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Official reprint from UpToDate
www.uptodate.com 2014 UpToDate
Authors
Jon C Aster, MD
Richard M Stone, MD
Section Editor
Richard A Larson, MD
Deputy Editor
Rebecca F Connor, MD
Clinical manifestations and diagnosis of the myelodysplastic syndromes
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2014. | This topic last updated: Jun 20, 2014.
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 years after exposure to potentially mutagenic
therapy (eg, radiation exposure, chemotherapy).
Patients with MDS have a variable reduction in the production of normal red blood cells, platelets, and mature granulocytes. This often results 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 poorly understood. MDS is a clonal process that is thought to develop from a single
transformed hematopoietic progenitor cell [1,2]. Studies suggest that the cell of origin has acquired multiple mutations resulting in dysplasia and ineffective hematopoiesis [3].
While the inciting mutation is unknown for the majority of cases, recurrent mutations in genes involved in the RNA splicing machinery (eg, SF3B1, U2AF1, SRSF2, ZRSR2, and
U2AF35) have been identified in a subset of cases [4-8]. 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) [4,9-14]. (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 [12]. 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 carries a negative prognostic impact [15].
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-) [16].
Telomere disruption [17,18] and aberrant or absent expression of microRNA species may be important in MDS pathophysiology [19].
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 TET2 (ten-eleven translocation), IDH1,
and IDH2 (isocitrate dehydrogenase-1 and -2, respectively), that influence DNA methylation directly or indirectly [20-25]. RUNX1 mutations may disturb expression of genes
related to normal hematopoietic aging [26]. The role of DNA methylation in the pathobiology of MDS is also supported by studies that have demonstrated disease response to
hypomethylating agents. (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 [27] and T cell dysregulation [28], 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 and presence of HLA-DR15 [29,30]. (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; however, estimates from cancer databases indicate that there are
approximately 10,000 cases diagnosed annually in the United States [31-33]. One series, for example, reported a crude annual incidence rate of 4.1 per 100,000 [32]. A similar
incidence rate has been reported in the United Kingdom and Ireland [34,35]. In comparison, lower incidence rates of 0.27 per 100,000 have been reported in Eastern Europe,
perhaps related to patterns in hospital use [34]. The actual incidence of MDS may be 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 [36-38].
MDS occurs most commonly in older adults with a median age at diagnosis in most series of 65 years and a male predominance [31,35,39-48]. Onset of the disease earlier than
age 50 is unusual [49,50], with the exception of treatment-induced MDS [47,51], but rare cases of MDS have been reported in children at a median age of six years [52-54]. 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 [55].
MDS has been associated with environmental factors (eg, exposure to chemicals, particularly benzene [56], radiation, tobacco, or chemotherapy drugs), genetic abnormalities
(eg, trisomy 21, Fanconi anemia, Bloom syndrome, ataxia telangiectasia), and other benign hematologic diseases (eg, paroxysmal nocturnal hemoglobinuria, congenital
neutropenia) (table 1) [57]. In addition, a rare autosomal dominant condition has been described associated with monocytopenia, susceptibility to infection with mycobacteria,
fungi, and papillomaviruses, and the development of myelodysplasia [58]. Familial MDS, while rare, has been associated with germ line RUNX1, CEBPA, TERC, TERT, and
GATA2 mutations [59-61]. Although connective tissue disorders such as relapsing polychondritis, polymyalgia rheumatica, Raynaud phenomenon and Sjgren's syndrome,
inflammatory bowel disease, pyoderma gangrenosum, Behet's disease, and glomerulonephritis have been reported in association with MDS, a causal relationship has not been
established [62-67].
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
[41,68-70]. 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) [41].
Hepatomegaly, splenomegaly, and lymphadenopathy are uncommon [71]. Sweets syndrome (neutrophilic dermatosis) may be the presenting symptom.
Infection Patients with MDS have a high incidence of infection related to neutropenia and granulocyte dysfunction (eg, impaired chemotaxis and microbial killing) [72,73].
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
Myeloid sarcoma (also called granulocytic sarcoma or chloroma) of the skin may also herald disease transformation into acute leukemia [93-95]. 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 [96]. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section
on 'Myeloid sarcoma'.)
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 [47]. 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 [47]. Unlike anemia, isolated thrombocytopenia is not a
common early manifestation of MDS [97]. However, a thrombocytopenic presentation with minimal morphologic dysplasia has been described in patients in whom del(20q)
was the sole karyotypic abnormality [98]. 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 [99]. 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.)
Red cells are usually normocytic or macrocytic [74,100], although patients with refractory anemia with ringed sideroblasts (RARS) may present with a variable population of
hypochromic, microcytic red cells [101]. (See "Clinical aspects, diagnosis, and treatment of the sideroblastic anemias".)
Ovalomacrocytosis is the best-recognized morphologic abnormality of erythrocytes. In some cases, however, elliptocytes [102,103], teardrops, stomatocytes, or
acanthocytes (Spur cells) [104] may predominate, reflecting intrinsic alterations in cytoskeletal proteins [103,105].
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 [74,106].
Reticulocytosis may be indicative of a superimposed autoimmune hemolytic anemia [107] or may be a marker of delayed reticulocyte maturation, so-called
pseudoreticulocytosis [108,109].
Granulocytes commonly display reduced segmentation, the so-called pseudo-Pelger-Huet (Pelgeroid) abnormality [44], often accompanied by reduced or absent granulation
(picture 4 and picture 5) [110,111].
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
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Bone marrow aspirate and biopsy
Bone marrow aspirate 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 [40]. Maturation of the cytoplasm may progress more rapidly than the nucleus [49].
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
[120]. 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) [121,122]. 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
[121,123]. Special techniques can reveal increased apoptosis in lower risk MDS [124].
The bone marrow is usually hypercellular and accompanied by single- or multi-lineage dysplasia (table 2) [123,125,126]. The classic paradox of peripheral pancytopenia despite
the presence of a hypercellular bone marrow reflects premature cell loss via intramedullary cell death (apoptosis) [127,128]. Although hypocellularity is uncommon, it is found with
greatest frequency in therapy-related MDS and must be distinguished from aplastic anemia [51]. (See 'Aplastic anemia' below.)
Cytochemistry and immunocytochemistry Cytochemical stains and immunophenotyping studies may demonstrate a decrease or loss of normal myeloid maturation
antigens [77], or the presence of antigens not normally expressed [142]. Myeloperoxidase [73] and alkaline phosphatase [74] activities may be diminished in myeloid elements,
whereas monocyte-specific esterase may be increased [75].
Useful cytochemical methods include:
Immunocytochemistry may be helpful in order to:
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 [149,150]. Automated flow cytometric systems (multiparameter flow cytometry) for scoring dyspoiesis in MDS have been developed [151]. These systems
appear to have both diagnostic and prognostic value in patients with MDS [151-157]. 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 [156].
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 [158].
(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 [120] (see "Clinical manifestations, pathologic features, and
diagnosis of acute myeloid leukemia", section on 'Bone marrow infiltration'):
fragmentation associated with loss of segmentation [112,113]. Ring-shaped nuclei and nuclear sticks may be identified [114], particularly in therapy-related MDS. Rarely, a
pseudo-Chediak-Higashi anomaly (picture 6) [115] or myelokathexis-like features (picture 7) may be evident [116]. (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 [117,118]. 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 [119].
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 [129].
Although erythroid hyperplasia may represent the predominant finding in association with ineffective erythropoiesis, red cell aplasia and/or hypoplasia rarely occur
[130].
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) [44,131,132]. Nonlobulated or mononuclear megakaryocytes may be identified, particularly in association with the 5q- syndrome. Antibodies to von Willebrand
factor and CD41 (a component of platelet GpIIa/IIIb) may be used to identify these atypical megakaryocytes [133]. (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 [123,134]. This
displacement of granulocyte precursors has been termed "abnormal localization of immature precursors" [123,134,135].
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 [136-139]. While
myelofibrosis occurs in all subtypes of MDS, it is most common in therapy-related MDS [51]. 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 [140]. The
degree of fibrosis can be graded using European consensus criteria [141].
Detect lineage infidelity (eg, myeloid lineage cells expressing nonmyeloid antigens) and confirm the presence of bi- or tri-lineage dysplasia [147,148]
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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 [120]:
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 [159,160]. It is likely that targeting exome
sequencing (deep sequencing) of DNA prepared from marrow or peripheral blood cells will become available as an additional diagnostic test in the future. Further details regarding
cytogenetic changes in patients with MDS are presented separately. (See "Cytogenetics and molecular genetics of myelodysplastic syndromes".)
EVALUATION The diagnosis of MDS should be considered in any patient with unexplained cytopenia(s) or monocytosis. A careful history should elicit details regarding
nutritional status, alcohol and drug use, medications, occupational exposure to toxic chemicals, prior treatment with antineoplastic agents or radiotherapy, and risk factors for
and/or treatment of human immunodeficiency virus (HIV) infection. Evaluation of the peripheral blood smear and a unilateral bone marrow biopsy and aspirate are key components
to the diagnosis of MDS. 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 [120]. While most cases of MDS will have these three features, some will not, as clarified in the
caveats presented.
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, 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 [120,161-164]. (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 [165]. 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.
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
-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)
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 10 /L (<1800/microL); platelets <100 x 10 /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.
9 9
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'.)
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 [169].
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"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 [199]. 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 [201,202]. 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 [203]. (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 [204,205], and zinc excess [206]. 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 [207]. (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 "Clinical aspects, diagnosis, and treatment of the sideroblastic anemias", section on 'Copper deficiency' and "Anemia in the older adult".)
Medications The use of a number of medications, including granulocyte colony stimulating factor [208], valproic acid [209], mycophenolate mofetil [210,211], ganciclovir
[211,212], and alemtuzumab [213], 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) [214]. 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) [167]. These classification systems are complicated and require morphologic evaluation by an expert hematopathologist
[215].
The WHO classification system distinguishes six general entities with the following estimated percentages [120,216]:
Childhood MDS is considered a distinct entity in the WHO classification system [120]. 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 [120]. 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 [217]:
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 [120]. 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 [117,218]. 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 [219]. (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 [120]. 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) [120]. 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 [220]. 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 [131,221,222]. 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). (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 [221-223]. The median age at diagnosis is 65 to 70 years, with a female predominance
of 7:3 (in contrast to a male predominance in other forms of MDS) [224]. Affected patients typically present with a refractory macrocytic anemia, normal or elevated platelet
counts, and the absence of significant neutropenia [223]. Because of the typical absence of thrombocytopenia and significant neutropenia, there is a low incidence of bleeding and
infection in these patients, but red blood cell transfusions are frequently required. (See "Cytogenetics and molecular genetics of myelodysplastic syndromes", section on
'Deletions of chromosome 5'.)
The bone marrow in 5q- syndrome is characterized by the presence of micromegakaryocytes with monolobulated and bilobulated nuclei. There are less than 5 percent blasts in
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
Refractory anemia Hemoglobin <10 g/dL
Refractory thrombocytopenia Platelet count <100,000/microL
Refractory neutropenia Absolute neutrophil count (ANC) <1800/microL
5/9/2014 Clinical manifestations and diagnosis of the myelodysplastic syndromes
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the marrow in approximately 80 percent of patients [223,224]. The del(5q) is typically interstitial. Approximately 75 percent of cases have a del(5)(q13q33); other interstitial
deletions include del(5)(q15q33) and del(5)(q22q33) [225-227]. (See "Cytogenetics and molecular genetics of myelodysplastic syndromes", section on 'Deletions of chromosome 5'
and "Cytogenetics and molecular genetics of myelodysplastic syndromes", section on '5q- syndrome'.)
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are
written in plain language, at the 5 to 6 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 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education
articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
SUMMARY
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REFERENCES
1. Walter MJ, Shen D, Ding L, et al. Clonal architecture of secondary acute myeloid leukemia. N Engl J Med 2012; 366:1090.
2. Will B, Zhou L, Vogler TO, et al. Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic
alterations. Blood 2012; 120:2076.
3. Pang WW, Pluvinage JV, Price EA, et al. Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes. Proc Natl Acad Sci U S A 2013;
110:3011.
4. Yoshida K, Sanada M, Shiraishi Y, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011; 478:64.
5. Graubert TA, Shen D, Ding L, et al. Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat Genet 2012; 44:53.
6. Makishima H, Visconte V, Sakaguchi H, et al. Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood 2012; 119:3203.
7. Damm F, Kosmider O, Gelsi-Boyer V, et al. Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic
syndromes. Blood 2012; 119:3211.
8. Papaemmanuil E, Gerstung M, Malcovati L, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 2013; 122:3616.
9. Visconte V, Makishima H, Jankowska A, et al. SF3B1, a splicing factor is frequently mutated in refractory anemia with ring sideroblasts. Leukemia 2012; 26:542.
10. Malcovati L, Papaemmanuil E, Bowen DT, et al. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms.
Blood 2011; 118:6239.
11. Patnaik MM, Lasho TL, Hodnefield JM, et al. SF3B1 mutations are prevalent in myelodysplastic syndromes with ring sideroblasts but do not hold independent prognostic
value. Blood 2012; 119:569.
12. Visconte V, Rogers HJ, Singh J, et al. SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes. Blood 2012; 120:3173.
13. Cazzola M, Rossi M, Malcovati L, Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative. Biologic and clinical significance of somatic
mutations of SF3B1 in myeloid and lymphoid neoplasms. Blood 2013; 121:260.
14. Thol F, Kade S, Schlarmann C, et al. Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. Blood
2012; 119:3578.
15. Wu SJ, Kuo YY, Hou HA, et al. The clinical implication of SRSF2 mutation in patients with myelodysplastic syndrome and its stability during disease evolution. Blood 2012;
120:3106.
16. Payne EM, Virgilio M, Narla A, et al. L-Leucine improves the anemia and developmental defects associated with Diamond-Blackfan anemia and del(5q) MDS by activating
the mTOR pathway. Blood 2012; 120:2214.
17. Gadji M, Adebayo Awe J, Rodrigues P, et al. Profiling three-dimensional nuclear telomeric architecture of myelodysplastic syndromes and acute myeloid leukemia defines
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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)")
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. (See 'Evaluation' above and 'Diagnosis' above.)
9 9
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.)