myelodysplastic syndrome

MDS arises from acquired somatic mutations in hematopoietic stem cells (e.g., SF3B1, TET2, ASXL1, TP53, DNMT3A) leading to clonal expansion of abnormal progenitors that undergo increased apoptosis in the marrow, resulting in peripheral cytopenias (anemia, neutropenia, thrombocytopenia) despite a hypercellular or normocellular bone marrow—termed 'ineffective hematopoiesis.' Peripheral blood smear often shows dysplastic features: macro-ovalocytes, hypogranular/hypolobated neutrophils (pseudo-Pelger-Huët anomaly), and giant/hypogranular platelets. Bone marrow biopsy reveals dysplasia in one or more cell lines, ringed sideroblasts (in some subtypes like MDS with ring sideroblasts, associated with SF3B1 mutations), and blasts <20% (distinguishing MDS from AML). Cytogenetic abnormalities are common, including deletion 5q (associated with a distinct subtype, del(5q) syndrome, seen more often in women, responsive to lenalidomide), monosomy 7, and complex karyotypes (poor prognosis). Classification uses the WHO system based on lineage dysplasia, blast percentage, and cytogenetics, and prognosis is stratified using the Revised International Prognostic Scoring System (IPSS-R), which considers cytopenias, blast percentage, and karyotype. Therapy-related MDS (t-MDS) occurs after alkylating agent or topoisomerase II inhibitor chemotherapy, often with high-risk cytogenetics and poor prognosis. Clinically, patients present with fatigue (anemia), infections (neutropenia), or bleeding (thrombocytopenia). Management ranges from supportive care (transfusions, growth factors) for low-risk disease to hypomethylating agents (azacitidine, decitabine) for intermediate/high-risk disease, and allogeneic stem cell transplantation for eligible high-risk patients—the only curative option. Approximately 30% of MDS cases progress to AML, particularly those with excess blasts or high-risk cytogenetics. Key USMLE associations: prior chemotherapy/radiation exposure, elderly patients, pancytopenia with hypercellular marrow, ringed sideroblasts, del(5q) treated with lenalidomide, and progression to AML.