T-cell Large Granular Lymphocytic Leukemia

Kaaren K. Reichard, MD

Key Facts

Clinical Issues

Asymptomatic
Symptomatic: Recurrent infections (neutropenia)
Rheumatoid arthritis/other autoimmune diseases
Splenomegaly
Pure red cell aplasia

Microscopic Pathology

Peripheral blood
- LGL lymphocytosis
- LGLs generally > 2 × 10⁹/L
Bone marrow (BM)
- Extent of involvement is variable
- Interstitial/intrasinusoidal patterns common
- May be morphologically occult
- Immunostains helpful to identify T-LGL infiltrate

Ancillary Tests

Immunophenotype
- CD3(+), CD8(+), CD57(+), CD94(+), TCR-α/β(+)
- Cytoplasmic granules TIA-1, perforin, GZMM(+)
- Uniform expression of TCR-Vβ or KIR molecules
Molecular
- T-cell receptor genes rearranged

Top Differential Diagnoses

Reactive/persistent LGL lymphocytosis
Chronic natural killer (NK) cell leukemia/lymphocytosis
- Immunophenotype: CD2(+), CD3(-), CD16(+), CD56(+)
Aggressive NK cell leukemia
- Epstein-Barr virus associated

Classic appearance of a large granular lymphocyte (LGL) is shown. LGLs constitute up to 15% of circulating white blood cells normally. Immunophenotyping shows that most are cytotoxic T cells.

CD3 immunostaining shows a marked increase in mature T cells in a case of T-LGL leukemia. The pattern of involvement is typically interstitial/intrasinusoidal and often morphologically occult.

TERMINOLOGY

Abbreviations

T-cell large granular lymphocytic leukemia (T-LGL leukemia)

Definitions

Persistent clonal proliferation of T-cell large granular lymphocytes (T-LGLs)

ETIOLOGY/PATHOGENESIS

Hypotheses

Chronic antigenic stimulation resulting in proliferation of T-cell large granular lymphocytes (T-LGLs)
- Exogenous antigens such as HTLV
- Endogenous autoantigens
Inhibition of apoptosis resulting in accumulation of T-LGLs
- Dysregulation of FAS/FAS-L

Infectious Agents

Role of retroviral infection unclear
Most patients do not show evidence of HTLV-I or HTLV-II infection
Reactivity against small peptide derived from an HTLV-I envelope protein has been reported

Etiology of Neutropenia

FAS/FAS-L-induced premature apoptosis of granulocytic precursors

CLINICAL ISSUES

Epidemiology

Incidence
- Comprises 2-3% of chronic lymphocytic leukemias
Age
- Median age: 60 years
- Predominantly affects adults
Gender
- No gender predilection

Site

Peripheral blood (PB)
Bone marrow (BM)
Spleen
Liver

Presentation

Asymptomatic
- Incidental discovery of T-LGL lymphocytosis
Asymptomatic
- Cytopenias
  - No clinically appreciated effects
- Rheumatoid arthritis or autoimmune disorder (25-35% of patients)
- Splenomegaly (20-50% of patients)
Symptomatic
- Development of cytopenias
  - Neutropenia
  - Thrombocytopenia
  - Anemia: May be due to red cell aplasia
- Development of recurrent infections
  - Often bacterial
  - Mucocutaneous
- Splenomegaly
- Systemic symptoms
LGL lymphocytosis: LGLs generally > 2 × 10⁹/L

Laboratory Tests

Clinical examination
Complete blood cell count with differential
PB examination
BM examination if needed
Flow cytometry of PB &/or BM
T-cell receptor clonality studies

Natural History

Clinically heterogeneous
Some spontaneous regressions
Association with immune disorders
High proportion of patients will require treatment at some point

Treatment

Asymptomatic
- Careful observation
Symptomatic
- Methotrexate or cyclophosphamide or cyclosporine A
  - Treatment should be continued for at least 4 months to assess response
- Corticosteroids
  - As monotherapy, not very effective long-term
  - Rapid improvements in symptoms/cytopenias if used in conjunction with methotrexate, cyclophosphamide, cyclosporine A
- Prophylactic use of antibiotics if severe neutropenia
- Hematopoietic growth factors
  - GM-CSF or G-CSF for neutropenia
  - Erythropoietin (EPO) for anemia
- Clinical trial
  - As available
- Progressive disease
  - Nucleoside analogues
  - Alemtuzumab: Anti-CD25 monoclonal antibody
  - Hematopoietic stem cell transplantation

Prognosis

Generally indolent
Related to control of cytopenias and associated symptoms

MICROSCOPIC PATHOLOGY

Peripheral Blood

LGL lymphocytosis
- LGLs generally > 2 × 10⁹/L
- Occasional cases LGLs < 2 × 10⁹/L
Circulating T-LGLs
- Intermediate size
- Round/slightly indented nucleus
- Inconspicuous nucleoli
- Abundant pale cytoplasm
- Cytoplasmic azurophilic granules
Variable degrees/types of cytopenias
Generally unremarkable red blood cell, platelet, and myeloid morphology