T-cell large granular lymphocyte leukemia

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T-cell large granular lymphocyte leukemia is a disease that exhibits a unexplained, chronic (> 6 months) elevation in large granular lymphocytes (LGLs) in the peripheral blood. [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 It is also known by the following terms: Proliferation of large granular lymphocytes (LGLs), LGL leukemia, Tγ-lymphoproliferative disorder, T-cell chronic lymphocytic leukemia

Epidemiology

T-LGL is a rare form of leukemia, comprising 2-3% of all cases of small lymphocytic leukemias.

Clinical Features

Etiology

The postulated cells of origin are a 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.

Clinical Presentation

This disease is known for an indolent clinical course and incidental discovery. 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.[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[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[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[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 Rheumatoid arthritis is commonly observed in patients with T-LGL, leading to a clinical presentation similar to Felty's syndrome. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3345230&query_hl=25&itool=pubmed_ExternalLink] Loughran TP Jr, Starkebaum G, Kidd P, Neiman P. "Clonal proliferation of large granular lymphocytes in rheumatoid arthritis." Arthritis Rheum. 1988 Jan;31(1):31-6. PMID: 3345230 Signs and symptoms of anemia are commonly found, due to the association between T-LGL and erythroid hypoplasia.[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=9930071&query_hl=14&itool=pubmed_ExternalLink] Kwong YL, Wong KF. "Association of pure red cell aplasia with T large granular lymphocyte leukaemia." J Clin Pathol. 1998 Sep;51(9):672-5. PMID: 9930071

Laboratory Findings

The requisite lymphocytosis of this disease is typically 2-20x109/L. Immunoglobulin derangements including hypergammaglobulinemia, autoantibodies, and circulating immune complexes are commonly seen. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=8388971&query_hl=16&itool=pubmed_ExternalLink] Oshimi K, Yamada O, Kaneko T, Nishinarita S, Iizuka Y, Urabe A, Inamori T, Asano S, Takahashi S, Hattori M, et al. "Laboratory findings and clinical courses of 33 patients with granular lymphocyte-proliferative disorders." Leukemia. 1993 Jun;7(6):782-8. PMID: 8388971 [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3345349&query_hl=19&itool=pubmed_ExternalLink] Loughran TP Jr, Starkebaum G, Aprile JA. "Rearrangement and expression of T-cell receptor genes in large granular lymphocyte leukemia." Blood. 1988 Mar;71(3):822-4. PMID: 3345349 [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3966754&query_hl=21&itool=pubmed_ExternalLink] Loughran TP Jr, Kadin ME, Starkebaum G, Abkowitz JL, Clark EA, Disteche C, Lum LG, Slichter SJ. "Leukemia of large granular lymphocytes: association with clonal chromosomal abnormalities and autoimmune neutropenia, thrombocytopenia, and hemolytic anemia." Ann Intern Med. 1985 Feb;102(2):169-75. PMID: 3966754

Sites of Involvement

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

Morphology

Peripheral blood

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. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=8978299&query_hl=28&itool=pubmed_ExternalLink] Semenzato G, Zambello R, Starkebaum G, Oshimi K, Loughran TP Jr. "The lymphoproliferative disease of granular lymphocytes: updated criteria for diagnosis." Blood. 1997 Jan 1;89(1):256-60. PMID: 8978299

Bone marrow

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.

Molecular Findings

Immunophenotype

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. Immunohistochemistry for perforin, TIA-1, and granzyme B are usually positive.

Genetic Findings

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. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=2546620&query_hl=30&itool=pubmed_ExternalLink] Vie H, Chevalier S, Garand R, Moisan JP, Praloran V, Devilder MC, Moreau JF, Soulillou JP. "Clonal expansion of lymphocytes bearing the gamma delta T-cell receptor in a patient with large granular lymphocyte disorder." Blood. 1989 Jul;74(1):285-90. PMID: 2546620

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