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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [6] Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [7] Maria Fernanda Villarreal, M.D. [8]

Synonyms and keywords: LGL leukemia; Tγ-lymphoproliferative disorder; T-cell chronic lymphocytic leukemia; proliferation of large granular lymphocytes (LGLs)

Overview

T-cell large granular lymphocyte leukemia (also known as T-GLL) is a rare type of leukemia that exhibits a unexplained, chronic (> 6 months) elevation in large granular lymphocytes (LGLs) in the peripheral blood. T-cell large granular lymphocyte leukemia was first discovered by McKenna, in 1977. T-cell large granular lymphocyte leukemia may be classified into 2 groups: T-cell large granular lymphocyte leukemia (T-LGL) and natural-killer (NK) granular lymphocyte leukemia (NK-LGL). The pathogenesis of T-cell large granular lymphocyte leukemia is characterized by involvement of cytotoxic-T cells. The postulated cells of origin of T-LGL leukemia are transformed CD8+ T-cell with clonal rearrangements of β chain T-cell receptor genes for the majority of cases and a CD8- T-cell with clonal rearrangements of γ chain T-cell receptor genes for a minority of cases. The molecular pathogenesis of T-cell large granular lymphocyte leukemia is characterized by the disregulation of signaling pathways, such as: FAS/FAS-L, phosphatidylinositol-3 kinase (PI3K), and mitogen-activated proteinkinase/extracellular signal-regulated kinase (MAPK/ERK). Patients of all age groups may develop T-cell large granular lymphocyte leukemia. T-cell large granular lymphocyte leukemia is more commonly observed among middle aged adults. Laboratory findings consistent with the diagnosis of T-cell large granular lymphocyte leukemia, include: neutropenia, anemia, hypergammaglobulinemia, and lymphocytosis (most common). The diagnosis of T-cell large granular lymphocyte leukemia is made when the following diagnostic criteria: clonal rearrangements of the T-cell receptor (TCR) gene, chronic (> 6 months) elevation in large granular lymphocytes (LGLs) in the peripheral blood, large granular lymphocyte count greater than 2.0 × 109/L, and lymphocytosis (typically 2-20x109/L).The mainstay of therapy for T-cell large granular lymphocyte leukemia is targeted-chemotherapy. Initial therapy for patients with T-cell large granular lymphocyte leukemia, may include: corticoesteroids, and methotrexate. Alemtuzumab and tipifarnib are the treatment of choice for patients with refractory T-cell large granular lymphocytic leukemia.

Historical Perspective

• T-cell large granular lymphocyte leukemia was first discovered by McKenna, in 1977.

Classification

• T-cell large granular lymphocyte leukemia may be classified into 2 groups:

• T-cell large granular lymphocyte leukemia (T-LGL)
• Natural-killer (NK) granular lymphocyte leukemia (NK-LGL)

Pathophysiology

• The pathogenesis of T-cell large granular lymphocyte leukemia is characterized by involvement of cytotoxic-T cells.
• The postulated cells of origin of T-LGL leukemia are transformed CD8+ T-cell with clonal rearrangements of β chain T-cell receptor genes for the majority of cases and a CD8- T-cell with clonal rearrangements of γ chain T-cell receptor genes for a minority of cases.
• The leukemia cells of T-cell large granular lymphocyte leukemia can be found in peripheral blood, bone marrow, spleen, and liver. Nodal involvement is rare.
• The molecular pathogenesis of T-cell large granular lymphocyte leukemia is characterized by the disregulation of signaling pathways, such as:

• FAS/FAS-L
• Phosphatidylinositol-3 kinase (PI3K),
• Mitogen-activated proteinkinase/extracellular signal-regulated kinase (MAPK/ERK)

• The increased expression of STAT3 has been associated with the development of T-cell large granular lymphocyte leukemia, involving the janus kinase family pathway.
• On gross pathology, characteristic findings of T-cell large granular lymphocyte leukemia, include:

• T-cell large granular lymphocyte leukemia can be found in peripheral blood, bone marrow, spleen, and liver

• On microscopic histopathological analysis, characteristic findings of T-cell large granular lymphocyte leukemia, include:

• Neoplastic lymphocytes (large in size)
• Presence of azurophilic granules (contains proteins involved in cell lysis such as perforin and granzyme B)
• Bone marrow involvement in this disease is often present, but to a variable extent
• The lymphocytic infiltrate is usually interstitial, but a nodular pattern rarely occurs

• On immunohistochemistry, characteristic findings of T-cell large granular lymphocyte leukemia, include:

• Positive perforin
• Positive TIA-1
• Positive granzyme B

Causes

• Common causes of T-cell large granular lymphocyte leukemia, include:

• Autoimmune disorders, such as:
• Systemic lupus erythematosus (SLE or lupus)
• Hashimoto’s thyroiditis
• Sjogren’s syndrome

Differentiating T-cell Large Granular Lymphocyte Leukemia from Other Diseases

• T-cell large granular lymphocyte leukemia must be differentiated from other diseases that cause recurrent infections, fatigue, and night fever, such as:

• Precursor T lymphoblastic leukaemia/lymphoma
• Mycosis fungoides
• Human immunodeficiency virus
• Burkitt lymphoma

Epidemiology and Demographics

• T-cell large granular lymphocyte leukemia is a rare form of leukemia, comprising 2-3% of all cases of chronic lymphoproliferative disorders.

Age

• Patients of all age groups may develop T-cell large granular lymphocyte leukemia.
• T-cell large granular lymphocyte leukemia is more commonly observed among middle aged adults.

Gender

• T-cell large granular lymphocyte leukemia affects men and women equally.

Race

• There is no racial predilection for T-cell large granular lymphocyte leukemia.

Risk Factors

• The most common risk factor in the development of T-cell large granular lymphocyte leukemia is exposure to radiation.

Natural History, Complications and Prognosis

• The majority of patients with T-cell large granular lymphocyte leukemia may be initially asymptomatic.
• Early clinical features include fever, night sweats, and weight loss.
• If left untreated, patients with T-cell large granular lymphocyte leukemia may progress to develop infections.
• Common complications of T-cell large granular lymphocyte leukemia, include:

• Bone marrow failure disorders
• Myelodysplastic syndromes
• Aplastic anemia
• Paroxysmal nocturnal hemoglobinuria

• Prognosis is generally good, and the 5 year survival rate of patients with T-cell large granular lymphocyte leukemia is approximately 89%.

Diagnosis

Diagnostic Criteria

• The diagnosis of T-cell large granular lymphocyte leukemia is made when the following diagnostic criteria is met:

• Clonal rearrangements of the T-cell receptor (TCR) gene
• Chronic (> 6 months) elevation in large granular lymphocytes (LGLs) in the peripheral blood
• Large granular lymphocyte count greater than 2.0 × 109/L
• Lymphocytosis (typically 2-20x109/L)

Symptoms

• T-cell large granular lymphocyte leukemia may be initially asymptomatic.
• Symptoms of T-cell large granular lymphocyte leukemia may include the following:
  • Generalised weakness and fatigue
  • Anorexia
  • Joint pain
  • Night sweating
  • Epistaxis
  • Bone pain
  • Dyspnea

Physical Examination

• Patients with T-cell large granular lymphocyte leukemia usually appear pale and malnourished.
• Physical examination may be remarkable for:

• Cardiac flow murmur
• High-grade fever
• Hepatomegaly
• Splenomegaly

Laboratory Findings

• Laboratory findings consistent with the diagnosis of T-cell large granular lymphocyte leukemia, include:
  • Neutropenia
  • Anemia
  • Hypergammaglobulinemia
  • Lymphocytosis (most common)

Imaging Findings

• There are no specific imaging findings associated with T-cell large granular lymphocyte leukemia.

Other Diagnostic Studies

• T-cell large granular lymphocyte leukemia may also be diagnosed using the following studies:

Immunophenotyping

• The following table demonstrates common immunophenotype findings.
• The neoplastic cells of this disease display a mature T-cell immunophenotype, with the majority of cases showing a CD4-/CD8+ T-cell subset immunophenotype versus other permutations of those markers. Variable expression of CD11b, CD56, and CD57 are observed.

Type	Immunophenotype
Common type (80% of cases)	CD3+, TCRαβ+, CD4-, CD8+
Rare variants	CD3+, TCRαβ+, CD4+, CD8-
	CD3+, TCRαβ+, CD4+, CD8+
	CD3+, TCRγδ+, CD4 and CD8 variable

Peripheral blood smear

• Large neoplastic lymphocytes
• Azurophilic granules

Treatment

Medical Therapy

• The mainstay of therapy for T-cell large granular lymphocyte leukemia is targeted-chemotherapy.
• Initial therapy for patients with T-cell large granular lymphocyte leukemia, may include:

• Corticoesteroids
• Methotrexate

• Alemtuzumab and tipifarnib are the treatment of choice for patients with refractory T-cell large granular lymphocytic leukemia.

Prevention

• There are no primary preventive measures available for T-cell large granular lymphocyte leukemia.
• Once diagnosed and successfully treated, patients with T-cell large granular lymphocyte leukemia are followed-up every 3, 6 or 12 months.
• Follow-up testing includes complete blood count, physical examination, and peripheral blood smear.