What cancers can cause elevated white blood cell (WBC) count, neutrophilia, and lymphocytosis?

Cancers Causing Elevated WBC, Neutrophilia, and Lymphocytosis

The simultaneous elevation of total WBC count, neutrophils, and lymphocytes most commonly occurs in chronic lymphocytic leukemia (CLL), myeloproliferative neoplasms with overlapping features (particularly chronic myelomonocytic leukemia), and occasionally in acute leukemias with mixed phenotypes or during disease evolution.

Primary Hematologic Malignancies

Chronic Lymphocytic Leukemia (CLL)

• CLL characteristically presents with absolute lymphocytosis (>4,000/μL) and can have concurrent neutrophilia, particularly in proliferative variants or with infection 1.
• The diagnosis requires peripheral blood lymphocytes with characteristic immunophenotype, though total WBC elevation includes both lymphocytes and can include elevated neutrophils 1.
• Patients with CLL and WBC counts between 10,000-100,000/μL treated with fludarabine are at intermediate risk for tumor lysis syndrome, indicating significant disease burden 1.
• Low neutrophil-to-lymphocyte ratio (NLR) is strongly associated with CLL/small lymphocytic lymphoma (SLL) development (HR 0.38; 95% CI, 0.33-0.42), reflecting the relative lymphocyte predominance 2.

Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN)

• Chronic myelomonocytic leukemia (CMML) presents with both neutrophilia and can have lymphocytosis, classified as proliferative-type when WBC ≥13 × 10⁹/L 1.
• CMML demonstrates overlapping dysplastic and proliferative features with peripheral blood monocyte count ≥1 × 10⁹/L and variable neutrophil elevation 1.
• Atypical chronic myeloid leukemia (aCML), BCR-ABL1 negative, presents with neutrophilia similar to chronic neutrophilic leukemia and can have concurrent lymphocyte elevations 1.

Acute Leukemias

• Acute myeloid leukemia (AML) can present with markedly elevated WBC counts including both neutrophils and lymphocytes, particularly in monocytic subtypes 1.
• Patients with AML and WBC >40,000/μL at diagnosis require screening for CNS involvement and are at higher risk for leukostasis 1.
• Mixed phenotype acute leukemias demonstrate features of both myeloid and lymphoid lineages with concurrent elevation of multiple cell types 1.

Myeloid/Lymphoid Neoplasms with Tyrosine Kinase Fusions

• These neoplasms present with variable blood count abnormalities including neutrophilia, basophilia, monocytosis, and lymphocytosis depending on the specific fusion gene 1.
• Blast phase disease may present as AML, ALL, or mixed-lineage acute leukemias with concurrent eosinophilia and other cell line elevations 1.

Solid Tumors with Paraneoplastic Leukocytosis

Leukemoid Reactions

• Solid tumors, particularly lung carcinomas, can cause extreme leukocytosis (WBC ≥50,000/μL) with predominantly neutrophils but occasionally concurrent lymphocytosis 3.
• These leukemoid reactions show segmented neutrophils, bands, and occasional metamyelocytes without evidence of leukemia (normal chromosomes, normal leukocyte alkaline phosphatase) 3.
• High WBC in solid malignancies is typically a late phenomenon occurring shortly before death, likely due to tumor production of granulocytopoietins 3.
• Elevated WBC is associated with increased cancer incidence overall (HR 1.05; 95% CI, 1.03-1.06), particularly for lung cancer (HR 1.14; 95% CI, 1.08-1.20) and breast cancer 2.

Clinical Implications and Risk Stratification

Thrombosis and Mortality Risk

• Baseline leukocytosis (WBC >11 × 10⁹/L) in cancer patients initiating chemotherapy is strongly associated with venous thromboembolism (4.5% vs 1.8%, HR 2.1; 95% CI 1.3-3.4) 4.
• Early mortality is significantly increased with leukocytosis (7.3% vs 2.4%, HR 2.2; 95% CI 1.5-3.3), with greatest mortality when both leukocytosis and VTE are present 4.

Important Caveats

• In patients with WBC >5,000/μL, routine differential counts rarely alter cancer management and primarily add cost, though this does not apply to suspected hematologic malignancies 5.
• Elevated NLR (indicating relative neutrophil predominance over lymphocytes) is associated with kidney cancer but inversely associated with CLL/SLL 2.
• The absolute lymphocyte count alone should not trigger treatment in CLL; clinical context including lymphocyte doubling time, organomegaly, and cytopenias must be considered 1.