Large granular lymphocytic leukemia

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Large granular lymphocytic leukemia
Classification and external resources
ICD-O 9831/3
MeSH D054066

Large granular lymphocytic (LGL) leukemia is a chronic lymphoproliferative disorder that exhibits an unexplained, chronic (> 6 months) elevation in large granular lymphocytes (LGLs) in the peripheral blood.[1]

It is divided in two main categories: T-cell LGL (T-LGL) leukemia and natural-killer (NK)-cell LGL (NK-LGL) leukemia. As the name suggests, T-cell large granular lymphocyte leukemia is characterized by involvement of cytotoxic-T cells).[2]

It is also known by the following terms: proliferation of large granular lymphocytes (LGLs), LGL leukemia, Tγ-lymphoproliferative disorder, and, in common with other T cell leukemias such as T-cell prolymphocytic leukemia, T-cell chronic lymphocytic leukemia.[1]

Epidemiology[edit]

T-LGL is a rare form of leukemia, comprising 2-3% of all cases of chronic lymphoproliferative disorders.

Etiology[edit]

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.[1]

Clinical features[edit]

Clinical presentation[edit]

This disease is known for an indolent clinical course and incidental discovery.[1] The most common physical finding is moderate splenomegaly. B symptoms are seen in a third of cases, and recurrent infections due to the associated neutropenia are seen in almost half of cases.[3][4][5][6]

Rheumatoid arthritis is commonly observed in patients with T-LGL, leading to a clinical presentation similar to Felty's syndrome.[7] Signs and symptoms of anemia are commonly found, due to the association between T-LGL and erythroid hypoplasia.[8]

Laboratory findings[edit]

The requisite lymphocytosis of this disease is typically 2-20x109/L.[8]

Immunoglobulin derangements including hypergammaglobulinemia, autoantibodies, and circulating immune complexes are commonly seen.[6][9][10][11]

Sites of involvement[edit]

The leukemic cells of T-LGL can be found in peripheral blood, bone marrow, spleen, and liver. Nodal involvement is rare.[1][3]

Prognosis[edit]

The 5 year survival has been noted as 89% in at least one study from France of 201 patients with T-LGL leukemia.[12]

Morphology[edit]

Peripheral blood[edit]

The neoplastic lymphocytes seen in this disease are large in size with azurophilic granules that contains proteins involved in cell lysis such as perforin and granzyme B.[13]

Bone marrow[edit]

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.[1]

Molecular Findings[edit]

Immunophenotype[edit]

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.[4][5] Variable expression of CD11b, CD56, and CD57[6] are observed. Immunohistochemistry for perforin, TIA-1, and granzyme B are usually positive.[1]

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

Genetic findings[edit]

Clonal rearrangements of the T-cell receptor (TCR) genes are a necessary condition for the diagnosis of this disease. The gene for the β chain of the TCR is found to be rearranged more often than the γ chain. of the TCR.[10][14]

Treatment[edit]

Alemtuzumab has been investigated for use in treatment of refractory T-cell large granular lymphocytic leukemia.[15]

References[edit]

  1. ^ a b c d e f g Elaine Sarkin Jaffe; Nancy Lee Harris; World Health Organization; International Agency for Research on Cancer; Harald Stein; J.W. Vardiman (2001). Pathology and genetics of tumours of haematopoietic and lymphoid tissues. World Health Organization Classification of Tumors. 3. Lyon: IARC Press. ISBN 92-832-2411-6. 
  2. ^ Epling-Burnette PK, Sokol L, Chen X, et al. (December 2008). "Clinical improvement by farnesyltransferase inhibition in NK large granular lymphocyte leukemia associated with imbalanced NK receptor signaling". Blood. 112 (12): 4694–8. doi:10.1182/blood-2008-02-136382. PMC 2597136free to read. PMID 18791165. 
  3. ^ a b "Large Granular Lymphocyte Leukemia". Cancer Control. 5 (1): 25–33. January 1998. PMID 10761014. 
  4. ^ a b Chan WC, Link S, Mawle A, Check I, Brynes RK, Winton EF (November 1986). "Heterogeneity of large granular lymphocyte proliferations: delineation of two major subtypes". Blood. 68 (5): 1142–53. PMID 3490288. 
  5. ^ a b Pandolfi F, Loughran TP, Starkebaum G, et al. (January 1990). "Clinical course and prognosis of the lymphoproliferative disease of granular lymphocytes. A multicenter study". Cancer. 65 (2): 341–8. doi:10.1002/1097-0142(19900115)65:2<341::AID-CNCR2820650227>3.0.CO;2-2. PMID 2403836. 
  6. ^ a b c Lamy T, Loughran TP (July 2003). "Clinical features of large granular lymphocyte leukemia". Semin. Hematol. 40 (3): 185–95. doi:10.1016/S0037-1963(03)00133-1. PMID 12876667. 
  7. ^ Loughran TP, Starkebaum G, Kidd P, Neiman P (January 1988). "Clonal proliferation of large granular lymphocytes in rheumatoid arthritis". Arthritis Rheum. 31 (1): 31–6. doi:10.1002/art.1780310105. PMID 3345230. 
  8. ^ a b Kwong YL, Wong KF (September 1998). "Association of pure red cell aplasia with T large granular lymphocyte leukaemia". J. Clin. Pathol. 51 (9): 672–5. doi:10.1136/jcp.51.9.672. PMC 500904free to read. PMID 9930071. 
  9. ^ Oshimi K, Yamada O, Kaneko T, et al. (June 1993). "Laboratory findings and clinical courses of 33 patients with granular lymphocyte-proliferative disorders". Leukemia. 7 (6): 782–8. PMID 8388971. 
  10. ^ a b Loughran TP, Starkebaum G, Aprile JA (March 1988). "Rearrangement and expression of T-cell receptor genes in large granular lymphocyte leukemia". Blood. 71 (3): 822–4. PMID 3345349. 
  11. ^ Loughran TP, Kadin ME, Starkebaum G, et al. (February 1985). "Leukemia of large granular lymphocytes: association with clonal chromosomal abnormalities and autoimmune neutropenia, thrombocytopenia, and hemolytic anemia". Ann. Intern. Med. 102 (2): 169–75. doi:10.7326/0003-4819-102-2-169. PMID 3966754. 
  12. ^ Bareau, B; Rey, J; Hamidou, M; Donadieu, J; Morcet, J; Reman, O; Schleinitz, N; Tournilhac, O; et al. (2010). "Analysis of a French cohort of patients with large granular lymphocyte leukemia: A report on 229 cases". Haematologica. 95 (9): 1534–41. doi:10.3324/haematol.2009.018481. PMC 2930955free to read. PMID 20378561. 
  13. ^ Semenzato G, Zambello R, Starkebaum G, Oshimi K, Loughran TP (January 1997). "The lymphoproliferative disease of granular lymphocytes: updated criteria for diagnosis". Blood. 89 (1): 256–60. PMID 8978299. 
  14. ^ Vie H, Chevalier S, Garand R, et al. (July 1989). "Clonal expansion of lymphocytes bearing the gamma delta T-cell receptor in a patient with large granular lymphocyte disorder". Blood. 74 (1): 285–90. PMID 2546620. 
  15. ^ Rosenblum MD, LaBelle JL, Chang CC, Margolis DA, Schauer DW, Vesole DH (March 2004). "Efficacy of alemtuzumab treatment for refractory T-cell large granular lymphocytic leukemia". Blood. 103 (5): 1969–71. doi:10.1182/blood-2003-11-3951. PMID 14976065.