Sandbox: T-cell large granular lymphocyte leukemia
Synonyms and keywords: LGL leukemia; T-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  chain T-cell receptor genes for the majority of cases and a CD8- T-cell with clonal rearrangements of  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  chain T-cell receptor genes for the majority of cases and a CD8- T-cell with clonal rearrangements of  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)
- Hashimotos thyroiditis
- Sjogrens 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
- 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)
- 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.
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.