Myelodysplastic Syndromes (MDS) are a group of blood cancers characterized by the production of defective, immature blood cells in the bone marrow, leading to low counts of healthy red cells, white cells, and platelets. This results in ineffective hematopoiesis. MDS can be misdiagnosed because its symptoms and initial blood test results often mimic those of many other, less serious conditions. This diagnostic ambiguity frequently leads to delays or errors in identifying the true nature of the disorder.
The Inherently Complex Nature of MDS Diagnosis
The difficulty in diagnosing Myelodysplastic Syndromes stems from the fact that it is a spectrum of disorders with highly variable presentations. Initial signs often involve nonspecific symptoms like fatigue, weakness, or frequent infections. Diagnosis is typically first suspected when a routine complete blood count (CBC) shows cytopenia—a low count in one or more cell lines—but this finding alone is insufficient to confirm MDS.
Confirmation of MDS relies heavily on the subjective assessment of cell morphology, specifically looking for dysplasia, which is the abnormal size, shape, and appearance of blood cell precursors in the bone marrow. Early stages can present with subtle dysplastic changes that are difficult to distinguish from those caused by non-malignant factors, complicating the pathologist’s review. This ambiguity often results in temporary classification under holding-pattern terms, such as Clonal Cytopenias of Undetermined Significance (CCUS) or Idiopathic Cytopenia(s) of Undetermined Significance (ICUS), until further information clarifies the true diagnosis.
Common Conditions Mistaken for Myelodysplastic Syndromes
A major reason for misdiagnosis is the long list of non-cancerous conditions that mimic MDS in initial tests and bone marrow samples. The most common look-alike conditions are severe nutritional deficiencies, particularly a lack of vitamin B12 or folate. These deficiencies cause megaloblastic anemia, which produces abnormally large red blood cell precursors that can be mistaken for dysplastic cells. Correcting these vitamin deficiencies resolves the cytopenia, making the distinction from MDS important.
Aplastic Anemia (AA) is another frequent misdiagnosis. AA is a condition where the bone marrow is severely hypocellular and fails to produce enough blood cells. Differentiating hypocellular MDS from AA is challenging because both result in low blood counts. However, AA is often considered an autoimmune disorder, while MDS is a clonal blood cancer, meaning their treatments and long-term outlooks are different.
Other conditions also mimic MDS. These include:
- Viral infections, such as HIV or Cytomegalovirus, which can transiently suppress the bone marrow, leading to low blood counts and subtle dysplastic changes.
- Drug-induced bone marrow suppression, particularly from chemotherapy or medications like methotrexate, which can injure blood-forming stem cells.
- Other myeloid disorders, including Myeloproliferative Neoplasms (MPNs) or certain chronic leukemias, which share overlapping features.
- The recently recognized VEXAS syndrome, an inflammatory condition with hematologic features, which requires specialized testing to distinguish.
Advanced Testing Required for Definitive Confirmation
Achieving a definitive diagnosis of Myelodysplastic Syndromes requires integrating clinical information with highly specialized laboratory and genetic testing, moving far beyond a simple blood count. The cornerstone of the diagnostic process is the bone marrow aspirate and biopsy. This allows a hematopathologist to microscopically examine the cellularity and morphology of the blood-forming tissue and accurately identify the percentage of blasts (immature cells) and the presence of dysplasia.
Cytogenetic analysis is performed to identify non-random chromosomal abnormalities characteristic of MDS. This testing, which includes techniques like Fluorescence In Situ Hybridization (FISH), detects structural changes in the chromosomes. Examples include the deletion of part of chromosome 5 (del(5q)) or the gain of chromosome 8 (trisomy 8). These specific changes are strongly associated with MDS and help confirm the diagnosis even when morphological features are subtle.
Molecular diagnostics, typically performed using Next-Generation Sequencing (NGS), is the newest tool for confirming MDS. This technology scans for mutations in a panel of genes frequently altered in myeloid cancers, such as SF3B1, TET2, ASXL1, and DNMT3A. The presence of these somatic mutations provides strong evidence of clonal hematopoiesis, a hallmark of MDS. Integrating the findings from morphology, cytogenetics, and molecular sequencing is the current standard for accurately classifying the MDS subtype.
Consequences of Delayed or Incorrect MDS Diagnosis
The failure to accurately and promptly diagnose Myelodysplastic Syndromes has serious negative consequences for the patient’s health and treatment trajectory. A misdiagnosis can lead to patients receiving inappropriate or even toxic treatments. For instance, mistaking a benign condition for high-risk MDS might lead to unnecessary chemotherapy, while mistaking MDS for a simple vitamin deficiency results in no effective cancer treatment.
Delayed diagnosis means missing the optimal window for initiating disease-modifying therapies designed for MDS. The syndrome has the potential to progress into Acute Myeloid Leukemia (AML), which occurs in up to 40% of cases. Early, accurate risk stratification allows clinicians to monitor or treat the condition before this transformation occurs. The prolonged uncertainty and need for repeated specialist testing also increase the burden on patients.