Sandbox: T-cell large granular lymphocyte leukemia
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.[1] T-cell large granular lymphocyte leukemia was first discovered by McKenna, in 1977.[2] 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.[3] 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.[2]
Classification
- T-cell large granular lymphocyte leukemia may be classified into 2 groups:[4]
- 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.[4]
- 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:[4]
- 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:[2]
- 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.[3]
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.[3]
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:[3]
- 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%.[4]
Diagnosis
Diagnostic Criteria
- 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 2-20x109/L)
Symptoms
- T-cell large granular lymphocyte leukemia may be initially asymptomatic.
- Symptoms of T-cell large granular lymphocyte leukemia may include the following:[3]
Physical Examination
- Patients with T-cell large granular lymphocyte leukemia usually appear pale and malnourished.
- Physical examination may be remarkable for:[5][3][6][4]
- 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.
References
- ↑ [1] Jaffe E.S., Harris N.L., Stein H., Vardiman J.W. (eds): World Health Organization Classification of Tumors. Pathology and Genetics of Tumours of Haemopoietic and Lymphoid Tissues. IARC Press: Lyon 2001
- ↑ 2.0 2.1 2.2 Leblanc F, Zhang D, Liu X, Loughran TP (2012). "Large granular lymphocyte leukemia: from dysregulated pathways to therapeutic targets". Future Oncol. 8 (7): 787–801. doi:10.2217/fon.12.75. PMC 3464048. PMID 22830400.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 [2] Chan WC, Link S, Mawle A, Check I, Brynes RK, Winton EF. "Heterogeneity of large granular lymphocyte proliferations: delineation of two major subtypes." Blood. 1986 Nov;68(5):1142-53. PMID: 3490288
- ↑ 4.0 4.1 4.2 4.3 4.4 [3] Lamy T, Loughran TP Jr. "Clinical features of large granular lymphocyte leukemia." Semin Hematol. 2003 Jul;40(3):185-95. PMID: 12876667
- ↑ [4] Lamy T, Loughran TP. "Large Granular Lymphocyte Leukemia." Cancer Control. 1998 Jan;5(1):25-33. PMID: 10761014
- ↑ [5] Pandolfi F, Loughran TP Jr, Starkebaum G, Chisesi T, Barbui T, Chan WC, Brouet JC, De Rossi G, McKenna RW, Salsano F, et al. "Clinical course and prognosis of the lymphoproliferative disease of granular lymphocytes. A multicenter study." Cancer. 1990 Jan 15;65(2):341-8. PMID: 2403836