What Tests Are Included in a Complete MDS Diagnosis?

A diagnosis of myelodysplastic syndrome (MDS) cannot be made with a single test. Because MDS can be difficult to distinguish from other conditions, confirming the diagnosis requires a comprehensive “workup” that integrates blood tests, bone marrow evaluation, and specialized genetic testing, while ruling out other causes of low blood counts ^[1][2].

Every patient’s situation is unique, so not everyone needs every test listed here. Your hematologist will tailor the evaluation based on your symptoms and blood count patterns. You should not delay urgent medical care (such as treatments for severe bleeding, chest pain, or infections) while waiting to complete every possible diagnostic test.

1. Ruling Out “Mimics” and Other Conditions

Before diagnosing MDS, doctors must evaluate whether other conditions are causing your low blood counts and abnormal-looking cells ^[3][4]. This involves taking a careful medical history and running targeted laboratory tests based on your specific situation:

• Nutritional and organ function tests: Checking levels of vitamin B12, folate, copper, and iron, as well as evaluating your kidney, liver, and thyroid function ^[3].
• Inflammatory and autoimmune conditions: Testing for conditions like lupus. In select cases where a patient has characteristic systemic inflammation, doctors may test for a genetic condition called VEXAS syndrome ^[5].
• Infections: Testing for viruses such as HIV, hepatitis, or parvovirus B19.
• Toxins, medications, and past treatments: Reviewing current medications, supplements, and alcohol use. Importantly, if you have had past chemotherapy or radiation, your doctor needs to know the exact agents and dates. These previous exposures can cause “therapy-related” myeloid neoplasms rather than just temporary count suppression ^[3][6].
• Other bone marrow disorders: The doctor will also consider other diseases like aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH), or inherited marrow-failure syndromes ^[4].

2. Initial Blood Tests

• Serial Complete Blood Counts (CBC) with differential: Evaluating your counts over time to see if the low counts (cytopenias) are persistent ^[7]. Doctors will also check your reticulocyte count (the number of newly produced red blood cells).
• Peripheral blood smear: A pathologist examines your blood under a microscope to look for abnormal shapes or features (dysplasia) in your circulating cells ^[1][7].

3. Bone Marrow Examination

A definitive MDS diagnosis typically requires examining the bone marrow, the factory where blood cells are made ^[8]. This procedure is usually done with a local anesthetic and involves two complementary samples:

• Bone marrow aspirate: Withdrawing the liquid portion of the marrow to assess individual cells ^[9].
• Bone marrow core biopsy: Removing a small piece of bone and marrow to look at the overall cellular architecture and check for scarring (fibrosis) ^[8][9].
• Morphology: A specialist evaluates these samples to look for dysplasia, count the percentage of immature cells (blasts), and check for ring sideroblasts. Ring sideroblasts are immature red blood cell precursors in the bone marrow that have an abnormal ring of iron around their nucleus ^[8].
• The Blast Threshold: Historically, having fewer than 20% blasts in the bone marrow helped distinguish MDS from acute myeloid leukemia (AML) ^[8]. However, this threshold is not absolute. Under current classification systems (such as the WHO or ICC), certain genetic findings can establish an AML diagnosis even with fewer than 20% blasts, and cases with 10–19% blasts are classified carefully based on a combination of genetics, morphology, and clinical context.

4. Genetic and Specialized Testing

MDS is driven by acquired genetic changes. Your doctor will likely order advanced tests on your marrow sample to support the diagnosis, classify your disease, and determine your risk level:

• Cytogenetic Karyotyping: Examines the chromosomes in your marrow cells to look for major missing, extra, or rearranged parts ^[10]. This is crucial for determining your prognostic risk score ^[11].
• FISH (Fluorescence in situ hybridization): A targeted test for specific chromosomal abnormalities ^[11]. It is often used if karyotyping fails to grow enough cells for analysis. Keep in mind that a normal FISH or karyotype result does not completely rule out MDS ^[10][11].
• Flow Cytometry: Analyzes the proteins on the surface of your marrow cells ^[12]. It can reveal abnormal patterns and provide supporting evidence when a diagnosis is uncertain ^[13].
• Next-Generation Sequencing (NGS): A DNA test that looks for specific gene mutations within your bone marrow cells ^[14]. Finding a mutation helps guide treatment, but a mutation alone does not automatically mean you have MDS. Healthy older adults can have age-related genetic changes, known as clonal hematopoiesis of indeterminate potential (CHIP) ^[14][15]. If you have unexplained low blood counts and a mutation but do not meet the full criteria for MDS, your condition may be classified as clonal cytopenia of undetermined significance (CCUS), which requires careful monitoring ^[16][17].

5. When Special Circumstances Apply

Depending on your initial results, your doctor may recommend additional steps to ensure accuracy:

• Expert Pathology Review: Because identifying dysplasia can be subjective, having your marrow samples reviewed by an expert hematopathologist (a doctor specializing in blood and bone marrow diseases) is highly recommended if initial results are borderline or conflicting ^[2].
• Repeat Bone Marrow Testing: If your initial samples were inadequate, or if you have persistent unexplained low blood counts, a repeat biopsy may be needed. Sometimes it is safer to monitor your blood counts and repeat the biopsy later to catch emerging features, rather than prematurely labeling a borderline result as cancer ^[9][18].
• Germline Testing and Genetic Counseling: While most MDS mutations are acquired over time, some are inherited (germline mutations), such as those in the DDX41 or RUNX1 genes ^[19][20]. You may need a referral for genetic counseling and germline testing if you are young, have a lifelong history of low blood counts, or have a family history of blood cancers ^[21]. Importantly, certain inherited syndromes (like DDX41 mutations) often present in older adults with no clear family history ^[22]. Germline testing requires using non-blood tissues (like a skin biopsy or saliva) because blood and marrow samples can be compromised by your acquired cancer mutations ^[23]. Finally, if you are considering a stem cell transplant, any family member being considered as a donor must be evaluated for these inherited mutations to ensure they are a safe match ^[24].