mutations in JAK2, CALR, and MPL. Mutations in one of these three genes is seen in greater than 90 percent of PMF, whereas only JAK2 mutations are found in MDS, and these are seen in only 5 percent of cases [197]. (See "Clinical manifestations and diagnosis of primary myelofibrosis".)

HIV infection — Dysplastic hematopoiesis and variable degrees of cytopenia are common findings accompanying human immunodeficiency virus (HIV) infection [198,199]. (See "Hematologic manifestations of HIV infection: Anemia" and "Hematologic manifestations of HIV infection: Neutropenia" and "Hematologic manifestations of HIV infection: Thrombocytopenia and coagulation abnormalities".)

As an example, a detailed morphologic review was performed in a blinded fashion on 216 bone marrow specimens from 178 patients with HIV infection [198]. Among the most common bone marrow findings were hypercellularity (53 percent of specimens), dysplasia (69 percent), increased marrow iron stores (65 percent), megaloblastic hematopoiesis (38 percent), fibrosis (20 percent), plasmacytosis (25 percent), lymphocytic aggregates (36 percent), and granulomas (13 percent).

Hematopoietic dysplasia in such patients may result from medications, opportunistic infection, and/or a direct effect of HIV on hematopoietic progenitors [200,201]. Thus, serologic screening for HIV should be considered in patients with unexplained cytopenia(s) and/or dysplasia. MDS that occurs in patients with HIV infection are more likely to have complex cytogenetics (including 7q-/7-) and shorter survival than non-HIV-infected patients [202]. (See "Acute and early HIV infection: Treatment".)

Poor nutritional status — Many patients with MDS have macrocytic red cells, reduced reticulocyte percentage, and pancytopenia (anemia, leukopenia, and thrombocytopenia), findings that may also be present in the megaloblastic anemias, copper deficiency [203,204], and zinc excess (likely due to impaired copper absorption by zinc) [205]. While reduced neutrophil lobulation is characteristic of MDS, the combination of increased neutrophil lobulation along with macrocytosis is pathognomonic of megaloblastic anemia. Accordingly, zinc excess and vitamin B12, folate, and copper deficiencies should be excluded in all patients. It is important to distinguish MDS from the other causes of anemia in the elderly [206]. (See "Anemia in the older adult" and "Sideroblastic anemias: Diagnosis and management", section on 'Copper deficiency' and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)

Medications — The use of a number of medications, including granulocyte colony-stimulating factor [207], valproic acid [208], mycophenolate mofetil [209,210], ganciclovir [210,211], and alemtuzumab [212], has been associated with acquired dysplastic changes, including macrocytosis, abnormal (reduced) neutrophil lobulation, neutropenia, thrombocytopenia, and dysplastic changes in all three cell lines on bone marrow examination. Methotrexate or alkylating agents such as cyclophosphamide, sometimes used to treatment autoimmune disorders, can cause dysplasia. In most of the reported cases, these changes were reversible on reduction or discontinuation of these medications, usually over a period of several weeks. Repeat bone marrow examinations may be necessary in complicated cases to confirm the diagnosis.

Inherited and acquired sideroblastic anemias — The sideroblastic anemias comprise a wide spectrum of relatively uncommon heritable and acquired erythropoietic disorders that are due to various abnormalities in heme synthesis and mitochondrial function (table 12 and table 13). (See "Sideroblastic anemias: Diagnosis and management" and "Causes and pathophysiology of the sideroblastic anemias".)

The evaluation of a patient with suspected MDS with ring sideroblasts (or MDS/MPN with ring sideroblasts and thrombocytosis) should exclude other causes of acquired sideroblastic anemia (eg, copper deficiency, medications, excessive alcohol use). In addition, women should be evaluated for X-linked sideroblastic anemia (XLSA) since women with XLSA may present in adulthood with pathologic features indistinguishable from MDS with ring sideroblasts. While genetic testing is available for XLSA (ALAS2 gene mutation testing), XLSA can also be excluded with moderate confidence in those with persistent sideroblasts following a two to three month trial of vitamin B6 supplementation (pyridoxine 50 mg daily). Testing for XLSA is not necessary in individuals with one of the commonly acquired mutations in the SF3B1 or the JAK2 gene, which confirms an MDS or myeloproliferative neoplasm (MPN) and excludes a congenital sideroblastic anemia.

WHO CLASSIFICATION — The MDS are classified using the World Health Organization (WHO) classification system based upon a combination of morphology, immunophenotype, genetics, and clinical features (table 14) [151,213]. This classification attempts to identify biologic entities in the hopes that future work will elucidate molecular pathways that might be amenable to targeted therapies. The WHO classification system was built upon the French-American-British (FAB) Cooperative Group classification, which continues in the vernacular (table 15) [179]. These classification systems are complicated and require morphologic evaluation by an expert hematopathologist [214].

The WHO classification system distinguishes six general entities with the following estimated percentages (table 14) [128,151,215]:

MDS with single lineage dysplasia (previously called "refractory cytopenia with unilineage dysplasia," which includes refractory anemia, refractory neutropenia, and refractory thrombocytopenia) – <5 percent

MDS with ring sideroblasts, which includes subgroups with single lineage dysplasia and multilineage dysplasia (previously called "refractory anemia with ring sideroblasts") – <5 percent

MDS with multilineage dysplasia (previously called "refractory cytopenia with multilineage dysplasia") – 70 percent

MDS with excess blasts (MDS-EB, previously called "refractory anemia with excess blasts"), which can be further subclassified into MDS-EB-1 and MDS-EB-2 based on blast percentages – 25 percent

MDS with isolated del(5q) – 5 percent

MDS, unclassified – <5 percent

Childhood MDS is considered a distinct entity in the WHO classification system [128,151]. Refractory cytopenia of childhood accounts for approximately half of childhood MDS and is the most common subtype in this setting.

MDS with single lineage dysplasia — MDS with single lineage dysplasia (previously called "refractory cytopenia with unilineage dysplasia," which included refractory anemia, refractory neutropenia, and refractory thrombocytopenia) is characterized by <5 percent blasts in the bone marrow and ≤1 percent blasts in the peripheral blood (table 14) [128,151]. Monocytosis, significant numbers of ringed sideroblasts, and Auer rods are absent. The recommended level for defining dysplasia is ≥10 percent in the affected cell lineage, and the recommended values for defining cytopenia are [216]:

Refractory anemia – Hemoglobin <10 g/dL

Refractory thrombocytopenia – Platelet count <100,000/microL

Refractory neutropenia – Absolute neutrophil count (ANC) <1800/microL

While the majority of patients with MDS with single lineage dysplasia will demonstrate a single cytopenia (usually corresponding to the dysplastic line), patients with two cytopenias but with unilineage dysplasia are also included in this classification. In contrast, patients with refractory pancytopenia and unilineage dysplasia are not considered to have MDS with single lineage dysplasia, and are instead included in the category of MDS, unclassifiable.

MDS with ring sideroblasts — MDS with ring sideroblasts (previously called "refractory anemia with ring sideroblasts") fulfills all of the criteria for refractory anemia, but also demonstrates >15 percent ring sideroblasts (table 14) [128]. Pathologic sideroblasts containing more than five iron-laden mitochondria per cell may be evident on bone marrow specimens stained for the presence of iron (picture 9). Sideroblasts in which five or more iron-laden mitochondria occupy more than one-third of the nuclear rim are termed "ring" sideroblasts [125,217]. Ring sideroblasts and increased storage iron can be found in any of the MDS subtypes; however, the former is characteristic of MDS with ring sideroblasts. MDS with ring sideroblasts can be further subclassified into cases with single lineage dysplasia and those with multilineage dysplasia.

MDS with ring sideroblasts is usually associated with a good prognosis. However, the 15 percent cutoff value used to define MDS with ring sideroblasts is arbitrary and has been questioned. In a study of 200 patients with MDS without excess blasts who had >1 percent ring sideroblasts, the percentage of ring sideroblasts was not an independent predictor of leukemia-free or overall survival [218]. In another study of 293 patients with a myeloid neoplasm and 1 percent or more ring sideroblasts, an SF3B1 mutation was associated with isolated erythroid dysplasia and a favorable prognosis while those with wild-type SF3B1 had multilineage dysplasia and an unfavorable prognosis [22]. (See "Prognosis of the myelodysplastic syndromes in adults", section on 'FAB classification'.)  

MDS with multilineage dysplasia — MDS with multilineage dysplasia (previously called "refractory cytopenia with multilineage dysplasia") is characterized by less than 5 percent bone marrow blasts and severe dysplasia in two or more cell lineages (table 14) [128].

MDS with excess blasts — MDS with excess blasts (MDS-EB, previously called "refractory anemia with excess blasts" [RAEB]) is characterized by 5 to 19 percent bone marrow blasts (table 14). Prior classification systems had further subdivided RAEB into RAEB-I (5 to 9 percent blasts) and RAEB-II (10 to 19 percent blasts) [128]. In a study of 558 patients who met these WHO criteria for RAEB, there were no significant differences (other than blast count) between those with RAEB-I or RAEB-II with respect to their clinical, morphologic, hematologic, or cytogenetic parameters [219]. However, RAEB-II was associated with a shorter median survival (9 versus 16 months) and an increased risk of developing acute myeloid leukemia (40 versus 22 percent).

In the 2016 WHO classification system, MDS-EB-1 includes cases with no Auer rods that have 5 to 9 percent bone marrow blasts and/or 2 to 4 percent peripheral blood blasts [151]. MDS-EB-2 includes cases with 10 to 19 percent bone marrow blasts and/or 5 to 19 percent peripheral blood blasts and/or Auer rods.

MDS with isolated del(5q) — Approximately 5 percent of patients with MDS present with "5q- syndrome" characterized by severe anemia, preserved platelet counts, and an interstitial deletion of the long arm of chromosome 5 as the sole cytogenetic abnormality (table 14) [140,220,221]. 5q- syndrome may follow a relatively benign course that extends over several years. It has a low incidence of transformation into acute leukemia and is well known for its responsiveness to treatment with novel agents (eg, lenalidomide). The response of MDS with isolated del(5q) to lenalidomide may be explained by the deletion of one copy of the gene for casein kinase 1A1 [222], which is located in the commonly deleted region of chromosome 5q. Cells that are haploinsufficient for CK1A1 are unusually susceptible to killing by lenalidomide, which binds and directs ubiquitination complexes containing the factor cereblon (CRBN) to CK1A1, thereby mediating its destruction. (See "Treatment of intermediate, low, or very low risk myelodysplastic syndromes", section on 'Patients with 5q deletion'.)

The 5q- syndrome is a distinctive type of primary MDS that primarily occurs in older women [220,221,223]. The median age at diagnosis is 65 to 70 years, with a female predominance of 7:3 (in contrast to a male predominance in other forms of MDS) [224]. Affected patients typically present with a refractory macrocytic anemia, normal or elevated platelet counts, and the absence of significant neutropenia [223]. Because of the typical absence of thrombocytopenia and significant neutropenia, there is a low incidence of bleeding and infection in these patients, but red blood cell transfusions are frequently required. (See "Cytogenetics and molecular genetics of myelodysplastic syndromes", section on 'Deletions of chromosome 5'.)

The bone marrow in 5q- syndrome is characterized by the presence of micromegakaryocytes with monolobulated and bilobulated nuclei. There are less than 5 percent blasts in the marrow in approximately 80 percent of patients [223,224]. The del(5q) is typically interstitial. Approximately 75 percent of cases have a del(5)(q13q33); other interstitial deletions include del(5)(q15q33) and del(5)(q22q33) [225-227]. (See "Cytogenetics and molecular genetics of myelodysplastic syndromes", section on 'Deletions of chromosome 5' and "Cytogenetics and molecular genetics of myelodysplastic syndromes", section on '5q- syndrome'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Myelodysplastic syndromes (MDS) (The Basics)")

Beyond the Basics topics (see "Patient education: Myelodysplastic syndromes (MDS) in adults (Beyond the Basics)")


The myelodysplastic syndromes (MDS) comprise a heterogeneous group of malignant hematopoietic stem cell disorders characterized by dysplastic and ineffective blood cell production. MDS occur most commonly in older adults and may occur de novo or arise years after exposure to potentially mutagenic therapy (eg, radiation exposure, chemotherapy). (See 'Epidemiology' above and 'Pathogenesis' above.)

The diagnosis of MDS should be considered in any patient with unexplained cytopenia(s) or monocytosis. Careful inspection of the peripheral blood smear and bone marrow aspirate is necessary to document the requisite dysplastic cytologic features identifiable in any or all of the hematopoietic lineages (table 3). Detection of certain chromosomal abnormalities distinguishes between MDS and acute myeloid leukemia (AML) in some cases, aids in the classification of MDS, and is a major factor in determining prognostic risk group and therapy. Some centers routinely incorporate DNA sequencing. (See 'Evaluation' above and 'Diagnosis' above.)

The diagnosis of MDS requires both of the following:

Otherwise unexplained quantitative changes in one or more of the blood and bone marrow elements (ie, red cells, granulocytes, platelets). The values used to define cytopenia are: hemoglobin <10 g/dL (100 g/L); absolute neutrophil count <1.8 x 109/L (<1800/microL); and platelets <100 x 109/L (<100,000/microL). However, failure to meet the threshold for cytopenia does not exclude the diagnosis of MDS if there is definite morphologic evidence of dysplasia.

Morphologic evidence of significant dysplasia (ie, ≥10 percent of erythroid precursors, granulocytes, or megakaryocytes) upon visual inspection of the peripheral blood smear, bone marrow aspirate, and bone marrow biopsy in the absence of other causes of dysplasia (table 3). In the absence of morphologic evidence of dysplasia, a presumptive diagnosis of MDS can be made in patients with otherwise unexplained refractory cytopenia in the presence of certain genetic abnormalities. (See 'Genetic features' above.)

Importantly, blast forms must account for less than 20 percent of the total cells of the bone marrow aspirate and peripheral blood. In addition, the presence of myeloid sarcoma or certain genetic abnormalities, such as those with t(8;21), inv(16), or t(15;17), are considered diagnostic of AML, irrespective of the blast cell count. (See 'Acute myeloid leukemia' above.)

MDS must be distinguished from other entities that may also present with cytopenias and/or dysplasia. Conditions that present with features similar to MDS include HIV infection, deficiencies of vitamin B12, folate, or copper, and zinc excess. Other entities considered in a specific case depend largely upon the presenting features. (See 'Differential diagnosis' above.)

MDS is classified using the World Health Organization (WHO) classification system based upon a combination of morphology, immunophenotype, genetics, and clinical feature (table 14). (See 'WHO classification' above.)

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