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.

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)

Subtype	Blood	Marrow
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)	Cytopenia(s) 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)	Anemia No Blasts	Only one cytopenia with dysplasia in >10% cells <5%Blasts <15% Ring sideroblasts
Refractory Anemia with Ring sideroblasts (RARS)	Anemia 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)	Anemia Normal or elevated platelets = 1% blasts	5% blasts, no Auer rods Hypolobulated megakaryocytes
MDS-Unclassifiable (MDS-U)	Cytopenia = 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 (%)	Karyotype	Median survival (years)	Time to 25% AML evolution (years)
Very good	4%	-Y, del(11q)	5.4	NR
Good	72%	Normal, del(5q), del(12p), del(20q), double including del(5q)	4.8	9.4
Intermediate	13%	del(7q), +8, +19, i(17q), any other single or double independent clones	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	0.7	0.7

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

Prognostic variable	0	0.5	1	1.5	2	3	4
Cytogenetics	Very Good		Good		Intermediate	Poor	Very Poor
BM blasts (%)	=2%		> 2-< 5%	5-10%	5-10%	> 10%
Hemoglobin (g/dL)	=10		8 < 10	> 8
Platelets (G/L)	=100	50 < 100	< 50
ANCs (G/L)	=0,	< 0.8

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

RISK GROUP	RISK SCORE
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)

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