What is the differential diagnosis of monocytosis?

Differential Diagnosis of Monocytosis

Monocytosis (absolute monocyte count >1.0 × 10⁹/L) requires systematic evaluation to distinguish between reactive causes—particularly infections, inflammatory conditions, and solid tumors—and clonal hematologic disorders, most importantly chronic myelomonocytic leukemia (CMML), which carries significant mortality risk. 1, 2

Reactive (Non-Clonal) Causes

Infectious Etiologies

• Chronic bacterial infections: Tuberculosis and bacterial endocarditis are classic causes 3
• Viral infections: HIV, hepatitis C, and post-transfusion CMV (occurring approximately 1 month after transfusion with high fever and atypical lymphocytosis) 1, 2, 3
• Ehrlichiosis: Presents with monocytosis alongside leukopenia, thrombocytopenia, elevated hepatic transaminases, and morulae visible within monocytes on peripheral smear 1, 2, 3
• Parasitic infections: Particularly Strongyloides in patients with travel history 3

Inflammatory and Autoimmune Disorders

• Systemic lupus erythematosus: Frequently produces monocytosis 1, 2, 3
• Adult-onset Still's disease: Produces striking leukocytosis with monocytosis, typically WBC >15×10⁹/L 1, 3
• Inflammatory bowel disease: Both Crohn's disease and ulcerative colitis cause chronic monocytosis 1, 3
• Rheumatoid arthritis: Associated with increased monocyte percentages 1, 3

Other Reactive Causes

• Solid tumors: Can produce reactive monocytosis 4, 1
• Recovery from bone marrow suppression: Represents physiologic transient monocytosis 1
• Cardiovascular disease: Atherosclerosis and hypertension correlate with increased monocyte counts, particularly CD14++CD16+ populations 3
• Allergic disorders and drug reactions: Less common but recognized causes 2

Clonal (Neoplastic) Causes

Chronic Myelomonocytic Leukemia (CMML)

CMML is the prototypical malignant cause requiring immediate recognition due to poor prognosis. 4, 1, 2 WHO 2008 diagnostic criteria include:

• Persistent peripheral blood monocytosis >1×10⁹/L 4
• No Philadelphia chromosome or BCR-ABL1 fusion gene 4
• No rearrangement of PDGFRA or PDGFRB (must be specifically excluded with eosinophilia) 4
• Less than 20% blasts in peripheral blood and bone marrow (includes myeloblasts, monoblasts, and promonocytes) 4
• At least one of: (a) dysplasia in one or more cell lines, (b) acquired clonal cytogenetic or molecular genetic abnormality, or (c) persistence of monocytosis ≥3 months with no evidence of reactive causes 4

Myelodysplastic Syndromes (MDS)

• Can present with monocytosis, though absolute monocyte count typically remains <1×10⁹/L 1, 2
• Presence of dyserythropoiesis, macrocytosis, pseudo Pelger-Huet anomaly, or predominance of small megakaryocytes with monolobated nuclei suggests MDS rather than CMML 4, 2

Acute Myeloid Leukemia with Monocytic Differentiation

• Presents with monocytosis and typically more acute clinical presentation 1

Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Fusion Genes

• May present with neutrophilia, basophilia, thrombocytosis, monocytosis, and myeloid immaturity on peripheral smear 1, 2

Algorithmic Diagnostic Approach

Step 1: Confirm True Monocytosis

• Calculate absolute monocyte count from CBC with differential—never rely on percentage alone, as relative monocytosis without absolute elevation does not warrant extensive workup 1, 2, 3

Step 2: Targeted History

• Travel exposure (parasitic infections, endemic tuberculosis) 1, 2, 3
• New medications or drug reactions 1, 2
• Recurrent infections (HIV, hepatitis C, ehrlichiosis) 1, 2, 3
• Family history of hematologic malignancies 1, 3
• Constitutional symptoms (fever, night sweats, weight loss) 1, 2
• Chronic inflammatory conditions (IBD, rheumatoid arthritis, SLE) 1, 3

Step 3: Physical Examination

• Spleen size: Mild splenomegaly may occur in younger patients with ITP, but moderate/massive splenomegaly suggests alternative diagnosis 4, 1, 2
• Cutaneous lesions: May indicate CMML or systemic disease 4
• Lymphadenopathy and hepatomegaly: Suggests lymphoproliferative disorder or systemic disease 4, 1, 2

Step 4: Peripheral Blood Smear Examination

Critical step that must be performed by qualified hematologist or pathologist 1, 2, 3:

• Monocyte morphology and presence of dysgranulopoiesis 4, 1
• Promonocytes, blasts, and neutrophil precursors 4, 1
• Rouleaux formation (suggests plasma cell dyscrasia) 1, 2
• Morulae in monocytes (diagnostic of ehrlichiosis) 1, 2, 3
• Schistocytes (suggests TTP-HUS) 4

Step 5: Initial Laboratory Testing

• Comprehensive metabolic panel including calcium, albumin, creatinine, liver function tests 1
• Serum protein electrophoresis with immunofixation and serum-free light chains if plasma cell dyscrasia suspected 1

Step 6: Bone Marrow Evaluation Indications

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

• Persistent unexplained monocytosis without clear reactive cause
• Absolute monocyte count ≥1×10⁹/L sustained over 3-4 months
• Concurrent cytopenias or other blood count abnormalities
• Constitutional symptoms or organomegaly
• Dysplastic features on peripheral smear

Bone marrow workup must include 4:

• Aspiration for dysplasia assessment in myeloid lineages, granulocytic hyperplasia, and blast percentage (including myeloblasts, monoblasts, promonocytes)
• Biopsy with hematoxylin-eosin staining, immunostaining for CD34+ and monocytic cells (CD68R and CD163)
• Gomori's silver impregnation for fibrosis 4, 1, 3

Step 7: Cytogenetic and Molecular Testing

Conventional cytogenetic analysis to 4, 1, 2, 3:

• Identify clonal abnormalities (most frequent: chromosome 7 abnormalities, trisomy 8, complex karyotype)
• Exclude t(9;22) characteristic of chronic myeloid leukemia
• Exclude t(5;12) characteristic of MDS/MPN with eosinophilia

Molecular assays 4, 1, 2, 3:

• BCR-ABL1 fusion gene to definitively exclude chronic myeloid leukemia if t(9;22) negative
• PDGFRA and PDGFRB rearrangement if eosinophilia present and t(5;12) negative
• Mutations in TET2, SRSF2, ASXL1, NRAS, KRAS, CBL, JAK2 (93% of CMML patients carry at least one somatic mutation in recurrently mutated genes)

Critical Clinical Pitfalls

Failing to calculate absolute monocyte count leads to unnecessary workup for relative monocytosis or missed diagnoses when percentage appears normal but absolute count is elevated 1, 2

Attributing monocytosis solely to inflammatory conditions without excluding infectious causes (particularly ehrlichiosis, CMV, tuberculosis) delays appropriate antimicrobial therapy 1, 2, 3

Not performing bone marrow evaluation for persistent monocytosis (≥3-4 months) delays diagnosis of CMML and other treatable malignancies, directly impacting mortality 4, 1, 2

Overlooking the requirement to exclude reactive causes before diagnosing CMML—WHO criteria specifically require ruling out infections, inflammation, and solid tumors 4

Missing dysplastic features on peripheral smear by not having qualified hematologist/pathologist review—this is paramount to distinguishing reactive from neoplastic monocytosis 4, 1, 2