What does the presence of metamyelocytes on a peripheral blood smear indicate and how should it be evaluated and managed?

Metamyelocytes in Peripheral Blood

The presence of metamyelocytes in peripheral blood represents an abnormal "left shift" indicating premature release of immature granulocytic precursors from the bone marrow, requiring immediate evaluation with complete blood count, peripheral smear review for dysplasia and blasts, and bone marrow examination if cytopenias, persistent unexplained findings, or suspicion of hematologic malignancy exists. 1

Pathophysiological Significance

Metamyelocytes are immature granulocytic cells that normally mature within the bone marrow before release as mature neutrophils. 1 Their presence in peripheral blood indicates:

• Myelodysplastic syndromes (MDS) - particularly when accompanied by dysplastic features such as abnormal nuclear configuration or cytoplasmic granulation 1
• Myeloproliferative neoplasms - including atypical CML and chronic myelomonocytic leukemia (CMML) where metamyelocytes may comprise a significant percentage of the differential 1
• Reactive processes - severe infections, inflammation, tissue necrosis, or severe hemorrhage can trigger significant left shift 1

Immediate Diagnostic Workup

Complete Blood Count and Differential

• Perform 500-cell differential count to ensure reliable determination of metamyelocyte percentage and absolute count 2
• Assess for cytopenias (anemia, thrombocytopenia, neutropenia) which suggest MDS or bone marrow failure 1
• Evaluate for monocytosis >1×10⁹/L which, combined with <5% blasts, suggests CMML 2

Peripheral Blood Smear Examination

• Look for dysplastic features in all cell lines - hypogranular neutrophils, pseudo-Pelger-Huët anomaly, oval macrocytes, giant platelets 1
• Check for blasts - their presence indicates more advanced disease requiring urgent hematology consultation 1, 2
  • Blasts ≥20% indicate acute leukemia 2
  • Blasts 2-4% with MDS features indicate RAEB-1 2
  • Blasts <1% suggest aplastic anemia rather than MDS 2
• Assess for Auer rods which indicate RAEB-2 even with lower blast counts 3

Bone Marrow Examination Indications

Bone marrow aspiration and biopsy with cytogenetics are mandatory when: 1, 2

• Persistent unexplained cytopenias exist for >6 months 1
• Suspicion of hematologic malignancy based on peripheral blood findings 1
• Dysplastic features are present on peripheral smear 1
• Any circulating blasts are identified (requires same-day hematology consultation) 2

The bone marrow examination should assess: 1

• Cellularity (hypercellular in myeloproliferative neoplasms, variable in MDS)
• Dysplasia in erythroid, myeloid, and megakaryocytic lineages (≥10% of cells required for MDS diagnosis) 3
• Blast percentage (morphologic count takes precedence over flow cytometry) 2
• Megakaryocyte morphology (small hypolobated in MDS vs. large hyperlobulated in essential thrombocythemia) 3
• Cytogenetics (minimum 20 metaphases) - chromosomal abnormalities occur in 50-60% of MDS cases 2

Distinguishing Malignant from Reactive Causes

Features Suggesting Myelodysplastic Syndrome

• Persistent cytopenias for ≥6 months with dysplastic features 1, 4
• Multilineage dysplasia (≥10% of cells in ≥2 myeloid lineages) 3
• Specific cytogenetic abnormalities - del(5q), del(7q), +8, del(20q), complex karyotype 3
• Ring sideroblasts ≥15% of erythroid precursors 3

Features Suggesting Reactive Process

• Acute onset with identifiable trigger (infection, inflammation) 1
• Resolution with treatment of underlying condition 1
• Absence of dysplastic features in other cell lines 1
• Normal cytogenetics if bone marrow performed 2

Critical Pitfalls to Avoid

• Do not diagnose MDS prematurely - if only unilineage dysplasia is present without increased blasts or specific cytogenetic abnormalities, observe for 6 months with repeat evaluation 3, 1
• Exclude mimicking conditions - vitamin B12/folate deficiency (causes giant metamyelocytes), copper deficiency, medications, recent infections 4, 5, 6
• Ensure blood count stability for 4-6 weeks to exclude transient causes before pursuing extensive workup 4
• Use CD34 immunohistochemistry in hypocellular or fibrotic bone marrow where morphologic blast assessment is inadequate 2

Clinical Significance and Follow-Up

If Malignancy Suspected

• Immediate hematology referral for any patient with circulating blasts 2
• Risk stratification using International Prognostic Scoring System (IPSS) for MDS based on blast percentage, cytogenetics, and cytopenias 2
• Higher peripheral blast percentages correlate with shorter survival and increased risk of leukemic transformation 2

If Reactive Process Confirmed

• Treat underlying condition (infection, inflammation) 1
• Repeat CBC in 2-4 weeks to document resolution 1
• Transient appearance of metamyelocytes should resolve with treatment of the underlying condition 1

If Findings Equivocal

• Observation period of 6 months with repeat bone marrow investigation to ensure clinical and morphologic features persist 3
• Monitor CBC with differential every 3-6 months 4
• Persistent circulation of metamyelocytes without obvious cause warrants close follow-up as it may represent early manifestation of a myeloid neoplasm 1