Differential Diagnosis of Leukocytosis with Left Shift and Basophilia in a 78-Year-Old Woman
The combination of neutrophilia, left shift with metamyelocytes, and basophilia in this patient should prompt immediate evaluation for chronic myeloid leukemia (CML), though bacterial infection and other myeloproliferative neoplasms must also be considered.
Primary Diagnostic Considerations
Chronic Myeloid Leukemia (CML)
- CML is the most critical diagnosis to exclude given the presence of both left shift and basophilia, which together have 100% sensitivity and specificity for CML when both are present 1.
- The hallmark presentation includes leukocytosis with left-shifted neutrophilia (metamyelocytes, myelocytes, promyelocytes), basophilia, and variable eosinophilia 2, 3.
- Diagnosis requires confirmation of the BCR-ABL1 fusion gene by either cytogenetics showing t(9;22) (Philadelphia chromosome) or RT-PCR demonstrating BCR-ABL1 transcripts 2.
- Immediate testing should include peripheral blood BCR-ABL1 by RT-PCR and/or FISH, as this can be performed on blood without requiring bone marrow initially 2, 4.
- Note that approximately 5% of CML cases are Philadelphia chromosome-negative by conventional cytogenetics but BCR-ABL1-positive by molecular testing 2.
Bacterial Infection
- In elderly patients, a left shift (≥6% band neutrophils/metamyelocytes or absolute band count ≥1,500 cells/mm³) with leukocytosis warrants careful assessment for bacterial infection 5.
- This patient's absolute metamyelocyte count of 232 cells/mm³ and 2.0% metamyelocytes represents a left shift that could indicate bacterial infection 5.
- The WBC of 11,600 is only mildly elevated, which is less typical for severe bacterial infection but does not exclude it 5.
- Critical distinction: Bacterial infections typically show toxic granulation, Döhle bodies, and vacuolization of neutrophils on peripheral smear, which are absent in CML 6.
- Search for localizing signs of infection (pneumonia, urinary tract infection, skin/soft tissue infection, intra-abdominal source) 5.
Other Myeloproliferative Neoplasms (MPNs)
- Chronic neutrophilic leukemia (CNL) presents with marked neutrophilic leukocytosis (≥13-25 × 10⁹/L depending on classification), hepatosplenomegaly, and requires CSF3R mutation (particularly T618I) for diagnosis 7.
- This patient's WBC of 11.6 is below typical CNL thresholds, making this less likely 7.
- Atypical CML (aCML/MDS/MPN with neutrophilia) features dysplastic neutrophilia with ≥10% circulating precursors and requires leukocytosis ≥13 × 10⁹/L 7.
- Basophilia is rare in aCML, which helps distinguish it from CML 8.
Chronic Myelomonocytic Leukemia (CMML)
- CMML requires sustained monocytosis ≥0.5 × 10⁹/L with monocytes ≥10% of leukocyte count 9.
- The presence of prominent basophilia makes CMML less likely, as this is more characteristic of CML 9.
- If monocyte count is elevated, bone marrow examination with cytogenetics and molecular testing (TET2, SRSF2, ASXL1) would be indicated 9.
Reactive/Non-Malignant Causes
Reactive Leukocytosis
- Stress-induced leukocytosis from surgery, trauma, exercise, or emotional stress can cause neutrophilia with left shift but typically resolves within hours to days 10.
- Other reactive causes include medications (corticosteroids, G-CSF), smoking, obesity, chronic inflammatory conditions, and asplenia 10.
- Basophilia in reactive conditions is uncommon and should raise suspicion for a clonal process 11.
Allergic/Parasitic Conditions
- Basophilia can occur with allergic conditions, parasitic infections, or chronic inflammatory states 10.
- However, the concurrent left shift with metamyelocytes makes a purely reactive basophilia less likely 11.
Recommended Diagnostic Algorithm
Immediate Evaluation
- Review peripheral blood smear manually to confirm automated differential, assess neutrophil morphology for toxic changes (suggesting infection) versus normal maturation (suggesting MPN), and evaluate basophil morphology 6.
- Order BCR-ABL1 testing by RT-PCR on peripheral blood to exclude CML 2, 1.
- Assess for infection: Complete history for fever, localizing symptoms; physical examination for splenomegaly (suggests MPN); chest X-ray, urinalysis, and blood cultures if infection suspected 5.
If BCR-ABL1 Positive
- Proceed with bone marrow aspiration and biopsy with cytogenetics to confirm CML and assess disease phase 2.
- Initiate tyrosine kinase inhibitor therapy 2.
If BCR-ABL1 Negative and No Infection Identified
- Bone marrow examination with comprehensive testing including:
- Morphology to assess for dysplasia, megakaryocyte abnormalities, and fibrosis 12
- Conventional cytogenetics 4
- JAK2 V617F, CALR, and MPL mutation testing to evaluate for other MPNs 12, 13
- Consider CSF3R mutation testing if CNL suspected 7
- NGS panel including ASXL1, SETBP1, TET2, SRSF2 if aCML or CMML suspected 9, 7
If Infection Confirmed
- Treat infection appropriately and repeat CBC with differential after resolution to determine if leukocytosis and left shift persist 5.
- Persistent abnormalities after infection clearance warrant hematologic evaluation 14.
Critical Pitfalls to Avoid
- Do not dismiss basophilia as insignificant—the combination of neutrophilia, left shift, and basophilia is highly specific for CML and warrants immediate BCR-ABL1 testing 1.
- Do not rely solely on WBC count—CML can present with modest leukocytosis or even aleukemic presentation in rare cases 15.
- Do not delay BCR-ABL1 testing pending bone marrow—peripheral blood testing is adequate for initial diagnosis and allows faster initiation of therapy 2, 4.
- Do not assume infection without toxic changes on smear—the presence of immature forms without toxic granulation, vacuolization, or Döhle bodies suggests a myeloproliferative rather than reactive process 6.
- Serial monitoring is essential—if initial workup is negative but abnormalities persist, repeat evaluation in 4-8 weeks with consideration for bone marrow examination 14, 10.