T-cell large granular lymphocyte leukemia

T-cell large granular lymphocyte leukemia (also known as T-GLL) is a rare type of leukemia that exhibits an 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 the involvement of cytotoxic T cells. The postulated cells of origin of T-LGL leukemia are transformed CD8+ T-cells 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 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, and lymphocytosis (typically 2-20×109/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 includes corticosteroids and methotrexate. Alemtuzumab and tipifarnib are the treatment of choice for patients with refractory T-cell large granular lymphocytic leukemia.

• T-cell large granular lymphocyte leukemia was first discovered by McKenna, in 1977.^[1]

T-cell large granular lymphocyte leukemia may be classified into 2 groups:^[2]

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

• The pathogenesis of T-cell large granular lymphocyte leukemia is characterized by the 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.^[2]
• 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 protein kinase/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 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

Common causes of T-cell large granular lymphocyte leukemia include:^[1]

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

• 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 leukemia/lymphoma
• Mycosis fungoides
• HIV AIDS
• Burkitt lymphoma

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

• 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.^[3]

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

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

• The most common risk factor in the development of T-cell large granular lymphocyte leukemia is exposure to radiation.^[3]

• 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:^[3]

• Bone marrow failure disorders
• Myelodysplastic syndrome
• 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%.^[2]

The diagnosis of T-cell large granular lymphocyte leukemia is made when the following diagnostic criteria is met:^[3]

• 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 2-20×109/L)

• T-cell large granular lymphocyte leukemia may be initially asymptomatic.
• Symptoms of T-cell large granular lymphocyte leukemia may include the following:^[3]
  • Generalized weakness and fatigue
  • Anorexia
  • Joint pain
  • Night sweats
  • Epistaxis
  • Bone pain
  • Difficulty breathing

• Patients with T-cell large granular lymphocyte leukemia usually appear pale and malnourished.
• Physical examination may be remarkable for:^[4][3][5][2]

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

Laboratory findings consistent with the diagnosis of T-cell large granular lymphocyte leukemia include:

• Neutropenia
• Anemia
• Hypergammaglobulinemia
• Lymphocytosis (most common)

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

• 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.

Peripheral blood smear

• Large neoplastic lymphocytes
• Azurophilic granules

• 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:

• Corticosteroids
• Methotrexate

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

• 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.

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