Definition/General
Introduction:
Large Granular Lymphocytic Leukemia (LGL leukemia) is a rare chronic lymphoproliferative disorder characterized by clonal expansion of large granular lymphocytes
It comprises T-cell LGL leukemia (T-LGL) and NK-cell LGL leukemia (NK-LGL)
LGL cells are cytotoxic lymphocytes with characteristic azurophilic granules
The disease represents 2-3% of all lymphoid leukemias.
Origin:
T-LGL arises from CD8+ cytotoxic T-lymphocytes with post-thymic maturation
NK-LGL originates from natural killer cells with cytotoxic function
Both variants show clonal proliferation of mature lymphocytes
The cells have cytotoxic granules containing perforin, granzyme, and TIA-1
Chronic antigenic stimulation may trigger clonal expansion.
Classification:
WHO classification recognizes two main subtypes: T-cell Large Granular Lymphocytic Leukemia (85% of LGL cases)
Chronic Lymphoproliferative Disorder of NK cells (15% of cases)
Both require sustained lymphocytosis (>2000/μL for >6 months) and clonal expansion
Aggressive NK-cell leukemia is a separate, more aggressive entity.
Epidemiology:
Rare disease with incidence 0.2-0.7 per 100,000 per year
Median age 60 years (range 20-80 years)
No significant gender predilection
T-LGL more common than NK-LGL
Associated with autoimmune disorders in 25-30% cases
Indolent course in most patients.
Clinical Features
Presentation:
Neutropenia (most common finding - 80% cases)
Anemia (60-70% cases)
Thrombocytopenia (25-30% cases)
Splenomegaly (mild to moderate - 50% cases)
Recurrent bacterial infections due to neutropenia
Asymptomatic presentation in 25-30% cases.
Symptoms:
Recurrent infections (oral ulcers, skin infections, pneumonia)
Fatigue secondary to anemia
Easy bruising if thrombocytopenic
Constitutional symptoms uncommon
Lymphadenopathy rare
Skin rashes in some cases (NK-LGL).
Risk Factors:
Autoimmune disorders (rheumatoid arthritis 25-30% association)
Advanced age (peak incidence 6th decade)
Chronic antigenic stimulation (viral infections, autoimmunity)
Immunosuppression (organ transplant recipients)
No hereditary predisposition
No environmental exposures identified.
Screening:
No routine screening guidelines
Suspect in patients with chronic neutropenia of unknown cause
Consider in patients with rheumatoid arthritis and cytopenias
Complete blood count shows lymphocytosis with large granular lymphocytes
Flow cytometry confirms clonality
TCR gene rearrangement studies for T-LGL.
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Gross Description
Appearance:
Mild splenomegaly (weight 200-500g, normal 150-200g)
Spleen has normal external appearance with minimal enlargement
Red pulp expansion with preserved white pulp architecture
Hepatomegaly uncommon and mild when present
Lymphadenopathy rare.
Characteristics:
Spleen shows red pulp infiltration by large granular lymphocytes
Sinusoidal distribution of LGL cells
White pulp relatively preserved
Liver may show portal tract infiltration
Bone marrow shows increased LGL cells but normal architecture.
Size Location:
Spleen enlargement typically 2-5 cm below left costal margin
Rarely exceeds 10 cm enlargement
Liver enlargement <3 cm when present
Lymph nodes normal size in most cases
Bone marrow cellularity usually normal.
Multifocality:
Systemic involvement with circulating LGL cells
Bone marrow infiltration in most cases
Splenic involvement common but mild
Hepatic involvement less common
Nodal involvement rare
Skin involvement more common in NK-LGL.
Microscopic Description
Histological Features:
LGL cells are medium to large lymphocytes (12-15 μm diameter)
Eccentric, kidney-shaped nuclei with clumped chromatin
Abundant pale cytoplasm containing azurophilic granules
Cytotoxic granules visible on routine stains
Low proliferation rate (Ki-67 <5%).
Cellular Characteristics:
Reniform or oval nuclei with mature chromatin pattern
Prominent azurophilic granules in cytoplasm (pathognomonic)
Granules contain perforin and granzyme
Moderate amount of cytoplasm
Nuclear indentations may be present
Binucleated forms occasionally seen.
Architectural Patterns:
Bone marrow shows interstitial infiltration by LGL cells
Normal hematopoietic architecture preserved
Spleen shows red pulp infiltration with sinusoidal pattern
White pulp architecture maintained
Portal tract infiltration in liver when involved.
Grading Criteria:
Diagnosis requires sustained lymphocytosis >2000/μL for >6 months
LGL morphology in >15% of lymphocytes
Clonal T-cell or NK-cell population by flow cytometry
No blast transformation in typical cases
Indolent clinical course distinguishes from aggressive variants.
Immunohistochemistry
Positive Markers:
T-LGL: CD3+, CD8+ (most common phenotype - 85%)
CD57+ (natural killer-like T-cells)
TIA-1, granzyme B, perforin (cytotoxic markers)
NK-LGL: CD56+, CD16+ (NK-cell markers)
CD2+ (both T-LGL and NK-LGL)
CD94, CD158 (KIR receptors).
Negative Markers:
T-LGL: CD4 usually negative (CD4+ variant rare)
CD56 may be negative in T-LGL
NK-LGL: CD3 negative (distinguishes from T-LGL)
CD5 usually negative
TdT negative (mature phenotype)
CD34 negative.
Diagnostic Utility:
T-LGL immunophenotype: CD3+, CD8+, CD57+, TIA-1+, perforin+
NK-LGL immunophenotype: CD3-, CD56+, CD16+, TIA-1+, perforin+
Flow cytometry essential for clonality assessment
TCR Vβ analysis shows restricted usage in T-LGL
KIR expression may be aberrant.
Molecular Subtypes:
CD8+ T-LGL (most common, 85% of T-LGL cases)
CD4+ T-LGL (rare variant, 5-10%)
CD4+CD8+ T-LGL (very rare)
γδ T-LGL (rare variant with TCR γδ expression)
Aggressive NK-cell leukemia (distinct aggressive entity).
Molecular/Genetic
Genetic Mutations:
STAT3 mutations in 30-40% of T-LGL cases (GOF mutations)
STAT5B mutations in 5-10% of cases
JAK3 mutations rare but reported
PIK3CD mutations in some cases
TNFAIP3 mutations (tumor suppressor)
NK-LGL shows different mutation spectrum.
Molecular Markers:
TCR gene rearrangements clonal in T-LGL (Southern blot or PCR)
Restricted TCR Vβ usage by flow cytometry
NK-cell clonality assessed by HUMARA or KIR expression
STAT3/STAT5B pathway activation
Fas-mediated apoptosis resistance.
Prognostic Significance:
STAT3 mutations associated with more symptomatic disease
Neutropenia severity correlates with clinical course
Autoimmune associations may affect prognosis
NK-LGL generally more indolent than T-LGL
Transformation to aggressive lymphoma rare but reported.
Therapeutic Targets:
JAK/STAT pathway inhibitors for STAT3-mutated cases
Immunosuppressive therapy (methotrexate, cyclophosphamide)
Cyclosporine effective in some cases
Alemtuzumab (anti-CD52) for refractory cases
Purine analogues have limited efficacy.
Differential Diagnosis
Similar Entities:
Reactive LGL expansion (viral infections, autoimmune disorders)
NK/T-cell lymphoma (aggressive, EBV-associated)
Peripheral T-cell lymphoma (aggressive course, different morphology)
Aggressive NK-cell leukemia (rapidly progressive)
T-cell prolymphocytic leukemia (different morphology, aggressive).
Distinguishing Features:
LGL leukemia: Chronic course, cytotoxic granules, CD57+ (T-LGL)
Reactive LGL: Polyclonal, self-limited, underlying cause
NK/T lymphoma: EBV+, aggressive, nodal/extranodal masses
PTCL: Aggressive course, different immunophenotype
Aggressive NKCL: Rapid progression, high LDH, organomegaly.
Diagnostic Challenges:
Distinguishing clonal from reactive LGL expansion (clonality studies essential)
T-LGL versus NK-LGL (CD3 expression key)
Chronic versus aggressive variants (clinical course)
Minimal disease versus normal variant LGL population
Autoimmune-associated cytopenias versus LGL-related.
Rare Variants:
γδ T-LGL leukemia: rare variant with aggressive behavior
CD4+ T-LGL: uncommon variant, different clinical features
Hepatosplenic T-cell lymphoma: related entity, aggressive course
Primary cutaneous γδ T-cell lymphoma: skin-limited disease
Intestinal T-cell lymphoma with LGL features.
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
Peripheral blood, bone marrow aspirate and biopsy (if performed)
Peripheral Blood Findings
Lymphocytosis ([count]/μL) with [X]% large granular lymphocytes
LGL Morphology
Medium to large lymphocytes with reniform nuclei and prominent cytoplasmic granules
Associated Cytopenias
Neutropenia: [present/absent], Anemia: [present/absent], Thrombocytopenia: [present/absent]
Flow Cytometry
[T-cell/NK-cell] immunophenotype: [specific markers and results]
Clonality Studies
TCR gene rearrangement: [clonal/polyclonal] (for T-LGL)
Bone Marrow (if performed)
[X]% cellularity with interstitial infiltration by LGL cells
Molecular Studies
STAT3/STAT5B mutations: [detected/not detected] (if performed)
Final Diagnosis
[T-cell/NK-cell] Large Granular Lymphocytic Leukemia