What is the differential diagnosis (DDX) of monocytosis?

Differential Diagnosis of Monocytosis

Monocytosis (absolute monocyte count >1.0 × 10⁹/L) results from either reactive conditions or clonal hematologic disorders, with chronic myelomonocytic leukemia (CMML) being the prototypical malignant cause requiring persistent monocytosis, absence of BCR-ABL1 fusion, and <20% blasts. 1, 2

Reactive (Non-Clonal) Causes

Infectious Etiologies

• Chronic infections: Tuberculosis, endocarditis, and parasitic infections (particularly Strongyloides) commonly produce monocytosis 2, 1
• Viral infections: HIV, hepatitis C, and post-transfusion CMV (presenting ~1 month after transfusion with fever, atypical lymphocytosis, and mild transaminase elevations) 2, 1
• Ehrlichiosis (E. chaffeensis, E. ewingii): Presents with monocytosis alongside leukopenia, thrombocytopenia, elevated hepatic transaminases, and morulae visible within monocytes on peripheral smear 1, 2

Inflammatory and Autoimmune Conditions

• Systemic lupus erythematosus and other autoimmune disorders frequently cause monocytosis 2, 1
• Adult-onset Still's disease demonstrates monocytosis as part of its inflammatory profile 2, 1
• Inflammatory bowel disease and rheumatoid arthritis are associated with elevated monocyte counts 2, 1

Other Reactive Causes

• Recovery from bone marrow suppression represents a physiologic cause of transient monocytosis 2
• Solid tumors can produce reactive monocytosis 2
• Allergic disorders and drug reactions are less common but recognized causes 2

Clonal (Neoplastic) Causes

Chronic Myelomonocytic Leukemia (CMML)

• Diagnostic criteria (WHO 2008): Persistent peripheral blood monocytosis (≥1.0 × 10⁹/L), no Philadelphia chromosome or BCR-ABL1 fusion gene, <20% blasts in peripheral blood and bone marrow 1, 2
• Molecular signature: Absence of TET2, SRSF2, or ASXL1 mutation has ≥90% negative predictive value for CMML 3
• Flow cytometry: Monocyte repartitioning can distinguish CMML from reactive causes 4

Myelodysplastic Syndromes (MDS)

• MDS can present with monocytosis, though absolute monocyte count typically remains <1.0 × 10⁹/L 1, 2
• Morphologic clues: Dyserythropoiesis, macrocytosis, pseudo Pelger-Huet anomaly, or predominance of small megakaryocytes with monolobated nuclei suggest MDS rather than other entities 5, 2

Myeloproliferative Neoplasms (MPN)

• MDS/MPN overlap syndromes: Chronic myelomonocytic leukemia, clonal cytopenia with monocytosis of undetermined significance, clonal monocytosis of undetermined significance 5
• Myeloid/lymphoid neoplasms with tyrosine kinase fusion genes: May present with neutrophilia, basophilia, thrombocytosis, monocytosis, and myeloid immaturity 1, 2
• Essential thrombocythemia: Monocytosis may be present but is not a defining feature 5

Acute Leukemias

• Acute myeloid leukemia with monocytic differentiation presents with monocytosis and typically more acute clinical presentation 2
• Acute myelomonocytic leukemia can present with mature monocytosis 3

Lymphoproliferative Disorders

• Chronic lymphocytic leukemia (CLL): Elevated absolute monocyte count correlates with inferior outcomes and accelerated disease progression 1
• Marginal zone lymphomas: Small monoclonal component may be detected; differential diagnosis from lymphoplasmacytic lymphoma may be necessary 5

Diagnostic Approach Algorithm

Step 1: Confirm Absolute Monocytosis

• Calculate absolute monocyte count from complete blood count with differential (not just percentage) 2, 1
• Threshold: >1.0 × 10⁹/L defines monocytosis per WHO criteria 1

Step 2: Assess for Reactive Causes

• History: Travel exposure, new medications, recurrent infections, constitutional symptoms (fever, night sweats, weight loss), bleeding or bruising 1, 2
• Physical examination: Spleen size, cutaneous lesions, lymphadenopathy, signs of organ damage 1, 2
• Laboratory studies: Comprehensive metabolic panel including calcium, albumin, creatinine, liver function tests 1

Step 3: Peripheral Blood Smear Examination

• Monocyte morphology: Assess for dysgranulopoiesis, promonocytes, blasts, neutrophil precursors 1, 2
• Critical findings: Rouleaux formation (suggests plasma cell dyscrasia), morulae in monocytes (suggests ehrlichiosis) 1

Step 4: Indications for Bone Marrow Evaluation

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

• Persistent unexplained monocytosis without clear reactive cause
• Absolute monocyte count ≥1.0 × 10⁹/L sustained over time (≥3 months) 1
• Concurrent cytopenias or other blood count abnormalities
• Constitutional symptoms or organomegaly
• Dysplastic features on peripheral smear

Step 5: Advanced Testing When Malignancy Suspected

• Conventional cytogenetics: Identify clonal abnormalities, exclude Philadelphia chromosome, BCR-ABL1 fusion gene, t(5;12), t(9;22) 1, 5
• Molecular testing: TET2, SRSF2, ASXL1, RAS mutations (commonly found in CMML) 1, 3
• Bone marrow biopsy staining: Gomori's silver impregnation for fibrosis 1
• Flow cytometry: For monocyte repartitioning and immunophenotyping 4

Critical Clinical Pitfalls

• Failing to distinguish relative from absolute monocytosis: Always calculate absolute count, not just percentage 2, 1
• Missing underlying infections: Ehrlichiosis morulae and CMV timing are easily overlooked 1, 2
• Inadequate bone marrow evaluation: Not performing comprehensive workup in persistent unexplained monocytosis delays diagnosis of treatable malignancies 2, 1
• Overinterpretation of clonal hematopoiesis: CH mutations (DNMT3A, TET2, ASXL1) occur with aging and do not necessarily indicate CMML unless accompanied by appropriate clinical and morphologic features 6, 3
• Ignoring sustained monocytosis: Persistent monocytosis over 3-4 months significantly increases risk of underlying malignancy and warrants hematology referral 1, 6