What is the significance of metamyelocytes on a peripheral blood smear and how should they be evaluated and managed?

Metamyelocytes on Peripheral Blood Smear

Metamyelocytes in peripheral blood represent a "left shift" indicating either reactive bone marrow stress (infection, inflammation) or, more concerning, an underlying hematologic malignancy requiring immediate diagnostic workup with bone marrow examination and cytogenetics. 1

Clinical Significance

Normal vs. Pathologic Presence

• Metamyelocytes are normally confined to bone marrow and should not appear in peripheral blood of healthy individuals 2, 3
• Their presence constitutes part of the "immature granulocyte" population (which includes metamyelocytes, myelocytes, and promyelocytes) and signals enhanced bone marrow activity 4
• A "left shift" is defined as ≥1% metamyelocytes, myelocytes, or promyelocytes in the peripheral blood differential 5

Reactive (Benign) Causes

• Severe bacterial or fungal infections drive accelerated neutrophil production and premature release of immature forms 4
• Systemic inflammatory response syndrome, severe acute pancreatitis, and post-cardiac surgery states commonly produce left shifts 4
• COVID-19 infection severity correlates with immature granulocyte counts, with higher counts predicting worse outcomes, longer hospitalization, and increased mortality 4

Malignant Causes Requiring Urgent Evaluation

• Myelodysplastic syndromes (MDS): Metamyelocytes may appear as part of myeloid dysplasia, particularly when accompanied by hypogranulation, hypolobation (pseudo-Pelger-Huët), or bizarre nuclear shapes 1
• Chronic myelomonocytic leukemia (CMML): Immature myeloid cells including metamyelocytes appear with persistent monocytosis >1×10⁹/L 6
• Acute leukemia: In acute lymphocytic leukemia, paradoxically, a left shift at diagnosis predicts better prognosis with 74% complete remission duration at 92 months versus 42% without left shift, possibly reflecting lower tumor burden 5

Diagnostic Algorithm

Immediate Assessment Required

1. Obtain complete blood count with 500-cell manual differential to accurately quantify metamyelocytes and other immature forms 6

2. Examine peripheral blood smear for dysplastic features: 1

   • Nuclear hypolobation or hypersegmentation
   • Cytoplasmic hypogranulation/degranulation
   • Presence of blasts (any percentage demands urgent workup)
   • Giant platelets, nucleated red blood cells

3. Assess clinical context immediately: 4

   • Active infection or sepsis (most common benign cause)
   • Recent surgery or trauma
   • Inflammatory conditions
   • Medication history (G-CSF administration)

When to Proceed to Bone Marrow Examination

Mandatory bone marrow aspiration and biopsy with cytogenetics if: 1, 6

• Any dysplastic features present in erythroid, myeloid, or megakaryocytic lineages
• Any circulating blasts detected (requires same-day hematology consultation)
• Persistent unexplained cytopenias lasting >2 months with dysplasia or >6 months without dysplasia
• Left shift persists after resolution of acute illness
• Monocytosis >1×10⁹/L accompanies the left shift

Bone marrow evaluation must include: 1

• Aspirate with Prussian blue stain for ring sideroblasts
• Biopsy for cellularity, fibrosis, and topography assessment
• Cytogenetic analysis (minimum 20 metaphases by G-banding) - detects clonal abnormalities in 50-60% of MDS cases 6
• Flow cytometry for CD34+ blast enumeration and immunophenotyping 1

Additional Laboratory Studies

• Serum erythropoietin, vitamin B12, RBC folate, serum ferritin to exclude nutritional causes 1
• Copper levels to exclude copper deficiency which mimics MDS with dysplastic features 6
• HIV screening if clinically indicated 1
• Paroxysmal nocturnal hemoglobinuria (PNH) screening if hypoplastic features present 1

Critical Pitfalls to Avoid

• Do not attribute left shift to MDS without excluding reactive causes first - infections and inflammation are far more common 6, 4
• Do not rely on flow cytometry blast percentage for prognostic stratification - morphologic assessment by experienced hematopathologist takes precedence 6
• Do not delay bone marrow examination if any blasts are present - even <1% blasts with dysplasia may indicate MDS 6
• Metamyelocytes alone without dysplasia or cytopenias in the setting of acute illness likely represent reactive marrow response and can be observed after infection resolves 4

Prognostic Implications

• In acute lymphocytic leukemia, left shift paradoxically indicates favorable prognosis (74% vs 42% complete remission duration), possibly reflecting lower leukemia burden 5
• In MDS, presence of immature myeloid cells with dysplasia indicates higher-risk disease requiring International Prognostic Scoring System (IPSS) stratification 6
• In severe infections, higher immature granulocyte counts correlate with disease severity and predict complications, intubation, and mortality 4