What is the differential diagnosis for elevated monocytes (monocytosis)?

Differential Diagnosis for Elevated Monocytes

Monocytosis has two major categories: reactive (benign) conditions and clonal hematologic malignancies, with chronic myelomonocytic leukemia (CMML) being the primary malignant cause that must be systematically excluded in all cases of persistent elevation. 1, 2

Reactive (Non-Clonal) Causes

Infectious Etiologies

• Chronic infections are the most common infectious triggers, particularly tuberculosis and bacterial endocarditis 2
• Parasitic infections including Strongyloides should be considered, especially with travel history 3
• Ehrlichiosis (E. chaffeensis, E. ewingii) presents with monocytosis alongside characteristic findings of leukopenia, thrombocytopenia, and elevated hepatic transaminases 3

Inflammatory and Autoimmune Conditions

• Adult-onset Still's disease presents with marked leukocytosis including monocytosis, often with WBC counts >15×10⁹ cells/L 2
• Inflammatory bowel disease (Crohn's disease and ulcerative colitis) causes chronic monocyte elevation 2
• Atherosclerosis and coronary artery disease are associated with elevated monocyte counts due to their pathogenic role in plaque formation 2
• Any chronic inflammatory condition can trigger monocyte expansion through persistent cytokine stimulation 2

Malignancy-Associated Reactive Monocytosis

• Solid tumors frequently cause spontaneous elevation of monocytes, particularly metastatic gastrointestinal carcinoma where CD16+ monocytes can account for 46% of total monocytes (versus 5% in controls) 4
• This represents a host immune response to malignancy rather than clonal expansion 4

Recovery States

• Recovery from bone marrow suppression can cause transient monocytosis 1
• Tissue injury of any cause may lead to reactive monocyte elevation 2

Clonal (Neoplastic) Causes

Chronic Myelomonocytic Leukemia (CMML)

CMML is the primary hematologic malignancy causing persistent monocytosis and requires specific WHO 2008 diagnostic criteria: 2

• Persistent peripheral blood monocytosis >1×10⁹/L 2
• Absence of Philadelphia chromosome or BCR-ABL1 fusion gene 2
• <20% blasts in peripheral blood and bone marrow 1, 2
• Common molecular mutations include TET2, SRSF2, ASXL1, and RAS 1, 2

Other Myeloid Neoplasms

• Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase (TK) fusion genes may present with monocytosis on peripheral blood smear 3
• Myelodysplastic syndromes (MDS) can present with monocytosis, though absolute monocyte count typically remains <1×10⁹/L 3, 5
• Acute myeloid leukemia should be considered when blasts are present 1

Diagnostic Algorithm

Initial Evaluation

• Obtain detailed history focusing on: travel exposure, new medications, recurrent infections, family history of eosinophilia or hematologic malignancies, and symptoms of immunodeficiency 3
• Physical examination must assess spleen size, cutaneous lesions, lymphadenopathy, and signs of organ damage 3, 1
• Laboratory studies: CBC with differential, comprehensive metabolic panel, liver function tests, peripheral blood smear examination 3, 1

Peripheral Blood Smear Assessment

Critical morphologic features to evaluate: 1

• Monocyte morphology and presence of dysgranulopoiesis
• Presence of promonocytes or blasts
• Neutrophil precursors
• Rouleaux formation (suggests plasma cell dyscrasia) 3
• Morulae in monocytes (suggests ehrlichiosis) 3

When to Pursue Bone Marrow Evaluation

Bone marrow aspiration and biopsy are indicated when: 1, 2

• Absolute monocyte count >1×10⁹/L persists beyond 3 months without clear reactive cause 2
• Any persistent unexplained monocytosis regardless of duration 1
• Hematologic malignancy is suspected based on other cytopenias or dysplasia 1

Essential Bone Marrow Studies

• Morphologic assessment: percentage of blasts (myeloblasts, monoblasts, promonocytes), dysplasia evaluation 1
• Gomori's silver staining for fibrosis 1
• Conventional cytogenetics to exclude t(9;22), t(5;12), and identify clonal abnormalities 3, 1
• Molecular testing: PCR for BCR-ABL1 fusion gene and mutations in TET2, SRSF2, ASXL1, RAS 3, 1, 2

Additional Testing Based on Clinical Context

• Serum tryptase and vitamin B12 levels if myeloproliferative variant suspected 3
• Serology for Strongyloides and other parasites with appropriate travel history 3
• Antineutrophil cytoplasmic antibodies and antinuclear antibodies if vasculitis suspected 3
• Flow cytometry to assess monocyte repartitioning, which can distinguish CMML from reactive causes 6

Critical Pitfalls to Avoid

• Failing to distinguish absolute versus relative monocytosis can lead to misdiagnosis; always calculate absolute monocyte count 1
• Not performing comprehensive bone marrow evaluation in persistent unexplained monocytosis delays diagnosis of CMML 1
• Overlooking molecular testing may miss specific myeloid neoplasms requiring targeted therapy 1
• Missing underlying infections or malignancies by attributing monocytosis to benign causes without adequate workup 1
• Diagnostic confusion can occur when monocytosis is present but <1×10⁹/L in MDS patients who later progress to CMML; these cases may represent a distinct subgroup requiring close monitoring 5