What diagnosis should be considered in a patient with an otherwise normal complete blood count (CBC) and differential but isolated monocytosis?

Isolated Monocytosis: Differential Diagnosis

In a patient with an otherwise normal CBC except for isolated elevated absolute monocytes (≥1.0 × 10⁹/L), the most important diagnoses to consider are chronic myelomonocytic leukemia (CMML), reactive causes (infections, inflammatory conditions), and other myeloid neoplasms, with CMML being the primary concern when monocytosis persists beyond 3 months without an identifiable reactive etiology. 1

Initial Diagnostic Approach

Define True Monocytosis

• Confirm absolute monocytosis ≥1.0 × 10⁹/L (≥1000/μL), not just relative percentage elevation, as this is the WHO diagnostic threshold for clinically significant monocytosis 1, 2
• Verify the finding is sustained over time, as transient monocytosis is common with reactive conditions 3

Evaluate for Reactive Causes First

Infectious etiologies:

• Tuberculosis and bacterial endocarditis are common bacterial causes 2
• Viral infections including HIV, hepatitis C, and other viral syndromes can produce monocytosis clinically indistinguishable from primary hematologic disorders 2
• Ehrlichiosis presents with monocytosis alongside leukopenia, thrombocytopenia, and elevated hepatic transaminases; examine peripheral smear for morulae within monocytes 2
• Parasitic infections, particularly Strongyloides in patients with travel history 2

Inflammatory and autoimmune conditions:

• Adult-onset Still's disease produces striking leukocytosis with monocytosis, typically WBC >15×10⁹/L 2
• Inflammatory bowel disease (Crohn's disease and ulcerative colitis) causes chronic monocytosis 2
• Systemic lupus erythematosus and rheumatoid arthritis frequently elevate monocyte counts 2

Other reactive causes:

• Recovery from bone marrow suppression 1
• Solid tumors 1
• Atherosclerosis and cardiovascular disease 2

When to Suspect Clonal/Malignant Monocytosis

Red Flags Requiring Bone Marrow Evaluation

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

• Persistent absolute monocyte count ≥1.0 × 10⁹/L for ≥3 months without clear reactive cause
• Accompanying cytopenias or other blood count abnormalities
• Constitutional symptoms (weight loss, fever, night sweats) or organomegaly (splenomegaly)
• Dysplastic features on peripheral blood smear (dysgranulopoiesis, promonocytes, immature neutrophil precursors)

Primary Hematologic Diagnoses to Consider

Chronic Myelomonocytic Leukemia (CMML):

• Most important diagnosis to exclude in persistent monocytosis 1, 2
• WHO 2008 diagnostic criteria require: 1, 2
  • Persistent peripheral blood monocytosis ≥1.0 × 10⁹/L
  • No Philadelphia chromosome or BCR-ABL1 fusion gene
  • <20% blasts in peripheral blood and bone marrow
  • Dysplasia in one or more myeloid lineages
• The absence of TET2, SRSF2, or ASXL1 mutations has ≥90% negative predictive value for CMML 4
• Peripheral smear shows dysgranulopoiesis, promonocytes, and neutrophil precursors 2

Myelodysplastic Syndromes (MDS):

• Can present with monocytosis, though absolute monocyte count typically remains <1.0 × 10⁹/L 1
• The combination of anemia, leukopenia, and elevated monocyte percentage suggests dysplastic bone marrow disorders 1
• MDS with monocytosis may represent a distinct subgroup with better survival than typical RAEB but higher risk of progression to CMML 5, 6
• Bone marrow blasts 5-9% define RAEB-1; 10-19% define RAEB-2 1

Other Myeloid Neoplasms:

• Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusion genes (PDGFRA, PDGFRB, FGFR1 rearrangements) may present with monocytosis 1
• Chronic myeloid leukemia (CML) presents with leukocytosis, basophilia, and immature granulocytes; requires exclusion of BCR-ABL1 7
• Acute myeloid leukemia with monocytic differentiation (AML-M4/M5) 4

Chronic Lymphocytic Leukemia (CLL):

• Elevated absolute monocyte count in CLL correlates with inferior outcomes and accelerated disease progression 1

Comprehensive Diagnostic Workup

Essential Laboratory Studies

Peripheral blood evaluation: 1, 2

• Complete blood count with differential to confirm absolute monocyte count and assess for concurrent cytopenias
• Peripheral blood smear examination for:
  • Monocyte morphology
  • Dysgranulopoiesis
  • Promonocytes and blasts
  • Neutrophil precursors
  • Rouleaux formation (suggests plasma cell dyscrasia)
  • Morulae in monocytes (suggests ehrlichiosis)

Additional blood tests: 1

• Comprehensive metabolic panel including calcium, albumin, creatinine
• Liver function tests
• If plasma cell dyscrasia suspected: serum protein electrophoresis with immunofixation, serum-free light chains

Bone Marrow Evaluation (When Indicated)

Bone marrow aspiration and biopsy should include: 1, 2

• Morphology assessment for cellularity, dysplasia, and blast percentage (including myeloblasts, monoblasts, promonocytes)
• Gomori silver impregnation staining for reticulin fibrosis
• CD138 stains if plasma cell dyscrasia suspected

Cytogenetic analysis: 1, 2

• Conventional cytogenetic analysis (chromosome banding analysis) to:
  • Exclude t(9;22) Philadelphia chromosome (CML)
  • Exclude t(5;12) translocation
  • Identify other clonal abnormalities

Molecular testing: 1, 2, 4

• BCR-ABL1 fusion gene testing (to exclude CML)
• Testing for PDGFRA and PDGFRB rearrangements if eosinophilia present
• Mutations commonly found in CMML: TET2, SRSF2, ASXL1, RAS genes
• Consider JAK2 V617F mutation testing

Clinical Pearls and Common Pitfalls

Critical Distinctions

Absolute vs. relative monocytosis:

• Always calculate absolute monocyte count; relative percentage can be misleading with neutropenia 2
• Monocytosis is defined as absolute count ≥1.0 × 10⁹/L, not percentage 1

Timing matters:

• Sustained monocytosis for ≥3 months without evidence of infection, inflammation, or malignancy warrants hematology referral 1
• In primary care, sustained monocytosis (at least two measurements over 3 months) increases CMML risk, though absolute risk remains low (0.1%) 3

Age considerations:

• Monocyte counts and prevalence of monocytosis increase with advancing age 8
• Older individuals with monocytosis more frequently carry clonal hematopoiesis (50.9% vs 35.5% in controls) 8
• Persistent monocytosis over 4 years is associated with 63% prevalence of clonal hematopoiesis 8

Risk Stratification

Higher concern for malignancy when: 3

• Monocytosis is sustained over multiple measurements
• Clinical presentation includes constitutional symptoms, organomegaly, or other cytopenias
• Peripheral smear shows dysplastic features
• Patient has unexplained symptoms despite treatment of potential reactive causes

Lower concern when:

• Single isolated finding without other abnormalities
• Clear reactive etiology identified (active infection, inflammatory condition)
• Monocytosis resolves with treatment of underlying condition

Avoid These Mistakes

• Do not dismiss persistent monocytosis as "reactive" without thorough evaluation for underlying causes 1
• Do not delay bone marrow evaluation in patients with sustained monocytosis ≥3 months without identifiable cause 1, 2
• Do not rely solely on monocyte percentage; always calculate absolute count 2
• Do not overlook the need for molecular testing, as it significantly aids in distinguishing CMML from reactive causes 4
• Do not assume monocytosis in older adults is simply age-related without excluding clonal disorders 8