What is the further workup for elevated monocytes (monocytosis)?

Workup for Elevated Monocytes (Monocytosis)

For persistent monocytosis without an obvious reactive cause, proceed directly to bone marrow aspiration and biopsy with cytogenetic and molecular testing to exclude chronic myelomonocytic leukemia (CMML) and other myeloid neoplasms. 1

Initial Assessment

Confirm True Monocytosis

• Verify absolute monocyte count ≥0.5 × 10⁹/L (not just relative percentage) on complete blood count with differential 1, 2
• Review peripheral blood smear for monocyte morphology, dysgranulopoiesis, promonocytes, blasts, and neutrophil precursors 1
• Look for rouleaux formation (suggests plasma cell dyscrasia) and morulae in monocytes (suggests ehrlichiosis) 1

Targeted History

• Infectious exposures: Travel history (parasitic infections including Strongyloides), tick exposure (ehrlichiosis), HIV risk factors, hepatitis C 1
• Inflammatory conditions: Symptoms of systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, adult-onset Still's disease 1
• Malignancy history: Known solid tumors or hematologic malignancies 1, 3
• Constitutional symptoms: Fever, night sweats, weight loss, recurrent infections 1
• Family history: Eosinophilia or hematologic malignancies 1

Physical Examination

• Assess spleen size (organomegaly suggests myeloproliferative process) 1
• Examine for cutaneous lesions and lymphadenopathy 1
• Look for signs of organ damage or immunodeficiency 1

Laboratory Workup

Initial Laboratory Studies

• Complete blood count with differential to assess for concurrent cytopenias or other abnormalities 1
• Comprehensive metabolic panel including calcium, albumin, and creatinine 4
• Liver function tests 1
• Peripheral blood smear examination (mandatory) 1

Additional Testing Based on Clinical Context

• If infection suspected: HIV, hepatitis C, ehrlichiosis serology 1
• If inflammatory disease suspected: ESR, CRP, ANA, rheumatoid factor 1
• If plasma cell dyscrasia suspected: Serum protein electrophoresis with immunofixation, serum-free light chains, 24-hour urine collection for electrophoresis and immunofixation 4

Indications for Bone Marrow Evaluation

Proceed to bone marrow aspiration and biopsy if any of the following are present: 1

• Persistent unexplained monocytosis without clear reactive cause
• Absolute monocyte count ≥1 × 10⁹/L sustained over time (particularly concerning for CMML)
• Concurrent cytopenias or other blood count abnormalities
• Constitutional symptoms or organomegaly
• Dysplastic features on peripheral smear

Bone Marrow Studies to Include

• Aspirate and biopsy: Assess marrow cellularity, presence of dysplasia, percentage of blasts (including myeloblasts, monoblasts, and promonocytes) 1
• Special stains: Gomori's silver impregnation for fibrosis 1
• Conventional cytogenetics: Exclude t(9;22) (Philadelphia chromosome/BCR-ABL1), t(5;12), and other clonal abnormalities 1
• Molecular testing: Test for mutations commonly found in CMML (TET2, SRSF2, ASXL1, RAS) 1
• CD138 stains: If plasma cell dyscrasia suspected 4

Key Diagnostic Considerations

Reactive Causes (Most Common)

• Viral infections (HIV, hepatitis C) 1
• Bacterial infections (ehrlichiosis with characteristic leukopenia, thrombocytopenia, elevated transaminases) 1
• Autoimmune disorders (SLE, rheumatoid arthritis, inflammatory bowel disease) 1
• Adult-onset Still's disease 1
• Recovery from bone marrow suppression 1

Clonal/Neoplastic Causes

• CMML: Requires persistent monocytosis ≥1 × 10⁹/L for ≥3 months, <20% blasts in blood/marrow, no Philadelphia chromosome or BCR-ABL1 1
• Acute myeloid leukemia 1
• Myelodysplastic syndromes (though absolute monocyte count typically <1 × 10⁹/L) 1
• Chronic lymphocytic leukemia (elevated monocytes correlate with inferior outcomes) 1
• Solid tumors (CD16+ monocyte expansion is common in metastatic cancer) 3

Clinical Pitfalls to Avoid

• Failing to distinguish relative from absolute monocytosis: Always calculate absolute monocyte count 1
• Not performing comprehensive bone marrow evaluation: This is essential for persistent unexplained monocytosis 1
• Overlooking molecular testing: Critical to exclude specific myeloid neoplasms 1
• Missing underlying infections or malignancies: Can lead to incorrect diagnosis and treatment 1

Risk Stratification

• Sustained monocytosis (at least two measurements over 3 months) significantly increases CMML risk, though diagnosis remains rare (0.1% of individuals with sustained monocytosis) 2
• In primary care settings, monocytosis has low absolute risk for hematological malignancy but highest relative risk for CMML (OR 105.22) 2
• Monocytosis in cancer patients may represent a host immune response, with CD16+ monocytes accounting for up to 46% of total monocytes versus 5% in controls 3