What is the recommended work‑up for an asymptomatic adult with persistent monocytosis for two years?

Work-Up for Asymptomatic Monocytosis Persisting for 2 Years

For an adult with asymptomatic monocytosis lasting 2 years, you must perform a comprehensive bone marrow evaluation with cytogenetics and molecular testing to exclude chronic myelomonocytic leukemia (CMML), as persistent monocytosis ≥1×10⁹/L for >3 months carries significant risk of underlying clonal hematologic malignancy. 1, 2

Initial Laboratory Confirmation

Confirm absolute monocytosis by calculating the absolute monocyte count from a complete blood count with differential—the diagnostic threshold is >1×10⁹/L (not just a relative percentage increase). 1, 2, 3

Essential Baseline Testing

• Complete blood count with manual differential and reticulocyte count to assess for concurrent cytopenias (hemoglobin <12 g/dL, platelets <100×10⁹/L, neutropenia) that would increase suspicion for myeloid malignancy. 4, 1

• Comprehensive metabolic panel including calcium, albumin, creatinine, and liver function tests to evaluate for organ involvement and metabolic derangements. 1, 2

• Peripheral blood smear examination is critical—specifically look for dysgranulopoiesis (pseudo-Pelger-Huët anomaly, hypogranular neutrophils), promonocytes, blasts, immature myeloid precursors, and abnormal monocyte morphology. 1, 2, 3

Bone Marrow Evaluation—Mandatory in This Case

Given 2 years of persistent monocytosis, bone marrow aspiration and biopsy are indicated regardless of other findings. 1, 2, 3 The duration alone (>3 months) meets criteria for invasive evaluation, and the 2-year persistence substantially increases pre-test probability of CMML.

Required Bone Marrow Studies

• Morphologic assessment evaluating cellularity, dysplasia in all three lineages, blast percentage (including myeloblasts, monoblasts, and promonocytes—must be <20% to diagnose CMML), and granulocytic hyperplasia. 2, 3

• Gomori's silver impregnation staining to assess for bone marrow fibrosis. 1, 3

• Conventional cytogenetic analysis (karyotype) to identify clonal abnormalities—specifically exclude Philadelphia chromosome t(9;22), BCR-ABL1 fusion, and t(5;12) translocation. 1, 2, 3 The most common CMML cytogenetic abnormalities are chromosome 7 lesions (monosomy 7 or deletions), trisomy 8, and complex karyotypes. 2

• Molecular testing panel including BCR-ABL1 fusion (to definitively exclude chronic myeloid leukemia), PDGFRA and PDGFRB rearrangements (especially if eosinophilia present), and targeted sequencing for TET2, SRSF2, ASXL1, and RAS pathway mutations—approximately 93% of CMML patients harbor at least one of these mutations. 2, 3, 5 The absence of TET2, SRSF2, or ASXL1 mutations has ≥90% negative predictive value for CMML. 5

• Flow cytometry immunophenotyping to identify aberrant monocytic markers such as abnormal CD11b/HLA-DR expression, altered CD36/CD14 patterns, or CD56 overexpression. 3

Diagnostic Criteria for CMML

CMML diagnosis requires all of the following 2, 3:

1. Persistent peripheral blood monocytosis >1×10⁹/L
2. Absence of Philadelphia chromosome and BCR-ABL1 fusion gene
3. No PDGFRA or PDGFRB rearrangements
4. Blasts <20% in peripheral blood and bone marrow
5. Either dysplasia in ≥1 hematopoietic lineage, a clonal cytogenetic abnormality, or monocytosis persisting >3 months without another identifiable cause

CMML is subclassified as:

• Myelodysplastic CMML (MD-CMML): WBC <13×10⁹/L
• Myeloproliferative CMML (MP-CMML): WBC ≥13×10⁹/L 4, 2, 3

Additional Workup to Exclude Reactive Causes

While the 2-year duration makes reactive causes less likely, you should still document:

• Targeted history focusing on chronic infections (tuberculosis, endocarditis, HIV, hepatitis C), autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease), solid tumors, and recent splenectomy. 1, 2

• Physical examination measuring spleen size (distance from costal margin), assessing for lymphadenopathy, cutaneous lesions (which may indicate CMML), and constitutional symptoms (fever, weight loss, night sweats). 2, 3

• Serum protein electrophoresis with immunofixation and serum-free light chains if plasma cell dyscrasia is suspected based on other findings. 2

Follow-Up Strategy if Initial Workup is Indeterminate

If bone marrow shows only mild dysplasia, normal karyotype, and ≤15% ring sideroblasts without meeting definitive CMML criteria 3:

• Observe without definitive myelodysplastic syndrome diagnosis for 6 months
• Repeat bone marrow examination at 6 months
• Perform serial complete blood counts every 3 months

Critical Pitfalls to Avoid

• Do not rely on relative monocyte percentage alone—always calculate absolute monocyte count, as relative monocytosis can be misleading. 1, 3

• Do not delay bone marrow biopsy in persistent monocytosis lasting >3-4 months—the 2-year duration in this case makes bone marrow evaluation mandatory regardless of other findings. 1, 2, 3

• Do not omit BCR-ABL1 testing—atypical presentations of chronic myeloid leukemia can mimic CMML. 2, 3

• Do not attribute persistent monocytosis to benign causes without comprehensive evaluation—sustained monocytosis over 3-4 months significantly increases malignancy risk and warrants hematology referral. 3, 6

• Do not perform incomplete molecular workup—the combination of negative TET2, SRSF2, and ASXL1 mutations has high negative predictive value and can help avoid misdiagnosis. 5

Risk Stratification Data

Population-based data show that monocytosis in primary care carries an odds ratio of 105.22 for CMML (though absolute risk remains low at 0.1% even with sustained monocytosis). 6 However, in patients with monocytosis persisting 2 years, the pre-test probability is substantially higher, and approximately 50-63% of older individuals with persistent monocytosis carry clonal hematopoiesis mutations. 7