T-cell large granular lymphocyte leukemia: Difference between revisions

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==Overview==
==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]].<ref name="who1">[http://www.iarc.fr/WHO-BlueBooks/BBwebsite/bb3.html] 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 </ref> T-cell large granular lymphocyte leukemia was first discovered by McKenna, in 1977.<ref name="pmid22830400">{{cite journal |vauthors=Leblanc F, Zhang D, Liu X, Loughran TP |title=Large granular lymphocyte leukemia: from dysregulated pathways to therapeutic targets |journal=Future Oncol |volume=8 |issue=7 |pages=787–801 |year=2012 |pmid=22830400 |pmc=3464048 |doi=10.2217/fon.12.75 |url=}}</ref>  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 cell|cytotoxic-T cells]]. The postulated cells of origin of T-LGL leukemia are transformed [[CD8+ T cells|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.<ref name="cha1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3490288&query_hl=6&itool=pubmed_ExternalLink]
T-cell large granular lymphocyte leukemia (also known as T-GLL) is a rare type of [[leukemia]] that exhibits an unexplained, [[Chronic (medical)|chronic]] (> 6 months) elevation in large [[Granule (cell biology)|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 [[Classification|classified]] into 2 groups: T-cell large granular lymphocyte leukemia (T-LGL) and [[Natural Killer T cell|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 cell|cytotoxic T cells]]. The postulated [[Cell (biology)|cells]] of origin of T-LGL leukemia are transformed [[CD8+ T cells|CD8+]] [[T cell|T-cells]] with clonal rearrangements of β chain [[T cell receptor|T-cell receptor]] [[Gene|genes]] for the majority of cases and a CD8- [[T cell|T-cell]] with clonal rearrangements of γ chain [[T-cell receptor]] [[Gene|genes]] for a minority of cases. The [[Molecule|molecular]] [[pathogenesis]] of T-cell large granular lymphocyte leukemia is characterized by the disregulation of [[Signal transduction|signaling pathways]], such as: FAS/FAS-L, phosphatidylinositol-3 kinase (PI3K), and mitogen-activated proteinkinase/extracellular signal-regulated kinase (MAPK/ERK). [[Patient|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 [[Adult|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|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 [[Chemotherapy|targeted-chemotherapy]]. Initial [[therapy]] for [[Patient|patients]] with T-cell large granular lymphocyte leukemia includes [[Corticosteroid|corticosteroids]] and [[methotrexate]]. [[Alemtuzumab]] and [[tipifarnib]] are the treatment of choice for [[Patient|patients]] with [[refractory]] T-cell large granular lymphocytic leukemia.  
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</ref> 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==
==Historical Perspective==
*T-cell large granular lymphocyte leukemia was first discovered by McKenna, in 1977.<ref name="pmid22830400">{{cite journal |vauthors=Leblanc F, Zhang D, Liu X, Loughran TP |title=Large granular lymphocyte leukemia: from dysregulated pathways to therapeutic targets |journal=Future Oncol |volume=8 |issue=7 |pages=787–801 |year=2012 |pmid=22830400 |pmc=3464048 |doi=10.2217/fon.12.75 |url=}}</ref>
*T-cell large granular lymphocyte leukemia was first discovered by McKenna, in 1977.<ref name="pmid22830400">{{cite journal |vauthors=Leblanc F, Zhang D, Liu X, Loughran TP |title=Large granular lymphocyte leukemia: from dysregulated pathways to therapeutic targets |journal=Future Oncol |volume=8 |issue=7 |pages=787–801 |year=2012 |pmid=22830400 |pmc=3464048 |doi=10.2217/fon.12.75 |url=}}</ref>
==Classification==
==Classification==
*T-cell large granular lymphocyte leukemia may be classified into 2 groups:<ref name="lam1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12876667&query_hl=10&itool=pubmed_ExternalLink]
T-cell large granular lymphocyte leukemia may be [[Classification|classified]] into 2 groups:<ref name="lam1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12876667&query_hl=10&itool=pubmed_ExternalLink]
Lamy T, Loughran TP Jr. "Clinical features of large granular lymphocyte leukemia." '''Semin Hematol'''. 2003 Jul;40(3):185-95. PMID: 12876667</ref>
Lamy T, Loughran TP Jr. "Clinical features of large granular lymphocyte leukemia." '''Semin Hematol'''. 2003 Jul;40(3):185-95. PMID: 12876667</ref>
:*T-cell large granular lymphocyte leukemia (T-LGL)
* T-cell large granular lymphocyte leukemia (T-LGL)
:*[[Natural-killer]] (NK) granular lymphocyte leukemia (NK-LGL)
* [[Natural-killer]] (NK) granular lymphocyte leukemia (NK-LGL)
 
==Pathophysiology==
==Pathophysiology==
*The pathogenesis of T-cell large granular lymphocyte leukemia is characterized by involvement of cytotoxic-T cells.
*The [[pathogenesis]] of T-cell large granular lymphocyte leukemia is characterized by the involvement of [[Cytotoxic T cell|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.<ref name="lam1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12876667&query_hl=10&itool=pubmed_ExternalLink]
*The postulated [[Cell (biology)|cells]] of origin of T-LGL leukemia are transformed [[Cytotoxic T cell|CD8+ T-cell]] with clonal rearrangements of β chain [[T-cell receptor]] [[Gene|genes]] for the majority of cases and a CD8- [[T cell|T-cell]] with clonal rearrangements of γ chain [[T-cell receptor]] [[Gene|genes]] for a minority of cases.<ref name="lam1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12876667&query_hl=10&itool=pubmed_ExternalLink]
Lamy T, Loughran TP Jr. "Clinical features of large granular lymphocyte leukemia." '''Semin Hematol'''. 2003 Jul;40(3):185-95. PMID: 12876667</ref>
Lamy T, Loughran TP Jr. "Clinical features of large granular lymphocyte leukemia." '''Semin Hematol'''. 2003 Jul;40(3):185-95. PMID: 12876667</ref>
*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 [[leukemia]] [[Cell (biology)|cells]] of T-cell large granular lymphocyte leukemia can be found in [[peripheral blood]], [[bone marrow]], [[spleen]], and [[liver]]. [[Lymph node|Nodal]] involvement is rare.
*The molecular pathogenesis of T-cell large granular lymphocyte leukemia is characterized by the disregulation of signaling pathways, such as:  
*The [[Molecule|molecular]] [[pathogenesis]] of T-cell large granular lymphocyte leukemia is characterized by the disregulation of [[Signal transduction|signaling pathways]], such as:  
:*FAS/FAS-L
:*FAS/FAS-L
:*Phosphatidylinositol-3 kinase (PI3K),
:*[[Phosphoinositide 3-kinase|Phosphatidylinositol-3 kinase (PI3K)]],
:*Mitogen-activated proteinkinase/extracellular signal-regulated kinase (MAPK/ERK)
:*[[Mitogen-activated protein kinase]]/[[Extracellular signal-regulated kinases|extracellular signal-regulated kinase]] ([[Mitogen-activated protein kinase|MAPK]]/[[Extracellular signal-regulated kinases|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.
*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:<ref name="lam1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12876667&query_hl=10&itool=pubmed_ExternalLink]
 
Lamy T, Loughran TP Jr. "Clinical features of large granular lymphocyte leukemia." '''Semin Hematol'''. 2003 Jul;40(3):185-95. PMID: 12876667</ref>
*On [[microscopic]] [[Histopathology|histopathological]] [[analysis]], 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]]
:*[[Cancer|Neoplastic]] [[Lymphocyte|lymphocytes]] (large in size)  
*On microscopic histopathological analysis, characteristic findings of T-cell large granular lymphocyte leukemia, include:
:*Presence of [[azurophilic granules]] (contains [[Protein|proteins]] involved in [[Lysis|cell lysis]] such as [[perforin]] and [[granzyme B]])
:*Neoplastic lymphocytes (large in size)  
:*[[Bone marrow]] involvement in this [[disease]] is often present, but to a variable extent
:*Presence of [[azurophilic granules]] (contains proteins involved in cell lysis such as [[perforin]] and [[granzyme B]])
:*The [[Lymphocyte|lymphocytic]] infiltrate is usually [[interstitial]], but a [[nodular]] pattern rarely occurs
:*[[Bone marrow]] involvement in this disease is often present, but to a variable extent
*On [[immunohistochemistry]], characteristic findings of T-cell large granular lymphocyte leukemia include:
:*The lymphocytic infiltrate is usually [[interstitial]], but a [[nodular]] pattern rarely occurs
:*Positive [[perforin]]
*On immunohistochemistry, characteristic findings of T-cell large granular lymphocyte leukemia, include:
:*Positive [[perforin]]
:*Positive [[TIA-1]]
:*Positive [[TIA-1]]
:*Positive [[granzyme B]]
:*Positive [[granzyme B]]


==Causes==
==Causes==
*Common causes of T-cell large granular lymphocyte leukemia, include:<ref name="pmid22830400">{{cite journal |vauthors=Leblanc F, Zhang D, Liu X, Loughran TP |title=Large granular lymphocyte leukemia: from dysregulated pathways to therapeutic targets |journal=Future Oncol |volume=8 |issue=7 |pages=787–801 |year=2012 |pmid=22830400 |pmc=3464048 |doi=10.2217/fon.12.75 |url=}}</ref>
Common causes of T-cell large granular lymphocyte leukemia include:<ref name="pmid22830400">{{cite journal |vauthors=Leblanc F, Zhang D, Liu X, Loughran TP |title=Large granular lymphocyte leukemia: from dysregulated pathways to therapeutic targets |journal=Future Oncol |volume=8 |issue=7 |pages=787–801 |year=2012 |pmid=22830400 |pmc=3464048 |doi=10.2217/fon.12.75 |url=}}</ref>
:*[[Autoimmune disorders]], such as:  
* [[Autoimmune disorders]] such as:
:*[[Systemic lupus erythematosus]] (SLE or lupus)
** [[Systemic lupus erythematosus|Systemic lupus erythematosus (SLE or lupus)]]
:*[[Hashimoto's Thyroiditis|Hashimoto’s thyroiditis]]
** [[Hashimoto's Thyroiditis|Hashimoto’s thyroiditis]]
:*[[Sjogren’s syndrome]]
** [[Sjogren’s syndrome]]


==Differentiating T-cell Large Granular Lymphocyte Leukemia from Other Diseases==
==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:
*T-cell large granular lymphocyte leukemia must be differentiated from other [[Disease|diseases]] that cause recurrent [[Infection|infections]], [[fatigue]], and night [[fever]], such as:
:*Precursor T lymphoblastic leukaemia/lymphoma
:*Precursor T lymphoblastic leukemia/[[lymphoma]]
:*[[Mycosis fungoides]]
:*[[Mycosis fungoides]]
:*[[Human Immunodeficiency Virus|Human immunodeficiency virus]]
:*[[HIV AIDS]]
:*[[Burkitt's lymphoma|Burkitt lymphoma]]
:*[[Burkitt's lymphoma|Burkitt lymphoma]]


==Epidemiology and Demographics==
==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.
*  T-cell large granular lymphocyte leukemia is a rare form of [[leukemia]], comprising 2 - 3% of all cases of [[Chronic (medical)|chronic]] [[lymphoproliferative disorders]].
   
   
===Age===
===Age===
*Patients of all age groups may develop T-cell large granular lymphocyte leukemia.
*[[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.<ref name="cha1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3490288&query_hl=6&itool=pubmed_ExternalLink]
*T-cell large granular lymphocyte leukemia is more commonly observed among middle aged [[Adult|adults]].<ref name="cha1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3490288&query_hl=6&itool=pubmed_ExternalLink]
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</ref>
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</ref>


===Gender===
===Gender===
*T-cell large granular lymphocyte leukemia affects men and women equally.
*T-cell large granular lymphocyte leukemia affects [[Male|men]] and [[Female|women]] equally.


===Race===
===Race===
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==Risk Factors==
==Risk Factors==
*The most common risk factor in the development of T-cell large granular lymphocyte leukemia is exposure to radiation.<ref name="cha1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3490288&query_hl=6&itool=pubmed_ExternalLink]
*The most common [[risk factor]] in the development of T-cell large granular lymphocyte leukemia is exposure to [[Radiation therapy|radiation]].<ref name="cha1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3490288&query_hl=6&itool=pubmed_ExternalLink]
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</ref>
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</ref>


== Natural History, Complications and Prognosis==
== Natural History, Complications and Prognosis==
*The majority of patients with T-cell large granular lymphocyte leukemia may be initially asymptomatic.  
*The majority of [[Patient|patients]] with T-cell large granular lymphocyte leukemia may be initially [[asymptomatic]].  
*Early clinical features include fever, night sweats, and weight loss.
*Early clinical features include [[fever]], [[Sleep hyperhidrosis|night sweats]], and [[weight loss]].
*If left untreated, patients with T-cell large granular lymphocyte leukemia may progress to develop infections.  
*If left untreated, [[Patient|patients]] with T-cell large granular lymphocyte leukemia may progress to develop [[Infection|infections]].  
*Common complications of T-cell large granular lymphocyte leukemiainclude:<ref name="cha1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3490288&query_hl=6&itool=pubmed_ExternalLink]
*Common [[complications]] of T-cell large granular lymphocyte leukemia include:<ref name="cha1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3490288&query_hl=6&itool=pubmed_ExternalLink]
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</ref>
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</ref>
:*Bone marrow failure disorders
:*[[Bone marrow suppression|Bone marrow failure]] [[Disorder (medicine)|disorders]]
:*Myelodysplastic syndromes
:*[[Myelodysplastic syndrome]]
:*Aplastic anemia
:*[[Aplastic anemia]]
:*Paroxysmal nocturnal hemoglobinuria
:*[[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%.<ref name="lam1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12876667&query_hl=10&itool=pubmed_ExternalLink]
*[[Prognosis]] is generally good, and the 5 year survival rate of [[patients]] with T-cell large granular lymphocyte leukemia is approximately 89%.<ref name="lam1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12876667&query_hl=10&itool=pubmed_ExternalLink]
Lamy T, Loughran TP Jr. "Clinical features of large granular lymphocyte leukemia." '''Semin Hematol'''. 2003 Jul;40(3):185-95. PMID: 12876667</ref>
Lamy T, Loughran TP Jr. "Clinical features of large granular lymphocyte leukemia." '''Semin Hematol'''. 2003 Jul;40(3):185-95. PMID: 12876667</ref>


== Diagnosis ==
== Diagnosis ==
===Diagnostic Criteria===
===Diagnostic Study of Choice===
*The diagnosis of T-cell large granular lymphocyte leukemia is made when the following diagnostic criteria is met:<ref name="cha1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3490288&query_hl=6&itool=pubmed_ExternalLink]
The [[diagnosis]] of T-cell large granular lymphocyte leukemia is made when the following diagnostic criteria is met:<ref name="cha1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3490288&query_hl=6&itool=pubmed_ExternalLink]
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</ref>
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</ref>
:*Clonal rearrangements of the [[T-cell receptor]] (TCR) gene
* Clonal rearrangements of the [[T-cell receptor|T-cell receptor (TCR)]] [[gene]]
:*Chronic (> 6 months) elevation in large granular lymphocytes (LGLs) in the peripheral blood
* [[Chronic (medical)|Chronic]] (> 6 months) elevation in large granular lymphocytes (LGLs) in the [[peripheral blood]]
:*Large granular lymphocyte count greater than 2.0 × 109/L
* Large [[Granule (cell biology)|granular]] [[lymphocyte]] count greater than 2.0 × 109/L
:*Lymphocytosis (typically 2-20x109/L)
* [[Lymphocytosis]] (typically 2-20x109/L)


=== Symptoms ===
=== Symptoms ===
*T-cell large granular lymphocyte leukemia may be initially asymptomatic.
*T-cell large granular lymphocyte leukemia may be initially [[asymptomatic]].
*Symptoms of T-cell large granular lymphocyte leukemia may include the following:<ref name="cha1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3490288&query_hl=6&itool=pubmed_ExternalLink]
*[[Symptom|Symptoms]] of T-cell large granular lymphocyte leukemia may include the following:<ref name="cha1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3490288&query_hl=6&itool=pubmed_ExternalLink]
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</ref>
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</ref>
** Generalised weakness and [[Fatigue (physical)|fatigue]]
** Generalized weakness and [[Fatigue (physical)|fatigue]]
** [[Anorexia]]
** [[Anorexia]]
**Joint pain
**[[Arthralgia|Joint pain]]
** Night sweating
** [[Sleep hyperhidrosis|Night sweats]]
** [[Epistaxis]]
** [[Epistaxis]]
** [[Bone pain]]
** [[Bone pain]]
** [[Dyspnea]]
** [[Dyspnea|Difficulty breathing]]


=== Physical Examination ===
=== Physical Examination ===
*Patients with T-cell large granular lymphocyte leukemia usually appear pale and malnourished.  
*[[Patient|Patients]] with T-cell large granular lymphocyte leukemia usually appear [[Pallor|pale]] and [[Malnutrition|malnourished]].  
*Physical examination may be remarkable for:<ref name="lam2">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10761014&query_hl=22&itool=pubmed_ExternalLink]
*[[Physical examination]] may be remarkable for:<ref name="lam2">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10761014&query_hl=22&itool=pubmed_ExternalLink]
Lamy T, Loughran TP. "Large Granular Lymphocyte Leukemia." '''Cancer Control'''. 1998 Jan;5(1):25-33. PMID: 10761014</ref><ref name="cha1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3490288&query_hl=6&itool=pubmed_ExternalLink]
Lamy T, Loughran TP. "Large Granular Lymphocyte Leukemia." '''Cancer Control'''. 1998 Jan;5(1):25-33. PMID: 10761014</ref><ref name="cha1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3490288&query_hl=6&itool=pubmed_ExternalLink]
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</ref><ref name="pan1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=2403836&query_hl=8&itool=pubmed_ExternalLink]
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</ref><ref name="pan1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=2403836&query_hl=8&itool=pubmed_ExternalLink]
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</ref><ref name="lam1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12876667&query_hl=10&itool=pubmed_ExternalLink]
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</ref><ref name="lam1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12876667&query_hl=10&itool=pubmed_ExternalLink]
Lamy T, Loughran TP Jr. "Clinical features of large granular lymphocyte leukemia." '''Semin Hematol'''. 2003 Jul;40(3):185-95. PMID: 12876667</ref>
Lamy T, Loughran TP Jr. "Clinical features of large granular lymphocyte leukemia." '''Semin Hematol'''. 2003 Jul;40(3):185-95. PMID: 12876667</ref>
:*Cardiac flow murmur
:*[[Heart murmur|Cardiac flow murmur]]
:*High-grade fever
:*High-grade [[fever]]
:*[[Hepatomegaly]]
:*[[Hepatomegaly]]
:*[[Splenomegaly]]
:*[[Splenomegaly]]


=== Laboratory Findings ===
=== Laboratory Findings ===
*Laboratory findings consistent with the diagnosis of T-cell large granular lymphocyte leukemia, include:
[[Medical laboratory|Laboratory]] findings consistent with the [[diagnosis]] of T-cell large granular lymphocyte leukemia include:
**Neutropenia
*[[Neutropenia]]
**Anemia
*[[Anemia]]
**Hypergammaglobulinemia
*[[Hypergammaglobulinemia]]
**Lymphocytosis (most common)
*[[Lymphocytosis]] (most common)
 
===Imaging Findings===
===Imaging Findings===
*There are no specific imaging findings associated with T-cell large granular lymphocyte leukemia.
*There are no specific [[imaging]] findings associated with T-cell large granular lymphocyte leukemia.


=== Other Diagnostic Studies ===
=== Other Diagnostic Studies ===
*T-cell large granular lymphocyte leukemia may also be diagnosed using the following studies:
*T-cell large granular lymphocyte leukemia may also be [[Diagnosis|diagnosed]] using the following studies:
'''Immunophenotyping'''
'''Immunophenotyping'''
*The following table demonstrates common immunophenotype findings.  
*The following table demonstrates common [[Immunophenotyping|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.
*The [[Cancer|neoplastic]] [[Cell (biology)|cells]] of this [[disease]] display a mature [[T-cell]] [[immunophenotype]], with the majority of cases showing a [[CD4]]-/[[CD8]]+ [[T cell|T-cell]] subset [[immunophenotype]] versus other permutations of those markers. Variable expression of [[CD11b]], [[CD56]], and [[CD57]] are observed.


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'''Peripheral blood smear'''
'''Peripheral blood smear'''
*Large neoplastic lymphocytes  
*Large [[Cancer|neoplastic]] [[Lymphocyte|lymphocytes]]
*Azurophilic granules
*[[Azurophil|Azurophilic]] [[Granule (cell biology)|granules]]


== Treatment ==
== Treatment ==
=== Medical Therapy ===
=== Medical Therapy ===
*The mainstay of therapy for T-cell large granular lymphocyte leukemia is targeted-chemotherapy.  
*The mainstay of [[therapy]] for T-cell large granular lymphocyte leukemia is [[Chemotherapy|targeted-chemotherapy]].  
*Initial therapy for patients with T-cell large granular lymphocyte leukemia, may include:  
*Initial [[therapy]] for [[Patient|patients]] with T-cell large granular lymphocyte leukemia may include:  
:*Corticoesteroids
:*[[Corticosteroid|Corticosteroids]]
:*Methotrexate  
:*[[Methotrexate]]
*Alemtuzumab and tipifarnib are the treatment of choice for patients with refractory T-cell large granular lymphocytic leukemia.
*[[Alemtuzumab]] and [[tipifarnib]] are the treatment of choice for [[Patient|patients]] with [[refractory]] T-cell large granular lymphocytic leukemia.


=== Prevention ===
=== Prevention ===
*There are no primary preventive measures available for T-cell large granular lymphocyte leukemia.
*There are no [[Prevention (medical)|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.  
*Once [[Diagnosis|diagnosed]] and successfully treated, [[Patient|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.
*Follow-up [[Test|testing]] includes [[complete blood count]], [[physical examination]], and [[Blood film|peripheral blood smear]].


==References==
==References==

Latest revision as of 17:38, 30 April 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5] Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [6] Maria Fernanda Villarreal, M.D. [7]

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 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 2-20x109/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 includes corticosteroids 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.[1]

Classification

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)

Pathophysiology

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

Causes

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

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:

Epidemiology and Demographics

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

  • Prognosis is generally good, and the 5 year survival rate of patients with T-cell large granular lymphocyte leukemia is approximately 89%.[2]

Diagnosis

Diagnostic Study of Choice

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

Symptoms

Physical Examination

Laboratory Findings

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

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

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

Treatment

Medical Therapy

Prevention

References

  1. 1.0 1.1 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.
  2. 2.0 2.1 2.2 2.3 [1] Lamy T, Loughran TP Jr. "Clinical features of large granular lymphocyte leukemia." Semin Hematol. 2003 Jul;40(3):185-95. PMID: 12876667
  3. 3.0 3.1 3.2 3.3 3.4 3.5 [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. [3] Lamy T, Loughran TP. "Large Granular Lymphocyte Leukemia." Cancer Control. 1998 Jan;5(1):25-33. PMID: 10761014
  5. [4] 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

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