Clinical manifestations and diagnosis of the myelodysplastic syndromes

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All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2016. | This topic last updated: Dec 01, 2015.

INTRODUCTION — The myelodysplastic syndromes (MDS) comprise a heterogeneous group of malignant hematopoietic stem cell disorders characterized by dysplastic and ineffective blood cell production and a variable risk of transformation to acute leukemia. These disorders may occur de novo or arise after exposure to potentially mutagenic therapy (eg, radiation exposure, chemotherapy).

Patients with MDS have a variable reduction in the production of red blood cells, platelets, and mature granulocytes. In addition, these formed elements sometimes exhibit qualitative functional defects. These quantitative and qualitative abnormalities often result in a variety of systemic consequences including anemia, bleeding, and an increased risk of infection. (See "Management of the complications of the myelodysplastic syndromes".)

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

PATHOGENESIS — The pathogenesis of the myelodysplastic syndromes (MDS) is incompletely understood, but like other cancers involves the stepwise acquisition of oncogenic driver mutations. MDS is a clonal process that is thought to develop from a single transformed hematopoietic progenitor cell [1-3]. Studies suggest that the cell of origin has acquired multiple mutations resulting in dysplasia and ineffective hematopoiesis [4]. Of interest, up to 10 percent of asymptomatic older adults (older than age 70) have clonal hematopoiesis of indeterminant potential (CHIP) associated with a MDS-associated mutation [5,6]. CHIP may be a common precursor of MDS (akin to monoclonal gammopathy of uncertain significance), but further studies are needed to determine its natural history. (See 'Clonal hematopoiesis of indeterminant potential' below.)

Together with cytogenetic testing, targeted DNA sequencing is increasingly being used to evaluate patients with MDS and has revealed that a large majority (>90 percent) of cases are associated with one or more driver mutations. Among the most commonly mutated genes are ASXL1, TP53, DNMT3A, RUNX1, and genes that are components of the 3’ RNA splicing machinery (eg, SF3B1, U2AF1, SRSF2, ZRSR2, and U2AF35) [7-12]. In particular, somatic mutations in the SF3B1 gene that encodes components of the RNA splicing machinery occurs in 60 to 80 percent of the MDS subtype refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis (RARS-T) [7,13-19]. (See "Cytogenetics and molecular genetics of myelodysplastic syndromes", section on 'Gene mutations'.)

SF3B1 knockout mice develop ring sideroblasts; SF3B1 mutant patients have mitochondria that have more coarse mitochondrial deposits than in RARS patients with the wild type version of the gene [16]. In contrast to the favorable prognosis of RARS, another splicing factor mutation (SRSF2) occurs in approximately 15 percent of MDS patients, and this "founder" mutation, presumptively one of the first pathophysiological events in progression toward clinical disease, carries a negative prognostic impact [20].

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-) [21]. Other factors that may be important in MDS pathophysiology include congenital or acquired telomere disruption and aberrant or absent expression of microRNA species [22-24].

MDS genomes are characterized by global DNA hypomethylation with concomitant hypermethylation of gene-promoter regions relative to normal controls. These hypermethylated genes are not expressed (ie, they are silenced). As such, DNA methylation provides an epigenetic mechanism for controlling gene expression. While the underlying mechanism of altered-DNA methylation in MDS genomes is unclear, several studies have implicated mutations in genes that encode enzymes, such as DNMT3A, TET2 (ten-eleven translocation), IDH1, and IDH2 (isocitrate dehydrogenase-1 and -2, respectively), that influence DNA methylation directly or indirectly [25-31]. RUNX1 mutations may disturb expression of genes related to normal hematopoietic aging [32]. The role of DNA methylation in the pathobiology of MDS is also supported by studies that have demonstrated disease response to hypomethylating agents, although whether such responses are on the basis of expression of silenced anticancer genes or antimetabolite-induced cytotoxicity is controversial. (See "Treatment of intermediate, low, or very low risk myelodysplastic syndromes", section on 'Azacitidine' and "Treatment of intermediate, low, or very low risk myelodysplastic syndromes", section on 'Decitabine'.)

Factors extrinsic to the hematopoietic cell, such as stromal abnormalities [33] and T cell dysregulation [34], may occur causally or secondarily to the primary genetic lesions. Studies demonstrating the response of MDS to treatment with immunosuppressive agents (eg, cyclosporine, antithymocyte globulin) in some patients with MDS, suggest that abnormalities of the immune system may also be responsible for the myelosuppression and/or marrow hypocellularity seen in patients with MDS, especially younger subjects with lower-risk disease, low platelet count, and presence of HLA-DR15 [35,36]. (See 'Aplastic anemia'below and "Treatment of intermediate, low, or very low risk myelodysplastic syndromes", section on 'Immunosuppressive therapy'.)

EPIDEMIOLOGY — The precise incidence of de novo myelodysplastic syndrome (MDS) is not known; conservative estimates from cancer databases suggest that there are approximately 10,000 cases diagnosed annually in the United States [37-39]. One series, for example, reported a crude annual incidence rate of 4.1 per 100,000 [38]. A similar incidence rate has been reported in the United Kingdom and Ireland [40,41]. In comparison, lower incidence rates of 0.27 per 100,000 have been reported in Eastern Europe, perhaps related to patterns in hospital use [40]. The actual incidence of MDS is likely higher than that predicted by cancer databases since the nonspecific symptoms may evade detection in early stages of the disease and suspected cases may not undergo definitive testing (ie, bone marrow biopsy) due to comorbidities [42-44]. Investigations that have analyzed reimbursement claims have estimated the incidence in the United States to be 30,000 to 40,000 new cases per year [43,45].

MDS occurs most commonly in older adults with a median age at diagnosis in most series of ≥65 years and a male predominance [37,41,46-55]. Onset of the disease earlier than age 50 is unusual [56,57], with the exception of treatment-induced MDS [54,58], but rare cases of MDS have been reported in children at a median age of six years [59-61]. 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 years of age; 50 to 59; 60 to 69; 70 to 79; and >80 years, respectively [62].

MDS has been associated with environmental factors (eg, exposure to chemicals, particularly benzene [63], radiation, tobacco, or chemotherapy drugs), inherited genetic abnormalities (eg, trisomy 21, Fanconi anemia, Bloom syndrome, ataxia telangiectasia), and other benign hematologic diseases (eg, paroxysmal nocturnal hemoglobinuria, congenital neutropenia) (table 1) [64]. A rare autosomal dominant condition linked to mutations in GATA2 has been described that is associated with monocytopenia, susceptibility to infection with mycobacteria, fungi, and papillomaviruses, and the development of myelodysplasia [65]. Familial MDS, while rare, has been associated with germ line RUNX1, CEBPA, TERC, TERT, and GATA2 mutations [66-68]. Although connective tissue disorders such as relapsing polychondritis, polymyalgia rheumatica, Raynaud phenomenon and Sjögren's syndrome, inflammatory bowel disease, pyoderma gangrenosum, Behçet's syndrome, and glomerulonephritis have been reported in association with MDS, a causal relationship has not been established [69-74].

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

Anemia is the most common cytopenia and can manifest as fatigue, weakness, exercise intolerance, angina, dizziness, cognitive impairment, or an altered sense of well being [45,48,75,76]. Less commonly, infection, easy bruising, or bleeding precipitate a hematologic evaluation. Systemic symptoms such as fever and weight loss are uncommon, and generally represent late manifestations of the disease or its attendant complications.

Physical findings in MDS are non-specific. Sixty percent of patients are pale (reflecting anemia), and 26 percent have petechiae and/or purpura (due to thrombocytopenia) [48]. Hepatomegaly, splenomegaly, and lymphadenopathy are uncommon [77]. Sweet’s syndrome (neutrophilic dermatosis) may be the presenting symptom.

Infection — Patients with MDS may develop infections related to neutropenia and granulocyte dysfunction (eg, impaired chemotaxis and microbial killing) [78,79]. Bacterial infections predominate with the skin being the most common site involved. Although fungal, viral, and mycobacterial infections can occur, they are rare in the absence of concurrent administration of immunosuppressive agents. The evaluation and treatment of infections in patients with MDS are discussed in more detail separately. (See "Management of the complications of the myelodysplastic syndromes", section on 'Infection'.)

Myeloperoxidase [79] and alkaline phosphatase [80] activities may be diminished in myeloid cells, whereas monocyte-specific esterase may be increased [81]. As a consequence, granulocytes may be dysfunctional and display defective phagocytosis, bactericidal activity, adhesion, and chemotaxis [79], leading to impaired resistance to bacterial infections. Natural killer cell levels may be depressed.

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

Autoimmune abnormalities — Autoimmune abnormalities, although uncommon, may complicate the course of MDS [69-74,88]. In an analysis of the SEER database that compared 2471 patients with MDS with 42,886 controls from the Medicare population, patients with MDS were more likely to demonstrate autoimmune phenomena (23 versus 14 percent) [89]. The most common autoimmune conditions in patients with MDS were chronic rheumatic heart disease (7 percent), rheumatoid arthritis (6 percent), pernicious anemia (6 percent), psoriasis (2 percent), and polymyalgia rheumatica (2 percent). Other autoimmune abnormalities include Sweet syndrome, pericarditis, pleural effusions, skin ulcerations, iritis, myositis, peripheral neuropathy, and pure red cell aplasia. On occasion, patients may present with an acute clinical syndrome characterized by cutaneous vasculitis, fever, arthritis, peripheral edema, and pulmonary infiltrates [69]. (See "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Paraneoplastic disease' and "Acquired pure red cell aplasia in the adult", section on 'Etiology and pathogenesis'.)

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

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

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

 

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

 

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

Complete blood count — Complete blood count with leukocyte differential almost always demonstrates a macrocytic or normocytic anemia; neutropenia and thrombocytopenia are more variable. Pancytopenia (ie, anemia, leukopenia, and thrombocytopenia) is present at the time of diagnosis in up to 50 percent of patients. While isolated anemia is not uncommon, less than 5 percent of patients present with an isolated neutropenia, thrombocytopenia, or monocytosis in the absence of anemia [77].

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

 

●Leukopenia – Approximately half of patients have a reduced total white blood cell count (ie, leukopenia), usually resulting from absolute neutropenia [54]. Circulating immature neutrophils (myelocytes, promyelocytes, and myeloblasts) may be identified, but blasts constitute fewer than 20 percent of the leukocyte differential.

 

●Thrombocytopenia – Varying degrees of thrombocytopenia are present in roughly 25 percent of patients with MDS [54]. Unlike anemia, isolated thrombocytopenia is not a common early manifestation of MDS [103]. However, a thrombocytopenic presentation with minimal morphologic dysplasia has been described in patients in whom del(20q) was the sole karyotypic abnormality [104]. Such patients may be easily misdiagnosed as having immune thrombocytopenia (ITP). (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Differential diagnosis'.)

 

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

 

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

Red blood cells — The following erythroid findings have been noted in the peripheral blood of patients with MDS (table 2):

●Red cells are usually normocytic or macrocytic [80,106], although patients with refractory anemia with ringed sideroblasts (RARS) may present with a variable population of hypochromic, microcytic red cells [107]. (See "Sideroblastic anemias: Diagnosis and management".)

 

●Ovalomacrocytosis is the best-recognized morphologic abnormality of erythrocytes. In some cases, however, elliptocytes [108,109], teardrops, stomatocytes, or acanthocytes (Spur cells) [110] may predominate, reflecting intrinsic alterations in cytoskeletal proteins [109,111].

 

●Basophilic stippling, Howell-Jolly bodies, and megaloblastoid nucleated red cells may also be found in the peripheral smear (picture 2 and picture 3). These peripheral blood findings are associated with dyserythropoietic features in bone marrow precursors, characterized by delayed and distorted nuclear and cytoplasmic maturation, erythroid hyperplasia with megaloblastoid features, nuclear budding, multinucleation, karyorrhexis, and cytoplasmic vacuolization [80,112].

 

●Reticulocytosis may be indicative of a superimposed autoimmune hemolytic anemia [113] or may be a marker of delayed reticulocyte maturation, so-called pseudoreticulocytosis [114,115].

 

White blood cells — Dysplastic neutrophils are commonly found in the peripheral blood smear. These cells may demonstrate increased size, abnormal nuclear lobation, and abnormal granularity (table 2). Monocytes may also demonstrate immature characteristics.

●Granulocytes commonly display reduced segmentation, the so-called pseudo-Pelger-Huet (Pelgeroid) abnormality [51], often accompanied by reduced or absent granulation (picture 4 and picture 5) [116,117].

 

●Occasionally, granulocytes have a clumped chromatin pattern in which blocks of chromatin are separated by a void in nuclear material, creating an appearance of nuclear fragmentation associated with loss of segmentation [118,119]. Ring-shaped nuclei and nuclear sticks may be identified [120], particularly in therapy-related MDS. Rarely, a pseudo-Chediak-Higashi anomaly (picture 6) [121] or myelokathexis-like features (picture 7) may be evident [122]. (See "Congenital neutropenia", section on 'Severe congenital neutropenia'.)

 

●Myeloblasts can be identified by their nuclear and cytoplasmic characteristics, which include a high nuclear:cytoplasmic ratio, easily visible nucleoli, fine nuclear chromatin, variable cytoplasmic basophilia, few or no cytoplasmic granules, and absent Golgi zone [123,124]. Auer rods within leukemic blasts (picture 8) are rare. The presence of Auer rods in a patient with a prior diagnosis of MDS is often a harbinger of transformation to AML [125].

 

Bone marrow aspirate and biopsy

Bone marrow aspirate — Optimally, the bone marrow aspirate provides material for a 500 cell differential count to determine the percentage of blasts in the marrow; it also allows for a detailed cytologic evaluation of the blasts and other cells. Impaired myeloid maturation is often readily apparent. The percentage of granulocytic precursors may be increased, and a relative maturation arrest may be seen at the myelocyte stage [47]. Maturation of the cytoplasm may progress more rapidly than the nucleus [56].

The myeloid:erythroid ratio is variable, but often decreased. There is a shift towards more immature precursors, but the blast percentage, by definition, is less than 20 percent [126]. Morphologic abnormalities in the erythroid precursors include large size, nuclear multilobation, nuclear budding, and other abnormal forms. The cytoplasm of erythroid progenitors may show vacuolization, coarse or fine periodic acid-Schiff-positive granules, or a "necklace" of iron-laden mitochondria surrounding the nuclei (ie, ring sideroblasts detected with Prussian blue staining) [127,128]. Granulocytic precursors may also demonstrate dysplastic features, such as abnormally large size, abnormal nuclear shape, and increased or decreased cytoplasmic granularity.

Bone marrow biopsy — The bone marrow biopsy gives a general overview of the degree of involvement and specific histologic features associated with the process (eg, fibrosis). Cellularity is usually increased, but may be normal or decreased. Other features include reactive lymphocytosis and mastocytosis, lymphoid aggregates, fibrosis, increased histiocytes, and pseudo-Gaucher histiocytes. In addition, clusters of immature cells may locate centrally in the marrow space rather than along the endosteal surface [127,129]. Special techniques can reveal increased apoptosis in lower risk MDS [130].

The bone marrow is usually hypercellular and features single- or multi-lineage dysplasia (table 2) [129,131-133]. The classic paradox of peripheral pancytopenia despite the presence of a hypercellular bone marrow reflects premature cell loss via intramedullary cell death (apoptosis) [134,135]. Although hypocellularity is uncommon, it is found with greatest frequency in therapy-related MDS and must be distinguished from aplastic anemia [58]. (See 'Aplastic anemia' below.)

●Red blood cells – Specific erythroid findings in the bone marrow include (table 2):

 

•Ring sideroblasts containing mitochondria laden with iron may be evident on bone marrow specimens stained for the presence of iron (picture 9) (see 'Refractory anemia with ring sideroblasts' below).

 

•Internuclear bridging characterized by chromatin threads tethering dissociated nuclei reflects impaired mitosis and may contribute to the addition and deletion of genetic material characteristic of MDS [136].

 

•Although erythroid hyperplasia may represent the predominant finding in association with ineffective erythropoiesis, red cell aplasia and/or hypoplasia rarely occur [137].

 

●Megakaryocytes – Megakaryocytes are normal or increased in number, and sometimes occur in clusters. Abnormal megakaryocytes, including micromegakaryocytes, large mononuclear forms, megakaryocytes with multiple dispersed nuclei ("Pawn ball" changes), and hypogranular megakaryocytes are common bone marrow findings (picture 10) [51,138,139]. Nonlobulated or mononuclear megakaryocytes may be identified, particularly in association with the 5q- syndrome. Antibodies to von Willebrand factor, CD41, or CD61 (the latter two both components of the platelet GpIIa/IIIb fibrinogen receptor) may be used to identify these atypical megakaryocytes [140]. (See 'MDS with isolated del(5q)' below.)

 

●Abnormal localization of immature precursors – Granulopoiesis may be displaced from its normal paratrabecular location to more central marrow spaces [129,141]. This displacement of granulocyte precursors has been termed "abnormal localization of immature precursors," or ALIP [129,141,142].

 

●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 [143-146]. While myelofibrosis occurs in all subtypes of MDS, it is most common in therapy-related MDS [58]. Importantly, deposition of mature collagen (detected with a trichrome stain) is uncommon in MDS. Instead, fibrosis takes the form of increases in the number and thickness of reticulin fibers, best detected with a silver impregnation stain [147]. The degree of fibrosis can be graded using European consensus criteria [148], and, if prominent enough, could lead to a diagnosis of MDS/myeloproliferative disorder overlap. (See 'MDS/MPN syndromes' below.)

 

Cytochemistry and immunocytochemistry — Cytochemical stains and immunophenotyping studies may demonstrate a decrease or loss of normal myeloid maturation antigens [83], or the presence of antigens not normally expressed [149]. Myeloperoxidase [79] and alkaline phosphatase [80] activities may be diminished in myeloid cells, whereas monocyte-specific esterase may be increased [81].

Useful cytochemical methods include:

●Iron stains for identification of ring sideroblasts

●PAS staining of erythroblasts to assess dyserythropoiesis

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

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

 

Immunocytochemistry may be helpful in order to:

●Exclude lymphoid origin of primitive blasts

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

●Quantify myeloid progenitors and blasts using antibodies to CD34, CD117, CD13, CD14, and CD33 [150]

●Detect dysplastic or immature megakaryocytes via antibodies with specificity for von Willebrand factor [140], factor VIII [151], CD41 [152], CD61, or the HPI-ID monoclonal antibody [153]

●Detect lineage infidelity (eg, myeloid lineage cells expressing nonmyeloid antigens) and confirm the presence of bi- or tri-lineage dysplasia [154,155]

 

Flow cytometry — Morphologic analysis of the peripheral blood and bone marrow for evidence of dysplasia is a key factor in the diagnosis of MDS but is subjective and has poor reproducibility [156,157]. Automated flow cytometric systems (multiparameter flow cytometry) for scoring dyspoiesis in MDS have been developed [158]. These systems appear to have both diagnostic and prognostic value in patients with MDS [158-164]. Findings on flow cytometry can suggest clonality and the presence of MDS. While flow cytometry findings are not considered diagnostic, they can provide further support for the diagnosis in suspected cases. Flow cytometry should be performed according to the standard methods proposed by the International Flow Cytometry Working Group of the European LeukemiaNet [163,165].

Genetic features — The diagnosis of MDS is made based upon an evaluation of the bone marrow and peripheral smear in the appropriate clinical context. Detection of certain chromosomal abnormalities by routine cytogenetic analysis, reverse transcriptase polymerase chain reaction (RT-PCR), or fluorescent in situ hybridization (FISH) distinguishes between MDS and acute myeloid leukemia (AML) in some cases, aids in the classification of MDS, and is a major factor in determining prognostic risk group and therapy [166]. (See "Overview of the treatment of myelodysplastic syndromes", section on 'Pretreatment evaluation' and "Cytogenetics and molecular genetics of myelodysplastic syndromes".)

Importantly, the following cytogenetic abnormalities, if found, result in the diagnosis of AML, regardless of blast count [126] (see "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Bone marrow infiltration'):

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

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

●t(15;17)(q22;q21.1); PML-RARA

 

Similarly, the presence of one of the following chromosomal abnormalities is presumptive evidence of MDS in patients with otherwise unexplained refractory cytopenia and no morphologic evidence of dysplasia [126]:

●-7/del(7q)

●-5/del(5q)

●del(13q)

●del(11q)

●del(12p) or t(12p)

●del(9q)

●idic(X)(q13)

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

●t(11;16)(q23;p13.3)

●t(3;21)(q26.2;q22.1)

●t(1;3)(p36.3;q21)

●t(2;11)(p21;q23)

●inv(3)(q21q26.2)

●t(6;9)(p23;q34)

 

Whether other methods to detect chromosomal abnormalities such as FISH, flow-FISH, comparative genomic hybridization (CGH), single nucleotide polymorphism array, and loss of heterozygosity (uniparental disomy) are superior prognostically or may be used to direct therapy remains to be determined [167,168]. Further details regarding cytogenetic changes in patients with MDS are presented separately. (See"Cytogenetics and molecular genetics of myelodysplastic syndromes".)

Some centers use targeted next-generation sequencing panels to aid in the diagnosis of MDS, and it seems likely that this will become a part of the standard work-up of known or suspected MDS patients over the next several years, both for confirming the diagnosis and for determining prognosis [28,169-172].

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

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

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

Careful inspection of the peripheral blood smear and bone marrow aspirate is necessary to document the requisite dysplastic cytologic features identifiable in any or all of the hematopoietic lineages. The bone marrow biopsy gives a general overview of the degree of involvement and specific histologic features associated with the process (eg, fibrosis). Since the diagnosis relies heavily on morphologic changes, the quality of the smears is of the utmost importance. Slides should be made from freshly obtained specimens; slides made from specimens exposed to anticoagulants for two or more hours are not satisfactory.

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

DIAGNOSIS — The diagnosis of MDS is made based upon findings in the peripheral blood and bone marrow as interpreted within the clinical context. Most cases of MDS are diagnosed based upon the presence of the three main features outlined below [126]. While most cases of MDS will have these three features, some will not, as clarified in the caveats presented.

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

 

●Morphologic evidence of significant dysplasia (ie, ≥10 percent of erythroid precursors, granulocytes, or megakaryocytes) upon visual inspection of the peripheral blood smear, bone marrow aspirate, and bone marrow biopsy in the absence of other causes of dysplasia (table 2). In the absence of morphologic evidence of dysplasia, a presumptive diagnosis of MDS can be made in patients with otherwise unexplained refractory cytopenia in the presence of certain genetic abnormalities. (See 'Genetic features' above.)

 

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

 

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

Idiopathic cytopenia of undetermined significance — The term "idiopathic cytopenia of undetermined significance" (ICUS) is used to classify cases of persistent cytopenia without significant dysplasia, without any of the specific cytogenetic abnormalities considered as presumptive evidence of MDS, and without a potentially related hematologic or non-hematologic disease [126,173-176]. (See 'Genetic features'above.)

The natural history of ICUS is not well known. A retrospective analysis of 67 patients with ICUS evaluated evidence of clonality at diagnosis, as well as patient outcomes [177]. In this population, 67 percent of patients presented with anemia. Cytopenias involved one, two, and three myeloid cell lines in 66, 18, and 12 percent, respectively. Eight patients developed acute myeloid leukemia (AML). The median overall survival of all patients with ICUS was 44 months. Clonality studies using human androgen receptor gene-based assays (HUMARA) were performed on 23 patients and identified clonal populations in six patients, two of whom developed AML. It is likely that many of these patients have MDS with subtle or minimal dysplastic features. It is possible that targeted DNA sequencing may be helpful in establishing a presumptive diagnosis of MDS in such cases, but this requires further evaluation.

Clonal hematopoiesis of indeterminant potential — The term "clonal hematopoiesis of indeterminant potential" (CHIP) has been proposed to classify cases with blood cells that contain somatic mutations of genes known to be recurrently mutated in hematologic malignancies in the absence of other diagnostic criteria for hematologic malignancy [178]. In such cases, the mutant allele fraction should be 2 percent or greater. The list of potentially involved genes is broad (eg, DNMT3A, TET2, JAK2, SF3B1, ASCL1, TP53, CBL, GNB1, BCOR, U2AF1, CREBBP, CUX1, SRSF2, MLL2, SETD2, SETDB1, GNAS, PPM1D, BCORL1) [171,172,178,179]. The cases should not meet the criteria for MDS, paroxysmal nocturnal hemoglobinuria, monoclonal gammopathy of undetermined significance, or monoclonal B cell lymphocytosis. Persons with CHIP may have normal blood counts, have cytopenias unrelated to MDS, or cytopenias that do not meet the criteria for MDS.

While the exact incidence is not known, it appears to increase with increasing age. As an example, in one large study, somatic mutations were rarely detectable in persons under the age of 40, were present in approximately 10 percent of persons aged 70 to 79 years, 12 percent of persons aged 80 to 89 years, and 18 percent of persons over age 90 [6]. Persons with CHIP develop a hematologic malignancy at a rate of approximately 0.5 to 1 percent per year [5,6,180]. As only a small minority progresses, it is important not to cause undue anxiety among such patients. We follow persons identified with CHIP at yearly intervals with a complete blood count with differential and review of the peripheral smear.

Acute myeloid leukemia — MDS and acute myeloid leukemia (AML) lie along a disease continuum with distinction between the two largely made based upon the blast percentage. In the current World Health Organization (WHO) classification system, blast forms must account for at least 20 percent of the total cellularity in AML [181]. In addition, the presence of myeloid sarcoma or any one of the following genetic abnormalities is considered diagnostic of AML without regard to the blast count:

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

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

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

 

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

Previously in the French-American-British (FAB) classification system, cases of MDS with Auer rods or with 21 to 30 percent blasts in the bone marrow or ≥5 percent blasts in the blood were classified as refractory anemia with excess blasts in transformation [182]. However, in the WHO classification system such cases are considered AML [126], although biologic differences between RAEB-T and AML have been described [183].

MDS/MPN syndromes — MDS is characterized by dysplasia and cytopenias. In contrast, the myelodysplastic/myeloproliferative neoplasms (MDS/MPN) include disorders where both dysplastic and proliferative features coexist [126]. These include:

●Chronic myelomonocytic leukemia (CMML) – CMML is characterized by the overproduction of maturing monocytic cells and sometimes dysplastic neutrophils, often accompanied by anemia and/orthrombocytopenia (table 3). This entity was previously considered to be a subtype of MDS, but is currently classified as a MDS/MPN. (See 'Chronic myelomonocytic leukemia' below.)

 

●Atypical chronic myeloid leukemia, BCR-ABL negative – Cases are usually characterized by marked neutrophilia with accompanying dysgranulopoiesis (table 4). (See "Clinical manifestations and diagnosis of chronic myeloid leukemia", section on '"Atypical CML"'.)

 

●Juvenile myelomonocytic leukemia – This rare disorder of infancy and early childhood is characterized by hepatosplenomegaly and lymphadenopathy, with or without evidence of dysgranulopoiesis (table 5). (See "Clinical manifestations and diagnosis of chronic myeloid leukemia", section on 'Juvenile myelomonocytic leukemia'.)

 

●MDS/MPN, unclassifiable (including refractory anemia with ring sideroblasts and thrombocytosis) (table 6)

 

●Isolated isochromosome 17p – Patients with this abnormality 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 [184].

 

Cases with prominent dysplastic and myeloproliferative features should be classified as MDS/MPN rather than MDS. Myeloproliferative features include significant thrombocytosis (eg, platelet count ≥450 x109/L) associated with megakaryocytic proliferation and leukocytosis (white blood cell count ≥13 x109/L), with or without prominent splenomegaly.

Chronic myelomonocytic leukemia — Chronic myelomonocytic leukemia (CMML) is a MDS/MPN characterized by the overproduction of maturing monocytic cells and sometimes dysplastic neutrophils, often accompanied by anemia and/or thrombocytopenia (table 3). Borderline or relative elevations in the monocyte count are common in MDS. In contrast, cases of CMML have a peripheral blood monocyte count >1000/microL and often display other proliferative features such as splenomegaly, leukocytosis, and constitutional symptoms (picture 11). While both may display dysplastic features, such features are generally more subtle in CMML compared with MDS and are often identified in <10 percent of mononuclear cells counted. (See "Chronic myelomonocytic leukemia".)

RARS with thrombocytosis — Some patients with the clinical and morphologic features of RARS (refractory anemia with ring sideroblasts) also have thrombocytosis (RARS-T) [185-187]. These patients demonstrate features of MDS (eg, ring sideroblasts) as well as MPN (eg, megakaryocytes resembling those seen in essential thrombocythemia, thrombocytosis), and have been provisionally designated by the WHO as RARS-T within the category of MDS/MPN, unclassifiable (MDS/MPN-U) [188]. (See "Diagnosis and clinical manifestations of essential thrombocythemia".)

Alternative possibilities are that these patients represent the simultaneous occurrence of two separate disorders (eg, RARS and essential thrombocythemia) or that RARS-T represents patients with essential thrombocythemia who have ring sideroblasts secondary to a non-MDS-associated defect [189]. However, the finding of the JAK2 V617F mutation in up to two-thirds of patients with RARS-T and in only 2 of 89 cases of typical MDS, suggests that RARS-T is best considered another JAK2 mutation-associated chronic MPN [190-193]. In one instructive report, three patients with RARS, who initially had low to normal platelet counts, progressed to RARS-T [194]. Two of the three acquired the JAK2 mutation at this time, suggesting that RARS-T may evolve from RARS through the acquisition of somatic mutations.

Aplastic anemia — Although most patients with MDS have normal or increased bone marrow cellularity, a minority have cellularity that is lower than expected based upon the patient's age (ie, cellularity <30 percent in patients <60 years or <20 percent in patients >60 years), termed hypoplastic MDS [126]. Hypocellularity is found with greatest frequency in therapy-related MDS [58]. Marrow cells in these patients are as a rule morphologically and karyotypically abnormal, features that enable distinction from aplastic anemia (AA). Many patients with both AA and MDS have small populations of glycosylphosphatidyl inositol-anchor deficient cells characteristic of paroxysmal nocturnal hemoglobinuria (PNH), but few patients with MDS alone either develop PNH or display typical PNH clinical manifestations [195]. (See"Aplastic anemia: Pathogenesis; clinical manifestations; and diagnosis".)

The presence of a clonal chromosomal abnormality (eg, 5q-, monosomy 7) identifies cases that are likely to follow a course typical of MDS [196]. A diagnosis of MDS is also suggested by an increase in the percentage of CD34-expressing cells in the bone marrow, the presence of ring sideroblasts, and granulocytic or megakaryocytic dysplasia [197]. Expression of the tumor necrosis factor (TNF) receptor on bone marrow stem cells by flow cytometry may discriminate AA from MDS [198] as patients with AA have a markedly greater TNF receptor expression than those with MDS.

The genetic relationship between MDS and AA was explored in a study that performed targeted DNA sequencing     on the peripheral blood cells of 439 adult patients carrying a diagnosis of AA [199]. Clonal hematopoiesis was documented in roughly 50 percent of AA cases, and somatic mutations in driver genes linked to MDS were found in about a third. However, these mutations tended to be present in small subclones and were not generally predictive of progression to myeloid neoplasia. Exceptions were mutations in ASXL1 and DNMT3A, which were more likely to be associated with progression to MDS and AML. Further work is needed to determine the role of DNA sequencing in distinguishing aplastic anemia from hypocellular MDS.

Myelofibrosis — Mild to moderate degrees of bone marrow fibrosis are common in patients with MDS, and a small percentage will display marked fibrosis similar to that seen in patients with primary myelofibrosis (PMF). Patients with hyperfibrotic MDS are often pancytopenic, with trilineage dysplasia and atypical megakaryocytic proliferation [145,146,200]. Most cases of hyperfibrotic MDS can be distinguished from PMF by the absence of splenomegaly (table 7). In complicated cases, evaluation for the JAK2V617F mutation may be of benefit. This mutation is evident in approximately 50 percent of cases of PMF [201,202], but is present in only 5 percent of patients with MDS [203]. (See "Clinical manifestations and diagnosis of primary myelofibrosis".)

HIV infection — Dysplastic hematopoiesis and variable degrees of cytopenia are common findings accompanying human immunodeficiency virus (HIV) infection [204,205]. (See "Hematologic manifestations of HIV infection: Anemia" and "Hematologic manifestations of HIV infection: Neutropenia" and "Hematologic manifestations of HIV infection: Thrombocytopenia and coagulation abnormalities".)

As an example, a detailed morphologic review was performed in a blinded fashion on 216 bone marrow specimens from 178 patients with HIV infection [204]. Among the most common bone marrow findings were hypercellularity (53 percent of specimens), myelodysplasia (69 percent), increased marrow iron stores (65 percent), megaloblastic hematopoiesis (38 percent), fibrosis (20 percent), plasmacytosis (25 percent), lymphocytic aggregates (36 percent), and granulomas (13 percent).

Hematopoietic dysplasia in such patients may result from medications, opportunistic infection, and/or a direct effect of HIV on hematopoietic progenitors [206,207]. Thus, serologic screening for HIV should be considered in patients with unexplained cytopenia(s) and/or myelodysplasia. MDS that occurs in patients with HIV infection are more likely to have complex cytogenetics (including 7q-/7-) and shorter survival than non-HIV infected patients [208]. (See "Acute and early HIV infection: Treatment".)

Poor nutritional status — Many patients with MDS have macrocytic red cells, reduced reticulocyte percentage, and pancytopenia (anemia, leukopenia, and thrombocytopenia), findings that may also be present in the megaloblastic anemias, copper deficiency [209,210], and zinc excess [211]. While reduced neutrophil lobulation is characteristic of MDS, the combination of increased neutrophil lobulation along with macrocytosis is pathognomonic of megaloblastic anemia. Accordingly, zinc excess and vitamin B12, folate, and copper deficiencies should be excluded in all patients. It is important to distinguish MDS from the other causes of anemia in the elderly [212]. (See "Etiology and clinical manifestations of vitamin B12 and folate deficiency", section on 'Laboratory findings' and "Diagnosis and treatment of vitamin B12 and folate deficiency", section on 'Initial diagnostic strategy' and "Anemia in the older adult" and "Sideroblastic anemias: Diagnosis and management", section on 'Copper deficiency'.)

Medications — The use of a number of medications, including granulocyte colony stimulating factor [213], valproic acid [214], mycophenolate mofetil [215,216], ganciclovir [216,217], and alemtuzumab [218], has been associated with acquired dysplastic changes, including macrocytosis, abnormal (reduced) neutrophil lobulation, neutropenia, thrombocytopenia, and dysplastic changes in all three cell lines on bone marrow examination. Methotrexate or alkylating agents such as cyclophosphamide, sometimes used to treatment autoimmune disorders, can cause dysplasia. In most of the reported cases these changes were reversible on reduction or discontinuation of these medications, usually over a period of several weeks. Repeat bone marrow examinations may be necessary in complicated cases to confirm the diagnosis.

WHO CLASSIFICATION — Myelodysplastic syndrome (MDS) is classified using the World Health Organization (WHO) classification system based upon a combination of morphology, immunophenotype, genetics, and clinical features (table 8) [219]. This classification attempts to identify biologic entities in the hopes that future work will elucidate molecular pathways that might be amenable to targeted therapies. The WHO classification system was built upon the French American British (FAB) Cooperative Group classification, which continues in the vernacular (table 9) [182]. These classification systems are complicated and require morphologic evaluation by an expert hematopathologist [220].

The WHO classification system distinguishes six general entities with the following estimated percentages [126,221]:

●Refractory cytopenia with unilineage dysplasia (refractory anemia, refractory neutropenia, or refractory thrombocytopenia) – <5 percent

●Refractory anemia with ring sideroblasts – <5 percent

●Refractory cytopenia with multilineage dysplasia – 70 percent

●Refractory anemia with excess blasts – 25 percent

●MDS with isolated del(5q) – 5 percent

●MDS, unclassified – <5 percent

 

Childhood MDS is considered a distinct entity in the WHO classification system [126]. Refractory cytopenia of childhood accounts for approximately half of childhood MDS and is the most common subtype in this setting.

Refractory cytopenia with unilineage dysplasia — Refractory cytopenia with unilineage dysplasia (RCUD) is characterized by <5 percent blasts in the bone marrow and ≤1 percent blasts in the peripheral blood [126]. Monocytosis, significant numbers of ringed sideroblasts, and Auer rods are absent. The recommended level for defining dysplasia is ≥10 percent in the affected cell lineage, and the recommended values for defining cytopenia are [222]:

●Refractory anemia – Hemoglobin <10 g/dL

●Refractory thrombocytopenia – Platelet count <100,000/microL

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

 

Values above these levels do not exclude MDS if there are definitive morphologic or cytogenetic features of MDS. While the majority of patients with refractory cytopenia with unilineage dysplasia will demonstrate a single cytopenia (usually corresponding to the dysplastic line), patients with two cytopenias but with unilineage dysplasia are also included in this classification. In contrast, patients with refractory pancytopenia and unilineage dysplasia are not considered to have RCUD, and are instead included in the category of MDS, unclassifiable.

Refractory anemia with ring sideroblasts — Refractory anemia with ring sideroblasts (RARS) fulfills all of the criteria for refractory anemia, but also demonstrates >15 percent ring sideroblasts [126]. Pathologic sideroblasts containing more than five iron-laden mitochondria per cell may be evident on bone marrow specimens stained for the presence of iron (picture 9). Sideroblasts in which five or more iron-laden mitochondria occupy more than one-third of the nuclear rim are termed "ring" sideroblasts [123,223]. Ring sideroblasts and increased storage iron can be found in any of the MDS subtypes; however, the former is characteristic of RARS.

RARS is usually associated with a good prognosis. However, the 15 percent cutoff value used to define RARS is somewhat arbitrary and has been questioned. In a study of 200 patients with MDS without excess blasts who had >1 percent ring sideroblasts, the percentage of ring sideroblasts was not an independent predictor of leukemia-free or overall survival [224]. 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 [19]. (See "Prognosis of the myelodysplastic syndromes in adults", section on 'FAB classification'.)  

Refractory cytopenia with multilineage dysplasia — Refractory cytopenia with multilineage dysplasia (RCMD) is characterized by less than 5 percent BM blasts and severe dysplasia in two or more cell lineages [126]. Some patients with RCMD have increased ring sideroblasts, a condition referred to as RCMD-RS.

Refractory anemia with excess blasts — Refractory anemia with excess blasts (RAEB) is characterized by 5 to 19 percent bone marrow blasts and is further subdivided into RAEB-I (5 to 9 percent blasts) and RAEB-II (10 to 19 percent blasts) [126]. In a study of 558 patients who met these WHO criteria for RAEB, there were no significant differences (other than blast count) between those with RAEB-I or RAEB-II with respect to their clinical, morphologic, hematologic, or cytogenetic parameters [225]. However, RAEB-II was associated with a shorter median survival (9 versus 16 months) and an increased risk of developing acute myeloid leukemia (40 versus 22 percent).

MDS with isolated del(5q) — Approximately 5 percent of patients with MDS present with "5q- syndrome" characterized by severe anemia, preserved platelet counts, and an interstitial deletion of the long arm of chromosome 5 as the sole cytogenetic abnormality [138,226,227]. 5q- syndrome may follow a relatively benign course that extends over several years. It has a low incidence of transformation into acute leukemia and is well known for its responsiveness to treatment with novel agents (eg, lenalidomide). The response of MDS with isolated del(5q) to lenalidomide may be explained by the deletion of one copy of the gene for casein kinase 1A1 [228], which is located in the commonly deleted region of chromosome 5q. Cells that are haploinsufficient for CK1A1 are unusually susceptible to killing by lenalidomide, which binds and directs ubiquitination complexes containing the factor cereblon (CRBN) to CK1A1, thereby mediating its destruction. (See "Treatment of intermediate, low, or very low risk myelodysplastic syndromes", section on 'Patients with 5q deletion'.)

The 5q- syndrome is a distinctive type of primary MDS that primarily occurs in older women [226,227,229]. The median age at diagnosis is 65 to 70 years, with a female predominance of 7:3 (in contrast to a male predominance in other forms of MDS) [230]. Affected patients typically present with a refractory macrocytic anemia, normal or elevated platelet counts, and the absence of significant neutropenia [229]. Because of the typical absence of thrombocytopenia and significant neutropenia, there is a low incidence of bleeding and infection in these patients, but red blood cell transfusions are frequently required. (See"Cytogenetics and molecular genetics of myelodysplastic syndromes", section on 'Deletions of chromosome 5'.)

The bone marrow in 5q- syndrome is characterized by the presence of micromegakaryocytes with monolobulated and bilobulated nuclei. There are less than 5 percent blasts in the marrow in approximately 80 percent of patients [229,230]. The del(5q) is typically interstitial. Approximately 75 percent of cases have a del(5)(q13q33); other interstitial deletions include del(5)(q15q33) and del(5)(q22q33) [231-233]. (See"Cytogenetics and molecular genetics of myelodysplastic syndromes", section on 'Deletions of chromosome 5' and "Cytogenetics and molecular genetics of myelodysplastic syndromes", section on '5q- syndrome'.)

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

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

 

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

 

SUMMARY

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

 

●The diagnosis of MDS should be considered in any patient with unexplained cytopenia(s) or monocytosis. Careful inspection of the peripheral blood smear and bone marrow aspirate is necessary to document the requisite dysplastic cytologic features identifiable in any or all of the hematopoietic lineages (table 2). Detection of certain chromosomal abnormalities distinguishes between MDS and acute myeloid leukemia (AML) in some cases, aids in the classification of MDS, and is a major factor in determining prognostic risk group and therapy. Some centers routinely incorporate DNA sequencing. (See'Evaluation' above and 'Diagnosis' above.)

 

●The diagnosis of MDS requires both of the following:

 

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

 

•Morphologic evidence of significant dysplasia (ie, ≥10 percent of erythroid precursors, granulocytes, or megakaryocytes) upon visual inspection of the peripheral blood smear, bone marrow aspirate, and bone marrow biopsy in the absence of other causes of dysplasia (table 2). In the absence of morphologic evidence of dysplasia, a presumptive diagnosis of MDS can be made in patients with otherwise unexplained refractory cytopenia in the presence of certain genetic abnormalities. (See 'Genetic features' above.)

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

 

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

 

●MDS is classified using the World Health Organization (WHO) classification system based upon a combination of morphology, immunophenotype, genetics, and clinical feature (table 8). (See 'WHO classification' above.)

 

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