What is the differential diagnosis for a patient with a monocyte predominant differential cell count on a Complete Blood Count (CBC)?

Differential Diagnosis for Monocyte Predominant Differential Cell Count on CBC

When monocytosis (absolute monocyte count ≥1.0 × 10⁹/L) is identified on CBC, the differential diagnosis must distinguish between reactive causes—including infections (tuberculosis, bacterial endocarditis, ehrlichiosis, HIV, hepatitis C), inflammatory/autoimmune diseases (adult-onset Still's disease, inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis), and recovery from bone marrow suppression—versus clonal hematologic malignancies, most critically chronic myelomonocytic leukemia (CMML), which requires immediate bone marrow evaluation if monocytosis persists ≥3 months without clear reactive etiology. 1, 2, 3

Reactive (Non-Clonal) Causes

Infectious Etiologies

• Bacterial infections: Tuberculosis and bacterial endocarditis are classic causes of persistent monocytosis 2
• Viral infections: HIV and hepatitis C produce monocytosis that can be clinically indistinguishable from primary hematologic disorders 1, 2
• Ehrlichiosis (E. chaffeensis, E. ewingii): Presents with monocytosis alongside leukopenia, thrombocytopenia, and elevated hepatic transaminases; look for morulae within monocytes on peripheral smear 1, 2
• Parasitic infections: Particularly Strongyloides in patients with travel history 1, 2

Inflammatory and Autoimmune Diseases

• Adult-onset Still's disease: Produces striking leukocytosis with monocytosis, typically WBC >15×10⁹/L 1, 2
• Inflammatory bowel disease (Crohn's disease, ulcerative colitis): Causes chronic monocytosis 1, 2
• Systemic lupus erythematosus: Frequently associated with elevated monocyte counts 1, 2
• Rheumatoid arthritis: Associated with increased monocyte percentages 1, 2

Other Reactive Causes

• Recovery from bone marrow suppression: Post-chemotherapy or following resolution of infection 1
• Solid tumors: Can produce reactive monocytosis 3
• Cardiovascular disease: Atherosclerosis and hypertension correlate with increased monocyte counts, particularly CD14++CD16+ subpopulations 2

Clonal (Hematologic Malignancy) Causes

Chronic Myelomonocytic Leukemia (CMML)

CMML is the prototypical myeloid neoplasm with monocytosis and must be excluded in persistent cases. 3, 4

WHO 2008 Diagnostic Criteria for CMML 3:

• 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

Key distinguishing features 3:

• Presence of dysgranulopoiesis, promonocytes, and neutrophil precursors on peripheral smear
• Bone marrow shows granulocytic hyperplasia and dysplasia in multiple lineages
• Flow cytometry may detect aberrancies: abnormal CD11b/HLA-DR, CD36/CD14, abnormal intensity of CD13, CD14, CD16, CD33, overexpression of CD56 (though none are specific for CMML)

Other Myeloid Neoplasms

• Juvenile myelomonocytic leukemia (JMML): Pediatric condition associated with SH2B3 mutations; requires physical examination with attention to liver and spleen size every 3-4 months during infancy 3
• Acute myeloid leukemia (AML): Particularly AML with monocytic or myelomonocytic differentiation; monoblasts and promonocytes (but not abnormal monocytes) are counted as blast equivalents 3
• Myelodysplastic syndromes (MDS): Can present with monocytosis, though absolute monocyte count typically remains <1×10⁹/L 1
• Chronic myeloid leukemia (CML): May show monocytosis alongside characteristic myelocyte "peak" and basophilia 5

Lymphoid Malignancies

• Chronic lymphocytic leukemia (CLL): Elevated absolute monocyte count correlates with inferior outcomes and accelerated disease progression 1

Genetic Predisposition Syndromes (Pediatric)

Multiple inherited bone marrow failure syndromes and predisposition conditions require CBC monitoring every 3-12 months 3:

• Fanconi anemia, Shwachman-Diamond syndrome, telomere biology disorders
• GATA2, RUNX1, DDX41, ANKRD26, ETV6, CEBPA mutations
• ERG-associated predisposition (recently linked to cytopenia, lymphedema, and hematologic malignancy)

Diagnostic Algorithm

Initial Evaluation

Step 1: Confirm absolute monocytosis 1, 2

• Calculate absolute monocyte count (not just percentage)
• Monocytosis defined as ≥1.0 × 10⁹/L

Step 2: Detailed history 1, 2

• Travel exposure (parasitic infections)
• New medications
• Recurrent infections
• Family history of hematologic malignancies or eosinophilia
• Constitutional symptoms (fever, night sweats, weight loss)
• Chronic inflammatory conditions

Step 3: Physical examination 3, 1, 2

• Spleen size (splenomegaly suggests CMML or other myeloproliferative neoplasm)
• Cutaneous lesions (CMML can present with skin involvement)
• Lymphadenopathy
• Signs of organ damage

Step 4: Laboratory studies 3, 1, 2

• Complete blood count with manual differential to assess for:
  • Concurrent cytopenias (suggests bone marrow pathology)
  • Basophilia (suggests CML if ≥200/mm³)
  • Eosinophilia
  • Thrombocytosis or thrombocytopenia
• Peripheral blood smear examination for:
  • Monocyte morphology
  • Dysgranulopoiesis
  • Promonocytes, blasts, neutrophil precursors
  • Rouleaux formation (suggests plasma cell dyscrasia)
  • Morulae in monocytes (suggests ehrlichiosis)
• Comprehensive metabolic panel, liver function tests 1

Indications for Bone Marrow Evaluation

Bone marrow aspiration and biopsy are mandatory when 3, 1, 2:

• Persistent unexplained monocytosis without clear reactive cause
• Absolute monocyte count ≥1×10⁹/L sustained for ≥3 months
• Concurrent cytopenias or other blood count abnormalities
• Constitutional symptoms or organomegaly
• Dysplastic features on peripheral smear

Bone marrow workup must include 3:

• Aspirate and biopsy with morphology assessment
• Conventional cytogenetic analysis to exclude t(9;22), t(5;12), and identify clonal abnormalities
• Molecular testing for BCR-ABL1 fusion gene (to exclude CML)
• Testing for PDGFRA and PDGFRB rearrangements if eosinophilia present
• Bone marrow biopsy staining: hematoxylin-eosin, CD34+ immunostaining, CD68R and CD163 for monocytic cells, Gomori's silver impregnation for fibrosis
• Consider molecular panel for mutations commonly found in CMML: SRSF2, TET2, ASXL1, JAK2, RAS 3, 1, 2

Additional Testing Based on Clinical Context

• If plasma cell dyscrasia suspected 3: Serum protein electrophoresis with immunofixation, serum-free light chains, 24-hour urine collection for electrophoresis and immunofixation, CD138 stains
• If pediatric patient with family history: Consider genetic testing for hereditary bone marrow failure syndromes 3

Critical Pitfalls to Avoid

1. Failing to calculate absolute monocyte count: Relative monocytosis (elevated percentage) without absolute monocytosis (≥1.0 × 10⁹/L) does not meet criteria for true monocytosis 1, 2

2. Not performing comprehensive bone marrow evaluation in persistent unexplained monocytosis: Delaying bone marrow biopsy when indicated can miss early CMML or other myeloid neoplasms 1, 2

3. Missing underlying infections or malignancies: Always exclude reactive causes before attributing monocytosis to primary hematologic disorder 3, 1, 2

4. Overlooking molecular testing: BCR-ABL1 testing is mandatory to exclude CML; PDGFRA/PDGFRB testing required if eosinophilia present 3

5. Not recognizing CMML variants: The distinction between myelodysplastic-type (WBC <13×10⁹/L) and myeloproliferative-type (WBC ≥13×10⁹/L) CMML affects prognosis and treatment approach 3

6. Inadequate follow-up: If initial workup is negative but monocytosis persists, repeat CBC every 2-4 weeks and consider bone marrow evaluation if sustained ≥3 months 1