Myelodysplastic syndromes (MDSs) are a heterogenous group of clonal hematopoietic neoplasms defined by abnormal blood and marrow cell morphology, one or more blood cytopenias, and an increased risk of clonal evolution to acute myeloid leukemia (AML). These disorders can occur at any age, but their incidence rises exponentially after age 50 years with a median age at diagnosis of around 70 years. Most are acquired de novo through the progressive accumulation of somatic mutations in hematopoietic stem cells; clonal hematopoiesis in the absence of cytopenias can be a precursor state for MDS and is common with aging. Some MDS disorders arise after exposure to DNA damaging agents, such as chemotherapy and radiation, which promote expansion of preexisting mutant clones at the expense of healthy hematopoietic stem cells. A minority are the result of inherited mutations that predispose to the development of MDS and related myeloid disorders.
Subtypes of MDS are largely defined by clinical features and range from cytopenias (typically including anemia) without an increase in blasts, to oligoblastic myeloid leukemia with an increase in marrow myeloblasts (5% to 19%). Patients with 20% or more myeloblasts in the marrow (an arbitrary boundary) or specific chromosomal translocations are defined as AML by the World Health Organization. The diagnostic criteria for MDS include dysmorphology in 1 or more blood cell lineages that is often accompanied by exaggerated apoptosis (detected by flow cytometry) during later stages of hematopoietic maturation. The marrow usually contains increased erythroid precursors with dysmorphic features, including nuclear distortions or lobar abnormalities; scanty, poorly hemoglobinized cytoplasm; or macroerythroblasts. Pathologic ring sideroblasts are a common feature used to define particular subtypes of MDS. Neutrophils in MDS may have bilobed or hypersegmented nuclei and hypogranulated cytoplasm in association with increased marrow granulocyte precursors. Giant or microcytic platelets, sometimes with abnormal or absent granulation, are associated with megakaryocytic hyperplasia and atypical lobulation of the nucleus, megakaryocyte clustering, and decreased marrow megakaryocyte size. Clonal cytogenetic abnormalities occur in approximately 50% of patients, typically as recurrent deletions of entire chromosomes or chromosomal segments. Trisomy 8 is the only frequent copy number gain and recurrent translocations are rare.
Prognostic models for MDS incorporate cytogenetic abnormalities along with marrow blast proportion and the number and degree of blood cytopenias to predict the mortality and risk of clonal evolution to AML. The selection and timing of therapy for MDS is largely driven by risk stratification using these models. Newer prognostic scoring systems have begun to consider somatic mutations as markers of disease-associated risk, as pathogenic driver mutations can be identified in almost all patients with MDS and several lesions have a prognostic significance that is independent of other known risk factors. As detectable somatic events, driver mutations are markers of clonal hematopoiesis and could help establish the diagnosis in some patients. Recurrent somatic mutations identify the heterogenous molecular pathways frequently disordered in MDS. These include mutations in multiple components of the RNA splicing machinery, several epigenetic regulators of DNA ...