Etiology and Pathogenesis
Myelodysplastic syndromes may present as primary (de novo) disorders or secondary conditions resulting from prior exposure to cytotoxic chemotherapy, ionizing radiation, or environmental toxins.
The central pathophysiological mechanism involves a somatic mutation in a pluripotent hematopoietic stem cell. These clonal alterations drive ineffective hematopoiesis. The paradox of MDS is that the bone marrow is typically normocellular or even hypercellular, reflecting active cell division. However, due to dysplasia, the progeny fail to mature properly and undergo intramedullary apoptosis. Consequently, insufficient mature blood cells are released into the peripheral circulation, resulting in pronounced cytopenias—specifically anemia, leukopenia, and/or thrombocytopenia.
Morphological Features of Dysplasia
The diagnosis of myelodysplastic syndromes relies on identifying morphological dysplastic changes across the major myeloid lineages:
- Dyserythropoiesis involves the erythroid lineage. Bone marrow aspirates may reveal multinucleated erythroblasts, ring sideroblasts, and cells exhibiting nuclear fragmentation (karyorrhexis). Asynchronous nuclear-cytoplasmic maturation and cytoplasmic vacuolization are common. In the peripheral blood, these abnormalities manifest as variation in erythrocyte size (anisocytosis) and abnormal shapes (poikilocytosis).
- Dysgranulopoiesis reflects pathology in the granulocytic series. Neutrophils frequently display abnormal nuclear shapes, such as pseudo-Pelger-Huët anomalies (hypolobated nuclei) or hypersegmentation. The cytoplasm often shows a marked decrease or complete absence of secondary granules.
- Dysmegakaryocytopoiesis characterizes abnormalities in the megakaryocytic lineage. The bone marrow contains atypical forms, including micromegakaryocytes (abnormally small, mononuclear megakaryocytes) and forms with multiple separated nuclei (multinucleated megakaryocytes).
Classification and Mixed Forms
According to the World Health Organization (WHO) classification, myelodysplastic syndromes are categorized into several subtypes based on morphological features and blast percentage:
- Refractory cytopenia with unilineage dysplasia (including refractory anemia, with or without ring sideroblasts).
- Refractory cytopenia with multilineage dysplasia, affecting multiple hematopoietic lineages.
- Refractory anemia with excess blasts.
- 5q- syndrome, a specific deletion subtype associated with distinct clinical and hematologic features.
- Myelodysplastic syndrome, unclassifiable.
Additionally, overlap syndromes exist, exhibiting features of both myelodysplastic and myeloproliferative neoplasms (MDS/MPN). These conditions feature dysplastic granulocytic and monocytic proliferation and typically follow an aggressive clinical course.