Classification of myelodysplastic syndromes 2015

2015-04-01   Virginie Eclache 

1.Laboratoire dhématologie 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.

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 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).

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 Fanconis 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.

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.

Note

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

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Summary

Note

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

Citation

Virginie Eclache

Classification of myelodysplastic syndromes 2015

Atlas Genet Cytogenet Oncol Haematol. 2015-04-01

Online version: http://atlasgeneticsoncology.org/haematological/1058/classifmdsid1058

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