When should a patient with elevated monocytes (monocytosis) be referred to a hematologist?

When to Refer a Patient with Monocytosis to a Hematologist

Patients with persistent monocytosis (>1×10^9/L) should be referred to a hematologist for evaluation, particularly when the monocytosis is sustained for at least 3 months without evidence of other causes such as infection, inflammation, or malignancy. 1

Causes of Monocytosis

Monocytosis can be either reactive or neoplastic:

• Reactive monocytosis - commonly seen in:

  • Infections (bacterial, viral, fungal, parasitic) 1
  • Inflammatory conditions 1
  • Non-hematologic malignancies 2

• Neoplastic monocytosis - most commonly seen in:

  • Chronic Myelomonocytic Leukemia (CMML) 1, 2
  • Other myeloid neoplasms (MDS, MPN, AML) 3

Referral Algorithm

Urgent Referral (within 1-2 weeks)

• Persistent monocytosis (>1×10^9/L) with any of the following:
  • Concurrent unexplained cytopenias 1
  • Presence of dysplastic features in blood cells 1
  • Abnormal peripheral blood smear showing immature myeloid cells 1
  • Splenomegaly or hepatomegaly 1
  • Classical monocytes (MO1) ≥94% on flow cytometry if available 4

Standard Referral (within 1 month)

• Persistent monocytosis (>1×10^9/L) for ≥3 months without clear reactive cause 1, 2
• Monocytosis with abnormal blood counts in other cell lines 1
• Monocytosis with unexplained symptoms (fatigue, weight loss, night sweats) 1

Monitoring Without Immediate Referral

• Mild, transient monocytosis with:
  • Clear reactive cause (infection, inflammation) 1, 2
  • Normal other blood cell lines 2
  • Resolution on follow-up testing 2

Diagnostic Workup Before Referral

Primary care physicians should consider the following workup before referral:

• Complete blood count with differential 1
• Peripheral blood smear examination 1
• Basic metabolic panel and liver function tests 1
• Inflammatory markers (ESR, CRP) 1
• Repeat CBC in 4-6 weeks if monocytosis is mild and other cell lines are normal 2

Key Distinguishing Features of CMML vs. Reactive Monocytosis

CMML is the most concerning diagnosis in patients with persistent monocytosis and has the following characteristics:

• Persistent peripheral blood monocytosis (>1×10^9/L) 1
• Monocytes accounting for ≥10% of white blood cells 1
• Dysplastic features in one or more cell lines 1
• Absence of Philadelphia chromosome or BCR-ABL1 fusion gene 1
• No rearrangement of PDGFRA or PDGFRB 1
• Less than 20% blasts in peripheral blood and bone marrow 1

Clinical Pearls and Pitfalls

• Pearl: Flow cytometry analysis of monocyte subsets can help distinguish CMML from reactive monocytosis. An increase in classical monocytes (MO1) ≥94% has high sensitivity (93.8%) and specificity (88.2%) for CMML 4, 5

• Pitfall: Transient monocytosis is common in primary care and has a low absolute risk for hematological malignancy. However, sustained monocytosis significantly increases the risk of CMML and other hematologic malignancies 2

• Pearl: Monocytosis with dysplastic features involving multiple cell lineages may represent a distinct subset of MDS with a higher risk of progression to CMML or AML 3

• Pitfall: Failing to recognize that post-treatment lymphocytosis, eosinophilia, neutrophilia, and monocytosis can be observed in patients receiving immune checkpoint inhibitors and are not typically clinically significant 1

• Pearl: In general, patients with unexplained cytopenias should be referred to hematology for evaluation 1