Definition/General
Introduction:
Hairy Cell Leukemia (HCL) is a rare B-cell lymphoproliferative disorder characterized by distinctive hairy cell morphology
It represents 2% of all leukemias
HCL cells have characteristic cytoplasmic projections resembling hair
The disease predominantly affects middle-aged men with a 4:1 male predominance.
Origin:
Arises from mature B-lymphocytes with features suggesting post-germinal center origin
Hairy cells express pan-B-cell markers with distinctive immunophenotype
The BRAF V600E mutation is present in >95% of classic HCL cases
This mutation leads to constitutive MAPK pathway activation and uncontrolled proliferation.
Classification:
WHO classification recognizes classic Hairy Cell Leukemia and Hairy Cell Leukemia-variant (HCL-v)
Classic HCL has BRAF V600E mutation and typical morphology
HCL-variant lacks BRAF mutation and has more prominent nucleoli
Splenic Red Pulp Lymphoma is a related entity with hairy cell features.
Epidemiology:
Rare disease with incidence 0.3 per 100,000 per year
Male predominance 4:1
Median age at diagnosis 50-55 years
More common in Western populations than Asian
In India, relatively rare with younger median age (45-50 years)
No clear environmental risk factors identified.
Clinical Features
Presentation:
Pancytopenia (80-90% cases) with monocytopenia being characteristic
Splenomegaly (massive, 80-90% cases)
Fatigue and weakness (most common symptom - 90%)
Recurrent infections due to neutropenia
Easy bruising and bleeding due to thrombocytopenia
Abdominal fullness due to splenomegaly.
Symptoms:
Asymptomatic presentation in 25% cases (incidental finding)
Fatigue (90% of symptomatic patients)
Shortness of breath on exertion (anemia)
Recurrent bacterial infections (neutropenia)
Petechiae and ecchymoses (thrombocytopenia)
Early satiety (massive splenomegaly).
Risk Factors:
Male sex (4-fold increased risk)
Advanced age (>50 years)
Jewish ancestry (slightly increased risk)
No occupational exposures identified
No radiation exposure association
No familial clustering reported
No viral associations established.
Screening:
No routine screening recommendations
Suspect in patients with unexplained pancytopenia and splenomegaly
Consider in middle-aged men with monocytopenia
Complete blood count shows characteristic findings
Peripheral blood smear reveals hairy cells
Flow cytometry confirms diagnosis.
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Gross Description
Appearance:
Massive splenomegaly is the hallmark finding (weight 1000-4000g, normal 150-200g)
Spleen has smooth, tense capsule with dark red cut surface
Red pulp expansion with obliteration of white pulp
Hepatomegaly in 30-40% cases (usually mild)
Lymphadenopathy is uncommon (unlike other lymphomas).
Characteristics:
Spleen shows red pulp infiltration by hairy cells creating "red pulp lymphoma" pattern
White pulp atrophy with loss of germinal centers
Splenic trabeculae may be thickened
Liver shows sinusoidal infiltration pattern
Portal tracts may contain hairy cells.
Size Location:
Spleen extends 10-20 cm below left costal margin in most cases
Can reach the pelvis in extreme cases
Liver enlargement typically 2-6 cm below right costal margin
Bone marrow shows patchy or diffuse infiltration
Lymph nodes rarely enlarged (helps distinguish from other lymphomas).
Multifocality:
Systemic disease involving bone marrow, spleen, and liver
Leukemic phase with circulating hairy cells
Extranodal involvement common (unlike nodal lymphomas)
Rare sites: lung, kidney, gastrointestinal tract
Central nervous system involvement is extremely rare.
Microscopic Description
Histological Features:
Hairy cells have oval to reniform nuclei with homogeneous chromatin
Abundant pale cytoplasm with characteristic hair-like projections
Cytoplasmic borders are irregular and indistinct
Bone marrow shows interstitial infiltration with increased reticulin
Dry tap common on bone marrow aspiration.
Cellular Characteristics:
Cells are medium-sized (12-15 μm diameter)
Oval, bean-shaped, or reniform nuclei with smooth nuclear contours
Homogeneous, ground-glass chromatin without prominent nucleoli
Moderate to abundant cytoplasm with characteristic projections
Hairy projections are 1-5 μm long and contain ribosome-lamella complexes.
Architectural Patterns:
Bone marrow shows interstitial and focal infiltration
Increased reticulin fibrosis (grade 1-2)
Spleen shows red pulp infiltration with hairy cells in sinusoids
Blood lakes formation in red pulp
Liver shows sinusoidal infiltration pattern.
Grading Criteria:
No formal grading system for HCL
Disease assessment based on extent of infiltration
Minimal residual disease assessment by flow cytometry
Complete remission: normal blood counts, no detectable hairy cells
Partial remission: improved counts but persistent disease
Progressive disease: worsening cytopenias or organomegaly.
Immunohistochemistry
Positive Markers:
CD20 (B-cell marker, positive in 95% cases)
CD22 (bright positive, more than normal B-cells)
CD11c (positive in 95% cases, characteristic)
CD25 (IL-2 receptor, positive in 95%)
CD103 (integrin, highly specific for HCL)
CD123 (IL-3 receptor, positive in 90%)
TRAP (tartrate-resistant acid phosphatase, pathognomonic).
Negative Markers:
CD5 and CD23 (helps distinguish from CLL)
CD10 (usually negative, unlike follicular lymphoma)
Cyclin D1 (negative, unlike mantle cell lymphoma)
CD3 and CD7 (T-cell markers, negative)
CD34 (negative, mature B-cell phenotype)
TdT (negative, mature lymphoid cells).
Diagnostic Utility:
TRAP staining is pathognomonic (shows characteristic punctate pattern)
CD11c and CD25 co-expression is highly characteristic
CD103 is highly specific for HCL
Annexin A1 by immunohistochemistry is positive
Flow cytometry shows bright CD22 and bright CD11c expression.
Molecular Subtypes:
Classic HCL: BRAF V600E positive, typical immunophenotype
HCL-variant: BRAF negative, CD25 negative, prominent nucleoli
Splenic Red Pulp Lymphoma: related entity, different immunophenotype
HCL-Japanese variant: CD11c negative, geographic distribution.
Molecular/Genetic
Genetic Mutations:
BRAF V600E mutation in >95% of classic HCL cases (pathognomonic)
Immunoglobulin heavy chain genes are clonally rearranged
TP53 mutations rare in classic HCL (more common in HCL-variant)
MYD88 mutations absent (helps distinguish from lymphoplasmacytic lymphoma)
CDK6 amplification reported in some cases.
Molecular Markers:
BRAF V600E can be detected by immunohistochemistry or sequencing
Clonal immunoglobulin rearrangement confirms B-cell monoclonality
Ribosome-lamella complexes seen by electron microscopy (characteristic)
IGHV gene usage shows specific patterns
Somatic hypermutation present in immunoglobulin genes.
Prognostic Significance:
BRAF V600E status predicts response to BRAF inhibitors
TP53 mutations (rare) associated with poor prognosis
Complex karyotype uncommon but indicates aggressive disease
Minimal residual disease monitoring by flow cytometry predicts relapse
CD38 expression may correlate with prognosis.
Therapeutic Targets:
BRAF V600E targeted by vemurafenib and dabrafenib
CD22 targeted by moxetumomab pasudotox (immunotoxin)
Purine analogues (cladribine, pentostatin) remain standard therapy
Anti-CD20 monoclonal antibodies (rituximab) used in combination
Ibrutinib (BTK inhibitor) effective in relapsed/refractory cases.
Differential Diagnosis
Similar Entities:
Hairy Cell Leukemia-variant (HCL-v): larger cells, prominent nucleoli, BRAF negative
Splenic Marginal Zone Lymphoma: splenomegaly, different immunophenotype
Chronic Lymphocytic Leukemia: CD5+, CD23+, different morphology
Splenic Red Pulp Lymphoma: related entity, CD11c negative
B-cell Prolymphocytic Leukemia: prominent nucleoli, different immunophenotype.
Distinguishing Features:
Classic HCL: BRAF V600E positive, CD11c+, CD25+, CD103+, TRAP+
HCL-variant: BRAF negative, CD25 negative, prominent nucleoli
SMZL: CD11c variable, CD25 negative, different spleen pattern
CLL: CD5 and CD23 positive, prolymphocytes <10%
SRPL: CD11c negative, different red pulp pattern.
Diagnostic Challenges:
Distinguishing classic HCL from HCL-variant (clinical and therapeutic implications)
Minimal involvement versus reactive changes
Post-treatment changes versus residual disease
Dry tap bone marrow aspiration (may require biopsy)
Monocytopenia as early clue to diagnosis.
Rare Variants:
HCL-Japanese variant: CD11c negative, geographic clustering
HCL-North variant: CD103 negative variant
Splenic Red Pulp Lymphoma: related B-cell neoplasm
Secondary HCL: transformation from other B-cell lymphomas (rare)
HCL with t(11;14): rare translocation variant.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Bone marrow aspirate and biopsy, [site], peripheral blood smear
Peripheral Blood Findings
Pancytopenia with circulating hairy cells ([X]% of lymphocytes)
Bone Marrow Morphology
[X]% cellularity with interstitial infiltration by hairy cells
Hairy Cell Morphology
Cells with oval nuclei, abundant cytoplasm, and characteristic hair-like projections
Cytochemistry
TRAP (tartrate-resistant acid phosphatase): Positive with characteristic pattern
Flow Cytometry
CD20+, CD22 (bright), CD11c+, CD25+, CD103+, CD123+
Molecular Studies
BRAF V600E mutation: [detected/not detected]
Additional Studies
Immunohistochemistry: [markers and results]
Cytogenetics: [if performed]
[other studies]: [results]
Final Diagnosis
Hairy Cell Leukemia, classic type [with BRAF V600E mutation]