Diagnosing myelodysplastic syndromes (MDS) is a multi-step process that starts with routine blood work and typically requires a bone marrow biopsy, genetic testing, and ruling out other causes of low blood counts. No single test confirms MDS on its own. Doctors piece together findings from several different analyses to reach a diagnosis and determine how aggressive the disease may be.
Blood Tests Are Usually the First Step
MDS is often first suspected when a routine complete blood count (CBC) reveals unexplained low blood cell counts, called cytopenias. At least one type of blood cell must be below normal thresholds: hemoglobin below 13 g/dL in men or below 12 g/dL in women (indicating anemia), platelets below 150,000 per microliter, or neutrophils (infection-fighting white blood cells) below 1,800 per microliter. Many people with MDS have low counts in two or even all three of these categories.
A blood smear, where a technician examines your blood under a microscope, can also reveal abnormally shaped or sized cells. But low blood counts alone don’t point to MDS. Plenty of other conditions cause the same pattern, so doctors need to investigate further before landing on a diagnosis.
Ruling Out Other Causes
Before pursuing a bone marrow biopsy, your doctor will typically check for more common explanations for low blood counts. Vitamin B12 and folate deficiencies can cause changes in blood cells that look remarkably similar to MDS under a microscope. Zinc and copper deficiencies are rarer but can also mimic the disease. Viral infections like parvovirus and HIV need to be excluded, along with medication side effects (particularly from drugs like methotrexate) and heavy alcohol use. Only after these causes have been investigated does the diagnostic workup move toward the bone marrow.
Bone Marrow Biopsy: The Central Test
A bone marrow biopsy is essential for confirming MDS. During the procedure, a needle is inserted into the back of the hip bone to withdraw a small sample of liquid marrow and a tiny core of bone tissue. The area is numbed with local anesthetic, and the whole process typically takes 15 to 30 minutes. Most people feel a deep pressure or brief sharp pain when the sample is drawn, but the discomfort is short-lived.
Pathologists examine the marrow sample for dysplasia, which means the blood-forming cells look abnormal in shape, size, or maturity. For a diagnosis of MDS, at least 10% of cells in one or more blood cell lines (red cells, white cells, or platelet-producing cells) must show these abnormal features. Pathologists also count the percentage of blasts, which are immature blood cells. In healthy marrow, blasts make up a small fraction of cells. MDS is generally defined by having fewer than 20% blasts. At 20% or above, the diagnosis shifts to acute myeloid leukemia (AML).
Flow Cytometry Adds Detail
Flow cytometry is a lab technique that analyzes thousands of individual cells from the marrow sample, tagging them with markers to identify what type they are and how mature they’ve become. In MDS, this test picks up subtle abnormalities that might not be visible under a microscope. For example, immature cells may carry surface markers that normally only appear on mature cells, or myeloid cells may express markers that belong to a completely different cell lineage, like T-cell markers appearing on cells that should be developing into neutrophils.
Neutrophils in MDS often show reduced internal complexity (a measurement called side scatter) that correlates with the hypogranulation pathologists see under the microscope. Red blood cell precursors may show irregular expression of maturation markers. Monocytes can lose their typical surface proteins or abnormally overexpress others. None of these findings alone clinch the diagnosis, but they strengthen the case when combined with other results.
Chromosome Analysis
Cytogenetic testing examines the chromosomes inside marrow cells for missing, extra, or rearranged segments. About half of MDS patients have detectable chromosomal abnormalities, and the specific changes found play a major role in both confirming the diagnosis and predicting outcomes. The most commonly tested abnormalities involve chromosomes 5, 7, 8, and 20. A deletion on the long arm of chromosome 5, known as del(5q), defines its own MDS subtype and generally carries a more favorable prognosis.
Two techniques are used in parallel. Conventional karyotyping cultures the marrow cells and photographs the full set of chromosomes, while fluorescence in situ hybridization (FISH) uses fluorescent probes to detect specific known deletions or additions. Together, they give a comprehensive picture. The findings are categorized into prognostic groups ranging from “very good” (such as a simple loss of the Y chromosome) to “very poor” (complex rearrangements involving more than three abnormalities).
Genetic Mutation Testing
Molecular testing has become a cornerstone of MDS diagnosis over the past few years. Next-generation sequencing panels screen marrow cells for mutations in dozens of genes associated with MDS. Two genes in particular now define their own diagnostic categories.
Mutations in the SF3B1 gene, when present at a variant allele frequency of 5% or higher, define a subtype called MDS with mutated SF3B1. This subtype tends to have a relatively favorable outlook and is characterized by ring sideroblasts, a distinctive type of abnormal red blood cell precursor. Importantly, the presence of certain co-mutations (like RUNX1) can exclude a patient from this category under some classification systems.
TP53 mutations carry a very different significance. When both copies of the TP53 gene are affected, either through two separate mutations or one mutation combined with a chromosomal deletion, the disease is classified as MDS with biallelic TP53 inactivation. This subtype is associated with complex chromosomal changes and a more aggressive course. The distinction between having one versus two TP53 hits matters enough that the updated classification systems treat them as fundamentally different situations.
How Results Are Classified
Two major classification systems were updated in 2022: the World Health Organization (WHO) system and the International Consensus Classification (ICC). Both use the same core ingredients, including blast counts, chromosomal findings, and gene mutations, but they draw some lines differently.
The most notable difference involves patients with 10 to 19% blasts. The ICC reclassifies these cases as “MDS/AML,” a hybrid category acknowledging that these patients are closer to leukemia than to lower-risk MDS. The WHO system keeps them within the MDS spectrum as “MDS with increased blasts.” The WHO also introduced categories for hypoplastic MDS (where the marrow is unusually sparse) and MDS with fibrosis (where scar tissue replaces normal marrow). Your hematologist will use whichever system your institution follows, and in practice, treatment decisions account for both frameworks.
Risk Scoring After Diagnosis
Once a diagnosis is confirmed, the results from all these tests feed into a risk scoring system that guides treatment. The most current version, called the Molecular International Prognostic Scoring System (IPSS-M), incorporates blood counts, chromosomal findings, and mutations across 31 genes to assign a risk category. Earlier scoring systems relied mainly on blast percentage, blood counts, and chromosomal data. Adding molecular information significantly sharpens the prediction of how quickly the disease may progress and how it’s likely to respond to treatment.
The IPSS-M treats certain mutations as binary variables, simply present or absent, but handles TP53 and SF3B1 with more nuance. TP53 is scored differently depending on whether one or both copies are mutated, and SF3B1’s impact is adjusted based on whether specific co-mutations or chromosomal changes are also present. The final score places patients into risk groups ranging from very low to very high, which directly shapes decisions about whether to pursue intensive treatment, supportive care, or a bone marrow transplant evaluation.