Written | 2015-04 | Virginie Eclache |
Laboratoire d'hématologie et de cytogénétique, Hôpital Avicenne, Bobigny, France virginie.eclache @avc.aphp.fr |
Abstract | 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. |
Keywords | Myelodysplastic syndromes; Refractory Anemia with excess blasts; Refractory Anemia with Ring sideroblasts; Refractory Cytopenia with Unilineage Dysplasia; Refractory Cytopenia with Multilineage Dysplasia; MDS-Unclassifiable; Thrombocytopenia; Neutropenia; Anemia |
Identity |
ICD-Topo | C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS |
ICD-Morpho | 9989/3 Myelodysplastic syndrome, unclassifiable |
Atlas_Id | 1058 |
Note | This paper is an update of " Classification of myelodysplasic syndromes 1999 " (Flandrin, 2002). |
Clinics and Pathology |
Disease | 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 / cell stem 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). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Etiology | 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 Fanconi's anemia (FA), neurofibromatosis, dyskeratosis, Down syndrome and familial platelet disorder (associated with germ line mutations of RUNX1 or CEBPa) predispose to MDS/ AML. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Epidemiology | 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Cytology | 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)
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Pathology | 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 | 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). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Evolution | Progression to acute myeloid leukaemia depends on prognosis factors. Rare cases progress to aplastic anemia. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Prognosis | 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)
AML =acute myeloid leukaemia. NR = not reached.
ANC: Absolute neutrophil count, BM: bone marrow Table 2 c: IPSS-R Prognostic risk Categories/Scores
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Genetics |
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) |
Cytogenetics |
Cytogenetics Morphological | Conventional cytogenetic in de novo MDS is abnormal in 35-40% of patients by conventional banding karyotyping, and cytogenetic aberrations are highly heterogeneous. Abnormal karyotype, especially those of unfavourable prognosis, are more frequent in cases with blast excess, with 75% RA presenting with Normal karyotype (NK), compared to 25-50% abnormal karyotype in RAEB1-2, or secondary MDS (80% versus 40% in de novo MDS). The most frequent types of abnormalities by frequency order are total or partial chromosome losses, total or partial chromosome gains, and unbalanced translocations. Balanced translocations are rare. Frequent alterations represent 40% of all abnormal karyotypes, including partial or total deletion of chromosome 5 (?5/5q?), partial or total deletion of chromosome 7 ( -7/del(7q)), trisomy 8 (+8), partial deletion of chromosome 20 (del(20q)), and Y chromosome loss (?Y). These last alterations are not specific of MDS and can be encountered in AML or in myeloproliferative neoplasm. Loss of chromosome Y can be found in elderly healthy subjects (Wiktor et al, 2000). Trisomy 8 and loss of Y may be present in a constitutional mosaicism. Thus a constitutional karyotype on blood sample cultivated with phytohemaglutin as mitogen can be performed in those two cases for correct interpretation of cytogenetic response after intensive therapy or transplantation. Chromosome 5 and 7 alterations and other infrequent alterations in AML are considered as "myelodysplasia related changes" in the current WHO classification, as they may reflect an underlying undiagnosed myelodysplasia. The remaining 60% of abnormal karyotype display rare alterations (<2% each). Their prognosis have recently been reappraised by studies of larger cohorts, as summarized in Table 2, allowing assignment of well-defined prognosis to about 95% patients (Haase el al., 2007) Del5q and the "5q- syndrome" |
Genes involved and Proteins |
Note | Somatic mutations are observed in approximately 80% of the MDS (Bejar et al, 2011). The most common genes are those involved in epigenetic regulation (TET2 , ASXL1, EZH2, DNMT3A, IDH1, IDH2 (Kosmider et al, 2009), splicing (SF3B1, correlated to RARS, SRSF2, U2AF35, ZRSR2)( Damm et al, 2012), transcription (RUNX1 , ETV6, CBL, NRAS , KRAS, NF1, PTPN1, TP53) and less often cohesin genes. TP53 mutated subclones may occur at early disease stage in MDS with del(5q) where they are associated with a lower response to lenalidomid and an increases risk of progression. (Jädersten et al, 2011). It has recently been described that approximately half of RARS with thrombocytosis (RARS-T) patients, along with a small subset of other MDS and mixed myelodysplastic/ myeloproliferative disorders, carry the JAK2 V617F mutation, and scarcely MPL mutations. RARS-T patients show clinical features of both RARS, essential thrombocytemia and to some extent myelofibrosis. However, the degree of anaemia and overall survival is more similar to RARS than to myeloproliferative disorders (Hellström-Lindberg et al., 2008) Over expression of the EVI1 gene is found in one third of MDS patients, particularly those with blast excess, even without 3q26 rearrangement in conventional cytogenetic. As in AML, the WT1 transcription factor is also over expressed in virtually all cases of MDS with blast excess, but also in a third of lower-risk MDS. The leukemogenic potential of this lesion is still unclear, but its over expression can provide a tool for minimal residual disease (MRD) monitoring in the context of intensive therapy, like in AML. |
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Citation |
This paper should be referenced as such : |
Virginie Eclache |
Classification of myelodysplastic syndromes 2015 |
Atlas Genet Cytogenet Oncol Haematol. 2016;20(3):155-161. |
Free journal version : [ pdf ] [ DOI ] |
On line version : http://AtlasGeneticsOncology.org/Anomalies/ClassifMDSID1058.html |
Other genes implicated (Data extracted from papers in the Atlas) [ 5 ] |
Genes | EPHA3 | IDH2 | IRS2 | TP53 | PIP4K2A |
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