Clinical Manifestations and Diagnosis of the Myelodysplastic Syndromes

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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.com2014 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 processis 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 t ransformation to acute leukemia. These disorders may occur de novo or arise years after exposure to potentially mutagenictherapy (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" .)

Thepathogenesis, epidemiology, clinical manifestations, pathologic features, and diagnosis of MD S 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 int he SF3B1 gene that encodes components of the RNA splicing machinery occurs in 6

to 80 percent of the MDS subtyper efractory 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 t he 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 seenin MDS c ases 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 o

altered-DNA methylation in MDS genomes is unclear, several studies have implicated mutations in genes that encode enzymes, s uch as TET2 (ten-eleven translocation), IDH1,

andIDH2 (isoci trate 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 inthe 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 wit

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 t here 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 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 associat ion 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
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concurrent administration of immunosuppressive agents. The evaluation and treatment of infections in patients with MDS are disc ussed 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), perniciousanemia (6 percent), psoriasis (2 percent), and polymyalgia rheumatica (2 percent). Other autoimmune abnormalities include Sweet syndrome, pericarditis, pleural effusions, sk in

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 s yndrome) 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 1and 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 Myelodysplast ic 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 t ime 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 Dysplast ic 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 cy tokines interleukin-6 and granulocyte colony-stimulating factorhave 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 t hat 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 dist ribution 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 st ippling, Howell-Jolly bodies, and megaloblastoid nucleated red cells may also be found in the peripheral smear (picture 2and 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 s o-called pseudo-Pelger-Huet (Pelgeroid) abnormality [44], often accompanied by reduced or absent granulation

(picture 4and picture 5) [110,111].

Occasionally, granulocytes have a clumped chromatin pattern in which blocks of chromatin are separated by a void in nuclear material, c reating an appearance of nuclear
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Bone marrow aspirate and biopsy

Bone marrow aspirate The bone marrow aspirate provides material for a 500 cell differential count t o 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 t he 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 sy stems (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 cy togenetic analysis , reverse transcriptase polymerase chain reaction (RT-PCR), or fluorescent in s itu 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 t reatment of myelodysplastic syndromes", sec tion 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 s tains 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 t o perform some of the t ests recommended for the pretreatment evaluation of patients with MDS in concert with the init ial evaluation. These are

described in more detail separately. (See "Overview of the t reatment 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 si te should be used i f 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", sect ion 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 c ell 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 cy topenia 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 c ell 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


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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 t ransformation [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 dysplast ic and myeloproliferative features should be c lassified 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 t he overproduction of maturing monocytic cells and

sometimes dysplast ic 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 exhibit ing features intermediate between myelocytes and monocytes, which are termed paramyeloid cells [173].

Cells of the monocytic line can be dist inguished from myeloid precursors using a combined esterase stain. There are


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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 clinicalmanifestations of vitamin B12 and folate deficiency", section on 'Laboratory findings'and "Diagnosis and treatment of vitamin B12 and folate deficiency", sect ion 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 Brit ish (FAB) Cooperative Group

classification, which continues in the vernacular (table 9) [167]. These classi fication 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 15 percent

ring sideroblasts [120]. Pathologic sideroblasts containing more than five iron-laden mitochondria per cell may be evident on bone marrow specimens s tained 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 sideroblast

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 mult ilineage 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 intoRAEB-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 t reatment 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]. A ffected 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 cy topenia with unilineage dysplasia (refractory anemia, refractory neutropenia, or refractory thrombocytopenia)


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the marrow in approximately 80 percent of patients [223,224]. The del(5q) is typically interst itial. Approximately 75 percent of cases have a del(5)(q13q33); other interstitial

deletions include del(5)(q15q33) and del(5)(q22q33) [225-227]. (See "Cytogenetics and molecular genetics of myelodysplastic syndromes", section on 'Deletions of chromosome 5

and "Cytogenetics and molecular genetics of myelodysplastic syndromes", section on '5q- syndrome'.)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are

written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best

for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more

detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education

articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

SUMMARY

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

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th th

th th

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


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Clinical Manifestations and Diagnosis of the Myelodysplastic Syndromes

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