Classification of myelodysplastic syndromes 2015

2015-04-01   Virginie Eclache 

1.Laboratoire dhématologie et de cytogénétique, Hôpital Avicenne, Bobigny, France virginie.eclache


The Myelodysplastic syndromes are a heterogeneous group of hematological malignancies difficult to diagnose and classify, for which novel treatments are beginning to emerge. Recent advance in diagnosis classification, prognosis scoring and genetics discovery are presented in this update.

Clinics and Pathology


Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders of the hematopoietic stem cell (HSC) characterized by peripheral cytopenias despite increased hematopoïetic precursors, leading to transformation into acute myeloid leukemia (AML) in 20-30% of cases (Mufti, 2004).
Clinical manifestations result from cytopenias (anemia, infection, and bleeding). Diagnosis is based on blood cytopenias and hypercellular bone marrow (BM) with dysplasia, with or without excess of blasts.

Phenotype stem cell origin

MDS is thought to result from the accumulation of genetic or epigenetic (such as promoter hypermethylation) lesions, occurring initially in an immature progenitor and leading to a proliferative advantage of the MDS clone over normal immature progenitors. MDS progenitors display abnormal terminal differentiation and increased susceptibility to apoptosis. These two features explain the clinical consequences of blast accumulation and peripheral cytopenias (Mufti, 2004).


Age-induced genetic, epigenetic, and immune-mediated changes in haemopoietic stem cells (HSC) lead to oligoclonal expansion of myelodysplastic stem cells, with defective differentiation, characterised by increased apoptosis of erythroid and myeloid progenitors (Corey et al., 2007). Microenvironmental changes and immune deregulation contribute to this differentiation defect.
Congenital bone marrow failure syndromes as Fanconis anemia (FA), neurofibromatosis, dyskeratosis, Down syndrome and familial platelet disorder (associated with germ line mutations of RUNX1 or CEBPa) predispose to MDS/ AML.


The median age at diagnosis is approximately 70 years. The incidence is 4 to 5 per 100,000 persons per year. The etiology is generally unknown, the role of exposure to environmental chemical and physical mutagens is sometimes suspected. In 15 to 20% of cases, however, MDS are secondary (sMDS) to chemotherapy and/or radiotherapy for a prior illness, usually cancer. More rarely, they are secondary to exposure to benzene or other aromatic hydrocarbons, or products used in agriculture.


MDS have received a variety of nomenclatures, until the first international classification by the French American British (FAB) group in 1982 (Bennett et al., 1982). This classification has been refined in 2001 then in 2008 by a WHO expert committee (Vardiman et al, 2002; and 2009), integrating novel prognostic factors in MDS, such as multilineage dysplasia. The marrow blast threshold of AML was lowered from 30% to 20%. This classification also designed the term MDS/MPN (Myeloproliferative Neoplasm) to regroup a heterogeneous set of rare entities including chronic myelomonocytic leukemia (CMML), previously considered as a MDS.
Three minimal criteria must be met for the diagnosis of MDS: 1) persistent (> 6 months) and significant cytopenia(s) (Hb < 10 g/dL, absolute neutrophil count < 1.8 G/L, platelets < 100 G/L), 2) significant bone marrow dysplasia, or blast excess or typical cytogenetic abnormality, and 3) exclusion of differential diagnoses (Kaloutsi V et al., 1994;Bennett et al., 2009).
Presence of dysplasia is the first key criterion for diagnosis and prognosis of MDS. A given lineage is considered dysplastic if two or more dysplastic features are found on > 10% cells. Multilineage dysplasia (MD) is defined as the coexistence of dysplasias in two or more lineages. Blast excess is frequent in MD but 40-60% of cases occur without blast excess. The term idiopathic cytopenias of undetermined signification (ICUS) has been coined to account for cases when differential diagnoses have been excluded, but cytopenias or dysplasias do not reach significant MDS diagnostic thresholds. The outcome of ICUS still remains undetermined, but probably evolves sometimes into MDS, and thus requires blood and BM monitoring (Wimazal et al., 2007).
Ringed sideroblasts (RS), ie. sideroblasts with ? 5 siderophilic granules contouring at least a third of the nucleus circumference, are not specific of MDS as they can be encountered in a variety of conditions such as alcohol consumption, copper deficiency or zinc excess, as well as a rare congenital condition called X recessive sideroblastic anemia. RS are considered significant when they represent > 15% of erythroid cells. However, in the absence of blast excess, RS define an entity with favourable prognosis, termed refractory anemia with ringed sideroblasts (RARS). Auer rods have historically been recognized as a poor prognostic marker and remain considered in the WHO classification.
Some morphologies can be strongly evocative of a precise underlying cytogenetic or genetic aberration. For instance, a characteristic dysgranulopoiesis combining pseudo-Pelger-Huüt anomaly and small vacuolated neutrophils has been associated with 17p deletions and TP53 tumour suppressor gene mutations (Lai et al., 1995). The "5q- syndrome" which was recognized in 2001 by the WHO classifications also has a distinct morphology.
Precise count of BM blasts is the second central criterion for diagnostic and prognostic classification of MDS. Myeloblasts are consensually defined by a high nuclear/cytoplasmic ratio and diffuse chromatin pattern, can be "agranular" or "granular". A third class of blasts defined by the presence of numerous (>20) azurophilic granules is included in the blast percentage, and can be distinguished from promyelocytes by the lack of Golgi structure (Mufti et al., 2008)
Table 1: WHO classification for MDS (Vardiman et al. 2009)


Refractory Anemia with excess blasts 1 (RAEB-I)

Cytopenia (s)
<5% Blasts
No auer rods
<1 G/L Monocytes

Unilineage or multilineage dysplasia
No Auer rods
5-9% Blasts

Refractory with anemia With excess blasts II (RAEB II)

5-19% blasts
Auer rods possible
<1 G/L Monocytes

Unilineage or multilineage dysplasia
10-19% Blasts
Auer rods possible

Refractory Cytopenia with Unilineage Dysplasia (RCUD) Uni-or Bicytopenia
Refractory Thrombocytopenia (RT)
Refractory Neutropenia (RN)
Refractory Anemia (RA)

No Blasts

Only one cytopenia with dysplasia in >10% cells
<15% Ring sideroblasts

Refractory Anemia with Ring sideroblasts (RARS)

No blasts

Dyserythropoiesis only
< 5% Blasts
>15% Ring sideroblasts

Refractory Cytopenia with Multilineage Dysplasia
with or without Ring sideroblasts (RCMD)

Cytopenia (s)
= 1% blasts
No Auer rods.
<1 G/L Monocytes

Dysplasia in >10% of the cells of 2 cell lines
< 5% Blasts, no Auer rods.
15% Ring sideroblasts

MDS with isolated del (5q)

Normal or elevated platelets
= 1% blasts

5% blasts, no Auer rods
Hypolobulated megakaryocytes

MDS-Unclassifiable (MDS-U)

= 1% blasts

Dysplasia in < 10% cells but cytogenetic abnormality considered as presumptive for MDS
< 5% blasts


BM biopsy first allows objective evaluation of BM cellularity, which physiologically declines with age. Application of a standardized age correction to cellularity brings the incidence of "hypoplastic" MDS from 29% to 7% (Thiele et al., 2005). Hypoplastic MDS raises the question of the differential diagnosis with aplastic anemia (AA). Features of MDS are the presence of circulating myeloblasts, megakaryocytic or granulocytic dysplasia. Mild erythroid dysplasia can be seen in AA. Other MDS criteria include abnormal sideroblasts, presence of two or more blast cell clusters. Clusters (3-5 cells) or aggregates (> 5 cells) of blasts cells away from endosteal or vascular niches, in the central portion of the BM, have been dubbed "abnormally localized immature myeloid progenitors" (ALIP). ALIP have been proposed as diagnostic and prognostic markers.
Immunohistochemistry with a CD34 antibody marks immature hematopoietic progenitors and megakaryocytes, and can be used to asses the blast percentage. However, some MDS have CD34- blasts in MDS: in those cases, CD117 has been proposed as a surrogate marker. Some authors have proposed that the presence of CD34+ cell clusters may better reflect prognosis than CD34+ cell percentage.


Treatment varies from symptomatic treatment of cytopenias, especially by transfusions for anemia, to allogeneic stem-cell transplantation. Treatment of patients with lower-risk myelodysplastic syndromes includes growth factors and lenalidomide. Higher-risk patients are treated with hypomethylating agents and, allogeneic stem-cell transplantation whenever possible (Fenaux et al. 2009).


Progression to acute myeloid leukaemia depends on prognosis factors. Rare cases progress to aplastic anemia.


Prognostic evaluation in MDS still largely relies on an International Prognostic Scoring System (IPSS) established on the basis of an international cohort of patients (IMRAW cohort) treated symptomatically and recently revised (IPSS-R) (Greenberg et al, 1997; and 2012). IPSS relies on number of cytopenias, marrow blast percentage and cytogenetic. Patients are regrouped into four risk categories (low, intermediate 1 and 2, and high). The IPSS has since been validated in many therapeutic contexts including intensive chemotherapy and allogeneic stem cell transplantation (ASCT). IPSS categories are often regrouped into lower-risk MDS (IPSS low and intermediate-1), and higher-risk MDS (IPSS intermediate-2 and high). Lower-risk MDS are patients with prolonged survival where the main objectives are to cope with chronic cytopenias notably anaemia, and to defer ASCT. On the other hand the treatment in higher-risk MDS should alter disease history and prolong survival. The approval of azacytidine in higher-risk underscores the importance of IPSS evaluation in all patients at diagnosis.
According to the IPSS-R, 27% of the lower-risk MDS patients of the original IPSS are reclassified as having a higher risk and they potentially need a more intensive treatment. Conversely18% of high-risk MDS patients, as defined by the original IPSS, are reclassified as low risk by the IPSS-R.
Table 2: Revised IPSS (R-IPSS) (Greenberg et al., 2012)

Table 2a: Karyotype (IPSS-R)

 Proportion of patients (%)KaryotypeMedian survival (years)

Time to 25% AML evolution (years)

Very good4%-Y,

double including del(5q)

any other single or double independent clones

double including -7/ del(7q)
Complex: 3 abnormalities

Very poor7%Complex > 3 abnormalities0.70.7

AML =acute myeloid leukaemia. NR = not reached.
Table 2b: IPSS-R Prognostic Score Values

Prognostic variable00.511.5234
CytogeneticsVery Good  Good IntermediatePoorVery Poor
BM blasts (%)=2% 

> 2-< 5%

5-10%5-10%> 10% 
Hemoglobin (g/dL)=10 8 < 10> 8   
Platelets (G/L)=10050 < 100< 50    
ANCs (G/L)=0, < 0.8     

ANC: Absolute neutrophil count, BM: bone marrow Table 2 c: IPSS-R Prognostic risk Categories/Scores

Very low=1. 5
Low> 1.5 - 3
Intermediate> 3 - 4.5
High> 4.5 - 6
Very High> 6


Clonality assays based on gene imprinting (HUMARA assays) have historically been the first molecular tools to confirm the clonal nature of normal karyotype MDS. They still can serve as diagnostic co-criterion, but novel genomic tools are now available that can both confirm clonality and provide valuable prognostic information. (Bejar R et al 2011)

Genes Involved and Proteins


Pubmed IDLast YearTitleAuthors
217146482011Clinical effect of point mutations in myelodysplastic syndromes.Bejar R et al
191446612009Diagnostic criteria to distinguish hypocellular acute myeloid leukemia from hypocellular myelodysplastic syndromes and aplastic anemia: recommendations for a standardized approach.Bennett JM et al
172519182007Myelodysplastic syndromes: the complexity of stem-cell diseases.Corey SJ et al
223439202012Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes.Damm F et al
182026582008Identification of RPS14 as a 5q- syndrome gene by RNA interference screen.Ebert BL et al
192307722009Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study.Fenaux P et al
90587301997International scoring system for evaluating prognosis in myelodysplastic syndromes.Greenberg P et al
227404532012Revised international prognostic scoring system for myelodysplastic syndromes.Greenberg PL et al
177261602007New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients.Haase D et al
214221142011CDKN1B, encoding the cyclin-dependent kinase inhibitor 1B (p27), is located in the minimally deleted region of 12p abnormalities in myeloid malignancies and its low expression is a favorable prognostic marker in acute myeloid leukemia.Haferlach C et al
190740582008The role of JAK2 mutations in RARS and other MDS.Hellström-Lindberg E et al
215190102011TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression.Jädersten M et al
81165651994Comparison of bone marrow and hematologic findings in patients with human immunodeficiency virus infection and those with myelodysplastic syndromes and infectious diseases.Kaloutsi V et al
196668692009TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs).Kosmider O et al
78850351995Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoïesis and a high incidence of P53 mutations.Lai JL et al
154942932004Pathobiology, classification, and diagnosis of myelodysplastic syndrome.Mufti GJ et al
188384802008Diagnosis and classification of myelodysplastic syndrome: International Working Group on Morphology of myelodysplastic syndrome (IWGM-MDS) consensus proposals for the definition and enumeration of myeloblasts and ring sideroblasts.Mufti GJ et al
178932272008Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q.Raza A et al
160791132005European consensus on grading bone marrow fibrosis and assessment of cellularity.Thiele J et al
44212851974Distinct haematological disorder with deletion of long arm of no. 5 chromosome.Van den Berghe H et al
193573942009The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes.Vardiman JW et al
194704552009A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by lenalidomide.Wei S et al
105645812000Clinical significance of Y chromosome loss in hematologic disease.Wiktor A et al
175070912007Idiopathic cytopenia of undetermined significance (ICUS) versus low risk MDS: the diagnostic interface.Wimazal F et al



This paper is an update of " Classification of myelodysplasic syndromes 1999 " (Flandrin, 2002).


Virginie Eclache

Classification of myelodysplastic syndromes 2015

Atlas Genet Cytogenet Oncol Haematol. 2015-04-01

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