Encyclopedia of Pathology

Living Edition
| Editors: J.H.J.M. van Krieken

Myelodysplastic Syndromes (MDS)

  • Valentina F. I. SangiorgioEmail author
  • Attilio Orazi
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-28845-1_4695-1

Synonyms

Definition

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal bone marrow disorders characterized by ineffective hematopoiesis due to functional abnormalities of maturing hematopoietic stem cell (HSC). Abnormal HSC actively proliferates, but is unable to undergo the normal differentiation necessary to produce mature circulating elements of the three hematopoietic lineages (i.e., erythroid, granulocytic, and megakaryocytic) and dies in the bone marrow through programmed cell death or apoptosis. This ineffective hematopoiesis manifests clinically with peripheral blood (PB) cytopenia(s) and morphologically with single lineage or multilineage dysplasia.

With disease progression, HSC in MDS acquires multistep alterations, the accumulation of which may eventually cause transformation to acute myeloid leukemia (AML).

Clinical Features

Incidence and Age

The annual incidence of MDS in the general population is 3–5 cases per 100,000. Incidence increases markedly with age, exceeding 20 cases per 100,000 in individuals >70 years and 30 cases per 100,000 in individuals >80 years. There is an overall male predominance, with a male to female ratio of 1.4:1. An exception is MDS with isolated del(5q) that affects more frequently females.

MDS developing after exposure to prior cytotoxic chemotherapy and/or radiotherapy, referred as “therapy-related” MDS (t-MDS), can affect patients of all ages. The latency period between exposure to the mutagenic event and the onset of disease is estimated of 5–6 years for the alkylating agents and radiation and 2–3 years for the topoisomerase II inhibitors.

MDS can occur also in childhood but are rare, with an annual incidence of 2–3 cases per million.

Clinical Presentation

Patients with MDS experience signs and symptoms related to PB cytopenia(s) and presence of cytopenia(s) is required for a diagnosis of MDS. Cytopenia is defined as having values below the standard reference range [hemoglobin <13 g/dL (males), <12 g/dL (females), absolute neutrophil count <1.8 × 109/L, platelets <150 × 109/L]. However, the IPSS-derived lower thresholds (see below) as used in the 2008 WHO Classification (hemoglobin <10 g/dL, absolute neutrophil count <1.8 × 109/L, platelet count <100 × 109/L and) are more specific and more strongly associated with diagnosis of MDS.

Anemia, especially of the macrocytic type, is the most common cytopenia observed; neutropenia and thrombocytopenia are less frequent. Thrombocytosis (platelet count >450 × 109/L) may be observed as in cases of MDS with isolated del (5q), inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2).

Treatment

The first issue in the treatment of patients with MDS is whether the aim is to extend patients survival or to palliate symptoms with supportive care. Therapeutic options are decided considering patients prognosis (according to IPSS-R and/or WPSS; see below), age, and performance status. “Low risk” MDS patients or patients with “high risk” MDS (see below) but poor general conditions and/or advanced age usually receive supportive care alone or low intensity therapies. Supportive care with red cell transfusions is used in patients with MDS and symptomatic anemia to improve quality of life. Giving the potential risk of iron overload in multitransfused patients, transfusions should be used only to alleviate symptoms and not simply to maintain high hemoglobin levels. Platelet transfusions are indicated in case of acute bleeding or as prophylaxis prior to surgery or following chemotherapy. Recombinant erythropoietin (EPO) is used to normalize hemoglobin level and to achieve transfusion independence. Granulocyte colony stimulating factor (G-CSF) is used to improve neutrophil counts and function and is usually reserved to patients with severe sepsis or recovering from intensive chemotherapy regimens.

Among the low intensity regimens, of great relevance are hypomethylating drugs. Promoters hypermethylation leading to epigenetic silencing of tumor-suppressor genes plays an important role in the molecular pathogenesis of MDS. Reversal of this process can be achieved with hypomethylating drugs, such as 5-azacitidine and decitabine. These agents reduce the degree of genome methylation, leading to improvements of symptoms, transfusion independence, and increased time to progression to AML.

Patients with MDS with isolated del(5q) have high response rate to lenalidomide, a multitarget agent with broad effects on bone marrow microenvironment, antiangiogenic activity, and cytokine suppressor.

Finally, the evidence of immune system dysfunction in MDS provides the rationale for the use of immunosuppressive agents such as rabbit antithymocyte globulin (ATG) in low risk patients.

High risk patients can receive intensive chemotherapy regimens followed by autologous stem cell transplantation (SCT) to consolidate remission. Unfortunately, AML induction regimens in MDS patients show low response rate compared with de novo AML, and autologous SCT is impaired by the difficulty of obtaining CD34+ cells in patients with MDS.

Allogeneic SCT is currently the only strategy of treatment with a potential for long term cure in MDS. For this reason, it should be offered whenever possible, especially to young patients with good performance status and high risk disease.

Outcome

To stratify outcome of patients with MDS, different prognostic scoring systems have been validated. Currently, the most widely used are the Revised International Prognostic Scoring System (IPSS-R) (Greenberg et al. 2012) and the WHO Classification-based Prognostic Scoring System (WPSS) (Malcovati et al. 2007). IPSS-R combines bone marrow blast percentage, cytogenetic abnormalities, and presence and degree of cytopenia(s) to identify five risks groups of prognostic relevance. WPSS combines MDS diagnostic categories according to WHO Classification (see below), cytogenetic abnormalities, and transfusion requirements. Its utility is observed primarily in lower risk cases and at time points after initial diagnosis.

Each MDS entity according to WHO classification is associated with a different prognosis and three risk groups can be identified. “Low risk” group contains MDS with single-lineage dysplasia (MDS-SLD), MDS with ring sideroblasts and single-lineage dysplasia (MDS-RS-SLD), and MDS with isolated del(5q). “Intermediate risk” group contains MDS with multilineage dysplasia (MDS-MLD) and MDS with multilineage dysplasia and ring sideroblasts (MDS-RS-MLD). “High risk” group contains MDS with excess blasts 1 and 2 (MDS-EB-1 and MDS-EB-2). Reported median overall survival range from 66 to 145 months in patients with low risk MDS, 36 months in patients with intermediate risk MDS, 16 months for MDS-EB-1, and 3–8 months for MDS-EB2.

Besides clinical and morphological parameters, molecular alterations identified by conventional karyotype have also an important prognostic meaning in MDS. The current Comprehensive Cytogenetic Scoring System (CCSS) for MDS identifies five subgroups defined by specific cytogenetic abnormalities; each category is associated with median overall survival and risk of developing AML (Table 1) (Greenberg et al. 2012). The incorporation of molecular data in risk-assessing index (such as IPSS-R) has been shown to improve their reliability of predicting prognosis in MDS patients.
Table 1

The Comprehensive Cytogenetic Scoring System (CCSS) for myelodysplastic syndromes

Prognostic groups, (% of patients)

Cytogenetic abnormalities

Median survival (years)

Median AML evolutions, 25% (years)

Very good (4%)

−Y, del(11q)

5.4

N.R (not reached)

Good (72%)

Normal, del(5q), del(12), del(20q), double including del(5q)

4.8

9.4

Intermediate (13%)

Del(7q), +8 + 19, i(17q), any other single or independent clone

2.7

2.5

Poor (4%)

−7, inv(3)/t(3q)/del(3q), double including −7/del(7q), complex: 3 abnormalities

1.5

1.7

Very poor (7%)

Complex: > 3 abnormalities

0.8

0.7

Microscopy

Morphological classification of MDS is based on three parameters: (1) presence of dysplasia (i.e., single lineage vs. multilineage dysplasia), (2) percentage of ring sideroblasts (i.e., erythroid precursors with at least 5 or more perinuclear iron granules), and (3) percentage of blasts in PB and BM. Blast count in MDS is expressed as in all myeloid neoplasms, as a percentage of all nucleated cells (including nucleated erythroid precursors) in the BM and as a percentage of leukocytes (excluding nucleated erythroid cells) in PB. Cells included in blast count are myeloblasts, monoblasts, and megakaryoblasts. Promonocytes are considered “blast equivalents” and included in the overall blast count.

Dyserythropoiesis in PB occurs as anisocytosis, poikilocytosis, and basophilic stippling of red blood cells (RBC); circulating nucleated RBC can be seen. A “dimorphic” pattern of normochromic, normocytic, or macrocytic cells with hypochromic cells is often observed as reflect of the admixture between clonal and residual normal hematopoietic cells. In BM, erythroid hyperplasia is common, but hypoplasia can also be seen. Megaloblastoid forms are common. Nuclear alterations include multinuclearity, internuclear bridging, budding, and bizarre nuclear shapes (Fig. 1a). Cytoplasmic alterations include formation of ring sideroblasts (Fig. 1b), vacuolizations, and aberrant acid-Schiff (PAS) positivity.
Fig. 1

Bone marrow aspirate smears showing dysplastic changes in MDS. (a) Dyserythropoiesis with nuclear alterations such as karyorrhexis and multinuclearity; megaloblastoid changes are also evident. (b) Ring sideroblasts. (c) Dysgranulopoiesis with nuclear hyposegmentations and cytoplasmic hypogranularity. (d) Dysplastic megakaryocyte with multiple separated nuclei

Dysgranulopoiesis is manifested mainly with hypogranularity of cytoplasm and nuclear hyposegmentation (pseudo-Pelger-Huet anomaly); granulocytic hypersegmentation is observed more rarely. Nuclear “sticks” or excrescences and hypercondensed, abnormally clumped chromatin are also common findings (Fig. 1c).

Dysmegakaryopoiesis is more easily detected on BM sections than on aspirate smears. Megakaryocytes are often increased in number, especially in cases with del(5q), but megakaryocytic hypoplasia can occur. Megakaryocyte dysplasia is characterized by micromegakaryocytes (i.e., megakaryocytes <15 microns in diameter), monolobation or hypolobation of nuclei, and megakaryocytes with multiple separated nuclei (Fig. 1d).

In 90–95% of patients with MDS, the marrow cellularity is normal or increased relative to that expected for patient’s age. A degree of architectural disorganization is frequently observed. In normal BM, granulopoietic precursors are mainly found close to bone trabeculae, while erythroid islands and megakaryocytes are preferentially confined to central marrow cavities. In MDS, topographical organization is lost, with precursors of different cell lines found in all marrow regions. Other common findings observed in BM sections include edema, increased microvessel density, plasmacytosis, increased mast cells, macrophages with abundant cellular debris and hemosiderin, and lymphocytosis with lymphoid follicles. Among the architectural alterations detected by bone marrow biopsy, a prognostic important finding is the presence of aggregates or clusters of “abnormally localized” immature myeloid precursor cells (“ALIP”), namely, the presence of myeloblasts and promyelocytes in an abnormal central marrow cavity location. ALIP are mainly found in aggressive subtypes of MDS, characterized by severe cytopenias and an increased incidence of progression to acute leukemia.

Single MDS entities are discussed below, and diagnostic criteria according to updated 2016 World Health Organization (WHO) classification of hematopoietic tumors are reported in Table 2 (Hasserjian et al. 2017).
Table 2

Diagnostic criteria for MDS entities (Hasserjian et al. 2017)

Name

Dysplastic lineage(s)

Cytopenia(s)

Ring sideroblasts (% of erythroid cells)

BM and PB blasts

Cytogenetics by conventional karyotyping analysis

MDS with single lineage dysplasia (MDS-SLD)

1

1 or 2

<15%, <5%

BM <5%, PB <1%; no Auer rods

Any, unless fulfills all criteria for MDS with isolated del (5q)

MDS with multilineage dysplasia (MDS-MLD)

2 or 3

1–3

<15%, <5%

BM <5%, PB <1%; no Auer rods

Any, unless fulfills all criteria for MDS with isolated del (5q)

MDS with ring sideroblasts and single lineage dysplasia (MDS-RS-SLD)

1

1 or 2

≥15%, ≥5%

BM <5%, PB <1%; no Auer rods

Any, unless fulfills all criteria for MDS with isolated del (5q)

MDS with ring sideroblasts with multilineage dysplasia (MDS-RS-MLD)

2 or 3

1–3

≥15%, ≥5%

BM <5%, PB < 1%; no Auer rods

Any, unless fulfills all criteria for MDS with isolated del (5q)

MDS with isolated del(5q)

1–3

1 or 2

None/ any

BM <5%, PB < 1%; no Auer rods

del(5q) alone or with 1 additional abnormalities except −7 or del(7q)

MDS with excess blasts 1 (MDS-EB-1)

1–3

1–3

None/ any

BM 5–9%, PB 2–4%; no Auer rods

Any

MDS with excess blasts 2 (MDS-EB-2)

1–3

1–3

None / any

BM 10–19%, PB 5–19%; no Auer rods

Any

MDS, unclassifiable (MDS, U)

• With 1% blood blasts

• With single lineage dysplasia and pancytopenia

• Based on cytogenetic abnormalities

• 1–3

• 1

• 0

• 1–3

• 3

• 1–3

• None/ any

• None/any

• < 15%

• BM <5%, PB = 1%; no Auer rods

• BM <5%, PB < 1%; no Auer rods

• BM <5%, PB < 1%; no Auer rods

• Any

• Any

• MDS-defining abnormalitiesa

Note: Cytopenias defined as: hemoglobin <10 g/dL; platelet count, <100 × 109/L; and absolute neutrophil count, <1.8 × 109/L. Rarely, MDS may present with mild anemia or thrombocytopenia above these levels. PB monocytes must be <1 × 109/L

aSee Table 3

MDS with Single Lineage Dysplasia (MDS-SLD)

This designation encompasses MDS that present cytopenia refractory to hematinic (Folate, B12, Iron) therapy (but may be responsive to growth factors, e.g., EPO), associated with dysplasia in ≥10% of cells in a single cell line. If a cytogenetic abnormality is not present, the cytopenia should be of at least 6 months in duration. This entity includes refractory anemia (RA) and the rare cases of isolated refractory neutropenia (RN) and refractory thrombocytopenia (RT). Refractory bi-cytopenia may be included in this category if accompanied by unilineage dysplasia. In PB, blasts represent <1% of circulating leukocytes; they account for <5% of nucleated marrow cells. No Auer rods are identified. The BM is usually hypercellular due to erythroid hyperplasia, and dyserythropoiesis is present, but ring sideroblasts constitute <15% of the erythroid cells.

MDS with Multilineage Dysplasia (MDS-MLD)

This designation encompasses MDS that present with one or more cytopenia(s) in the PB and dysplastic changes in ≥10% of cells in two or more myeloid lineages. In PB, blasts represent <1% of circulating leukocytes; they account for <5% of nucleated marrow cells. No Auer rods are identified.

MDS with Ring Sideroblasts with Single Lineage Dysplasia (MDS-RS-SLD) and MDS with Ring Sideroblasts with Multilineage Dysplasia (MDS-RS-MLD)

These designations encompass MDS-SLD or MDS-MLD as defined above, but characterized by the presence of ring sideroblasts accounting for ≥15% or more of erythroid precursors. MDS-RS are frequently associated with mutations in the spliceosome gene SF3B1. Although in the setting of multilineage dysplasia, there is no clear prognostic impact if ring sideroblasts are found, the presence of SF3B1 mutation seems to confer a better prognosis to a proportion of these cases.

MDS with Isolated del(5q)

This subtype of MDS is the only MDS entity defined by the presence of a specific cytogenetic alteration, an interstitial deletion of the long arm of chromosome 5q. One additional cytogenetic abnormality is allowed with the exclusion of −7 or del(7q). Blasts comprise <1% of PB leukocytes and <5% of nucleated marrow cells. No Auer rods are identified. Patients with MDS del(5q) present typically with macrocytic anemia, in association with normal or high platelet count. BM is variably cellular, often with erythroid hypoplasia. Megakaryocytes are increased in number, with nonlobated or hypolobated nuclei (Fig. 2).
Fig. 2

Bone marrow aspirate smear (a) and biopsy (b) in a case of MDS with isolated del(5q). An increased number of megakaryocytes is evident, with hypolobated and monolobated nuclei. These alterations of megakaryocytes are characteristic of this entity

MDS with isolated del(5q) may feature TP53 mutations, a finding associated with increased risk of leukemic transformation, inferior response to lenalidomide, and shorter overall survival. For this reason, each MDS with isolated del(5q) should be tested for TP53 mutations either by p53 immunohistochemistry or by sequencing to identify high risk cases.

MDS with Excess Blasts (MDS-EB-1 and MDS-EB-2)

MDS with excess blasts (MDS-EB) is a definition used to describe MDS with 5–19% blasts in the BM or PB. Two subcategories are recognized. MDS-EB-1 is defined as having 5–9% blasts in the BM or 2–4% in the PB. If blasts are 10% or more in BM, or 5% or more in PB, the designation should be MDS-EB-2 (Fig. 3). In case with <5% blasts in the bone marrow, the finding of 2–4% blasts in the peripheral blood is sufficient for the diagnosis.
Fig. 3

Bone marrow biopsy in a case of MDS with excess blasts 2 (MDS-EB-2). (a) Aggregates of “abnormally localized” immature myeloid precursors (“ALIP”) are seen in central marrow cavities. (b) On immunohistochemistry, ALIP stain positive for CD34

Importantly, in the last 2016 WHO Classification, myeloblasts are always counted as a percentage of total marrow cells (Hasserjian et al. 2017). This change was made in an attempt to achieve uniformity in expressing blast percentage across all myeloid neoplasms. Consequently, the category of erythroid/myeloid-type acute erythroid leukemia (erythroleukaemia) defined by maturing erythroblasts representing ≥50% of marrow cells and myeloblasts representing ≥20% of nonerythroid nucleated marrow cells has been eliminated. Such cases are now classified according to the blasts percentage calculated on all marrow cells, irrespective of marrow erythroid percentage, and those with 5–19% blasts are now classified as MDS-EB.

Myelodysplastic Syndrome, Unclassifiable (MDS, U)

This entity encompasses cases of MDS that do not fit into any other category of MDS. Three possible situations can occur: (1) MDS-SLD or MDS-MLD with 1% blasts in the blood found on two occasions, (2) MDS-SLD associated with pancytopenia, and (3) patients with persistent cytopenias lacking diagnostic morphologic features of MDS or of any specific subgroups of MDS (i.e., < 10% dysplastic cells in any lineage) but with cytogenetic abnormalities considered as presumptive evidence of MDS. However, recent data comparing the clinicopathologic features and mutational profiles of these three scenario have shown how only the first condition (MDS-SLD or MDS-MLD with 1% blasts in the blood on two occasions) is associated with higher rates of progression to AML and shorter median overall survival, comparable to what observed in MDS-EB. This finding could suggest the appropriateness of lowering the threshold of “excess blasts” in the PB from 2% to 1% and highlights the importance of an accurate blasts count in PB for classification and prognostic purposes (Margolskee et al. 2017).

Hypoplastic Myelodysplastic Syndrome (h-MDS)

In about 5–10% cases of MDS, the bone marrow is hypocellular. These cases are defined “hypoplastic MDS” (h-MDS), which however does not constitute a specific MDS subtype in the current 2016 WHO Classification. Hypocellularity is defined as bone marrow cellularity of <30% in a patient less than 60 years of age or <20% in patients older than 70 years of age. Generally, h-MDS is associated with pronounced cytopenias, a finding that may suggest a diagnosis of aplastic anemia (AA). In MDS, it is rare that marrow cellularity falls below 10% and such extreme hypocellularity is seen more frequently in severe (AA).

Myelodysplastic Syndrome with Fibrosis (MDS-F)

Approximately 5–10% of MDS cases show significant increase in marrow reticulin fibers or even collagen fibrosis (corresponding to grade 2 or 3 of the WHO grading system). These cases are classified as “MDS with fibrosis” (MDS-F). Overall, patients with MDS-F have shorter survival times than those without fibrosis. Bone marrow shows trilineage dysplasia with prominent dysmegakaryopoiesis. Often, cases of MDS-F have prominent megakaryopoiesis, characterized by a wide spectrum of sizes of megakaryocytes, ranging from micromegakaryocytes to enlarged forms (Fig. 4).
Fig. 4

MDS with fibrosis (MDS-F). (a) Bone marrow biopsy in a case of MDS-EB shows several dysplastic micromegakaryocytes. (b) An increase in reticulin fibers is evident with reticulin stain

Significant fibrosis does not qualify a specific MDS subtype in the current 2016 WHO Classification. However, many cases of MDS-F show an increased number of blasts and in this context the presence of fibrosis imparts an unfavorable prognosis.

Childhood Myelodysplastic Syndrome and Refractory Cytopenia of Childhood (RCC)

MDS in children have some differences compared to the ones affecting adults, especially when considering low risk cases. For example, they present more often with neutropenia and thrombocytopenia (rather than anemia) and bone marrow is more frequently hypocellular (rather than hypercellular). To address these differences, the last WHO Classification (Hasserjian et al. 2017) created a provisional entity named “refractory cytopenia of childhood” (RCC). RCC is defined by dysplasia in at least 10% of cells in one cell line, < 2% blasts in PB, and <5% blasts in BM. PB shows anisopoikilocytosis of red blood cells and platelets. Neutropenia with dysgranulopoiesis is the most striking finding in PB. Dysplastic neutrophils show pseudo-Pelger-Huët nuclei, hypogranularity, and/or agranularity of cytoplasms. The BM is hypocellular in about 80% of cases. Dyserytrophoiesis manifests with megaloblastoid changes, arrest in maturation with increased number of proerythroblasts and islands of immature erythroid precursors consisting of ≥20 cells. Megakararyocytes are usually reduced in number and show dysplasia with small nonlobated nuclei, separated nuclear lobes, and micromegakaryocytes. Micromegakaryocytes may be hard to appreciate, but their presence is an important indicator of RCC. For this reason, immunostaining for megakaryocytic markers (i.e., CD61, CD42b) is strongly suggested whenever MDS is suspected. Dysgranulopoiesis as described above is apparent also in BM sections.

For pediatric MDS with 2–19% blasts, the same categories apply as for adult cases of MDS with excess blasts (MDS-EB).

Immunophenotype

Immunostaining with antibody to CD34 (an antigen expressed in progenitor and early precursor marrow cells) can be useful to highlight blasts in BM sections, especially in cases of MDS-F and h-MDS in which blasts may be underestimated in smear preparations. Most of CD34+ cells found in MDS morphologically resemble blasts. However, a proportion of CD34+ cells show promyelocyte-like cytological features, but should be counted as blasts rather than promyelocytes for the purpose of blasts enumeration. CD34 can also be used as “surrogate marker” for the presence of ALIP. Both an increase in CD34+ cells and a tendency of CD34+ cells to form aggregates have been shown to predict progression to AML and poor survival in MDS, irrespective of MDS subtype. Aberrant expression of CD34 by megakaryocytes in MDS has also been reported.

CD117 (c-Kit) has been proposed as an additional marker to identify myeloid precursors in marrow biopsies of patients with MDS. However, it is a less reliable marker than CD34 due to its weak and variable expression in MDS myeloblasts and its reactivity with abnormal proerythroblasts.

Antibodies to CD42b and CD61 can highlight dysplastic megakaryocyte. They are particularly useful in distinguishing myelodysplastic syndrome with fibrosis (MDS-F), characterized by blasts that are CD34+ but negative for CD42b or CD61 from acute megakaryoblastic leukemia, which features megakaryoblasts that stain with CD42b or CD61, but are only variably positive for CD34.

Immunostaining for p53 correlates with TP53 mutations and serves as a prognostic marker.

Flow cytometry (FC) in MDS can be used to determine the number and immunophenotype of blasts and to assess the pattern of maturation of myeloid populations. Although there is often a reasonable good correlation between CD34+ percentage as measured by FC and blast count by morphology, the percentage of blasts determined by FC may be influenced by hemodilution of specimens at time of collection, processing artifacts, or marrow fibrosis, resulting in a poorly representative specimen. Therefore, analysis of blasts by FC should never be used in lieu of morphologic inspection of peripheral blood and bone marrow aspirate smears.

The detection of asynchronous antigen expression on maturing cells or other patterns of aberrant phenotypes by FC has been shown to correlate with morphologic and cytogenetic abnormalities. However, in cases with borderline dysplasia by morphology and no cytogenetic abnormalities, FC results are considered as suggestive of MDS only if there are three or more aberrant features in erythropoietic, granulocytic, and monocytic maturation. At present time, more studies are needed with age-matched controls with various cytopenic disorders to determine how specific MDS-associated flow cytometry changes may be.

Molecular Features

Cytogenetic abnormalities are present in 40–70% of patients with de novo MDS. Overall, loss of chromosomal material is the most common cytogenetic abnormality detected in MDS, while balanced translocations are uncommon. Recurrent chromosomal alterations in MDS and their frequency are reported in Table 3. Some of them such as −Y, +8, del (20q) can also be observed in nonneoplastic conditions and their findings as the sole cytogenetic abnormality is not considered definitive evidence for MDS in the absence of other morphologic criteria.
Table 3

Recurrent chromosomal abnormalities and their frequencies in MDS at diagnosis (Hasserjian et al. 2017)

Abnormality

Primary MDS

Therapy-related MDS

Unbalanced

Gain of chromosome 8a

10%

 

Loss of chromosome 7 or del(7q)

10%

50%

del(5q)

10%

40%

del(20q)a

5–8%

 

Loss of chromosome Ya

5%

 

Isochromosome 17q or t(17p)

3–5%

25–30%

Loss of chromosome 13or del(13q)

3%

 

del(11q)

3%

 

del(12p) or t(12p)

3%

 

del(9q)

1–2%

 

idic(X)(q13)

1–2%

 

t(11;16)(q23;p13.3)

  

t(3;21)(q26;q22.1)

 

3%

t(1;3)(p36.3;q21.2)

 

2%

t(2;11)(p21q23)

1%

 

inv(3)(q21q26.2)/t(3;3)(q21.3;q26.2)

1%

 

t(6;9)(p23;q34)

1%

 
 

1%

 

aCan be observed in non neoplastic conditions. It is not considered “MDS-defining” in the absence of diagnostic morphologic features of MDS.

There is an association between abnormal karyotype and survival. In general, patients with abnormal karyotype have worse survival and higher rates of progression to AML than those with normal karyotype. Certain alterations, such as del(5q) or del(20q), if present as sole abnormalities, confer a survival advantage. The finding of a complex karyotype (≥ 3 abnormalities) or loss of chromosome 7 infers a poor prognosis. Importantly, the presence of a normal karyotype does not exclude a diagnosis of MDS. Conversely, an abnormal karyotype may indicate MDS within the appropriate clinical context, even if morphologic findings are inconclusive.

In addition to cytogenetic abnormalities, recurrent somatic mutations in more than 50 genes have been identified in 80–90% of patients with MDS. Among these, the most common are SF3B1, TET2, SRSF2, ASXL1, DNMT3A, IDH1, IDH2, RUNX1, NRAS, U2AF1, ZRSR2, TP53, and EZH2. Recent evidence suggests that the presence of ≥1 mutations in selected gene(s) known to be implicated in the pathogenesis of myeloid diseases has a high predictive value in the differential diagnosis of unexplained cytopenia(s). Detecting 1 or more of these mutations has a positive predictive value (PPV) for myeloid neoplasm of 0.81. Mutations in spliceosome genes such as SF3B1, SRSF2, U2AF1, and RUNX2 have the highest PPV for myeloid neoplasms, ranging from 0.88 to 0.97. These mutations, as well as comutation pattern involving TET2, ASXL2 or DNMT3A, and RUNX1, EZH2, TP53, and IDH1/IDH2 are also highly specific for myeloid neoplasms with dysplasia. On the other side, absence of mutations in the same selected genes has a negative predictive value for myeloid neoplasms of 0.76. These data suggest how mutational analysis represents a valuable tool in the diagnostic workup of patients with unexplained cytopenia(s) (Malcovati et al. 2017).

Importantly, however, acquired clonal mutations identical to those seen in MDS can occur in hematopoietic cells of apparently healthy old individuals without MDS, so-called “clonal hematopoiesis of indeterminate potential” (“CHIP”). Although some patients with CHIP subsequently develop MDS, the natural history of this condition is not yet fully understood. For this reason, the presence of MDS-associated somatic mutations alone is not considered diagnostic of MDS in the current WHO Classification and should always be integrated with clinical and pathological findings.

Differential Diagnosis

Morphologic changes of myelodysplasia do not necessarily equate with a diagnosis of MDS. Reactive conditions associated with nonclonal dysplastic changes may resemble MDS. Vitamin B12 and folic acid deficiency lead to megaloblastic changes and often severe dyserythropoiesis; such conditions must always be excluded before making a diagnosis of MDS, particularly if dyserythropoiesis is the only finding. Heavy-metal intoxication, particularly arsenic poisoning, zinc overdose, as well as copper deficiency, can induce marked, sometimes bizarre morphologic abnormalities in the erythroid and granulocytic series. A number of drugs and medications, ranging from alcohol to hematopoietic growth factors, can also induce myelodysplastic features. Congenital dyserythropoietic anemia (CDA) may be difficult to distinguish from MDS-SLD. Anemia associated with high MCV and low reticulocytes may be seen in patients with hypothyroidism or liver failure. In most of these cases, the anemia, as in MDS, is macrocytic, but it is not associated with severe dysplasia. Other common causes of anemia are autoimmune diseases (these can also cause myelofibrosis, i.e., autoimmune myelofibrosis) as well as other hematopoietic neoplasms (as lymphomas) and nonhematopoietic malignancies (so-called “paraneoplastic myelodysplasia”). All of these can, to a certain extent, mimic the presentation of MDS. Viral disorders, particularly HIV infection, may be associated with myelodysplastic features in the blood and marrow. In HIV infection, cytopenia(s) are common, and the marrow is often hypercellular with evidence of apoptosis and a pink background of cellular debris. Increased marrow plasma cells and lymphocytes and a variable degree of fibrosis are also common. Dyserythropoiesis is the most frequently reported myelodysplastic change and has been described in up to 70% of patients with HIV infection, but dysmegakaryopoiesis and dysgranulopoiesis have also been described. There are several potential causes for the dyspoietic features in patients with HIV infection, including direct effects of the HIV virus, concomitant infections, medication, and autoimmune phenomena. Other viruses may also cause dysplastic changes, such as parvovirus infection. Cytomegalovirus infection has been associated with cytopenias and dysplastic features in immunocompromised as well as nonimmunocompromised patients. Hypolobulated neutrophils can be seen after cotrimoxazole therapy and are often frequent in patients receiving chemotherapy. EPO and cytokine treatment may produce cytologic alterations in cells of the “targeted” cell line. Awareness of recent cytokine therapy is always important when evaluating bone marrow and blood morphology.

Finally, both in children and adults, h-MDS can mimic aplastic anemia (AA) and vice versa. However, significant dysplasia is not observed in AA, neither an increased number of blasts. Presence of cytogenetic abnormalities (except trisomy 8, which may be seen in some cases of AA) may also rule out a diagnosis of AA.

References and Further Reading

  1. Greenberg, P. L., Tuechler, H., Schanz, J., et al. (2012). Revised international prognostic scoring system for myelodysplastic syndromes. Blood, 120(12), 2454–2465.CrossRefPubMedCentralPubMedGoogle Scholar
  2. Hasserjian, R. P., Orazi, A., Brunning, R. D., et al. (2017). Myelodysplastic syndromes Chapter 6. In S. H. Swerdlow et al. (Eds.), WHO classification of tumours of haematopoietic and lymphoid tissues (Revised 4th ed., pp. 97–120). Lyon: IARC.Google Scholar
  3. Malcovati, L., Germing, U., Kuendgen, A., et al. (2007). Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. Journal of Clinical Oncology, 25(23), 3503–3510.CrossRefPubMedGoogle Scholar
  4. Malcovati, L., Gallì, A., Travaglino, E., et al. (2017). Clinical significance of somatic mutation in unexplained blood cytopenia. Blood, 129(25), 3371–3378.PubMedCentralPubMedGoogle Scholar
  5. Margolskee, E., Hasserjian, R. P., Hassane, D., et al. (2017). Myelodysplastic syndrome, unclassifiable (MDS-U) with 1% blasts is a distinct dubgroup of MDS-U with a poor prognosis. American Journal of Clinical Pathology, 148(1), 49–57.CrossRefPubMedGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineWeill Cornell Medical CollegeNew YorkUSA
  2. 2.Universita’ degli Studi di MilanoMilanItaly