Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)

INTRODUCTION — Myelodysplastic syndromes/neoplasms (MDS) are a heterogeneous group of hematologic neoplasms characterized by clonal hematopoiesis, cytopenias (ie, anemia, neutropenia, and/or thrombocytopenia), and dysplastic cellular morphology. Patients may experience symptoms related to anemia, infection, bleeding, and other complications of MDS, including variable rates of transformation to acute myeloid leukemia or bone marrow failure. The natural history, preferred treatments, and prognosis are associated with clinical and pathologic features that are used to diagnose and classify subtypes of MDS.

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

Cytogenetic/genetic findings, pathophysiology, prognosis, and an overview of treatment of MDS are discussed separately.

●(See "Cytogenetics, molecular genetics, and pathophysiology of myelodysplastic syndromes/neoplasms (MDS)".)

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

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

EPIDEMIOLOGY — MDS are seen mostly in older adults. The precise incidence of MDS is not well-defined, in part, due to variable clinical presentations and evolving diagnostic criteria.

The annual incidence of MDS is approximately 4 per 100,000 people, according to the United States Surveillance, Epidemiology, and End Results database [1]. The median age at presentation is 70 years, and the risk of developing MDS increases with age. Disease onset before age 50 is unusual, and presentation in children is rare, except for therapy-related MDS and MDS arising in the context of a germline predisposition [2]. There is a male predominance in most categories of MDS, except for MDS with del(5q), which is more common in females.

MDS caused by germline predisposition is discussed separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)

CLINICAL PRESENTATION — Clinical manifestations of MDS are variable. Some patients present with fatigue, infections, bruising, or other manifestations of cytopenias, while others are asymptomatic and come to medical attention because of findings from routine blood counts.

Cytopenias — Anemia is the most common cytopenia associated with MDS and may manifest as fatigue, weakness, exercise intolerance, loss of appetite, angina, dizziness, cognitive impairment, or an altered sense of well-being [3-8]. Fatigue is nearly ubiquitous and is often out of proportion to the degree of anemia. Less commonly, complications of leukopenia (eg, infections, gingivitis) or thrombocytopenia (eg, easy bruising, bleeding) are present. Physical findings 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 an alternative diagnosis, such as a lymphoma. Systemic symptoms, such as fever, sweats, or weight loss are uncommon and generally represent late manifestations of MDS or transformation to acute leukemia.

Infections — Patients with MDS may develop infections related to neutropenia and granulocyte dysfunction [9].

The incidence of infections is not well documented, but in a retrospective study of 273 patients with lower-risk MDS, infections accounted for more than one-third of deaths; pneumonia accounted for 40 percent of the infectious deaths [10]. Bacterial infections predominate, with the skin being the most common site [9]. Although fungal, viral, and mycobacterial infections can occur, they are rare in the absence of treatment with immunosuppressive agents.

Abnormalities of adaptive immunity may also occur, even though lymphocytes are not generally derived from the malignant clone. Immunoglobulin production is variably affected, with hypogammaglobulinemia, polyclonal hypergammaglobulinemia, and monoclonal gammopathy reported in 13, 30, and 12 percent of patients, respectively [11].

Evaluation and treatment of infections in patients with MDS are discussed separately. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS", section on 'Neutropenia'.)

Autoimmune/inflammatory conditions — Autoimmune and inflammatory conditions are more prevalent in patients with MDS than in the general population.

Autoimmune abnormalities have been reported in 10 to 20 percent of patients of MDS and are more common in patients with higher-risk disease [12]. Analysis of US Surveillance, Epidemiology, and End Results (SEER) cancer registry data reported that autoimmune phenomena were more common among 2471 patients with MDS compared with 42,886 controls (23 percent versus 14 percent, respectively) [13]. 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.

Inflammaging refers to chronic, low-grade, systemic inflammation associated with physiologic aging [14]. Compared with representative Medicare controls, the prevalence of inflammaging disorders was increased in patients with MDS [15]. Examples include antecedent cardiovascular diseases (52 versus 36 percent; odds ratio [OR] 1.42 [95% CI 1.37-1.48]), pulmonary conditions (28 versus 19 percent; OR 1.27 [95% CI 1.22-1.33]), metabolic disorders (48 versus 33 percent; OR 1.28 [95% CI 1.23-1.34]), bone and joint diseases (50 versus 38 percent; OR 1.45 [95% CI 1.41-1.51]), and others (eg, fatty liver disease, chronic renal disease).

Acquired hemoglobin H disease — Acquired hemoglobin H disease (also called acquired alpha thalassemia) has been reported in <10 percent of cases of MDS [16-20]. Acquired hemoglobin H disease is associated with microcytosis, poikilocytosis, hypochromia, and hemoglobin H-containing red cells (picture 1). Acquired mutation of ATRX (an X-linked gene encoding a DNA helicase) and acquired deletions of alpha globin genes have been linked to the presence of hemoglobin H [16]. (See "Molecular genetics of the thalassemia syndromes", section on 'ATRX variants and alpha thalassemia'.)

Cutaneous manifestations — Skin lesions are uncommon in patients with MDS, but Sweet syndrome (acute febrile neutrophilic dermatosis) may herald transformation to acute leukemia [12]. (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 a patient suspected to have MDS involves clinical assessment, 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. (See 'Differential diagnosis' below.)

Physical examination may reveal pallor, dyspnea, tachycardia, mucosal ulceration, manifestations of infections, 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, while neutropenia and thrombocytopenia are more variable [8]. Isolated anemia is common, whereas isolated neutropenia, thrombocytopenia, or monocytosis without anemia is infrequent. Pancytopenia (ie, anemia, leukopenia, and thrombocytopenia) is present in up to half of patients at the time of diagnosis.

●Red blood cells – Anemia is generally associated with an inappropriately low reticulocyte response [21]. The mean corpuscular volume (MCV) is usually normal or macrocytic (>100 femtoL), except for cases associated with acquired hemoglobin H disease, in which microcytosis is often seen. The red cell distribution width (RDW) is often increased, reflecting the variability in red blood cell size (anisocytosis).

●Leukocytes – Approximately one-half of patients with MDS have a reduced total white blood cell (WBC) count, usually resulting from absolute neutropenia [21]. Circulating immature neutrophils (myelocytes, promyelocytes, and myeloblasts) may be identified but, by definition, blasts constitute <20 percent of the leukocyte differential count.

●Platelets – Variable levels of thrombocytopenia are present, but isolated thrombocytopenia is an uncommon manifestation of early MDS [22]. An exception is MDS with del(20q), which is more likely to manifest as isolated thrombocytopenia with minimal morphologic dysplasia [23].

Thrombocytosis is less common in patients suspected of having MDS. 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 [24]. Thrombocytosis is most often associated with abnormalities of chromosome 5q and MDS with ring sideroblasts and mutated SF3B1.

Blood smear — The peripheral blood smear usually demonstrates dysplasia in red cells and the white cells and may reveal platelet abnormalities (table 1).

●Red blood cells – Red blood cells (RBC) are usually normocytic or macrocytic, but some patients may have a population of hypochromic, microcytic red cells [21]. Macroovalocytosis 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 RBCs may be seen on the blood smear (picture 2 and picture 3). Reticulocytosis may reflect delayed reticulocyte maturation (so-called pseudo-reticulocytosis) 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 [25-28]. Rarely, a pseudo-Chediak-Higashi anomaly (picture 6) or myelokathexis-like features (ie, lengthening and thinning of nuclear segments) (picture 7) may be evident [29,30]. 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 aspect of evaluation, diagnosis, and classification of MDS.

Morphology — The bone marrow features single- or multi-lineage dysplasia (table 1) and is usually hypercellular [21,31]. An adequate bone marrow aspirate should provide material for a 500-cell differential count and a cytologic evaluation of blasts and other cells. Morphologic evidence of dysplasia has limited reproducibility when dysplastic changes are not overt and may be complemented by immunophenotypic methods [32,33]. (See 'Other analyses' below.)

Characteristic morphologic features of MDS in bone marrow include:

●Blasts – Myeloblasts are increased but, by definition, the blast percentage is <20 percent [21]. 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 [34,35]. 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.

●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 [36]. 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 [37]. 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) [38-41].

●Erythroid cells – Although erythroid hyperplasia (associated with ineffective erythropoiesis) is usually seen, red cell aplasia and/or hypoplasia also rarely occur [42]. Morphologic abnormalities in erythroid precursors include large size, nuclear multi-lobation, 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 [38,43]. 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 [44].

●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) [25,45,46]. 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 myeloid neoplasm), particularly in cases that are associated with activating mutations in the KIT tyrosine kinase gene [47]. (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 one-half of patients with MDS, and marked fibrosis is found in 10 to 15 percent [48-51]. While myelofibrosis occurs in all subtypes of MDS, it is most common in therapy-related MDS [52]. 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 [53]. The degree of fibrosis should be graded using European consensus criteria (table 2). (See 'MDS/MPN syndromes' below.)

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. Importantly, certain cytogenetic/molecular features exclude the diagnosis of MDS. (See 'Diagnosis' below and 'Classification' below.)

●Chromosomal abnormalities – Chromosomal abnormalities are detected by chromosome banding techniques and fluorescence in situ hybridization (FISH). (See "General aspects of cytogenetic analysis in hematologic malignancies".)

Chromosomal abnormalities are seen in approximately one-half of cases of de novo (primary) MDS; the likelihood of karyotypic abnormalities is increased in patients with advanced MDS. Numerical abnormalities (ie, monosomy [loss of a chromosome] or trisomy) are more common than balanced translocations. Complex karyotypes (ie, multiple abnormalities) are found in 10 to 15 percent of patients.

The most common numerical karyotypic abnormalities (eg, deletions of chromosome 5q, chromosome 7, others) and balanced translocations (eg, t(3;21), inv(3)/t(3;3), and t(11;16)) associated with MDS are described separately. (See "Cytogenetics, molecular genetics, and pathophysiology of myelodysplastic syndromes/neoplasms (MDS)".)

●Mutations – Gene mutations can be detected by targeted gene panels. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Detecting known mutations'.)

At least one oncogenic mutation is detected in nearly all cases of MDS. Mutations affect a broad range of cellular processes, including RNA splicing (eg, SRSF2, U2AF1, SF3B1), chromatin regulation (EZH2, BCOR, ASXL1), DNA damage response (TP53), lineage-specific transcription (eg, RUNX1, GATA2), DNA methylation (eg, DNMT3A, TET2, IDH1/2), and the cohesin complex (eg, STAG2) and RAS/MAPK signaling (NRAS, KRAS, PTPN11). Some mutations have independent prognostic significance in MDS.

MDS-associated mutations and their contributions to disease pathophysiology are discussed separately. (See "Cytogenetics, molecular genetics, and pathophysiology of myelodysplastic syndromes/neoplasms (MDS)".)

Other analyses — Other studies that may be useful include:

●Cytochemistry – Iron staining with Prussian blue is used to detect ring sideroblasts. Periodic acid-Schiff (PAS) staining can aid in detecting dyserythropoiesis; peroxidase, Sudan Black B, and alkaline phosphatase can highlight aberrant or incomplete myeloid differentiation.

●Immunohistochemistry – Immunohistochemical stains can be useful adjuncts for identifying cellular lineage and/or the extent and aberrancy of cellular maturation. Examples include:

•Erythroid precursor cells – Staining for glycophorin (CD235a), transferrin receptor (CD71), and/or GATA1 can aid in detecting erythroid precursor cells.

•Blasts – Staining for CD34, CD117, CD33, myeloperoxidase, and lysozyme can assist in quantifying blasts and myeloid progenitors.

•Megakaryocyte dysplasia – Staining for CD41 and/or CD61 can aid in detection of dysplastic or immature megakaryocytes.

•Lineage infidelity – Staining for myeloid and lymphoid markers can help to 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 [54-60]. Flow cytometry should be performed according to standardized methods proposed by the International Flow Cytometry Working Group of the European LeukemiaNet [59,61].

DIAGNOSIS — MDS should be considered in any patient with unexplained cytopenia(s) or clinical findings associated with anemia, infections, or bleeding/bruising; morphologic dysplasia of blood or marrow; or unexplained bone marrow failure.

Diagnosis of MDS requires persistent cytopenias and <20 percent blasts in peripheral blood (PB)/bone marrow (BM) plus either characteristic cytogenetic/molecular features or dysplastic morphology.

Diagnostic criteria for MDS are [62,63]:

●Cytopenia(s) – One or more cytopenias that cannot be explained by a drug, toxin, vitamin deficiency, infection, or other condition:

•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)

While cytopenias associated with MDS are typically chronic (eg, ≥4 months), there is no required minimal duration.

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. This condition was formerly called benign ethnic neutropenia and most often associated with the Duffy null [Fy(a-b-)] red blood cell phenotype. (See "Approach to the adult with unexplained neutropenia", section on 'Normal variants <1500/microL'.)

●Blasts – <20 percent blasts in bone marrow or peripheral blood.

●Dysplasia – Significant dysplasia in ≥10 percent of cells in a given hematopoietic lineage (ie, erythroid precursors, granulocytes, megakaryocytes) in bone marrow or peripheral blood, without another cause for dysplasia (table 1).

For the megakaryocytic lineage, micromegakaryocytes are the most specific indicator of MDS; a higher threshold of dysplasia may be warranted when other types of dysmegakaryopoiesis are included [31,64].

●Cytogenetic/molecular abnormalities – Certain cytogenetic and/or molecular abnormalities in patients with persistent cytopenia(s) are MDS-defining, irrespective of dysplasia. Conversely, some cytogenetic/molecular abnormalities exclude the diagnosis of MDS.

•MDS-defining – The following findings in association with cytopenia(s) are sufficient to diagnose MDS:

-Mutated SF3B1 (≥10 percent variant allele frequency [VAF])

-del(5q) with up to 1 additional cytogenetic abnormality, except -7/del(7q)

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).

•MDS-excluding – The following abnormalities are associated with AML and exclude the diagnosis of MDS:

-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

The role of cytogenetic and molecular findings in classification of MDS is discussed below. (See 'Classification' below.)

CLASSIFICATION

Preferred classification systems — There are two contemporary classification systems for MDS that share many features, but they differ in significant ways, as described below. The two systems are:

●International Consensus Classification (ICC) [62]

●World Health Organization 5^th edition (WHO5) [63]

We consider use of either ICC or WHO5 acceptable, and we prefer them over earlier classification systems because they better integrate cytogenetic and molecular features of MDS that are associated with prognosis and treatment. While both schemes use the abbreviation "MDS", ICC retained the name "Myelodysplastic syndromes," whereas WHO5 renamed these entities "Myelodysplastic neoplasms".

Both ICC and WHO5 recognize the significance of bone marrow blast count, extent of dysplasia, and cytogenetic and molecular abnormalities for categorizing MDS. However, they differ regarding their overall organization, category labels, diagnostic criteria, distinctions between MDS with excess blasts and acute myeloid leukemia (AML), and classification of treatment related MDS and MDS associated with germline genetic abnormalities. Broader discussion of ICC, WHO5, and other schemes for classification of hematologic malignancies is presented separately. (See "Classification of hematopoietic neoplasms", section on 'Myelodysplastic neoplasms/syndromes (MDS)'.)

International Consensus Classification (ICC) — The International Consensus Classification (ICC) categorizes MDS according to specific cytogenetic or karyotypic abnormalities, the degree of dysplasia, or presence of excess blasts [62].

Compared with the revised World Health Organization 4^th edition (WHO4R), significant changes in ICC include the designation "MDS/AML" for cases of MDS with 10 to 19 percent blasts; MDS with multi-hit TP53 mutations is grouped with "Myeloid neoplasms with mutated TP53" (rather than with other MDS subtypes); MDS that arises after cytotoxic treatment is indicated with the qualifier, "therapy-related"; MDS in children is considered a distinct entity; and cases of MDS associated with a pathogenic germline gene variant are grouped in "Pediatric and/or germline mutation-associated disorders".

MDS is classified using the following criteria, according to ICC:

●Specific genetic or karyotypic abnormalities – Two subtypes are defined according to specific molecular or cytogenetic features:

•MDS with mutated SF3B1 – This category was previously called MDS with ring sideroblasts, but ICC criteria do not require either dysplasia or ring sideroblasts. Diagnostic criteria are:

-Mutations – Mutant SF3B1 (≥10 percent variant allele frequency [VAF]) without multi-hit TP53 or RUNX1 mutations

-Blasts – Bone marrow (BM) blasts <5 percent and peripheral blood (PB) blasts <2 percent

-Cytogenetics – Any cytogenetic abnormality, except isolated del(5q), - 7/del(7q), abn3q26.2, or complex karyotype

-Cytopenias/cytoses – ≥1 cytopenia

-Dysplasia – ≥1 dysplastic lineage (not required)

•MDS with deletion of chromosome 5q – This category is defined by:

-Cytogenetics – del(5q) or monosomy 5, with up to one additional cytogenetic abnormality, except -7/del(7q)

-Mutations – Any mutations, except multi-hit TP53

-Blasts – BM blasts <5 percent and PB blasts <2 percent

-Cytopenias/cytoses – ≥1 cytopenia; thrombocytosis is allowed

-Dysplasia – ≥1 dysplastic lineage

MDS with multi-hit TP53 mutations is grouped with other TP53-mutated myeloid neoplasms, rather than MDS, per se. (See "Classification of hematopoietic neoplasms", section on 'Myeloid neoplasms with mutated TP53'.)

●Dysplasia – There are several categories of MDS, not otherwise specified (NOS), with varying degrees of dysplasia, defined as follows:

•MDS, NOS without dysplasia

-Dysplasia – No dysplastic lineages

-Cytopenias/cytoses – ≥1 cytopenia, but no cytoses

-Blasts – BM blasts <5 percent and PB blasts <2 percent

-Cytogenetics – 7/del(7q) or complex cytogenetics

-Mutations – Any mutations, except multi-hit TP53 or SF3B1 (≥10 percent VAF)

•MDS with single lineage dysplasia

-Dysplasia – 1 dysplastic lineage

-Cytopenias/cytoses – ≥1 cytopenia; no cytoses

-Blasts – BM blasts <5 percent and PB blasts <2 percent

-Cytogenetics – Any cytogenetics abnormalities, except del(5q) with other associated findings

-Mutations – Any mutations, except multi-hit TP53 and mutated SF3B1 with other associated findings

•MDS with multilineage dysplasia

-Dysplasia – ≥2 dysplastic lineages

-Cytopenias/cytoses – ≥1 cytopenia; no cytoses

-Blasts – BM blasts <5 percent and PB blasts <2 percent

-Cytogenetics – Any cytogenetic abnormalities, except del(5q) with other associated findings

-Mutations – Any mutations, except multi-hit TP53 and not meeting criteria for MDS with mutated SF3B1 with other associated findings

●Excess blasts – The presence of excess blasts supersedes any of the above MDS subtypes, except for MDS with mutated TP53. ICC has a single category of MDS with excessive blasts and describes cases with 10 to 19 percent blasts in a new category, "MDS/AML".

•MDS with excess blasts – This category is defined by:

-Blasts – BM blasts 5 to 9 percent and/or PB blasts 2 to 9 percent (or 1 percent on two occasions)

-Cytogenetics – Any cytogenetic abnormalities

-Mutations – Any mutations, except multi-hit TP53

-Cytopenias/cytoses – ≥1 cytopenia; no cytoses

-Dysplasia – Typically ≥1 dysplastic lineage

•MDS/AML – This category is defined by:

-Blasts – MDS with 10 to 19 percent BM or PB blasts

-Cytogenetics – Any cytogenetics abnormalities except AML-defining abnormalities

-Mutations – Any mutations, except NPM1, bZIP, CEBPA, or TP53

World Health Organization 5th edition (WHO5) — The World Health Organization 5^th edition (WHO5) categorizes MDS according to either defining genetic abnormalities or morphology [63].

●Key features – Important features of WHO5, compared with WHO4R and earlier classification schemes, include:

•New labels and diagnostic criteria for certain MDS subtypes, including distinct subtypes for MDS with bone marrow hypoplasia or fibrosis

•Unlike the ICC, WHO5 continues to distinguish MDS from most forms of AML using a 20 percent blast threshold

•Eliminated "MDS, unclassifiable"

•Assigns treatment-related myeloid neoplasms to a new category, "Myeloid neoplasms post-cytotoxic therapy"

•Retains MDS with germline pathogenic variants in the MDS category

•Describes childhood MDS as a distinct category

●WHO5 classification of MDS – Categories are:

●Defining genetic abnormalities – There are three subtypes defined according to genetic features:

•MDS with low blasts and isolated del(5q) – Defined by:

-Cytogenetics – 5q deletion or monosomy 5, alone or with one other abnormality other than monosomy 7 or 7q deletion

-Blasts – BM blasts <5 percent in BM and PB blasts <2 percent

-Mutations – Mutated SF3B1 or TP53 mutation (not multi-hit) permitted, if other criteria are met

•MDS with low blasts and SF3B1 mutation – Defined by:

-Mutations – SF3B1 mutation

-Cytogenetics – Absence of 5q deletion, monosomy 7, or complex karyotype

-Blasts – BM blasts <5 percent and PB blasts <2 percent

-Morphology – ≥15 percent ring sideroblasts can substitute for SF3B1 mutation in making this diagnosis

•MDS with biallelic TP53 inactivation – Defined by:

-Mutations – ≥2 TP53 mutations or one mutation with evidence of TP53 copy number loss or copy neutral loss of heterozygosity.

Biallelic TP53 abnormalities may be due to multiple mutations or a single mutation with either concurrent deletion of the other allele or copy-neutral loss of heterozygosity (CN-LOH); such "multi-hit" TP53 mutations lack residual p53 activity. TP53 VAF ≥50 percent is considered presumptive, but not definitive, evidence of loss on the other normal allele or copy neutral loss of heterozygosity.

-Cytogenetics – Typically complex cytogenetics.

-Blasts – BM and PB blasts <20 percent.

●Morphologically defined – Cases of MDS without a defining genetic abnormality are classified as follows:

•MDS with low blasts – BM blasts <5 percent and PB blasts <2 percent

•MDS, hypoplastic – Bone marrow cellularity ≤25 percent (adjusted for age)

This subtype is associated with T cell-mediated immune attack on hematopoietic stem and progenitor cells, oligoclonal expansion of CD8 cytotoxic T-cells (which overproduce interferon gamma and/or tumor necrosis factor alpha), and response to treatments used for aplastic anemia (eg, anti-thymocyte globulin). (See "Treatment of aplastic anemia in adults", section on 'Treatments'.)

•MDS with increased blasts (MDS-IB) – There are three categories:

-MDS-IB1 – BM blasts 5 to 9 percent or PB blasts 2 to 4 percent

-MDS-IB2 – BM blasts 10 to 19 percent, PB blasts 5 to 19 percent; or Auer rods with any number of blasts up to 19 percent

This category corresponds to MDS/AML by the ICC [62]. (See 'International Consensus Classification (ICC)' above.)

-MDS with increased blasts and fibrosis – BM fibrosis (WHO grade 2-3 of 3) with BM blasts 5 to 19 percent and PB blasts 2 to 19 percent

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.

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. 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 vitamin and mineral levels, toxins, and serology), cytogenetics, and molecular testing.

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 [21]:

●Nutritional deficiencies – Deficiency of vitamin B12, folate, or copper, or zinc excess (likely due to impaired copper absorption) 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 – Excess alcohol and heavy metal exposure (eg, arsenic, lead, zinc) should be excluded by clinical history and laboratory testing. (See "Causes and pathophysiology of the sideroblastic anemias".)

●Drugs and biologic agents – Numerous drugs and biologic agents can be associated with dysplasia, including chemotherapy, cotrimoxazole, tacrolimus, mycophenolate mofetil, valproic acid, ganciclovir, alemtuzumab, isoniazid, and granulocyte colony-stimulating factor [65-70]. Dysplastic changes associated with medications may be seen in all bone marrow lineages 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 examination 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 [71]. (See "HIV-associated cytopenias".)

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

●Congenital disorders – 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 abnormalities of heme synthesis and mitochondrial function (table 3 and table 4). Detection of ring sideroblasts requires exclusion of other causes of acquired sideroblastic anemia (eg, copper deficiency, medications, excessive alcohol use). Females 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 — Evaluation for cytopenias 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 can cause individual cytopenias or pancytopenia. 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) – ICUS refers to persistent cytopenias in the absence of significant dysplasia, evidence of other hematologic or nonhematologic cause for cytopenia, and any of the specific cytogenetic abnormalities that are considered presumptive evidence of MDS.

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.

ICUS and CCUS are described separately. (See "Idiopathic and clonal cytopenias of uncertain significance (ICUS and CCUS)", section on 'Diagnosis'.)

●Myelofibrosis – Mild to moderate bone marrow fibrosis is common with MDS, and a small percentage of patients 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 5 and table 6). 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 [72]. (See "Clinical manifestations and diagnosis of primary myelofibrosis".)

●Aplastic anemia (AA)/paroxysmal nocturnal hemoglobinuria (PNH) – Most patients with MDS have a 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. Although patients with MDS can have small populations of CD55/59-deficient PNH cells, few display typical PNH clinical manifestations (eg, robust hemolysis, thrombosis) [73]. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)

Clonal disorders — Certain non-malignant clonal disorders 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, in the absence of other diagnostic criteria for a hematologic malignancy [74]. 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)'.)

●Clonal cytopenia of uncertain significance (CCUS) – 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 and the distinction between them is based on the blast percentage and/or the presence of certain cytogenetic/molecular features. Diagnosis and classification of AML are discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

ICC and WHO5 classify cases of MDS with excess blasts differently (described above). (See 'Classification' above.)

Both ICC and WHO5 exclude the diagnosis of MDS from cases with any of the following genetic abnormalities, which are considered diagnostic for AML (without regard to the blast count):

●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)(q24.1;q21.1); PML-RARA

MDS/MPN syndromes — The myelodysplastic/myeloproliferative neoplasms (MDS/MPN) include disorders where both dysplastic and proliferative features coexist [62,63]. Cases with prominent dysplastic and myeloproliferative features should be classified as MDS/MPN, rather than MDS.

MDS/MPN syndromes include:

●Chronic myelomonocytic leukemia (CMML) – The most common MDS/MPN is CMML, which is characterized by sustained peripheral blood monocytosis and somatic mutations that overlap with those seen in MDS.

CMML manifests in the peripheral blood with monocytosis of ≥0.5 x 10⁹/L and ≥10 percent of white blood cells; cytopenias; <20 percent blasts; and evidence of clonality. Both ICC and WHO5 distinguish between a myeloproliferative subtype and a myelodysplastic subtype of CMML and exclude the diagnosis of MDS in cases with persistent leukocytosis (WBC ≥13.0 x 10⁹/L), thrombocytosis (platelets ≥450 x 10⁹/L), and monocytosis, although their names and diagnostic criteria for CMML subtypes differ [62,63].

●MDS/MPN with ring sideroblasts/SF3B1 mutation and thrombocytosis – This disorder includes platelets ≥450 x 10⁹/L and either ring sideroblasts or SF3B1 mutation, but ICC and WHO5 differ in naming and classification of these cases [62,63].

●Others – Other MDS/MPN subtypes include atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), and MDS/MPN, unclassifiable.

Further descriptions and diagnostic criteria are presented separately. (See "Classification of hematopoietic neoplasms", section on 'MDS/MPN syndromes'.)

VEXAS syndrome — This is a clonal disorder that occurs almost exclusively in males, which is associated with macrocytic anemia, thrombocytopenia, myeloid dyspoiesis, and inflammatory symptoms, such as alveolitis, ear and nose chondritis, and various skin conditions [75]. It is strongly associated with mutations in UBA1, an X-linked gene that encodes an E1 ubiquitin ligase required for initiation of ubiquitylation of proteins. Cytoplasmic vacuoles in erythroid and myeloid precursors may suggest VEXAS, but copper deficiency, excessive alcohol use, and other disorders may produce similar changes. Diagnosis requires identification of UBA1 mutations by DNA sequencing. Very rarely, VEXAS syndrome has been reported in females [76-79].

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

●Description – Myelodysplastic syndromes/neoplasms (MDS) are diverse hematologic malignancies characterized by cytopenias (ie, anemia, neutropenia, and/or thrombocytopenia), morphologic dysplasia, ineffective hematopoiesis, recurrent cytogenetic/genetic abnormalities, and increased risk for developing acute myeloid leukemia (AML) or bone marrow failure.

●Epidemiology – Median age is 70 years, and the incidence increases with age. Most MDS subtypes (except MDS with 5q deletion), have male predominance. (See 'Epidemiology' above.)

●Presentation – Fatigue, infections, bruising, or other symptoms associated with cytopenias are common, but some patients are asymptomatic and come to medical attention due to abnormalities on routine blood tests. (See 'Clinical presentation' above.)

●Initial evaluation – Includes:

•Clinical – Symptoms related to cytopenias (eg, fatigue, infections, bleeding/bruising), nutritional status, alcohol use, medications, toxins, prior cytotoxic treatments, comorbid illnesses.

•Laboratory – Complete blood count (CBC) and blood smear may reveal cytopenias and morphologic abnormalities (table 1).

•Bone marrow – Microscopy and cytogenetic/molecular features are required for diagnosis and classification. (See 'Bone marrow examination' above.)

●Diagnosis – MDS should be considered in any patient with unexplained cytopenia(s) or clinical symptoms associated with anemia, infections, or bleeding/bruising; morphologic dysplasia of blood or marrow; or unexplained bone marrow failure. (See 'Diagnosis' above.)

Diagnosis of MDS requires persistent cytopenia(s) and <20 percent blasts in peripheral blood (PB)/bone marrow (BM) plus either characteristic cytogenetic/molecular features or dysplastic features:

•Cytopenia(s) – One or more cytopenias not explained by a drug, toxin, vitamin deficiency, infection, or other condition:

-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)

•Blasts – <20 percent blasts

•Cytogenetic abnormalities – Specific cytogenetic/molecular findings are sufficient to diagnose MDS in a patient with unexplained cytopenias (even without dysplasia), while others exclude the diagnosis.

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

-Cytopenia – Cytopenia in ≥1 lineage

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

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

●Classification – MDS should be classified using either of the following systems; importantly, they apply different names and criteria to MDS subtypes:

•International Consensus Classification (ICC) – Organized according to (see 'International Consensus Classification (ICC)' above):

-Specific genetic or karyotypic abnormalities – Includes MDS with mutated SF3B1 and MDS with del(5q)

-Dysplasia – Various categories of MDS, not otherwise specified (NOS) according to 0, 1, or ≥2 affected lineages

-Excess blasts – Increased blasts; cases with BM/PB blasts 10-19 percent are labeled MDS/AML

•World Health Organization 5^th edition (WHO5) – Organized according to (see 'World Health Organization 5th edition (WHO5)' above):

-Defining genetic abnormalities – Includes MDS with low blasts and isolated del(5q), SF3B1 mutation, and biallelic TP53 inactivation

-Morphologically defined – Includes categories with low blasts, hypoplastic bone marrow, fibrosis, and increased blasts

●Differential diagnosis – MDS must be distinguished from other causes of cytopenias, dysplasia, and clonality, and from other hematologic malignancies (eg, AML, myelodysplastic/myeloproliferative neoplasms). (See 'Differential diagnosis' above.)