What is the differential diagnosis for hepatospleenomegaly with a raised White Blood Cell (WBC) count and predominant neutrophil count?

Differential Diagnosis for Hepatosplenomegaly with Elevated WBC and Neutrophil Predominance

The differential diagnosis for hepatosplenomegaly with raised WBC and predominant neutrophils should prioritize myeloproliferative neoplasms (particularly chronic myeloid leukemia and chronic neutrophilic leukemia), followed by infectious causes (visceral leishmaniasis, bacterial infections), and inflammatory conditions (Adult-Onset Still's Disease).

Myeloproliferative Neoplasms (Primary Consideration)

Chronic Myeloid Leukemia (CML) and related disorders are the most critical diagnoses to exclude given the combination of hepatosplenomegaly and marked neutrophilic leukocytosis.

Chronic Myeloid Leukemia

• Presents with marked hepatosplenomegaly and extreme leukocytosis with immature neutrophils 1, 2
• WBC counts can exceed 300 × 10³/μL with neutrophilic predominance 1
• Neutrophil alkaline phosphatase (NAP) score is characteristically low (typically <50) 1, 3
• Philadelphia chromosome or BCR-ABL gene rearrangement confirms diagnosis 1, 2
• Elevated vitamin B12 and LDH levels are common 1

Chronic Neutrophilic Leukemia (CNL)

• Characterized by persistent mature neutrophilia with hepatosplenomegaly 3, 4
• Key distinguishing feature: elevated NAP score (unlike CML) 3
• Philadelphia chromosome is absent 3, 4
• WBC counts typically range from 40,000-90,000/μL with >88% neutrophils 3
• May coexist with plasma cell disorders in up to 20% of cases 4

Other Myeloproliferative Disorders

• Polycythemia vera can transition to neutrophilic leukemia with hepatosplenomegaly 3
• Primary myelofibrosis presents with massive splenomegaly (>10 cm below costal margin) and variable WBC counts 5
• Uncontrolled myeloproliferation defined as platelet count >400 × 10⁹/L AND WBC >10 × 10⁹/L 5

Infectious Causes

Visceral Leishmaniasis

• Endemic in specific geographic regions; requires travel history to Leishmania-endemic areas 5
• Classic triad: chronic fever, hepatosplenomegaly, and pancytopenia (not leukocytosis) 5
• When leukocytosis occurs, absolute neutrophil count is typically <1.5 × 10⁹/L in 61% of cases 6
• This makes VL less likely with predominant neutrophilia 6
• Diagnosis requires bone marrow aspiration demonstrating Leishmania parasites 6

Bacterial Infections

• Bacterial sepsis can present with hepatosplenomegaly and marked neutrophilia 5
• Total band count >1500/mm³ has the highest likelihood ratio (14.5) for bacterial infection 5
• Left shift (>6% band neutrophils) with likelihood ratio of 4.7 for bacterial infection 5
• Splenic abscess (particularly with endocarditis) causes persistent fever and left upper quadrant pain 7

Inflammatory/Autoimmune Conditions

Adult-Onset Still's Disease (AOSD)

• Presents with high fever (100% of patients), hepatosplenomegaly (14-65% have splenomegaly), and marked leukocytosis 5
• Striking neutrophilia is characteristic, often with WBC >15 × 10⁹/L in 50% of patients 5
• 37% have WBC counts >20 × 10⁹/L 5
• Neutrophilia results from bone marrow granulocyte hyperplasia 5
• Associated features: salmon-pink rash (51-87%), sore throat (38-92%), arthritis/arthralgia (64-100%) 5
• Markedly elevated ESR and CRP are virtually universal 5

Diagnostic Algorithm

Initial Laboratory Evaluation

1. Complete blood count with differential 5

   • Total WBC count and absolute neutrophil count
   • Evaluate for left shift (band forms >6%) 5
   • Assess for cytopenias suggesting alternative diagnoses 7

2. Peripheral blood smear examination 1, 2

   • Look for immature forms (myelocytes, metamyelocytes) suggesting CML
   • Assess neutrophil morphology (toxic granulation, Döhle bodies) 4

3. Neutrophil alkaline phosphatase (NAP) score 1, 3

   • Low NAP (<50) strongly suggests CML 1
   • High NAP (>50) suggests CNL, infection, or inflammatory conditions 3

4. Additional blood tests

   • Vitamin B12 (elevated in CML) 1
   • LDH (elevated in myeloproliferative disorders) 1
   • ESR and CRP (markedly elevated in AOSD) 5

Confirmatory Testing

1. Cytogenetic studies and molecular testing 1, 2

   • Philadelphia chromosome/BCR-ABL for CML diagnosis
   • Essential to differentiate CML from other causes

2. Bone marrow examination 1, 2, 3

   • Indicated when myeloproliferative disorder suspected
   • Assess cellularity, M:E ratio, and megakaryocyte morphology
   • Rule out infectious causes (leishmaniasis) in endemic areas 6

3. Imaging studies 7

   • Abdominal ultrasound or CT to confirm hepatosplenomegaly and assess extent
   • Evaluate for portal hypertension, splenic vein thrombosis 7

Critical Pitfalls to Avoid

• Do not assume infection without confirming elevated band count >1500/mm³ 5
• Do not diagnose CML without cytogenetic confirmation - atypical CML (Ph-negative) exists but is rare 2
• Do not overlook AOSD in patients with persistent fever and neutrophilia - this diagnosis is often delayed 5
• Pancytopenia with hepatosplenomegaly suggests hemophagocytic syndrome or visceral leishmaniasis, not typical neutrophilic leukocytosis 5
• In patients >60 years with hepatosplenomegaly and neutrophilia, always consider coexistent plasma cell disorders with CNL 4