What is the diagnosis if a patient has hypersegmented neutrophils, vacuolate neutrophils, and large platelets on their complete blood count (CBC)?

Differential Diagnosis: Myelodysplastic Syndrome vs. Vitamin B12 Deficiency

The most likely diagnosis is vitamin B12 deficiency, which must be definitively excluded before diagnosing myelodysplastic syndrome (MDS), as both conditions present with hypersegmented neutrophils, vacuolated neutrophils, and large platelets. 1

Critical Diagnostic Distinction

The morphologic findings you describe—hypersegmented neutrophils, vacuolated neutrophils, and large platelets—are characteristic of both MDS and vitamin B12 deficiency, making this a high-stakes diagnostic challenge. 1, 2

Why Vitamin B12 Deficiency Should Be Your Primary Consideration:

• Copper deficiency can mimic MDS with vacuolation of myeloid precursors, and clinical features associated with copper deficiency include prior gastrointestinal surgery and a history of vitamin B12 deficiency 1
• Vitamin B12 deficiency causes extensive hematologic alterations including pancytopenia, macrocytosis, hypersegmentation of neutrophils, and hypercellular bone marrow with blastic differentiation that can mimic MDS or even acute leukemia 2
• Normal serum B12 levels do NOT exclude deficiency—patients can have seemingly normal vitamin B12 levels yet still have functional B12 deficiency 3, 4

Algorithmic Diagnostic Approach

Step 1: Immediate Laboratory Assessment

• Measure serum vitamin B12, methylmalonic acid (MMA), and homocysteine levels 3
• Check serum copper and ceruloplasmin levels, particularly if there is history of gastrointestinal surgery or prior B12 deficiency 1
• Obtain complete blood count with peripheral blood smear to assess platelet size and morphology 5

Step 2: Interpret B12 Studies Correctly

• If B12 is low: Diagnose B12 deficiency
• If B12 is normal but clinical suspicion remains high: Measure MMA and homocysteine—elevated levels confirm functional B12 deficiency despite normal serum B12 3, 4
• Serial follow-up of vitamin B12 levels may reveal fluctuations or gradual decrease that were not apparent on initial testing 4

Step 3: Therapeutic Trial

• Administer parenteral vitamin B12 for 7 days 4
• If complete blood count normalizes within 7 days: Diagnosis is B12 deficiency, not MDS 4
• Patients with B12 deficiency show rapid improvement in pancytopenia and blastic changes with parenteral supplementation 2

Step 4: If B12 Deficiency Is Excluded, Proceed with MDS Workup

• Bone marrow biopsy with morphologic assessment for dysplasia in multiple lineages 1
• Conventional karyotype analysis of bone marrow cells (20-25 metaphases should be analyzed) 1
• Assess for MDS-defining cytogenetic abnormalities 1
• Confirm relative stability of peripheral blood counts for 4-6 weeks to exclude other causes 1

Key Morphologic Features in MDS (When B12 Deficiency Excluded)

MDS diagnosis requires dysplastic changes in blood cells including: 6

• Erythroid lineage: Megaloblasts, dissociated nuclear-cytoplasmic maturation, multinucleated erythroblasts, ringed sideroblasts
• Granulocytic lineage: Hypersegmented or hyposegmented neutrophils (pseudo Pelger-Huët anomaly), reduced/absent granules, peroxidase-negative neutrophils
• Megakaryocytic lineage: Micromegakaryocytes, megakaryocytes with multiple isolated disc-shaped nuclei, giant platelets

Critical Pitfalls to Avoid

• Do not diagnose MDS based solely on morphological abnormalities without excluding B12 deficiency 3—this can lead to unnecessary aggressive treatment including consideration of chemotherapy 2
• Do not rely on a single normal B12 level to exclude deficiency—functional B12 deficiency can exist with normal serum levels 3, 4
• Morphological abnormalities (hypersegmented neutrophils, vacuolated cells, large platelets) are NOT specific to MDS and are also seen in B12 deficiency and other conditions 6
• The presence of cellular/hypercellular bone marrow does not distinguish between MDS and B12 deficiency, as both can present this way 2, 6

When to Suspect MDS Over B12 Deficiency

Consider MDS more likely if: 1

• MDS-defining cytogenetic abnormalities are present (del(5q), del(20q), chromosome 7 anomalies, complex karyotype)
• Increased blast percentage in bone marrow (≥5%) or peripheral blood (≥1%)
• No response to 7-day parenteral B12 trial 4
• Clonal chromosomal abnormalities detected on conventional karyotype 1

Bottom line: Administer parenteral vitamin B12 for 7 days and reassess complete blood counts before pursuing an MDS diagnosis. 4 This simple intervention prevents misdiagnosis and avoids potentially harmful treatments while definitively establishing the correct diagnosis.