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5/9/2014 Clinical manifestations and diagnosis of the myelodysplastic syndromes

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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

5/9/2014 Clinical manifestations and diagnosis of the myelodysplastic syndromes


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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:
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].
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):
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.
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'.)

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
5/9/2014 Clinical manifestations and diagnosis of the myelodysplastic syndromes
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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].

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
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]
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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.

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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'.)

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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:
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:
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 x10 /L) associated with megakaryocytic proliferation and leukocytosis (white blood cell count 13 x10 /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
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
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].

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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
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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
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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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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.)

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 10 /L (<1800/microL); and 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.)
Importantly, blast forms must account for less than 20 percent of the total cells of the bone marrow aspirate and peripheral blood. In addition, the presence of myeloid
sarcoma or certain genetic abnormalities, such as those with t(8;21), inv(16), or t(15;17), are considered diagnostic of acute myeloid leukemia, irrespective of the blast
cell count. (See 'Acute myeloid leukemia' above.)

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

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

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191. Pu JJ, Hu R, Mukhina GL, et al. The small population of PIG-A mutant cells in myelodysplastic syndromes do not arise from multipotent hematopoietic stem cells.
Haematologica 2012; 97:1225.
192. Appelbaum FR, Barrall J, Storb R, et al. Clonal cytogenetic abnormalities in patients with otherwise typical aplastic anemia. Exp Hematol 1987; 15:1134.
193. Malcovati L, Hellstrm-Lindberg E, Bowen D, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European
LeukemiaNet. Blood 2013; 122:2943.
194. Kasahara S, Hara T, Itoh H, et al. Hypoplastic myelodysplastic syndromes can be distinguished from acquired aplastic anaemia by bone marrow stem cell expression of the
tumour necrosis factor receptor. Br J Haematol 2002; 118:181.
195. Della Porta MG, Malcovati L, Boveri E, et al. Clinical relevance of bone marrow fibrosis and CD34-positive cell clusters in primary myelodysplastic syndromes. J Clin Oncol
2009; 27:754.
196. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365:1054.
197. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352:1779.
198. Steensma DP, Dewald GW, Lasho TL, et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and
myelodysplastic syndromes. Blood 2005; 106:1207.
199. Karcher DS, Frost AR. The bone marrow in human immunodeficiency virus (HIV)-related disease. Morphology and clinical correlation. Am J Clin Pathol 1991; 95:63.
200. Scadden DT, Zon LI, Groopman JE. Pathophysiology and management of HIV-associated hematologic disorders. Blood 1989; 74:1455.
201. Sakaguchi M, Sato T, Groopman JE. Human immunodeficiency virus infection of megakaryocytic cells. Blood 1991; 77:481.
202. Chelucci C, Hassan HJ, Locardi C, et al. In vitro human immunodeficiency virus-1 infection of purified hematopoietic progenitors in single-cell culture. Blood 1995; 85:1181.
203. Takahashi K, Yabe M, Shapira I, et al. Clinical and cytogenetic characteristics of myelodysplastic syndrome in patients with HIV infection. Leuk Res 2012; 36:1376.
204. Kumar N, Elliott MA, Hoyer JD, et al. "Myelodysplasia," myeloneuropathy, and copper deficiency. Mayo Clin Proc 2005; 80:943.
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205. Huff JD, Keung YK, Thakuri M, et al. Copper deficiency causes reversible myelodysplasia. Am J Hematol 2007; 82:625.
206. Willis MS, Monaghan SA, Miller ML, et al. Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination. Am J Clin Pathol 2005;
123:125.
207. Pang WW, Schrier SL. Anemia in the elderly. Curr Opin Hematol 2012; 19:133.
208. Schmitz LL, McClure JS, Litz CE, et al. Morphologic and quantitative changes in blood and marrow cells following growth factor therapy. Am J Clin Pathol 1994; 101:67.
209. Singh NK, Nagendra S. Reversible neutrophil abnormalities related to supratherapeutic valproic acid levels. Mayo Clin Proc 2008; 83:600.
210. Banerjee R, Halil O, Bain BJ, et al. Neutrophil dysplasia caused by mycophenolate mofetil. Transplantation 2000; 70:1608.
211. Kennedy GA, Kay TD, Johnson DW, et al. Neutrophil dysplasia characterised by a pseudo-Pelger-Huet anomaly occurring with the use of mycophenolate mofetil and
ganciclovir following renal transplantation: a report of five cases. Pathology 2002; 34:263.
212. Taegtmeyer AB, Halil O, Bell AD, et al. Neutrophil dysplasia (acquired pseudo-pelger anomaly) caused by ganciclovir. Transplantation 2005; 80:127.
213. Gibbs SD, Westerman DA, McCormack C, et al. Severe and prolonged myeloid haematopoietic toxicity with myelodysplastic features following alemtuzumab therapy in
patients with peripheral T-cell lymphoproliferative disorders. Br J Haematol 2005; 130:87.
214. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and
important changes. Blood 2009; 114:937.
215. Naqvi K, Jabbour E, Bueso-Ramos C, et al. Implications of discrepancy in morphologic diagnosis of myelodysplastic syndrome between referral and tertiary care centers.
Blood 2011; 118:4690.
216. Wang XQ, Ryder J, Gross SA, et al. Prospective analysis of clinical and cytogenetic features of 435 cases of MDS diagnosed using the WHO (2001) classification: a
prognostic scoring system for predicting survival in RCMD. Int J Hematol 2009; 90:361.
217. Brunning RD, Orazi A, Hasserjian RP, et al. Refractory cytopenia with unilineage dysplasia. In: World Health Organization Classification of Tumours of Haematopoietic and
Lymphoid Tissues, Swerdlow SH, Campo E, Harris NL, et al (Eds), IARC Press, Lyon 2008. p.94.
218. Hast R. Sideroblasts in myelodysplasia: their nature and clinical significance. Scand J Haematol Suppl 1986; 45:53.
219. Patnaik MM, Hanson CA, Sulai NH, et al. Prognostic irrelevance of ring sideroblast percentage in World Health Organization-defined myelodysplastic syndromes without
excess blasts. Blood 2012; 119:5674.
220. Germing U, Strupp C, Kuendgen A, et al. Refractory anaemia with excess of blasts (RAEB): analysis of reclassification according to the WHO proposals. Br J Haematol
2006; 132:162.
221. Nimer SD. Clinical management of myelodysplastic syndromes with interstitial deletion of chromosome 5q. J Clin Oncol 2006; 24:2576.
222. Patnaik MM, Lasho TL, Finke CM, et al. WHO-defined 'myelodysplastic syndrome with isolated del(5q)' in 88 consecutive patients: survival data, leukemic transformation
rates and prevalence of JAK2, MPL and IDH mutations. Leukemia 2010; 24:1283.
223. Boultwood J, Lewis S, Wainscoat JS. The 5q-syndrome. Blood 1994; 84:3253.
224. Vardiman JW, Brunning RD, Arber DA, et al. Introduction and overview of the classification of the myeloid neoplasms. In: WHO classification of tumors of hematopoietic and
lymphoid tissues, Swerdlow SH, Campo E, Harris NL, et al (Eds), WHO press, 2008. p.18.
225. Boultwood J, Fidler C, Strickson AJ, et al. Narrowing and genomic annotation of the commonly deleted region of the 5q- syndrome. Blood 2002; 99:4638.
226. Zhao N, Stoffel A, Wang PW, et al. Molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases to 1-1.5 Mb and
preparation of a PAC-based physical map. Proc Natl Acad Sci U S A 1997; 94:6948.
227. Pedersen B. 5q(-)survival: importance of gender and deleted 5q bands and survival analysis based on 324 published cases. Leuk Lymphoma 1998; 31:325.
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GRAPHICS
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.
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Electrophoresis for hemoglobin H: Alkaline cellulose
acetate gel
This is a hemoglobin electrophoresis run at alkaline pH on cellulose
acetate gel. Lane 2 is a commercial standard containing approximately
equal amounts of hemoglobins A, F, S, and C. Lane 1 is a hemoglobin
sample from a patient with myelodysplastic syndrome/acute myeloid
leukemia, a population of hypochromic-microcytic red cells, and
acquired hemoglobin H disease. A minor fast-migrating band,
hemoglobin H, is seen along with hemoglobin A.
Kindly supplied by Dr. German Pihan, Department of Pathology, Beth Israel
Deaconess Medical Center.
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Hgb H inclusions
Red cells from a patient with acquired hemoglobin H disease were
incubated in vitro with new methylene blue. Multiple ("golf ball-like")
small inclusions due to precipitation of hemoglobin H are seen as a
result of interaction with this dye.
Kindly provided by Dr. German Pihan, Pathology Department, Beth Israel
Deaconess Medical Center, Boston.
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Morphologic abnormalities in myelodysplastic syndromes
Lineage Peripheral blood Bone marrow
Erythroid Ovalomacrocytes Megaloblastoid erythropoiesis
Elliptocytes Nuclear budding
Acanthocytes Ringed sideroblasts
Stomatocytes Internuclear bridging
Teardrops Karyorrhexis
Nucleated erythrocytes Nuclear fragments
Basophilic stippling Cytoplasmic vacuolization
Howell-Jolly bodies Multinucleation
Myeloid Pseudo-Pelger Huet anomaly Defective granulation
Auer rods Maturation arrest at myeolocyte stage
Hypo-granulation Increase in monocytoid forms
Nuclear sticks Abnormal localization of immature precursors
Hypersegmentation
Ringed shaped nuclei
Megakaryocyte Giant platelets Micromagakaryocytes
Hypogranular or agranular platelets Large mononuclear forms
Hypogranulation
Multiple small nuclei
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.
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Dysplastic red blood cell in myelodysplastic syndrome
Dysplastic nucleated red blood cell, peripheral blood. The nucleus shows an
abnormal shape and size.
Reproduced with permission from: Farhi DC. Myelodysplastic syndromes. In: Pathology
of Bone Marrow and Blood Cells, 2nd ed, Farhi DC (Ed), Lippincott Williams & Wilkins,
Philadelphia 2009. Copyright 2009 Lippincott Williams & Wilkins. www.lww.com.
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Red blood cell dysplasia in myelodysplastic syndrome
Dysplastic nucleated red blood cells, peripheral blood. Abnormal nuclear shape
(black arrow) and basophilic stippling (red arrow) are present.
Reproduced with permission from: Farhi DC. Myelodysplastic syndromes. In: Pathology
of Bone Marrow and Blood Cells, 2nd ed, Farhi DC (Ed), Lippincott Williams & Wilkins,
Philadelphia 2009. Copyright 2009 Lippincott Williams & Wilkins. www.lww.com.
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Decreased nuclear lobes in myelodysplasia (pseudo
Pelger-Huet anomaly)
Peripheral blood smear from a patient with refractory anemia with
excess blasts (RAEB) shows a neutrophil with a bilobed pseudo-
Pelger-Huet (Pelgeroid) nucleus. The two lobes are connected by a
thin strand (arrow) giving a "pince-nez" appearance. These nuclei look
identical to the those seen in the inherited Pelger-Huet anomaly. This
neutrophil also has markedly reduced granulation, a finding commonly
seen in the myelodysplastic syndromes.
From Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of
tumor pathology (electronic fascicle), Third series, fascicle 9, 1994,
Washington, DC. Armed Forces Institute of Pathology.
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Dysplastic neutrophils in myelodysplastic syndrome
Dysplastic neutrophils, peripheral blood. The cells are nearly agranular. The
nuclear segmentation is also abnormal.
Reproduced with permission from: Farhi DC. Myelodysplastic syndromes. In: Pathology
of Bone Marrow and Blood Cells, 2nd ed, Farhi DC (Ed), Lippincott Williams & Wilkins,
Philadelphia 2009. Copyright 2009 Lippincott Williams & Wilkins. www.lww.com.
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Giant neutrophil granules in Chediak-Higashi
syndrome
Peripheral blood smear from a patient with Chediak-Higashi syndrome
shows giant granules in the cytoplasm of both a neutrophil and a band
form. These granules are formed by the inappropriate fusion of
lysosomes and endosomes.
Courtesy of Robert L Baehner, MD.
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Myelokathexis
Bone marrow smear from a patient with neutropenia due to
myelokathexis. There is an increased number of mature and
hypersegmented neutrophils. The myelokathexis morphology is
characterized by pyknotic nuclei with lengthening and thinning of
intrasegmented filaments and vacuoles.
Courtesy of Robert L Baehner, MD.
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Myeloblasts with Auer rod in acute myeloid leukemia
Peripheral smear from a patient with acute myeloid leukemia. There
are two myeloblasts, which are large cells with high nuclear-to-
cytoplasmic ratio and nucleoli. Each myeloblast has a pink/red rod-like
structure (Auer rod) in the cytoplasm (arrows).
From Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of
tumor pathology (electronic fascicle), Third series, fascicle 9, 1994,
Washington, DC. Armed Forces Institute of Pathology.
Graphic 78291 Version 2.0
Normal peripheral blood smear
High power view of a normal peripheral blood smear. Several
platelets (black arrows) and a normal lymphocyte (blue arrow) can
also be seen. The red cells are of relatively uniform size and shape.
The diameter of the normal red cell should approximate that of the
nucleus of the small lymphocyte; central pallor (red arrow) should
equal one-third of its diameter.
Courtesy of Carola von Kapff, SH (ASCP).
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Ring sideroblasts in refractory anemia with ring
sideroblasts (RARS)
Prussian blue stain of the bone marrow in a patient with refractory
anemia and ring sideroblasts (RARS). Blue-stained ferritin iron deposits
in the mitochondria of erythroid precursors form an apparent ring
around the nucleus (see arrows).
Courtesy of Stanley L Schrier, MD.
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Myelodysplastic syndrome with abnormal
megakaryocytic maturation
Bone marrow aspirate from a patient with myelodysplastic syndrome.
The megakaryocytes are abnormal, with multiple small lobes seemingly
disconnected from each other ("Pawn ball" changes, arrows). (Wright-
Giemsa).
Courtesy of David S Rosenthal, MD.
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Diagnostic criteria for chronic myelomonocytic leukemia
Persistent peripheral blood monocytosis >1x10 /L
No Philadelphia chromosome or BCR-ABL1 fusion gene
No rearrangement of PDGFRA or PDGFRB (should be specifically excluded in cases with eosinophilia)
Fewer than 20 percent blasts* in the blood and in the bone marrow
Dysplasia in one or more myeloid lineages. If myelodysplasia is absent or minimal, the diagnosis of CMML may still be made if the other requirements
are met, and:
An acquired, clonal cytogenetic or molecular genetic abnormality is present in the haemopoietic cells, or
The monocytosis has persisted for at least three months and
All other causes of monocytosis have been excluded
CMML: chronic myelomonocytic leukemia.
* Blasts include myeloblasts, monoblasts, and promonocytes. Promonocytes are monocytic precursors with abundant light grey or slightly basophilic
cytoplasm with a few scattered, fine lilac-colored granules, finely-distributed, stippled nuclear chromatin, variably prominent nucleoli, and delicate nuclear
folding or creasing, and in this classification are equivalent to blasts. Abnormal monocytes that can be present both in the peripheral blood and bone marrow
are excluded from the blast count.
From Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW. World Health Organization Classification of Tumours of Haematopoietic
and Lymphoid Tissues. IARC, Lyon, 2008. Reproduced with permission. Copyright 2008 IARC.
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Diagnostic criteria for atypical chronic myeloid leukemia, BCR-ABL negative (aCML)
Peripheral blood leukocytosis (WBC 13x10 /L) due to increased numbers of neutrophils and their precursors with prominent dysgranulopoiesis
No Ph chromosome or BCR-ABL1 fusion gene
No rearrangement of PDGFRA or PDGFRB
Neutrophil precursors (promyelocytes, myelocytes, metamyelocytes) 10 percent of leukocytes
Minimal absolute basophilia; basophils usually <2 percent of leukocytes
No or minimal absolute monocytosis; monocytes <10 percent of leukocytes
Hypercellular bone marrow with granulocytic proliferation and granulocytic dysplasia, with or without dysplasia in the erythroid and megakaryocytic
lineages
Less than 20 percent blasts in the blood and in the bone marrow
From Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW. World Health Organization Classification of Tumours of Haematopoietic
and Lymphoid Tissues. IARC, Lyon, 2008. Reproduced with permission. Copyright 2008 IARC.
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Diagnostic criteria for juvenile myelomonocytic leukemia
Peripheral blood monocytosis >1x10 /L
Blasts (including promonocytes)* are >20 percent of the leukocytes in the blood and of the nucleated bone marrow cells
No Ph chromosome or BCR-ABL1 fusion gene
Plus two or more of the following:
Hemoglobin F increased for age
Immature granulocytes in the peripheral blood
WBC count >10x10 /L
Clonal chromosomal abnormality (may be monosomy 7)
GM-CSF hypersensitivity of myeloid progenitors in vitro
* In this classification, promonocytes are equivalent to blasts.
From Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW. World Health Organization Classification of Tumours of Haematopoietic
and Lymphoid Tissues. IARC, Lyon, 2008. Reproduced with permission. Copyright 2008 IARC.
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Diagnostic criteria for myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN, U)
The case has clinical, laboratory, and morphological features of one of the categories of MDS (refractory cytopenia with unilineage dysplasia, refractory
anemia with ring sideroblasts, refractory cytopenia with multilineage dysplasia, refractory anemia with excess of blasts) and <20 percent blasts in the
blood and bone marrow
And
Has prominent myeloproliferative features, eg platelet count 450x10 /L associated with megakaryocytic proliferation, or WBC count 13x10 /L,
with or without prominent splenomegaly and has no preceding history of an underlying MPN or of MDS, no history of recent cytotoxic or growth
factor therapy that could explain the myelodysplastic or myeloproliferative features, and no Philadelphia chromosome or BCR-ABL1 fusion gene,
no rearrangement of PDGFRA, PDGFRB, FGFR1, and no isolated del(5q), t(3;3)(q21;q26) or inv(3)(q21q26)
Or
The patient has de novo disease with mixed myeloproliferative and myelodysplastic features and cannot be assigned to any other category of
MDS, MPN, or of MDS/MPN
MDS: myelodysplastic syndrome; MPN: myeloproliferative neoplasm
From Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW. World Health Organization Classification of Tumours of Haematopoietic
and Lymphoid Tissues. IARC, Lyon, 2008. Reproduced with permission. Copyright 2008 IARC.
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Chronic myelomonocytic leukemia peripheral smear
Chronic myelomonocytic leukemia, peripheral blood. Monocytes are increased
and show a higher nucleus:cytoplasm ratio compared with normal cells.
Reproduced with permission from: Farhi DC. Myelodysplastic syndromes. In: Pathology
of Bone Marrow and Blood Cells, 2nd ed, Farhi DC (Ed), Lippincott Williams & Wilkins,
Philadelphia 2009. Copyright 2009 Lippincott Williams & Wilkins. www.lww.com.
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Italian Consensus Conference diagnostic criteria for myelofibrosis with myeloid metaplasia
Major criteria
Diffuse bone marrow fibrosis, defined as microscopic evidence of reticulin fibers at 100x in any area of bone sections in biopsies no smaller than 3 x 15
mm
Absence of Philadelphia chromosome or bcr-abl rearrangement in peripheral blood cells
Splenomegaly
Minor criteria
Anisopoikilocytosis with tear-drop erythrocytes
Circulating immature myeloid cells
Circulating erythroblasts (nucleated red blood cells)
Clusters of megakaryoblasts and anomalous megakaryocytes in bone marrow sections
Presence of myeloid metaplasia
The diagnosis of myelofibrosis with myeloid metaplasia is acceptable in the presence of all three major criteria plus any two of the minor criteria OR
the presence of the first two major criteria and any four minor criteria.
Adapated from Barosi, G, Ambrosetti, A, FInelli, C, et al, Br J Haematol 1999; 104:730.
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Peripheral blood and bone marrow findings in myelodysplastic syndromes
Disease Blood findings Bone marrow findings
Refractory cytopenias with unilineage dysplasia
(RCUD)
Unicytopenia or bicytopenia*
No or rare blasts (<1 percent)
Unilineage dysplasia: 10 percent of the cells in
one myeloid lineage
<5 percent blasts
<15 percent of erythroid precursors are ring
sideroblasts
Refractory anemia (RA); refractory neutropenia
(RN); refractory thrombocytopenia (RT)
Refractory anemia with ring sideroblasts (RARS) Anemia
No blasts
15 percent of erythroid precursors are ring
sideroblasts
Erythroid dysplasia only
<5 percent blasts
Refractory cytopenia with multilineage dysplasia
(RCMD)
Cytopenia(s)
No or rare blasts (<1 percent)
No Auer rods
<1x10 /L monocytes
Dysplasia in 10 percent of the cells in two
myeloid lineages (neutrophil and/or erythroid
precursors and/or megakaryocytes)
<5 percent blasts in marrow
No Auer rods
15 percent ring sideroblasts
Refractory anemia with excess blasts-1 (RAEB-1) Cytopenia(s)
<5 percent blasts
No Auer rods
<1x10 /L monocytes

Unilineage or multilineage dysplasia
5 to 9 percent blasts
No Auer rods
Refractory anemia with excess blasts-2 (RAEB-2) Cytopenia(s)
5 to 19 percent blasts
Auer rods
<1x10 /L monocytes

Unilineage or multilineage dysplasia
10 to 19 percent blasts
Auer rods
Myelodysplastic syndrome - unclassified (MDS-U) Cytopenias
1 percent blasts
Unequivocal dysplasia in less than 10 percent of
cells in one or more myeloid cell lines when
accompanied by a cytogenetic abnormality
considered as presumptive evidence for a
diagnosis of MDS
<5 percent blasts
MDS associated with isolated del(5q) Anemia
Usually normal or increased platelet count
No or rare blasts (<1 percent)
Normal to increased megakaryocytes with
hypolobated nuclei
<5 percent blasts
Isolated del(5q) cytogenetic abnormality
No Auer rods
* Bicytopenia may occassionally be observed. Cases with pancytopenia should be classified as MDS-U.
If the marrow myeloblast percentage is <5 percent but there are 2 to 4 percent myeloblasts in the blood, the diagnostic classification is RAEB-1. Cases of
RCUD and RCMD with 1 percent myeloblasts in the blood should be classified as MDS-U.
Cases with Auer rods and <5 percent myeloblasts in the blood and <10 percent in the marrow should be classified as RAEB-2.
From Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW. World Health Organization Classification of Tumours of Haematopoietic
and Lymphoid Tissues. IARC, Lyon, 2008. Reproduced with permission. Copyright 2008 IARC.
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French-American-British (FAB) cooperative group criteria for myelodysplastic syndrome subtypes
Type
Bone marrow
blasts, percent

Peripheral blood
blasts, percent
Auer
rods
Monocytes
>1000/L
Ringed sideroblasts, >15 percent of
nucleated erythroid cells
RA <5 1 No No No
RARS <5 1 No No Yes
RAEB 5-20 <5 No No
CMML 20 <5 No Yes
RAEB-
T*
21-30 OR 5
FAB: French-American-British; RA: refractory anemia; RARS: refractory anemia with ringed sideroblasts; RAEB: refractory anemia with excess blasts; CMML:
chronic myelomonocytic leukemia; RAEB-T: refractory anemia with excess blasts in transformation.
* Editor's note: The World Health Organization (WHO) classification considers RAEB-T to represent either an evolving acute myeloid leukemia (AML) or AML
with multilineage dysplasia.
Adapted from Bennett, JM, Catovsky, D, Daniel, MT, et al. FAB Cooperative Group: Proposal for the classification of the myelodysplastic syndromes. Br J Haematol
1982; 51:189., and Greenberg, PL. The Myelodysplastic Syndromes. In: Hematology: Basic Principles and Practice, 2nd ed, Hoffman, R, Benz, E, Shattil, S (Eds),
Churchill Livingstone, New York, 1994, p. 1098.
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Di scl osures: Jon C Aster, MD Nothing to disclose. Richard M Stone, MD Consultant/Advisory Boards: Celgene [MDS (azacitidine,
lenalidomide)]. Richard A Larson, MD Grant/Research/Clinical Trial Support: Amgen [leukemia (blinatumomab)]; Astellas [leukemia
(ASP2215)]; Erytech [leukemia (Erytech)]; Ariad [leukemia (ponatinib)]; Novartis [leukemia (nilotinib)]; Ambit Bioscience [leukemia
(quizartinib)]. Grant/Research/Clinical Trial Support (Spouse): Millennium[lymphoma (bortezomib)]; Janssen [lymphoma (inotuzumab)];
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[leukemia (imatinib, nilotinib)]; Ariad [leukemia (ponatinib)]; CVS/Caremark [leukemia (drug prior authorization)]; Pf izer [leukemia
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[DSMB, leukemia (dasatinib)]. Consultant/Advisory Boards (Spouse): Janssen [lymphoma (ibrutinib)]; Spectrum[lymphoma (ibritumomab
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