Clinical manifestations and diagnosis of the myelodysplastic syndromes

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.

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.
Studies suggest that the cell of origin has acquired multiple mutations resulting in dysplasia and
ineffective hematopoiesis.
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.
Factors extrinsic to the hematopoietic cell, such as stromal abnormalities and T cell dysregulation,
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.

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.
One series, for example, reported a crude annual incidence rate of 4.1 per 100,000.
A similar incidence rate has been reported in the United Kingdom and Ireland.
In comparison, lower incidence rates of 0.27 per 100,000 have been reported in Eastern Europe,
perhaps related to patterns in hospital use.
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.
MDS occurs most commonly in older adults with a median age at diagnosis in most series of 65
years and a male predominance.
Onset of the disease earlier than age 50 is unusual, with the exception of treatment-induced MDS,
but rare cases of MDS have been reported in children at a median age of six years.
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.
MDS has been associated with environmental factors (eg, exposure to chemicals, particularly
benzene, 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).
Myelodysplastic syndromes: predisposing factors and epidemiologic
associations
Heritable predisposition
Constitutional genetic disorders
Down syndrome (trisomy 21)
Trisomy 8 mosaicism
Familial monosomy 7
Neurofibromatosis 1
Germ cell tumors (embryonal dysgenesis)
Congenital neutropenia (Kostmann's or Shwachman-Diamond syndrome)
DNA repair deficiencies
Fanconi's anemia
Ataxia telangiectasia
Bloom's syndrome
Xeroderma pigmentosum
Mutagen-detoxification (GSTq1-null)
Acquired
Senescence
Mutagen exposure
Genotoxic therapy
Alkylators
Topoisomerase II interactive agents
Beta-emitters (eg, radioactive P-32)
Hematopoietic cell transplantation
Environmental/occupational (eg, benzene)
Tobacco use
Aplastic anemia
Paroxysmal nocturnal hemoglobinuria (PNH)
Polycythemia vera
Obesity
Reproduced with permission from: List AF, Doll DC. The Myelodysplastic Syndromes. Wintrobe's Clinical
Hematology, 10th edition, Lee GR (Ed), Lippincott Williams & Wilkins, Baltimore 1999. Copyright 1999
Lippincott Williams & Wilkins. www.lww.com.
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.
Familial MDS, while rare, has been associated with germ line RUNX1, CEBPA, TERC, TERT, and
GATA2 mutations.
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.

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 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 [73] and alkaline phosphatase [74] activities may be diminished in myeloid
elements, whereas monocyte-specific esterase may be increased [75]. As a consequence,
granulocytes may be dysfunctional and display defective phagocytosis, bactericidal activity,
adhesion, and chemotaxis [73], leading to impaired resistance to bacterial infections. Quantitative
decreases in natural killer cells are routinely seen.
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 [76]. Lymphopenia,
due largely to a reduced number of CD4+ cells, is inversely related to the number of transfusions
received [77,78]. However, CD8+ cells are normal or slightly increased [79]. Immunoglobulin
production is variably affected, with hypogammaglobulinemia, polyclonal
hypergammaglobulinemia, and monoclonal gammopathy reported in 13, 30, and 12 percent of
patients, respectively [80,81].
Autoimmune abnormalities Autoimmune abnormalities, although uncommon, may complicate
the course of MDS [62-67,82]. 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) [83]. 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 [62]. (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 [84-87], 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) [88]. An acquired somatic mutation of ATRX, an X-linked gene
encoding a chromatin-associated protein, has been linked to this entity [84], 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 [89-92]. Paracrine and autocrine elaboration of the
cytokines interleukin-6 and granulocyte colony-stimulating factor have been implicated in the
pathogenesis of this condition [91]. (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 [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'.)
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 [71].
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.)
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 [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].
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 [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 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].
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.)
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].
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:
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 a glycophorin-A-reactive antibody
Quantify myeloid progenitors and blasts using antibodies to CD34, CD117, CD13, CD14, and
CD33 [143]
Detect dysplastic or immature megakaryocytes via antibodies with specificity for von Willebrand
factor [133], factor VIII [144], CD41 [145], or the HPI-ID monoclonal antibody [146]
Detect lineage infidelity (eg, myeloid lineage cells expressing nonmyeloid antigens) and confirm
the presence of bi- or tri-lineage dysplasia [147,148]
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'):
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 [120]:
-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 [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.
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, 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.
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 [166]. 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 [167]. However, in the WHO
classification system such cases are considered AML [120], although biologic differences between
RAEB-T and AML have been described [168].
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 [120]. These include:
Chronic myelomonocytic leukemia (CMML) CMML is characterized by the overproduction of
maturing monocytic cells and sometimes dysplastic neutrophils, often accompanied by anemia
and/or thrombocytopenia (table 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 [169].
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) [170-172].
Splenomegaly is massive in up to 25 percent of patients with CMML and is often accompanied by
hepatomegaly, lymphadenopathy, and nodular cutaneous leukemic infiltrates [173-177]. Pleural
and pericardial effusions and ascites can occur in CMML patients with exceedingly high or
uncontrolled monocytosis [178] that often resolves with antileukemic therapy.
Serologic polyclonal gammopathy was found in 47 percent of patients in one series [174].
Muramidase (lysozyme) activity may be increased in the blood or urine, reflecting heightened
monocytopoiesis and cell turnover [179]. Lysozymuria may be associated with urinary potassium
wasting, hypokalemia, and elevated serum creatinine levels. A coagulopathy may be present due
to binding of factor X to abnormal monocytes, leading to an acquired factor X deficiency. (See
"Causes of hypokalemia", section on 'Salt-wasting nephropathies'.)
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 (picture 11). The bone marrow is
uniformly hypercellular, with mononuclear cells exhibiting features intermediate between
myelocytes and monocytes, which are termed paramyeloid cells [173]. Cells of the monocytic line
can be distinguished from myeloid precursors using a combined esterase stain. There are <20
percent blasts in the bone marrow or peripheral blood. Blasts include myeloblasts, monoblasts,
and promonocytes. Monocytes displaying atypical cytologic features are common and are
excluded from the blast count. Auer rods are absent and ring sideroblasts may or may not be
present. Cases by definition do not exhibit the Philadelphia chromosome, the BCR-ABL1 fusion
gene, or rearrangements of platelet derived growth factor receptor (PDGFRA or PDGFRB).
Although PDGFRB rearrangements are rarely seen in patients with CMML, if present they are
classified as a distinct entity, and there are important therapeutic implications (ie, imatinib
sensitivity) [180].
RARS with thrombocytosis Some patients with the clinical and morphologic features of RARS
(refractory anemia with ring sideroblasts) also have thrombocytosis (RARS-T) [181-183]. 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/MPD, unclassifiable
(MDS/MPD-U) [184]. (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 [185]. 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 MPD [186-189]. In one instructive report,
three patients with RARS, who initially had low to normal platelet counts, progressed to RARS-T
[190]. 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 [120]. Hypocellularity is found with greatest frequency in therapy-related MDS
[51]. Marrow cells in these patients are as a rule morphologically and karyotypically abnormal,
features that enable distinction from aplastic anemia (AA). Many patients with both AA and MDS
have small populations of glycosylphosphatidyl inositol-anchor deficient cells characteristic of
paroxysmal nocturnal hemoglobinuria (PNH), but few patients with MDS alone either develop PNH
or display typical PNH clinical manifestations [191]. (See "Aplastic anemia: Pathogenesis; clinical
manifestations; and diagnosis", section on 'Diagnostic criteria'.)
The presence of a clonal chromosomal abnormality (eg, 5q-, monosomy 7) confirms the diagnosis
of MDS [192]. A diagnosis of MDS is also suggested by an increase in the percentage of CD34-
expressing cells in the bone marrow, the presence of ring sideroblasts, and granulocytic or
megakaryocytic dysplasia [193]. Expression of the tumor necrosis factor (TNF) receptor on bone
marrow stem cells by flow cytometry may discriminate AA from MDS [194] as patients with AA
have a markedly greater TNF receptor expression than those with MDS.
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 [138,139,195]. 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 [196,197], but is present in only 5 percent of
patients with MDS [198]. (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 [199,200]. (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 [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]:
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 [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]:
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
[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 the marrow in
approximately 80 percent of patients [223,224]. The del(5q) is typically interstitial. Approximately
75 percent of cases have a del(5)(q13q33); other interstitial deletions include del(5)(q15q33) and
del(5)(q22q33) [225-227]. (See "Cytogenetics and molecular genetics of myelodysplastic
syndromes", section on 'Deletions of chromosome 5' and "Cytogenetics and molecular genetics of
myelodysplastic syndromes", section on '5q- syndrome'.)
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials,
"The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain
language, at the 5th to 6th grade reading level, and they answer the four or five key questions a
patient might have about a given condition. These articles are best for patients who want a general
overview and who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to
12th grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)
Basics topics (see "Patient 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. (See 'Evaluation' above
and 'Diagnosis' above.)
The diagnosis of MDS requires both of the following:
Otherwise unexplained quantitative changes in one or more of the blood and bone marrow
elements (ie, red cells, granulocytes, platelets). The values used to define cytopenia are:
hemoglobin <10 g/dL (100 g/L); absolute neutrophil count <1.8 x 109/L (<1800/microL); and
platelets <100 x 109/L (<100,000/microL). However, failure to meet the threshold for cytopenia
does not exclude the diagnosis of MDS if there is definite morphologic evidence of dysplasia.
Morphologic evidence of significant dysplasia (ie, 10 percent of erythroid precursors,
granulocytes, or megakaryocytes) upon visual inspection of the peripheral blood smear, bone
marrow aspirate, and bone marrow biopsy in the absence of other causes of dysplasia (table 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.)