What further evaluation is indicated for an asymptomatic adult with isolated monocytopenia on a complete blood count?

Further Workup for Isolated Monocytopenia in an Asymptomatic Adult

In an asymptomatic adult with isolated monocytopenia, immediately review the peripheral blood smear for hairy cells and consider hairy cell leukemia as the primary diagnosis, as monocytopenia is a relatively sensitive and specific manifestation of this condition. 1

Initial Diagnostic Approach

Peripheral Blood Smear Review

• Examine the smear carefully for hairy cells, which appear as medium-sized cells with moderately abundant pale blue cytoplasm, reniform nuclei, open chromatin, absent nucleoli, and characteristic serrated cytoplasmic borders. 1
• Leukemic cells in hairy cell leukemia are often rare on peripheral smear, so careful inspection is essential. 1
• Look for other abnormalities including schistocytes (suggesting thrombotic microangiopathy), dysplasia in multiple lineages (suggesting myelodysplastic syndrome), or circulating blasts. 1

Complete Blood Count Analysis

• Verify that other cell lines are truly normal—isolated monocytopenia should have normal hemoglobin, normal platelet count, and normal neutrophil count. 1
• If anemia, thrombocytopenia, or neutropenia coexist (pancytopenia or bicytopenia), this substantially changes the differential diagnosis toward bone marrow disorders. 1, 2
• Confirm the monocyte count is truly low by direct morphological enumeration on the differential, as automated counts can be inaccurate. 3

Specific Testing Based on Clinical Context

If Hairy Cell Leukemia is Suspected

• Order flow cytometry on peripheral blood and bone marrow aspirate looking for CD20, CD25 (positive in classic hairy cell leukemia), CD103, CD123, annexin-1, FMC7, CD11c, and CD22. 1
• Test for BRAFV600E mutation in exon 15, which is present in all cases of classic hairy cell leukemia and has high specificity and sensitivity for diagnosis. 1
• Perform bone marrow trephine biopsy with immunohistochemistry including stains for CD20, annexin-1, BRAFV600E, and VE1 to establish diagnosis and assess degree of infiltration. 1
• Note that splenomegaly is less common now due to earlier detection, so its absence does not exclude the diagnosis. 1

If Other Hematologic Malignancies are Considered

• Bone marrow examination with aspirate and biopsy is indicated if there is dysplasia affecting ≥10% of cells in any lineage, circulating blasts (5-19%), or any accompanying cytopenia. 1, 2, 4
• Include flow cytometry on bone marrow to identify abnormal CD34+ populations or chronic lymphocytic leukemia, which can present with immune thrombocytopenia and altered monocyte counts. 1, 2, 3
• Obtain cytogenetic analysis to detect myelodysplastic syndrome-associated abnormalities such as del(5q), del(20q), trisomy 8, or -7/del(7q). 1, 2
• In pediatric patients or young adults with cytopenias and monocytes <1% by flow cytometry, strongly consider B-lymphoblastic leukemia even if blasts are rare (≤1%), as monocytopenia can be a diagnostic clue. 4

Exclude Secondary Causes

• Review all medications for drugs that can cause monocytopenia, particularly clozapine, which can cause agranulocytosis accompanied by monocytopenia affecting the CFU-GM precursor. 5
• Check for HIV and hepatitis C virus serologically, as these infections can cause cytopenias that mimic primary immune thrombocytopenia or other hematologic disorders. 1
• Test for Helicobacter pylori with urea breath test or stool antigen test in adults, as this may have clinical impact in immune thrombocytopenia workup. 1
• Assess for systemic lupus erythematosus, other autoimmune disorders, or lymphoproliferative diseases if constitutional symptoms, hepatomegaly, or lymphadenopathy are present. 1

When Bone Marrow Examination is Mandatory

Proceed directly to bone marrow aspiration and biopsy with cytogenetics if any of the following are present:

• Dysplasia affecting ≥10% of cells in one or more hematopoietic lineages on peripheral smear. 1, 2
• Circulating blasts (5-19% of white cells) raising suspicion for myelodysplastic syndrome. 1, 2
• Pancytopenia or bicytopenia accompanying the monocytopenia. 1, 2
• Monocytes <1% by flow cytometry in the setting of any cytopenia, even if peripheral blood flow cytometry is negative for leukemia. 4
• Persistent or worsening cytopenias despite adequate vitamin B12/folate replacement if macrocytosis is present. 2
• Failure to identify a cause after comprehensive workup. 2

Bone Marrow Examination Components

When bone marrow examination is performed, ensure the following:

• Aspirate with Prussian-blue stain to evaluate iron stores and identify ring sideroblasts (≥15% defines a specific myelodysplastic syndrome subtype). 2
• Core biopsy to assess cellularity, fibrosis, and topographic distribution of hematopoietic cells. 1, 2
• Cytogenetic analysis essential for detecting myelodysplastic syndrome-associated abnormalities. 1, 2
• Flow cytometry to identify abnormal CD34+ cell populations and clonal hematologic disorders. 1, 2
• If flow cytometry is performed on peripheral blood, acquire more than the standard 10,000 events to adequately assess for occult leukemia when monocytes are low. 4

Critical Pitfalls to Avoid

• Do not rely solely on automated monocyte counts—direct morphological enumeration on the differential is more accurate, particularly in chronic lymphocytic leukemia where automated counts may be incorrect. 3
• Do not dismiss the possibility of hairy cell leukemia based on absence of splenomegaly, as earlier detection has made this finding less common. 1
• Do not delay bone marrow examination when monocytes are <1% by flow cytometry in the setting of any cytopenia, even if peripheral blood flow cytometry is negative for leukemia. 4
• Do not assume isolated monocytopenia is benign—in myelodysplastic syndromes, an absolute monocyte count below 0.2 × 10⁹/L is associated with adverse disease features including lower hemoglobin, lower neutrophil and platelet counts, higher bone marrow blast percentage, and significantly higher risk of progression to acute myeloid leukemia. 6
• Do not overlook medication history, particularly clozapine, which can cause monocytopenia accompanying agranulocytosis by affecting the CFU-GM precursor. 5