Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)

INTRODUCTION — The myelodysplastic syndromes (MDS) comprise a group of hematologic malignancies characterized by clonal hematopoiesis, one or more cytopenias (ie, anemia, neutropenia, and/or thrombocytopenia), and abnormal cellular maturation. MDS shares clinical and pathologic features with acute myeloid leukemia (AML), but MDS has a lower percentage of blasts in peripheral blood and bone marrow (by definition, <20 percent). Patients with MDS are at risk for symptomatic anemia, infection, bleeding, and transformation to AML, the incidence of which varies widely across MDS subtypes.

The pathogenesis, epidemiology, clinical manifestations, pathologic features, and diagnosis of MDS are reviewed in this topic.

The cytogenetics, prognosis, and treatment of MDS and therapy-related myeloid neoplasms are discussed separately.

●(See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)

●(See "Overview of the treatment of myelodysplastic syndromes".)

●(See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis".)

●(See "Cytogenetics and molecular genetics of myelodysplastic syndromes".)

PATHOGENESIS — MDS are clonal neoplasms that arise from mutations in hematopoietic stem cells [1-5]. The precise cause of the mutations is unknown for most patients, but in some it is associated with exposure to cytotoxic chemotherapy and/or ionizing radiation (ie, therapy-related MDS) or environmental toxins (eg, tobacco, benzene) [6]. Overall, a high fraction of acquired mutations consist of C to T substitutions that are consistent with spontaneous deamination of cytosine, an event that occurs with clock-like regularity in hematopoietic stem cells and which may explain, at least in part, the association of MDS with aging [7].

In many cases, MDS arises in the setting of clonal hematopoiesis of indeterminate potential (CHIP), in which mutations that are associated with MDS are present, but characteristic manifestations of MDS (ie, dysplasia and ineffective hematopoiesis) are absent [8,9]. CHIP and related hematopoietic disorders are discussed separately. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis".)

Rarely, inherited genetic abnormalities (eg, trisomy 21, Fanconi anemia, Bloom syndrome, dyskeratosis congenita and other telomeropathies, Shwachman-Diamond syndrome, ataxia telangiectasia) or other hematologic conditions (eg, paroxysmal nocturnal hemoglobinuria, congenital neutropenia) (table 1) contribute to development of MDS [10]. Familial MDS have been reported in association with germline mutations in RUNX1, ANKRD26, CEBPA, DDX41, ETV6, TERC, TERT, SRP72, and GATA2 (table 2). Although such associations were previously considered rare, routine targeted sequencing of MDS genomes has increased the identification of cases with an underlying germline predisposition. Familial MDS is discussed in more detail separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)

Driver mutations are detected in >90 percent of cases of MDS. Among the most commonly mutated genes are DNMT3A, TET2, IDH genes, ASXL1, TP53, RUNX1, and genes that encode components of the 3' RNA splicing machinery (eg, SF3B1, U2AF1, SRSF2, and ZRSR2) [11-16]. Examples of functions of genes that are mutated in MDS include:

●Transcription factors – RUNX1 encodes a transcription factor that regulates normal hematopoietic and lymphoid development; alteration of Runx1 in mouse models induces MDS-like abnormalities and deranges hematopoietic stem cell homeostasis [17].

●Epigenetic regulators – DNMT3A, TET2, and IDH encode regulators of DNA methylation, and MDS genomes are associated with global DNA hypomethylation with concomitant hypermethylation of gene-promoter regions.

●Cohesin complex – Genes that encode regulators of higher order chromatin structure (eg, looping between long-range enhancers and gene promoters) that are mutated in MDS include STAG2, CTCF, SMC3, SMC1A, and RAD21; in total, cohesin gene mutations are found in approximately 15 percent of MDS [18,19].

●Aberrant splicing/translation – Mutations in genes that encode regulators of splicing may cause missplicing of numerous mRNA molecules; resultant aberrant proteins may contribute to MDS pathogenesis [20]. As an example, somatic mutations in SF3B1, which encodes components of the RNA splicing machinery, occurs in 60 to 80 percent of MDS with ring sideroblasts [11,21-27]. How splicing factor mutations contribute to the pathogenesis is uncertain, but aberrant 3' splice-site selection leading to abnormal mRNA transcripts may be involved [28]. Genes whose misspliced variants may contribute the pathophysiology of MDS include FAS, TNF, and ABCB7 [29].

Acquired 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-) [30]. Inherited mutations in SBDS, which also encodes a ribosomal protein, underlies Schwachman-Diamond syndrome.

●Telomerase dysfunction – Dysfunction of the telomerase apparatus may contribute to MDS pathophysiology [31,32].

●Altered microRNA species [33] – Details of mutations that are most commonly associated with MDS are presented separately. (See "Cytogenetics and molecular genetics of myelodysplastic syndromes", section on 'Gene mutations'.)

●Factors extrinsic to hematopoietic cells – Abnormalities in stromal cells and T cell dysregulation may contribute to the pathobiology of MDS [18,34,35]. Overproduction of inflammatory cytokines and inflammasome activity may exacerbate anemia; luspatercept, which binds transforming growth factor (TGF)-beta superfamily ligands, has clinical activity in MDS [36-38].

EPIDEMIOLOGY — MDS occurs most commonly in older adults, but the precise incidence is not well-defined.

The median age at presentation is 70 years and disease onset before age 50 is unusual (except for therapy-related MDS); rare cases have been reported in children [39-44]. 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 [45].

There is a male predominance in most categories of MDS, with the exception of MDS with isolated del(5q), which is more common in women. (See 'MDS with isolated del(5q)' below.)

The annual incidence of MDS has been estimated to be 1 to 5 cases per 100,000; however, for individuals aged >70 years the incidence is at least 20 cases/100,000 [46-54]. Due to underreporting of MDS in most cancer registries, the true annual incidence in individuals >65 years of age may be closer to 75 cases/100,000. As examples, the Surveillance, Epidemiology, and End Results (SEER) Program estimated 10,000 new cases of MDS diagnosed annually in the United States, but Medicare claims from the same time period were nearly 5 times higher in patients >65 years [46,48,52,55].

CLINICAL PRESENTATION — Clinical manifestations of MDS are variable. Some patients present with fatigue, infections, bruising, or other symptoms or complications of cytopenias, while others are asymptomatic and come to medical attention due to abnormalities on a routine complete blood count (CBC).

Cytopenias — Anemia is the most common cytopenia associated with MDS and may manifest as fatigue, weakness, exercise intolerance, angina, dizziness, cognitive impairment, or an altered sense of well-being [55-58]. Fatigue is nearly ubiquitous and often may be out of proportion to the degree of anemia [59]. Less commonly, complications associated with leukopenia (eg, infections, gingivitis) or thrombocytopenia (eg, easy bruising, bleeding) are present. Systemic symptoms such as fever, sweats, or weight loss are uncommon and generally represent late manifestations of MDS or transformation to acute leukemia. Physical findings of MDS are nonspecific but may include pallor, petechiae, purpura, mucosal ulceration/gingivitis, or stigmata of infections. Hepatomegaly, splenomegaly, and lymphadenopathy are uncommon and, if present, suggest another diagnosis (eg, lymphoma).

Infections — Patients with MDS may develop infections related to neutropenia and granulocyte dysfunction (eg, impaired chemotaxis and microbial killing) [60,61]. 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 treatment with immunosuppressive agents. Evaluation and treatment of infections in patients with MDS are discussed separately. (See "Management of the hematologic complications of myelodysplastic syndromes", section on 'Infections'.)

Abnormalities of adaptive immunity may also occur, even though lymphocytes are not generally derived from the malignant clone [5]. Immunoglobulin production is variably affected, with hypogammaglobulinemia, polyclonal hypergammaglobulinemia, and monoclonal gammopathy reported in 13, 30, and 12 percent of patients, respectively [62].

Autoimmune abnormalities — Autoimmune abnormalities may be present in up to one-quarter of patients of MDS. Analysis of a large database that compared 2471 patients with MDS with 42,886 controls from the Medicare population reported that patients with MDS were more likely to exhibit autoimmune phenomena (23 versus 14 percent) [63]. 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. (See "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Paraneoplastic and cancer treatment-related disease' and "Acquired pure red cell aplasia in adults", section on 'Pathogenesis'.)

Acquired hemoglobin H disease — Acquired hemoglobin H disease (also called acquired alpha thalassemia) has been reported in <10 percent of cases of MDS [64-68]. Acquired hemoglobin H disease is associated with a spectrum of morphologic findings (eg, microcytosis, poikilocytosis, hypochromia, hemoglobin H-containing red cells) (picture 1). Acquired (somatic) mutation of ATRX (an X-linked gene encoding a chromatin-associated protein) and acquired deletions of alpha globin genes have been linked to the presence of hemoglobin H [64]. (See "Molecular genetics of the thalassemia syndromes", section on 'Globin gene anatomy and physiology' and "Pathophysiology of thalassemia", section on 'Terminology and disease classification'.)

Cutaneous manifestations — Skin lesions are uncommon in patients with MDS. However, Sweet syndrome (acute febrile neutrophilic dermatosis) may herald transformation to acute leukemia [69-72]. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)

Development of myeloid sarcoma is considered diagnostic of transformation to acute myeloid leukemia. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Myeloid sarcoma'.)

EVALUATION — Evaluation of MDS involves clinical evaluation, laboratory studies, and bone marrow examination.

History and physical examination — The history should elicit details regarding consequences or complications of cytopenias (eg, fatigue, infections, bruising). It should also evaluate other potential causes for cytopenias and/or dysplasia, including nutritional status, alcohol and drug use, medications, exposure to toxic chemicals, prior treatment with antineoplastic agents or radiotherapy, and risk factors for HIV infection.

Physical examination may reveal findings related to cytopenias, including pallor, dyspnea, tachycardia; manifestations of infections or mucosal ulceration; and/or bleeding or bruising. Some patients may have splenomegaly, but adenopathy is uncommon.

Complete blood count — Complete blood count (CBC) with leukocyte differential usually demonstrates anemia, but neutropenia and thrombocytopenia are more variable [73]. While isolated anemia is often seen, few patients present with isolated neutropenia, thrombocytopenia, or monocytosis without anemia. Pancytopenia (ie, anemia, leukopenia, and thrombocytopenia) is present in up to half of patients at the time of diagnosis.

●Red blood cells – Anemia is almost uniformly present and is generally associated with an inappropriately low reticulocyte response [73]. The mean corpuscular volume (MCV) may be macrocytic (>100 femtoL) or normal. The red cell distribution width (RDW) is often increased reflecting the presence of increased variability in red cell size (anisocytosis). The mean corpuscular hemoglobin concentration (MCHC) is usually normal, reflecting a normal ratio of hemoglobin to cell size.

●Leukocytes – Approximately half of patients have a reduced total white blood cell count (ie, leukopenia), usually resulting from absolute neutropenia [73]. Circulating immature neutrophils (myelocytes, promyelocytes, and myeloblasts) may be identified, but blasts constitute fewer than 20 percent of the leukocyte differential.

●Platelets – Variable levels of thrombocytopenia are present in approximately one-quarter of patients, but isolated thrombocytopenia is not a common early manifestation of MDS [74]. However, isolated thrombocytopenia with minimal morphologic dysplasia has been described in patients in whom del(20q) was the sole karyotypic abnormality [75]. Thrombocytosis is less common. In a single institution study, 8 percent of 388 patients presented with a high platelet count; there was a low incidence of spontaneous bleeding or thromboembolic events [76]. Thrombocytosis may be associated with abnormalities of chromosome 5q and MDS/MPN with ring sideroblasts and thrombocytosis, which is often associated with activating mutations in JAK2 and SF3B1 [77].

Blood smear — The peripheral blood smear usually demonstrates dysplasia in the red and white blood cell series and may reveal platelet abnormalities (table 3).

●Red blood cells – Red blood cells are usually normocytic or macrocytic, but some patients may have a subpopulation of hypochromic, microcytic red cells [73]. Ovalomacrocytosis is the most common morphologic abnormality, but elliptocytes, teardrop cells, stomatocytes, or acanthocytes (spur cells) may be seen. Basophilic stippling, Howell-Jolly bodies, and megaloblastoid nucleated red cells may be seen on the blood smear (picture 2 and picture 3). Reticulocytosis may reflect delayed reticulocyte maturation (so-called pseudoreticulocytosis) or may indicate a superimposed autoimmune hemolytic anemia.

●White blood cells – Dysplastic neutrophils are commonly found on the blood smear. Neutrophils may demonstrate increased size, abnormal nuclear lobation, and abnormal granularity. Granulocytes commonly display reduced segmentation (pseudo-Pelger-Huet abnormality), often accompanied by reduced or absent granulation (picture 4 and picture 5) and/or ring-shaped nuclei or nuclear sticks [78-81]. Rarely, a pseudo-Chediak-Higashi anomaly (picture 6) or myelokathexis-like features (ie, lengthening and thinning of nuclear segments) (picture 7) may be evident [82,83]. Monocytes may appear immature or exhibit abnormalities of nuclear lobation. (See "Congenital neutropenia", section on 'Severe congenital neutropenia'.)

●Platelets – Platelets are usually morphologically normal. Less commonly, platelets may be smaller or larger than normal or hypergranular or hypogranular. Megakaryocytic fragments are not seen.

Bone marrow examination — Bone marrow examination is an essential component of the evaluation, diagnosis, and classification of MDS.

Morphology — The bone marrow features single- or multilineage dysplasia (table 3) and is usually hypercellular [73,84]. An adequate bone marrow aspirate should provide material for a 500 cell differential count and a cytologic evaluation of the blasts and other cells. Morphologic evidence of dysplasia has limited reproducibility when dysplastic changes are not overt and may be complemented by immunophenotypic methods [85,86].

Characteristic morphologic features of MDS in the bone marrow examination include:

●Blasts – Myeloblasts are increased, but by definition, the blast percentage is <20 percent [73]. Myeloblasts can be identified by their high nuclear:cytoplasmic ratio, easily visible nucleoli, fine nuclear chromatin, variable cytoplasmic basophilia, few or no cytoplasmic granules, and absent Golgi zone [87,88]. Auer rods within blasts (picture 8) are uncommon, but when present they are diagnostic for MDS with excess blasts, regardless of the percentage of blasts. (See 'MDS with excess blasts' below.)

●Myeloid cells – Impaired myeloid maturation is often readily apparent. There are variable percentages of granulocytic precursors and, not infrequently, a relative maturation arrest at the myelocyte stage [89]. In granulocytic precursors, the cytoplasm may mature more rapidly than the nucleus and cells may have large size, abnormal nuclear shape, and variable levels of cytoplasmic granularity [90]. Granulopoiesis may be displaced from its normal paratrabecular location to more central marrow spaces; clusters of immature cells may be located centrally in the marrow space rather than along the endosteal surface, a phenomenon known as abnormal localization of immature precursors (ALIP) [91-94].

●Erythroid cells – Although erythroid hyperplasia (associated with ineffective erythropoiesis) is usually seen, red cell aplasia and/or hypoplasia also rarely occur [95]. 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 ring sideroblasts [91,96]. Internuclear bridging characterized by chromatin threads that tether dissociated nuclei reflects impaired mitosis and may contribute to the addition and deletion of genetic material characteristic of MDS [97].

●Megakaryocytes – Megakaryocytes are usually normal or increased in number and sometimes occur in clusters. Abnormal megakaryocytes, including large or very small mononuclear forms (micromegakaryocytes or "dwarf megakaryocytes"), megakaryocytes with multiple dispersed nuclei ("pawn ball megakaryocytes"), and hypogranular megakaryocytes, are common findings (picture 9) [78,98,99]. Non-lobulated or mononuclear megakaryocytes may also be identified, particularly in association with abnormalities of chromosome 5q-.

●Other lineages – Reactive lymphocytosis, lymphoid aggregates, increased histiocytes/macrophages, and/or pseudo-Gaucher histiocytes may be seen. Increased numbers of mast cells, particularly when demonstrating spindled morphology or occurring in clusters of ≥15 cells, may be a manifestation of systemic mastocytosis, which sometimes accompanies MDS and other myeloid neoplasms (ie, systemic mastocytosis with associated hematologic neoplasm), particularly in cases that are associated with activating mutations in the KIT tyrosine kinase gene [100,101]. (See "Systemic mastocytosis: Determining the subtype of disease", section on 'Systemic mastocytosis with an associated hematologic neoplasm'.)

●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 [102-105]. While myelofibrosis occurs in all subtypes of MDS, it is most common in therapy-related MDS [44]. Fibrosis generally takes the form of increased numbers and/or thickness of reticulin fibers (best detected with a silver impregnation stain); importantly, deposition of mature collagen (detected with a trichrome stain) is uncommon in MDS [106]. The degree of fibrosis should be graded using European consensus criteria (table 4) and, if prominent enough, may lead to a diagnosis of MDS/myeloproliferative neoplasm overlap [107,108]. (See 'MDS/MPN syndromes' below.)

Cytochemistry and immunocytochemistry — Iron staining is required to detect ring sideroblasts. Other cytochemical and immunocytochemical stains can be useful adjuncts for identifying cellular lineage and/or the extent and aberrancy of cellular maturation.

Examples include:

●Iron staining with Prussian blue is required for detecting ring sideroblasts. (See 'MDS with ring sideroblasts' below.)

●Periodic acid-Schiff (PAS) staining can aid in detecting dyserythropoiesis, while peroxidase, Sudan Black B, and alkaline phosphatase can highlight aberrant or incomplete myeloid differentiation.

●Immunocytochemistry staining can be useful to:

•Distinguish erythroid precursors (eg, glycophorin [CD235a], transferrin receptor [CD71], GATA1)

•Quantify myeloid blasts and progenitors (eg, CD34, CD117, CD33, myeloperoxidase, lysozyme)  

•Detect dysplastic or immature megakaryocytes (eg, von Willebrand factor, factor VIII, CD41, CD61)

•Detect lineage infidelity, confirm the presence of bi- or tri-lineage dysplasia, and exclude a lymphoid origin of primitive blasts

Flow cytometry — Multiparameter flow cytometry is not required for the diagnosis of MDS but can be useful for assessing diagnostic and prognostic features of MDS [109-115]. Flow cytometry should be performed according to standardized methods proposed by the International Flow Cytometry Working Group of the European LeukemiaNet [114,116].

Cytogenetic and molecular features — Characterization of cytogenetic and molecular abnormalities is required for the diagnosis and classification of MDS, determining prognostic risk group, and selecting therapy [117]. (See 'Diagnosis and classification' below and "Cytogenetics and molecular genetics of myelodysplastic syndromes".)

Chromosomal abnormalities are detected by cytogenetic analysis and fluorescence in situ hybridization (FISH), while gene rearrangements and mutations can be detected by polymerase chain reaction (PCR) and targeted gene panels or next-generation sequencing. Details of cytogenetic findings in patients with MDS are presented separately. (See "Cytogenetics and molecular genetics of myelodysplastic syndromes".)

Cytogenetic features that support the diagnosis of MDS, exclude the diagnosis, or are non-diagnostic are described below. (See 'Diagnosis' below.)

DIAGNOSIS AND CLASSIFICATION — MDS should be categorized according to the World Health Organization (WHO) classification scheme, which has superseded the former French-American-British (FAB) classification system.

Diagnosis — MDS should be considered in any patient with unexplained cytopenias or clinical manifestations associated with these findings, such as symptoms of anemia, infections, or bleeding/bruising.

The diagnosis of MDS is made based on the presence of one or more cytopenias, ≥10 percent of nucleated cells in at least one lineage that are morphologically dysplastic, <20 percent blasts forms in blood and bone marrow, and/or characteristic cytogenetic or molecular findings, without evidence of an alternate cause of these findings. Distinguishing between MDS, acute myeloid leukemia (AML), and other causes of cytopenias and/or dysplasia is discussed below. (See 'Differential diagnosis' below.)

The diagnosis of MDS is based on:

●Cytopenias – Hemoglobin <10 g/dL (100 g/L); absolute neutrophil count (ANC) <1.8 x 10⁹/L (<1800/microL); platelets <100 x 10⁹/L (<100,000/microL).

Note that some individuals have ANC <1.5 x 10⁹/L with no associated infections or other cytopenias; such variants are most often encountered in individuals of African descent, Sephardic Jews, West Indians, Yemenites, Greeks, and Arabs and may be described as constitutional neutropenia (formerly called benign ethnic neutropenia). (See "Approach to the adult with unexplained neutropenia", section on 'Normal variants <1500/microL'.)

●Dysplasia – Morphologic or immunophenotypic evidence of significant dysplasia in ≥10 percent of erythroid precursors, granulocytes, or megakaryocytes on the blood smear or bone marrow examination, in the absence of other causes of dysplasia (table 3).

●Cytogenetic abnormalities – The following chromosomal abnormalities are presumptive evidence of MDS in patients with otherwise unexplained refractory cytopenia and no morphologic evidence of dysplasia [73]:

•Unbalanced chromosomal abnormalities:

-Loss of chromosome 7 or del(7q)

-del(5q) or t(5q)

-Isochromosome 17q or t(17p)

-Loss of chromosome 13 or del(13q)

-del(11q)

-del(12p) or t(12p)

-del(9q)

-idic(X)(q13)

•Balanced chromosomal abnormalities:

-t(11;16)(q23.3;p13.3)

-t(3;21)(q26.2;q22.1)

-t(1;3)(p36.3;q21.2)

-t(2;11)(p21;q23.3)

-inv(3)(q21q26.2) or t(3;3)(q21.2;q26.2)

-t(6;9)(p23;q34.1)

In contrast, the following cytogenetic/molecular findings exclude the diagnosis of MDS and instead are considered diagnostic of AML [73]:

•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

In the absence of dysplasia or abnormal blood counts, other clonal karyotypic changes lack diagnostic specificity and are not sufficient criteria by themselves for a diagnosis of MDS; examples include del(Y), trisomy 8, and del(20q) [73].

WHO classification — MDS is classified using the WHO classification system (table 5). WHO MDS categories are important for selection of treatment and estimating prognosis.

Classification criteria — The WHO classification system (table 5) uses the following criteria to classify MDS (table 6) [73,108]:

●Number of dysplastic lineages

●Percentage of blasts in bone marrow and peripheral blood

●Cytogenetic findings

●Percentage of ring sideroblasts

●Number of cytopenias (based on criteria from the International Prognostic Scoring System [IPSS]) (table 6) [117,118]:

•Hemoglobin <10 g/dL.

•Platelets <100,000/microL.

•Absolute neutrophil count <1800/microL; for all categories of MDS, peripheral blood monocytes must be <1000/microL. When monocytes are >1000/microL, the case should be diagnosed as chronic myelomonocytic leukemia or a related disorder. (See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis".)

Childhood MDS is considered a distinct entity in the WHO classification system [73].

Diagnostic criteria, clinical aspects, and differential diagnosis of individual categories of MDS are described in the sections below.

MDS with single lineage dysplasia — MDS with single lineage dysplasia (MDS-SLD) (table 5) was previously called refractory cytopenia with unilineage dysplasia, which included refractory anemia, refractory neutropenia, and refractory thrombocytopenia.

●Diagnostic criteria – MDS-SLD is defined by ≥10 percent dysplastic cells in a single lineage and otherwise unexplained cytopenia in one or two lineages; other diagnostic criteria include <5 percent blasts in bone marrow and <1 percent in peripheral blood; no Auer rods; <15 percent ring sideroblasts (or <5 percent if SF3B1 mutation is present); and any cytogenetic findings may be present unless the findings fulfill all criteria for MDS with isolated del(5q) [73]. The type of cytopenia usually corresponds to the dysplastic lineage (eg, anemia and erythroid dysplasia), but discordance may sometimes be seen. Cases of MDS-SLD do not require further subclassification according to the affected lineage(s). Ethnicity and sex should be taken into consideration when assessing cytopenias, and milder cytopenias do not exclude the diagnosis of MDS if definitive morphologic and/or cytogenetic evidence of MDS is present. If there is no clonal cytogenetic abnormality, the patient should be observed for at least six months before a definitive diagnosis of MDS-SLD is established, unless additional morphologic or cytogenetic evidence emerges during the period of observation.

●Clinical features – MDS-SLD accounts for 7 to 20 percent of all cases of MDS [73]. The median age at onset is 65 to 70 years and there is no significant sex predilection. The vast majority of cases presents with refractory anemia or bicytopenia; other isolated cytopenias are uncommon. At least 90 percent of patients have a low or intermediate-1 IPSS risk score (table 6) and approximately 85 percent have good or very good cytogenetic profiles [117,119]. Median overall survival (OS) is approximately 66 months, and the rate of progression to AML at five years is 10 percent [119-121]. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults", section on 'IPSS (Original IPSS)'.)

●Differential diagnosis – MDS-SLD should be distinguished from:

•Other categories of MDS:

-Cases with dysplastic changes ≥10 percent in two or three lineages should be classified as MDS with multilineage dysplasia. (See 'MDS with multilineage dysplasia' below.)

-Cases with erythroid dysplasia only and ≥15 percent ring sideroblasts (or ≥5 percent, if SF3B1 mutation is present) should be classified as MDS with ring sideroblasts and single lineage dysplasia. (See 'MDS with ring sideroblasts' below.)

-Cases with single lineage dysplasia and pancytopenia should be classified as MDS, unclassifiable. (See 'MDS, unclassifiable' below.)

-Cases with 1 percent blasts in peripheral blood on two successive evaluations and <5 percent blasts in bone marrow should be categorized as MDS, unclassifiable, due to the more aggressive clinical course [119]. (See 'MDS, unclassifiable' below.)

-Cases with 2 to 4 percent blasts in peripheral blood and <5 percent blasts in bone marrow should be classified as MDS with excess blasts-1, if other criteria for MDS are present. (See 'MDS with excess blasts' below.)

•Other conditions:

-Other causes of dysplasia and/or cytopenias, including drug and toxin exposure, growth factor therapy, viral infections, immunologic disorders, congenital disorders, vitamin or essential element deficiencies should be excluded, as described below. (See 'Differential diagnosis' below.)

-MDS-SLD should be distinguished from idiopathic cytopenia of undetermined significance (ICUS), which lacks the morphologic criteria required for the diagnosis of MDS [122]. (See "Idiopathic and clonal cytopenias of uncertain significance (ICUS and CCUS)", section on 'Idiopathic cytopenia of undetermined significance (ICUS)'.)

-The presence of mutations alone, even in a patient with a cytopenia, is not sufficient to diagnose MDS-SLD in the absence of ≥10 percent dysplastic cells in one lineage; this would instead be diagnosed as clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenia of uncertain significance (CCUS). (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis", section on 'Clonal hematopoiesis of indeterminate potential (CHIP)' and "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis", section on 'Clonal cytopenia of uncertain significance (CCUS)'.)

MDS with multilineage dysplasia — MDS with multilineage dysplasia (MDS-MLD) (table 5) was previously called refractory cytopenia with multilineage dysplasia.

●Diagnostic criteria – MDS-MLD is defined by ≥10 percent dysplastic cells in two or three lineages and one to three cytopenias; other diagnostic criteria include blasts of <5 percent in bone marrow and <1 percent in peripheral blood; no Auer rods; ring sideroblasts <15 percent (or <5 percent if SF3B1 mutation is present); and any cytogenetic findings may be present unless the findings fulfill all criteria for MDS with isolated del(5q) [73]. At least 200 erythroid precursors, 200 neutrophil precursors, and 30 megakaryocytes should be evaluated to document multilineage dysplasia; the presence of micromegakaryocytes or dysplasia in 30 to 40 percent of megakaryocytes are the most reliable ways for distinguishing normal marrow from dysplastic marrow [123-125]. Ethnicity and sex should be taken into consideration when assessing cytopenias, and milder cytopenias do not exclude the diagnosis of MDS if definitive morphologic and/or cytogenetic evidence of MDS is present.

●Clinical features – MDS-MLD accounts for approximately 30 percent of all cases of MDS [73]. The median age of presentation is 67 to 70 years and there is a higher incidence in men. The clinical course is variable and is influenced by karyotype and the degree of cytopenias and dysplasia [119,120,126,127]. Approximately 40 percent of patients with MDS-MLD had low IPSS risk score, and approximately 50 percent had intermediate-1 risk score; approximately 75 percent were in the good karyotype risk group, 8 percent in the intermediate group, and 17 percent in the poor risk group [117,119]. There is no definitive evidence that specific mutations influence prognosis within this category of MDS. Median OS was 36 months and evolution to AML was approximately 15 percent at two years and 28 percent at five years, according to a database of 1010 patients MDS-MLD [73]. Patients with complex karyotypes have outcomes similar to those with MDS with excess blasts [119].

●Differential diagnosis – MDS-MLD should be distinguished from:

•Other categories of MDS:

-Cases with 1 percent blasts in peripheral blood on two successive evaluations and <5 percent blasts in bone marrow should be categorized as MDS, unclassifiable, due to the more aggressive clinical course [119]. (See 'MDS, unclassifiable' below.)

-Cases with the features of MDS-MLD and 2 to 4 percent blasts in blood, and no Auer rods should be classified as MDS with excess blasts-1, even with <5 percent blasts in bone marrow; cases with 5 to 19 percent blasts in blood and/or Auer rods should be classified is MDS with excess blasts-2, even with <5 percent marrow blasts. (See 'MDS with excess blasts' below.)

-Cases with multilineage dysplasia and ≥15 percent ring sideroblasts (or ≥5 percent, if SF3B1 mutation is present) should be classified as MDS with ring sideroblasts and multilineage dysplasia. (See 'MDS with ring sideroblasts' below.)

•Other causes of hematologic disorders are described above and below. (See 'MDS with single lineage dysplasia' above and 'Differential diagnosis' below.)

MDS with ring sideroblasts — MDS with ring sideroblasts (MDS-RS) was previously called refractory anemia with ring sideroblasts. This category is further characterized by the number of dysplastic lineages (ie, single lineage versus multilineage).

●Diagnostic criteria – The distinguishing criterion for this category is ≥15 percent ring sideroblasts in bone marrow; 80 to 90 percent of cases are associated with SF3B1 mutation and, when the mutation is present, MDS-RS can be diagnosed with ≥5 percent ring sideroblasts [73]. Ring sideroblasts (picture 10) are erythroid precursors with five or more iron-laden mitochondria that occupy more than one-third of the nuclear rim [87,128-130]. Other causes of ring sideroblasts must be excluded (described below). Other diagnostic criteria include <5 percent blasts in bone marrow and <1 percent in blood; no Auer rods; and any cytogenetic findings may be present unless the findings fulfill all criteria for MDS with isolated del(5q).

Two categories of MDS-RS are recognized: MDS-RS-SLD (anemia plus dysplasia limited to the erythroid lineage) and MDS-RS-MLD (any number of cytopenias and dysplasia at least 10 percent in two or more lineages).

●Clinical features – MDS-RS accounts for 3 to 11 percent of all cases of MDS; MDS-RS-MLD is the more common subtype [73]. Median age at presentation is 60 to 73 years and there is a similar incidence in males and females [120,121,131]. There may be clinical findings related to progressive iron overload, with or without a history of RBC transfusions. For MDS-RS-SLD, approximately 1 to 2 percent of cases evolve to AML and the median OS is 69 to 108 months [132]. For MDS-RS-MLD, median OS is 28 months and approximately 8 percent progress to AML [131-133]. For MDS-RS-SLD, 64 percent and 34 percent, respectively, are low or very low IPSS-R risk categories. Patients with MDS-RS-MLD more frequently have a higher IPSS-R risk score [134]. In MDS-RS, adverse prognostic features include poor risk karyotype, multilineage dysplasia, and thrombocytopenia; it is uncertain if SF3B1 mutation is independent of multilineage dysplasia [23,27,135]. RUNX1 mutation is associated with shorter survival [27]. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults", section on 'IPSS (Original IPSS)'.)

The 15 percent ring sideroblast threshold is arbitrary and it is not clear if the percent of ring sideroblasts has prognostic significance. 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 survival or OS [136]. 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 [27]. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)

●Differential diagnosis

•Secondary causes of ring sideroblasts must be excluded; the presence of SF3B1 mutation in most cases supports the diagnosis of MDS-RS rather than another cause. Non-neoplastic causes of ring sideroblasts include alcohol, toxins (eg, lead, benzene), drugs (eg, isoniazid), copper deficiency (which may be caused by zinc administration or by malabsorption after gastro-duodenal bypass or resection), and congenital sideroblastic anemia [137]. Unlike MDS-RS, patients who have congenital sideroblastic anemia tend to present at a much younger age and have microcytic, rather than macrocytic, anemia [138]. (See "Sideroblastic anemias: Diagnosis and management".)

•Ring sideroblasts can be observed in other types of MDS and in other myeloid neoplasms, including AML [139,140].

•Cases of MDS with ring sideroblasts and excess blasts in peripheral blood or bone marrow are classified as MDS with excess blasts. (See 'MDS with excess blasts' below.)

•Cases that fulfill criteria for MDS with isolated del(5q) should be classified as such, even if ring sideroblasts and/or SF3B1 mutation is present. (See 'MDS with isolated del(5q)' below.)

MDS with isolated del(5q) — MDS with isolated del(5q) was previously called 5q- syndrome. It is a clinically and therapeutically distinct syndrome.

●Diagnostic criteria – This syndrome is distinguished by anemia, with or without other cytopenias and/or thrombocytosis, and the presence of an isolated del(5q) or with one additional abnormality, except loss of chromosome 7 or del(7q). Other diagnostic criteria include <5 percent bone marrow blasts and <1 percent blasts in peripheral blood; no Auer rods; one to three dysplastic lineages; one or two cytopenias; and any level of ring sideroblasts [73]. The bone marrow often exhibits micromegakaryocytes with monolobulated and bilobulated nuclei and erythroid hypoplasia [141].

The del(5q) is typically interstitial, but the size of the deletion and breakpoints vary; bands q31-q33 are invariably deleted; approximately 75 percent of cases have del(5)(q13q33); other common interstitial deletions include del(5)(q15q33) and del(5)(q22q33) [142-144]. Cases with one additional cytogenetic abnormality (except monosomy 7 or del(7q)) are included in this syndrome because they have similar clinical features and outcomes [145-147]. A subset of patients also has concomitant JAK2 V617F, MPL W515L, or SF3B1 mutation, but these mutations do not alter the clinical features or prognosis [22,27,148,149]. (See "Cytogenetics and molecular genetics of myelodysplastic syndromes", section on '5q- syndrome/MDS with an isolated del(5q)'.)

●Clinical features – MDS with isolated del(5q) primarily occurs in older women; the median age at diagnosis is 65 to 70 years, with a female predominance of 7:3 [150]. MDS with isolated del(5q) typically manifests as refractory macrocytic anemia, normal or elevated platelet counts, and the absence of significant neutropenia; pancytopenia is rare [151]. Because of the 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. This syndrome may follow a relatively benign course that extends over several years and has a low incidence of transformation into acute leukemia [148,151,152].

Multiple gene loci on chromosome 5q appear to contribute to the clinical features of this syndrome. Haploinsufficiency for RPS14, which encodes a ribosomal structural protein, may contribute to the disease phenotype by activation of the p53 pathway [153-155]. Haploinsufficiency for the microRNAs miR-145 and miR-146a may contribute to the megakaryocyte abnormalities and thrombocytosis [156]. Haploinsufficiency for CSNK1A1 (which encodes casein kinase 1, alpha 1) leads to deregulation of the WNT/beta-catenin pathway and supports clonal expansion but may also contribute to lenalidomide sensitivity [157]. Lenalidomide binds cereblon and directs cereblon-associated E3 ubiquitination ligase complexes to casein kinase 1A1, thereby mediating its destruction [158]. Haploinsufficiency for APC (another regulator of the WNT pathway) and EGR1 may also contribute to pathogenesis [159]. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Chromosome 5q deletion'.)

●Differential diagnosis – MDS with del(5q) together with either monosomy 7 or del(7q) is not included in this syndrome and should, instead, be classified as another MDS category, according to the other pathologic features [73].

Other conditions in the differential diagnosis are discussed below. (See 'Differential diagnosis' below.)

MDS with excess blasts — MDS with excess blasts (MDS-EB) (table 5) was previously called refractory anemia with excess blasts (RAEB). MDS-EB is further characterized as MDS-EB-1 or MDS-EB-2 based on the percentage of bone marrow and peripheral blood blasts.

●Diagnostic criteria – MDS-EB is characterized by 5 to 19 percent blasts in bone marrow or 2 to 19 percent blasts in blood, but blasts must be <20 percent in both blood and bone marrow [73]. Dysplasia is typically seen in all lineages and the bone marrow is usually hypercellular. In approximately 15 percent of cases, there is a significant degree of reticulin fibrosis. Two subcategories of MDS-EB have been defined:

•MDS-EB-1 is defined by 5 to 9 percent blasts in bone marrow or 2 to 4 percent blasts in blood, and no Auer rods [73].

•MDS-EB-2 is defined by 10 to 19 percent bone marrow blasts or 5 to 19 percent blasts in blood [118]. The presence of Auer rods designates any case of MDS as MDS-EB-2, regardless of the percentage of blasts [160]. Other criteria include one to three dysplastic lineages, one to three cytopenias, the presence of ring sideroblasts, and any cytogenetic findings.

●Clinical features – MDS typically presents with cytopenias and is characterized by bone marrow failure; approximately 25 percent of MDS-EB-1 and 33 percent of MDS-EB-2 progress to AML [73]. Median OS is approximately 16 months for MDS-EB-1, 9 months for MDS-EB-2, 12 months for MDS-EB-2 diagnosed only by the presence of Auer rods, and 3 to 8 months for patients with 5 to 19 percent blasts in peripheral blood [121,161-163].

MDS-EB appears to define a distinct disease phenotype, independent of specific cytogenetic findings or particular mutations [164]. Clonal cytogenetic findings are present in 30 to 50 percent of cases of MDS-EB [73]. The most common findings are gain of chromosome 8, del(5q) or t(5q), loss of chromosome 7 or del(7q), and del(20q). Complex karyotypes may be seen [121]. Mutations of splicing factors are common but are usually mutually exclusive and are less common in the presence of complex cytogenetics or TP53 mutations [14,165]. Other common mutations include IDH1, IDH2, ASXL1, CBL, RUNX1, RAS pathway genes, and cohesion complex genes [164,166,167]. FLT3 and NPM1 mutations are uncommon in MDS-EB, but when they are present there is an increased risk of transformation to AML [167-169].

●Differential diagnosis

•MDS-EB overlaps morphologically with AML, but MDS is distinguished by <20 percent blasts in bone marrow and blood and the absence of specific cytogenetic features described above. (See 'Diagnosis' above.)

•In cases with substantial reticulin fibrosis, MDS-EB must be distinguished from myeloproliferative neoplasms (eg, primary myelofibrosis, essential thrombocythemia, polycythemia vera), therapy-related myeloid neoplasms, and various reactive conditions (eg, autoimmune conditions, infections) [170].

Other conditions in the differential diagnosis are discussed below. (See 'Differential diagnosis' below.)

MDS, unclassifiable — MDS, unclassifiable (MDS-U) (table 5) has no distinguishing morphologic features and is subcategorized as described below.

●Diagnostic criteria – MDS-U is diagnosed and subclassified as follows:

•MDS-U with 1 percent blood blasts – Characterized by ≥1 percent blasts in peripheral blood on at least two separate occasions and blasts <5 percent in bone marrow; no Auer rods; dysplasia in one to three lineages; one to three cytopenias; any percentage of ring sideroblasts; and any cytogenetic findings [73].

•MDS-U with SLD and pancytopenia – Characterized by the presence of pancytopenia together with one dysplastic lineage; <5 percent blasts in bone marrow and <1 percent in peripheral blood; no Auer rods; any percentage of ring sideroblasts; and any cytogenetic findings [73].

•MDS-U based on a defining cytogenetic abnormality – Characterized by the presence of a cytogenetic abnormality that is considered presumptive evidence of MDS together with <2 percent blasts in blood, <5 percent blasts in bone marrow, and no significant dysplasia (ie, <10 percent in any lineage) or other unequivocal evidence of dysplasia. MDS-defining cytogenetic abnormalities are listed above. (See 'Diagnosis' above.)

If characteristics of another subtype of MDS develop later, the case should be reclassified accordingly.

●Clinical features – Median survival and five-year cumulative risk of progression to AML are as follows: MDS-U with 1 percent blood blasts (35 months and 14 percent, respectively), MDS-U and pancytopenia (30 months and 18 percent), and MDS-U based on a defining cytogenetic abnormality (uncertain) [119]. Outcomes for MDS-U are similar MDS-MLD.

•Differential diagnosis – MDS-U should be distinguished from other categories of MDS as follows:

-MDS-U with 1 percent blood blasts is distinguished from MDS-SLD, MDS-MLD, MDS-RS, or MDS with isolated del(5q) by the presence of 1 percent blasts.

-MDS-U with SLD and pancytopenia is distinguished from MDS-SLD, MDS-RS and single agent dysplasia, and MDS with isolated del(5q) by the presence of pancytopenia.

-MDS-U with a defining cytogenetic abnormality is defined by the absence of features of other categories of MDS, but the presence of a defining cytogenetic abnormality. (See 'Diagnosis' above.)  

Other conditions in the differential diagnosis are discussed below. (See 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS — MDS must be distinguished from other conditions that are associated with dysplasia, cytopenias, and/or clonality; some conditions in the differential diagnosis exhibit more than one of these features.

Findings that distinguish between categories of MDS are discussed with the individual categories. (See 'WHO classification' above.)

Causes of dysplasia — Morphologic dysplasia (even when prominent) is not definitive evidence of a malignant or clonal disorder; the differential diagnosis also includes nonmalignant causes, including nutritional deficiencies, toxic exposures, and medications. Distinguishing MDS from other causes requires correlating morphologic findings with clinical presentation, exposures, and family history and confirming the diagnosis by laboratory testing (eg, assays for vitamins, minerals, toxins and serology), cytogenetics, and molecular testing. Malignant (ie, clonal) disorders associated with dysplasia that must be distinguished from MDS are discussed below. (See 'Clonal disorders' below.)

The differential diagnosis of hematologic dysplasia is broad and includes [73]:

●Nutritional deficiencies – Deficiency of vitamin B12, folate, or copper, or zinc excess (likely due to impaired copper absorption caused by excess zinc) should be excluded by clinical evaluation and laboratory testing. (See "Sideroblastic anemias: Diagnosis and management", section on 'Copper deficiency' and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency" and "Diagnostic approach to anemia in adults", section on 'Older adults'.)

●Toxic exposures – Heavy metal exposure (eg, arsenic, lead, zinc) and excess alcohol should be excluded by clinical history and laboratory testing. (See "Causes and pathophysiology of the sideroblastic anemias".)

●Drugs and biologic agents – Examples of drugs and biologic agents associated with dysplasia include various chemotherapeutic agents, cotrimoxazole, tacrolimus or mycophenolate mofetil, valproic acid, ganciclovir, alemtuzumab, isoniazid, and granulocyte colony-stimulating factor [171-176]. Dysplastic changes associated with medications may be seen in all three lineages on bone marrow examination and may be accompanied by macrocytosis, reduced neutrophil lobulation, and cytopenias. In most cases, dysplastic changes are reversible over a period of weeks after reduction or discontinuation of the offending medication. Repeat bone marrow examinations may be necessary to confirm the improvement in some cases.

●Infection – HIV infection is associated with dysplastic hematopoiesis and variable degrees of cytopenias; HIV infection should be excluded by screening serology. Dysplasia in people living with HIV infection may result from medications, opportunistic infection, and/or a direct effect of HIV on hematopoietic progenitors. MDS in people living with HIV infection is more likely to have complex cytogenetics (including monosomy 7 and del(7q)) and is associated with shorter survival compared with non-HIV-infected patients [177]. (See "HIV-associated cytopenias".)

Parvovirus B19 may be associated with reticulocytopenia, erythroblastopenia, and giant pronormoblasts. (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Transient aplastic crisis'.)

●Congenital disorders – Both congenital dyserythropoietic anemia and Pelger-Huët anomaly can cause dysplasia in the erythroid lineage and granulocytic lineage, respectively. (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Congenital dyserythropoietic anemia' and "Evaluation of the peripheral blood smear", section on 'Lobulation'.)

●Sideroblastic anemias – Sideroblastic anemias comprise a spectrum of acquired and heritable erythropoietic disorders caused by various abnormalities of heme synthesis and mitochondrial function (table 7 and table 8). Detection of ring sideroblasts requires exclusion of other causes of acquired sideroblastic anemia (eg, copper deficiency, medications, excessive alcohol use). Women should be evaluated for X-linked sideroblastic anemia (XLSA) since they may present in adulthood with pathologic features indistinguishable from MDS with ring sideroblasts. Testing for XLSA is not necessary in individuals with one of the commonly acquired mutations in the SF3B1 gene, which confirms an MDS or myeloproliferative neoplasm/MDS overlap (ie, associated with JAK2 mutation) and excludes a congenital sideroblastic anemia. (See "Sideroblastic anemias: Diagnosis and management" and "Causes and pathophysiology of the sideroblastic anemias".)

Cytopenias — There are numerous causes of cytopenias, and evaluation includes history, physical examination, screening laboratory studies, and may require bone marrow examination and other specialized studies, as discussed separately. (See "Approach to the adult with pancytopenia".)

●Nutritional – Deficiency of vitamin B12, folate, or copper, or zinc excess should be excluded by clinical evaluation and laboratory testing. (See "Approach to the adult with pancytopenia", section on 'Initial evaluation'.)

●Medications – Numerous medications are associated with individual cytopenias or pancytopenia. The approach to evaluation of a suspected adverse effect of a medication is discussed separately. (See "Approach to the adult with pancytopenia", section on 'Suspected medications'.)

●Idiopathic cytopenia of undetermined significance (ICUS) and clonal cytopenia of undetermined significance (CCUS) (table 9) – ICUS refers to persistent cytopenias without significant dysplasia, evidence of other hematologic or nonhematologic cause for cytopenia, and none of the specific cytogenetic abnormalities that are considered presumptive evidence of MDS. The related disorder, CCUS, describes a patient with a clonal mutation that does not meet criteria for MDS (ie, is not an MDS-defining cytogenetic abnormality) and an unexplained cytopenia but no substantial dysplasia or other evidence of another hematologic neoplasm. (See "Idiopathic and clonal cytopenias of uncertain significance (ICUS and CCUS)", section on 'Diagnosis'.)

●Myelofibrosis – Mild to moderate bone marrow fibrosis is common in patients with MDS, and a small percentage display marked fibrosis that is similar to that in patients with primary myelofibrosis (PMF). Both conditions are associated with pancytopenia, but fibrotic MDS can be distinguished from PMF by the presence of significant dysplasia, diagnostic chromosomal abnormalities, lack of splenomegaly, and absence of mutations that are characteristic for PMF and other myeloproliferative neoplasms (table 10 and table 11). Mutations of JAK2, CALR, or MPL are present in >90 percent of patients with PMF, whereas only JAK2 mutations are found in MDS, and these are seen in only 5 percent of cases [178]. (See "Clinical manifestations and diagnosis of primary myelofibrosis".)

●Aplastic anemia (AA)/paroxysmal nocturnal hemoglobinuria (PNH) – Most patients with MDS have hypercellular bone marrow, but a minority have hypoplastic MDS that can resemble AA. MDS can generally be distinguished from AA by the characteristic dysplasia, ring sideroblasts, and/or karyotypic/molecular abnormalities. Patients with AA and MDS can have small populations of glycosylphosphatidyl inositol-anchor deficient cells, characteristic of PNH, but few patients with MDS display typical PNH clinical manifestations [179]. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)

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 [180]. Clonal hematopoiesis was documented in roughly 50 percent of AA cases, and somatic mutations in driver genes linked to MDS were found in approximately 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 acute myeloid leukemia.

Clonal disorders — Clonal disorders may be malignant (eg, AML) or not malignant (eg, CHIP) and may be associated with cytopenias and/or dysplasia.

●Clonal hematopoiesis of indeterminate potential (CHIP) – CHIP refers to somatic mutations of genes associated with hematologic malignancies but without other diagnostic criteria for a hematologic malignancy (table 9) [181]. Individuals with CHIP do not meet criteria for MDS, PNH, monoclonal gammopathy of undetermined significance, or monoclonal B cell lymphocytosis. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis", section on 'Clonal hematopoiesis of indeterminate potential (CHIP)'.)

The related disorder, CCUS, describes patients with unexplained cytopenias and a clonal mutation that does not meet criteria for MDS or another hematologic neoplasm. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis", section on 'Clonal cytopenia of uncertain significance (CCUS)'.)

●Acute myeloid leukemia (AML) – AML and MDS lie along a disease continuum. The distinction between MDS and AML is based on the blast percentage and/or the presence of certain cytogenetic/molecular features that are diagnostic of AML. The World Health Organization (WHO) classification system defines ≥20 percent blast forms as AML [73,108,182]. 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

•Acute promyelocytic leukemia (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 more reliably after >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' above and "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

MDS/MPN syndromes — The myelodysplastic/myeloproliferative neoplasms (MDS/MPN) include disorders where both dysplastic and proliferative features coexist [73,183]. Cases with prominent dysplastic and myeloproliferative features should be classified as MDS/MPN rather than MDS. Exams of myeloproliferative features include thrombocytosis (ie, platelet count ≥450 x 10⁹/L), megakaryocytic proliferation, and leukocytosis (white blood cell count ≥13 x 10⁹/L) with or without prominent splenomegaly.

MDS/MPN with ring sideroblasts and thrombocytosis — MDS/MPN with ring sideroblasts and thrombocytosis is a distinctive syndrome in the WHO classification that manifests features of MDS with ring sideroblasts plus thrombocytosis and megakaryocytes resembling those seen in essential thrombocythemia [73,108]. (See "Diagnosis and clinical manifestations of essential thrombocythemia".)

The diagnosis of MDS/MPN with ring sideroblasts and thrombocytosis requires all of the following (table 12) [73,108]:

●Anemia associated with erythroid dysplasia with or without multilineage dysplasia, ≥15 percent ring sideroblasts (even if SF3B1 mutation is present), <1 percent blasts in peripheral blood, and <5 percent blasts in 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; the diagnosis of MDS/MPN with ring sideroblasts and thrombocytosis is strongly supported by the presence of an SF3B1 mutation together with a mutation in JAK2 V617F, CALR, or MPL.

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

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

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 suggest that this disorder is better considered a JAK2 mutation-associated chronic MPN rather than a form of MDS [184-187]. However, other studies suggest a more complex interrelationship. 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; in two of these patients, JAK2 mutation coincided with development of thrombocytosis [188].

Other MDS/MPN syndromes — The other MDS/MPN syndromes include:

●Chronic myelomonocytic leukemia (CMML) – CMML is an MDS/MPN syndrome characterized by the overproduction of maturing monocytic cells and sometimes dysplastic neutrophils, often accompanied by anemia and/or thrombocytopenia. In CMML, blood monocyte count is >1000/microL and patients may have other proliferative features, such as splenomegaly, leukocytosis, and constitutional symptoms (picture 11); in MDS the monocyte count is more modest. Monocyte dysplasia is generally more subtle in CMML compared with MDS and usually in <10 percent of mononuclear cells. (See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis".)

●Atypical chronic myeloid leukemia (CML), BCR-ABL1 negative – Cases are usually characterized by marked neutrophilia with accompanying dysgranulopoiesis (table 13). (See "Clinical manifestations and diagnosis of chronic myeloid leukemia", section on '"Atypical CML"'.)

●Juvenile myelomonocytic leukemia (JMML) – This rare disorder of infancy and early childhood is characterized by hepatosplenomegaly and lymphadenopathy, with or without evidence of dysgranulopoiesis (table 14). (See "Clinical manifestations and diagnosis of chronic myeloid leukemia", section on 'Juvenile myelomonocytic leukemia' and "Juvenile myelomonocytic leukemia".)

●MDS/MPN, unclassifiable – MDS/MPN, unclassifiable is defined by clinical/morphologic features of one of the categories of MDS; <20 percent blasts in blood and bone marrow; clinical and morphologic features of an MPN manifest as platelets ≥450,000/microL associated with bone marrow megakaryocytic proliferation and/or white blood cell count ≥13,000/microL; no recent cytotoxic or growth factor therapy that could explain MDS/MPN features; and no rearrangement of PDGFRA, PDGFRB, or FGFR1 and no PCM1-JAK2 [73,108].

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 [189].

VEXAS syndrome — This is a clonal disorder frequently associated with macrocytic anemia, thrombocytopenia, and myeloid dyspoiesis, together with inflammatory symptoms such as alveolitis, ear and nose chondritis, and various skin conditions that occurs exclusively in men [190]. It is strongly associated with mutations in UBA1, an X-linked gene that encodes E1, an enzyme required for initiation of ubiquitylation of proteins. A cytologic clue to the diagnosis is the presence of cytoplasmic vacuoles in erythroid and myeloid precursors, but other disorders such as copper deficiency may produce similar changes. Diagnosis requires identification of UBA1 mutations by DNA sequencing.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Myelodysplastic syndromes" and "Society guideline links: Bone marrow failure syndromes".)

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 5^th to 6^th 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 10^th to 12^th 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 education" 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)")

SUMMARY

●Definition – Myelodysplastic syndromes (MDS) are a diverse group of hematologic malignancies characterized by cytopenias (ie, anemia, neutropenia, and/or thrombocytopenia), abnormal cellular maturation/dysplasia, ineffective hematopoiesis, recurrent cytogenetic/genetic abnormalities, and increased risk for developing acute myeloid leukemia (AML).

●Pathogenesis – MDS arises from stepwise acquisition of mutations in hematopoietic stem or progenitor cells. The cause is usually unknown, but some cases arise after exposure to cytotoxic chemotherapy, ionizing radiation, environmental toxins, or through inheritance of germline mutations. (See 'Pathogenesis' above.)

●Epidemiology – The precise incidence is not well-defined. The median age at presentation is 70 years and MDS is uncommon in individuals ≤50 years. There is a male predominance for most categories of MDS. (See 'Epidemiology' above.)

●Presentation – Some patients present with fatigue, infections, bruising, or other symptoms associated with cytopenias, while others are asymptomatic and come to medical attention due to abnormalities on routine blood tests. (See 'Clinical presentation' above.)

●Initial evaluation – Initial evaluation should include:

•Clinical – History of symptoms related to cytopenias (eg, fatigue, infections, bleeding/bruising), nutritional status, alcohol overuse, medications, exposure to toxic chemicals, treatment with antineoplastic agents or radiotherapy, comorbid illnesses.

•Laboratory – Complete blood count (CBC) with differential count and review of the blood smear are performed.

Characteristic morphologic findings of MDS are described in the table (table 3).

●Diagnostic evaluation – For patients with clinical findings (described above), cytopenias, and/or dysplastic features that are consistent with MDS, a bone marrow (BM) examination is performed for microscopy, immunophenotyping, cytogenetics, and molecular studies. (See 'Bone marrow examination' above.)

●Diagnosis – MDS is diagnosed according to the following findings from BM or blood (See 'Diagnosis' above.):

•Cytogenetic abnormalities – Specific cytogenetic findings are sufficient to diagnose MDS in a patient with unexplained cytopenias (even without dysplasia); other cytogenetic findings define AML and exclude the diagnosis of MDS. (See 'Diagnosis' above.)

•Others – For patients without MDS-defining cytogenetic findings, the diagnosis requires all of the following:

-Cytopenia – Cytopenia in ≥1 lineage (ie, hemoglobin <10 g/dL; absolute neutrophil count (ANC) <1800/microL; platelets <100,000/microL.  

-Dysplasia – Morphologic dysplasia of ≥10 percent of nucleated cells in ≥1 lineage

-Blast count – <20 percent blasts in blood and marrow

●Classification – MDS is categorized according to the World Health Organization (WHO) classification system (table 5):

•MDS with single lineage dysplasia (see 'MDS with single lineage dysplasia' above)

•MDS with multilineage dysplasia (see 'MDS with multilineage dysplasia' above)

•MDS with ring sideroblasts (see 'MDS with ring sideroblasts' above)

•MDS with isolated del(5q) (see 'MDS with isolated del(5q)' above)

•MDS with excess blasts (see 'MDS with excess blasts' above)

•MDS, unclassifiable (see 'MDS, unclassifiable' above)

●Differential diagnosis – MDS must be distinguished from other entities that are associated with dysplasia, cytopenias, and/or clonality, including nutritional disorders, alcohol overuse, liver disease, aplastic anemia, AML and myelodysplastic/myeloproliferative neoplasms, and VEXAS syndrome. (See 'Differential diagnosis' above.)