Hairy Cell Leukemia: Diagnosis and Clinical Manifestations
Hairy cell leukemia (HCL) is a rare B-cell chronic lymphoproliferative disorder characterized by splenomegaly, pancytopenia, and bone marrow involvement with fibrosis, affecting approximately 2% of all adult leukemias. 1
Definition and Epidemiology
- Represents approximately 2% of all lymphoid leukemias
- Approximately 1600 new cases diagnosed annually in Europe
- Median age at diagnosis: 52 years
- Male predominance with male-to-female ratio of 4:1
- Higher frequency among white Americans than African-Americans or Asians
- Possible association with exposure to herbicide "Agent Orange" 1
Pathophysiology
- B-cell malignancy with cells arrested at a late stage of maturation
- Characterized by BRAF V600E mutation in most classical HCL cases (not present in HCL variant)
- Somatic hypermutation in the IGHV gene present in 80-90% of cases
- Leukemic cells infiltrate bone marrow, spleen, and sometimes liver and lymph nodes 1
Clinical Manifestations
Common Presenting Symptoms
- Fatigue and weakness (80% of patients)
- Fever (56% of patients)
- Abdominal pain
- Recurrent opportunistic infections 1, 2
Physical Examination Findings
- Splenomegaly (92% of patients) - most common physical finding
- Hepatomegaly (28% of patients)
- Peripheral lymphadenopathy (uncommon) 1, 2
Laboratory Abnormalities
- Pancytopenia (most common)
- Anemia
- Monocytopenia (characteristic)
- Macrocytosis
- Occasionally normal blood counts or leukocytosis (rare) 1, 2
Diagnostic Features
Morphological Characteristics
- Hairy cells: small to medium-sized lymphoid cells with:
- Round, oval, or indented nucleus
- Well-defined nuclear border
- Loose chromatin
- Abundant pale cytoplasm with characteristic hair-like projections 1
Bone Marrow Findings
- Frequent "dry tap" (84% of cases) due to increased reticulin fibers
- Infiltration pattern varies from mild interstitial to diffuse
- "Fried egg" pattern: lymphoid cells surrounded by clear halo
- Occasionally hypocellular (can be mistaken for aplastic anemia) 1, 2
Immunophenotypic Profile
- Typical immunophenotype for classical HCL:
- CD19+, CD20+ (bright), CD22+
- CD11c+, CD25+, CD103+, CD123+
- CD5-, CD10-
- Cyclin D1+, annexin A1+, CD200+ (bright) 1
Special Diagnostic Tests
- Tartrate-resistant acid phosphatase (TRAP) staining: highly specific for classical HCL
- BRAF V600E mutation testing: present in most classical HCL cases
- Flow cytometry with comprehensive panel 1, 3
Distinguishing Classical HCL from HCL Variant
| Feature | Classical HCL | HCL Variant |
|---|---|---|
| Morphology | Typical hairy cells | Nucleolated cells |
| Monocytopenia | Present | Absent |
| Lymphocyte count | Usually low/normal | High |
| CD25 | Positive | Negative |
| CD123 | Positive | Negative |
| BRAF V600E | Positive | Negative |
| TRAP staining | Positive | Variable |
| Response to purine analogues | Good | Poor |
| [1,3] |
Diagnostic Pitfalls and Caveats
- Bone marrow aspiration frequently results in "dry tap" - rely on biopsy
- HCL can occasionally present with normal blood counts or even leukocytosis
- Rare cases may express CD10 (13%) or CD23 (19%)
- Absence of splenomegaly does not rule out HCL (occurs in 8% of cases)
- Unmutated IGHV is associated with poorer outcomes and primary refractoriness to purine analogue therapy 1, 2
Early diagnosis is critical as modern treatments with purine analogues (cladribine or pentostatin) can achieve high response rates and durable remissions, significantly improving prognosis in a disease that was historically considered uniformly fatal 4, 5.