Myelodysplastic Syndromes (MDS) are a group of bone marrow disorders classified as blood cancers. In MDS, hematopoietic stem cells fail to mature into healthy, functioning blood cells. This failure results in a deficit of mature cells circulating in the blood, a condition known as cytopenia. Since MDS shares features with other non-cancerous conditions, diagnosis requires a sequence of specialized tests and a thorough evaluation of the bone marrow’s architecture and cellular genetics.
Initial Indicators and Preliminary Testing
The first signs that lead a physician to suspect Myelodysplastic Syndrome are often non-specific and easily mistaken for other illnesses. People may experience persistent fatigue, shortness of breath, frequent infections, or easy bruising and bleeding, all common symptoms resulting from low blood cell counts. These complaints prompt the ordering of the Complete Blood Count (CBC) test.
The CBC provides a quantitative snapshot of the major blood cell lines: red blood cells, white blood cells, and platelets. In suspected MDS, the CBC typically reveals cytopenias, such as anemia (low red cells), neutropenia (low white cells), or thrombocytopenia (low platelets). Examination of the peripheral blood smear may also show unusually large red blood cells, known as macrocytosis. While these findings trigger further investigation, the CBC alone cannot confirm an MDS diagnosis because other conditions, such as vitamin deficiencies or autoimmune disorders, can also cause cytopenias.
The Definitive Diagnostic Procedure
The definitive step for an MDS diagnosis is the Bone Marrow Biopsy (BMB) and Aspiration, performed to collect samples directly from the site of blood cell production. The procedure is typically performed on the posterior iliac crest (the back of the hip bone) using a local anesthetic. A specialized hollow needle is used to obtain two different types of samples from the marrow space.
The first sample is the bone marrow aspirate. This liquid sample is spread onto slides so a hematopathologist can examine the morphology of individual cells and count the immature precursor cells, called blasts. The second sample is the core biopsy. This solid cylinder of tissue is preserved intact to assess the bone marrow’s overall structure, including its cellularity (the ratio of blood-forming tissue to fat).
The pathologist scrutinizes the samples for two main physical hallmarks of MDS: dysplasia and the percentage of blast cells. Dysplasia refers to the abnormal appearance, size, or shape of the developing blood cells, and must be confirmed in over ten percent of the cells within at least one hematopoietic lineage for diagnosis. MDS is defined by having less than 20 percent blasts in the bone marrow; a blast count of 20 percent or higher is diagnostic of Acute Myeloid Leukemia (AML).
Advanced Laboratory Confirmation
Advanced laboratory tests are performed to confirm the diagnosis and provide detailed genetic information about the disease. Cytogenetics, or karyotyping, is a test performed on the aspirate sample to look for large-scale structural abnormalities in the chromosomes of the bone marrow cells. This analysis can reveal common MDS-associated changes, such as the loss of a part of chromosome 5 (del(5q)), the loss of the entire chromosome 7 (monosomy 7), or the gain of an extra chromosome 8 (trisomy 8).
Fluorescence In Situ Hybridization (FISH) is a complementary technique that uses fluorescent probes to rapidly detect specific chromosomal abnormalities that may be missed by conventional karyotyping. Molecular Testing, typically performed using Next-Generation Sequencing (NGS), analyzes the DNA for specific gene mutations. Identifying somatic mutations in genes like SF3B1, TP53, ASXL1, or TET2 helps confirm the clonal nature of the disease. These genetic findings also help rule out conditions that mimic MDS and pinpoint the molecular drivers of the specific subtype.
Interpreting Results and Classification
The final diagnosis of Myelodysplastic Syndrome synthesizes information from peripheral blood counts, bone marrow morphology, and genetic test results. The World Health Organization (WHO) Classification system defines the specific MDS subtype. This system categorizes the disease based on the number of affected blood cell lines showing dysplasia, the percentage of blasts in the bone marrow, and the presence of certain genetic abnormalities.
Classification is necessary because the specific subtype dictates the expected progression of the disease. Physicians use risk assessment tools, such as the Revised International Prognostic Scoring System (IPSS-R), to determine the severity of the MDS. The IPSS-R score integrates the percentage of blasts, the number of cytopenias, and the type of chromosomal abnormalities present to place a patient into one of five risk categories. The Molecular Prognostic Scoring System (IPSS-M) further refines this risk assessment by incorporating specific somatic gene mutations, providing a more personalized understanding of the disease’s potential clinical course.