What is the most likely diagnosis and appropriate work‑up for a patient with leukopenia, mild normocytic‑to‑microcytic anemia, low hemoglobin and hematocrit, normal mean corpuscular volume, and elevated red‑cell distribution width?

Diagnostic Approach to Leukopenia with Anemia and Elevated RDW

The most likely diagnosis is myelodysplastic syndrome (MDS), and you should proceed immediately with bone marrow aspiration and biopsy with comprehensive ancillary studies including cytogenetics and flow cytometry. 1

Primary Differential Diagnosis

The combination of leukopenia (WBC 3.4), mild anemia (hemoglobin 11.8-12.1 g/dL), low-normal MCV (83.9-91.7 fL), and persistently elevated RDW (17.0-18.4%) strongly suggests a clonal bone marrow disorder, particularly MDS. 1 The elevated RDW with relatively preserved MCV indicates ineffective erythropoiesis with heterogeneous red cell populations, a hallmark of dysplastic hematopoiesis. 2

Key Clinical Context Required

Before proceeding with invasive testing, you must systematically exclude secondary causes:

• Medication history: Document all current and recent medications, particularly chemotherapy, immunosuppressive agents, or drugs known to cause marrow suppression 1, 3
• Exposure history: Benzene, radiation, or occupational toxins 1
• Nutritional deficiencies: Check vitamin B12, folate, iron studies (serum iron, TIBC, ferritin), and thyroid function 1
• Viral serologies: HIV, parvovirus B19, hepatitis B and C, and cytomegalovirus 1
• Autoimmune screening: Consider if clinical features suggest systemic disease 3

Mandatory Diagnostic Workup

Immediate Laboratory Studies

• Peripheral blood smear review: Manual differential to assess for dysplasia in neutrophils (hypolobation, hypogranulation), red cells (anisopoikilocytosis, macroovalocytes), and platelets 1, 4
• Reticulocyte count: To distinguish hypoproliferative from hemolytic processes 1
• Complete metabolic panel: Including LDH, bilirubin, and haptoglobin to exclude hemolysis 1, 5
• Nutritional studies: RBC folate, serum B12, iron panel (iron, TIBC, ferritin) 1

Bone Marrow Examination (Mandatory)

You must perform bone marrow aspiration and biopsy at a center with hematologic expertise. 1 The European LeukemiaNet guidelines emphasize this is non-negotiable for suspected MDS:

• Bone marrow aspirate: For morphologic evaluation of dysplasia in erythroid, myeloid, and megakaryocytic lineages; blast enumeration; and iron staining for ring sideroblasts 1
• Bone marrow biopsy: To assess cellularity, fibrosis, and topography 1
• Cytogenetic analysis: Conventional karyotyping is mandatory to identify MDS-defining chromosomal abnormalities (del 5q, monosomy 7, trisomy 8, etc.) 1
• Flow cytometry: Multicolor immunophenotyping to exclude acute leukemia and assess for aberrant myeloid maturation patterns 1

Critical Diagnostic Criteria

The diagnosis of MDS requires exclusion of reactive causes and demonstration of either:

• Dysplasia in ≥10% of cells in one or more lineages, OR
• ≥15% ring sideroblasts, OR
• MDS-defining cytogenetic abnormality, OR
• 5-19% blasts in blood or marrow 1

Important caveat: If only unilineage dysplasia is present without increased blasts, ring sideroblasts <15%, and normal cytogenetics, repeat bone marrow examination in 6 months is recommended before confirming MDS diagnosis. 1

Alternative Diagnoses to Consider

Aplastic Anemia

If bone marrow shows hypocellularity with fatty replacement rather than dysplasia, consider aplastic anemia. 3 This requires:

• Bone marrow cellularity <25% (or <50% with <30% hematopoietic cells) 3
• Absence of fibrosis or infiltrative process 3
• Flow cytometry to exclude paroxysmal nocturnal hemoglobinuria clone 1, 3

Early Acute Leukemia

Though less likely with this degree of cytopenia, if blasts are identified on peripheral smear or bone marrow shows ≥20% blasts, acute leukemia workup is required with comprehensive immunophenotyping and molecular studies. 1, 5

Common Pitfalls to Avoid

• Do not delay bone marrow biopsy while pursuing extensive nutritional or viral workup if MDS is suspected—these can be done concurrently 1
• Do not rely solely on automated CBC parameters—manual peripheral smear review is essential to detect dysplasia 4
• Do not assume iron deficiency based on elevated RDW alone—RDW elevation occurs in multiple conditions including MDS, B12 deficiency, and mixed deficiencies 2, 6, 7
• Do not perform bone marrow examination at a facility without cytogenetic capabilities—cytogenetics are mandatory for MDS diagnosis and risk stratification 1

Prognostic Implications

The elevated RDW in this context carries significant prognostic weight beyond simple anemia classification. Studies demonstrate that elevated RDW combined with abnormal MCV (particularly macrocytosis) predicts increased mortality even in non-anemic elderly patients. 7 This underscores the urgency of definitive diagnosis.