What are the key differences between Aplastic Anemia (AA) and Myelodysplastic Syndromes (MDS) in terms of clinical features and treatment approaches?

Distinguishing Aplastic Anemia from Myelodysplastic Syndromes

Aplastic anemia and MDS are distinct entities that require bone marrow biopsy for accurate diagnosis, with the critical differentiating features being the presence of dysplasia, blast percentage, cytogenetic abnormalities, and abnormal localization of immature precursors (ALIP) in MDS versus their absence in aplastic anemia. 1, 2

Key Diagnostic Features

Bone Marrow Cellularity

• Aplastic anemia shows severely reduced cellularity (<20% in severe cases, age-corrected) with fatty replacement of normal hematopoietic tissue and no dysplasia or abnormal blast clusters 2, 3
• Hypocellular MDS (H-MDS) presents with hypocellular marrow (7-29% of MDS cases) but demonstrates unequivocal dysplasia distinguishing it from aplastic anemia 2
• Age correction is mandatory when assessing bone marrow cellularity—failure to correct dramatically overestimates hypocellular cases (from 13% to 2.2% in AML when corrected) 2

Morphologic Criteria

• Aplastic anemia: Blast percentage below 1%, no moderate-to-severe erythroid dysplasia, no abnormal sideroblasts, no ALIP 2, 3
• H-MDS: Moderate to severe erythroid dysplasia, abnormal sideroblasts, blast percentage of 5% or higher (in absence of significant dysplasia), presence of ALIP 2
• A 500-cell differential count is necessary for accurate blast assessment—a 100-cell count has unacceptably wide confidence intervals (95% CI: 1.6-11.3% versus 3.3-7.3% for 500-cell count) 2

Cytogenetic Abnormalities

• Aplastic anemia: No clonal chromosomal abnormalities 1, 3
• MDS: Specific clonal chromosomal abnormalities can establish diagnosis even when morphological features are inconclusive 1
• Standard cytogenetics/interphase FISH is essential to rule out chromosomal abnormalities 3

Flow Cytometry and Additional Testing

• Flow cytometry abnormalities alone are not diagnostic of MDS in the absence of morphological and/or cytogenetic findings 1
• PNH screening by sensitive flow cytometry is mandatory in all cases to exclude paroxysmal nocturnal hemoglobinuria 2, 3
• Iron stain for ring sideroblast assessment helps exclude MDS 3

Clinical Implications and Prognosis

Risk of Leukemic Transformation

• MDS carries a much greater risk of progression to acute leukemia compared to aplastic anemia, making accurate diagnosis essential for treatment planning 2, 4
• Aplastic anemia has minimal risk of leukemic transformation unless clonal evolution occurs 4, 5

Treatment Approaches Differ Fundamentally

• Aplastic anemia: Immunosuppressive therapy (horse ATG plus cyclosporine) or hematopoietic stem cell transplantation for young patients with HLA-identical sibling donors 6
• H-MDS: Immunomodulatory treatment (similar to aplastic anemia) may be offered with limited success; hypomethylating agents (5-azacytidine, decitabine) are treatment options 1, 7
• MDS with 5q syndrome: Lenalidomide obtains cytogenetic responses in half of patients and significantly reduces red cell transfusion requirements 1
• Misdiagnosis leads to inappropriate treatment—aplastic anemia requires immunosuppression or transplant, while H-AML requires acute leukemia chemotherapy 2

Shared Pathophysiology

Despite being distinct entities, compelling evidence suggests these conditions share common immune-mediated mechanisms:

• Both involve damage to hematopoietic stem and progenitor cells (HSPCs) by cytotoxic T cells 5
• Expanded T cells overproduce proinflammatory cytokines (interferon-γ and tumor necrosis factor-α), resulting in decreased proliferation and increased apoptosis of HSPCs 5
• This overlap explains why hypoplastic MDS can sometimes respond to immunosuppressive therapy, though less effectively than aplastic anemia 1, 5

Critical Diagnostic Pitfalls

• Previous genotoxic exposure or therapy must be excluded as chemotherapy (particularly alkylating agents and purine analogues), benzene derivatives, and ionizing radiation can cause hypocellular marrows resembling aplastic anemia 2, 3
• Review by at least two observers is essential when diagnostic doubt exists, particularly for H-AML cases where concordance among experts is only 57% 2
• Bone marrow biopsy is critical and necessary to diagnose these variants in all patients, including children, due to paucicellular aspirates typically obtained in severe marrow hypocellularity 1
• Careful follow-up investigations (morphology and karyotyping) at regular intervals of several months are recommended when morphological and cytogenetic findings are inconclusive 1