- Breast Cancer
- Cancer Control
- Diagnostics and Screening
- Gastrointestinal Oncology
- Genitourinary Cancers
- Geriatric Oncology
- Gynecological Oncology
- Head, Neck and Thyroid Cancers
- Hematological Malignancies
- Infection in Hematology
- Lung Cancer
- Neurological Oncology
- Patient Care
- Pediatric Oncology
- Platelets, Hemostasis and Thrombosis
- Red Blood Cells
- Supportive Oncology
The Spectrum of T-cell and Natural Killer – Large Granular Lymphocytic Proliferations
European Haematology, 2010;4:65-9
AbstractLarge granular lymphocyte (LGL) disorders comprise a spectrum of conditions that result from the expansion of a T cell or natural killer (NK) cell with a distinct morphology. The World Health Organization (WHO) considers T-cell LGL leukaemia as a distinct entity and chronic lymphoproliferative disorders (CLD) of NK cells as a provisional category. Patients are asymptomatic or manifest cytopenia, splenomegaly and autoimmune phenomena. Morphology, immunophenotype and molecular analysis are important diagnostic investigations. Most T-cell LGL leukaemias are T-cell receptor (TCR)-αβ+ LGL expansions displaying a CD8+ CD4- CD57+ or rarely a CD4+CD8±dim phenotype; a minority are clonal expansions of TCRγδ+LGL. NK LGL proliferations are CD3-, TCR-, CD16+, CD56+ with variable expression of T-cell non-specific markers. Expression of cytotoxic antigens T1A-1, granzymes and perforins are seen in both diseases. The pathogenesis is unknown. It is postulated that these disorders result from an expansion of a terminal memory-activated cytotoxic lymphocyte or an NK cell due to persistent antigenic stimulation with failure to undergo activation-induced cell death as a consequence of an impaired apoptotic pathway. Gene profiling has shown dysregulation of genes involved in apoptosis. The course is chronic, and transformation or aggressive disease is rare. Treatment strategies comprise immunomodulatory agents, purine analogues and antibody therapy.
Acknowledgements: The author expresses her gratitude to Mr John Maynard for help with editing the manuscript, and to Mr Ricardo Morilla for Figure 3.
Keywords: T cells, natural killer, large granular lymphocyte (LGL), apoptosis, immunosuppressive, leukaemia, apoptosis, killer immunoglobulin receptor (KIR), T-cell receptor (TCR)
Disclosure: The author has no conflicts of interest to declare.
Received: September 11, 2009 Accepted February 23, 2010 Citation European Haematology, 2010;4:65-9
Correspondence: Estella Matutes, Section of Haemato-Oncology, Institute of Cancer Research, 203 Fulham Road, London SW3 6JJ, UK. E: email@example.com
Large granular lymphocytic (LGL) proliferations comprise a spectrum of conditions ranging from reactive non-clonal and self-limited LGL expansions to asymptomatic or frank leukaemic clonal LGL disease. They are defined by the polyclonal, oligoclonal and/or clonal expansion in the blood and bone marrow or, rarely, in other tissues of a lymphocyte with a distinct morphology for this designated LGL. Polyclonal expansions of LGL are usually transient and due to a viral infection such as Epstein-Barr virus (EBV), solid tumours, connective tissue disease, etc.,1 or develop post-splenectomy. This is in contrast to clonal LGL proliferations, which are sustained whether the patients are symptomatic or not. Oligoclonal and clonal expansions of T-cell LGL have been reported in patients with B-cell neoplasms2 following allogeneic bone marrow transplant3 or rituximab treatment for a B-cell lymphoma. These latter likely are the result of a profound B-cell depletion4 and a disturbance of the immunity.
In normal individuals, a minority of circulating blood lymphocytes display the morphological characteristics of LGL. The majority of these lymphocytes have a cytotoxic T-cell phenotype (CD3+ CD8+ CD4-) or correspond to natural killer (NK) cells (CD3- CD56+). Clonal expansions of LGL may comprise T- and NK-cell-derived diseases. The World Health Organization (WHO) considers two categories: T-cell LGL leukaemia and chronic lymphoproliferative disorders (CLD) of NK cells,5 the latter being considered a provisional entity.
We will focus on the clinical features, diagnosis, biology and molecular characteristics of the clonal T-cell LGL leukaemia and CLD of NK cells.
The aetiology of T-cell LGL leukaemia and CLD of NK cells is largely unknown. Over the last few years there have been advances in the understanding of the pathogenesis of these diseases. A number of studies strongly suggest that they may be triggered by a chronic stimulation with an auto or foreign infective antigen as an initial event. This would result in the expansion of a cytotoxic or NK LGL that is not eliminated from the body due to an impairment on the apoptotic pathway.6–8 However, no single infective agent has been identified in the most common form of T-cell LGL leukaemia (CD8+ CD4-) or in CLD of NK cells. Some studies suggested the role of EBV or human T-cell leukaemia viruses, but these findings have not been confirmed.
- Loughran TP Jr, Clonal diseases of large granular lymphocytes, Blood, 1993;82:1–14.
- Martinez A, Pitaluga S, Villamor N, et al., Clonal T-cell populations and increased risk for cytotoxic T-cell lymphoma in B-CLL patients: clinicopathologic observations and molecular analysis, Am J Surg Pathol, 2004;28:849–58.
- Au WY, Lam CC, Lie AK, et al., T-cell large granular lymphocyte leukemia of donor origin after allogeneic bone marrow transplantation, Am J Clin Pathol, 2003; 120:626–30.
- Stamatopoulos K, Papadaki T, Pontikoglou C, et al., Lymphocyte subpopulation imbalances, bone marrow hematopoiesis and histopathology in rituximab treated lymphoma patients with late onset netropenia, Leukemia, 2008;22:1446–9.
- Swerdlow SH, Campo E, Harris NL (eds) et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Lyon: IARC Press, 2008.
- Epling-Burnette PK, Loughran TP Jr, Survival signals in leukemic large granular lymphocytes, Semin Hematol, 2003;40:213–20.
- Wlodarski MW, O'Keefe C, Howe EC, et al., Pathologic clonal cytotoxic T-cell responses: nonrandom nature of the T-cell-receptor restriction in large granular lymphocyte leukemia, Blood, 2005;106:2769–80.
- Lima M, Almeida J, Monter AG, et al., Clinicobiological, immunophenotypic and molecular characteristics of CD56± dim chronic natural killer cells large granular lymphocytosis, Am J Pathol, 2004;165:1117–27.
- Rodriguez-Caballero A, Garcia-Montero AC, Barcena P, et al., Expanded cells in monoclonal TCR-ab+/CD4+/Nka+/ CD8-/+dim T-LGL lymphocytes recognize hCMV antigens, Blood, 2008;112:4609–16.
- Sokol L, Loughran TP Jr, Large granular lymphocyte leukemia, Oncologist, 2006;11:263–73.
- O’Malley DP, T-cell large granular lymphocyte leukaemia and related proliferations, Am J Clin Path, 2007;127:850–59.
- Starkebaum G, Chronic neutropenia associated with autoimmune disease, Semin Hematol, 2002;39:121–7.
- Starkebaum G, Loughran TP Jr, Gaur LK, et al., Immunogenetic similarities between patients with Felty’s syndrome and those with clonal expansion of large granular lymphocytes in rheumatoid arthritis, Arthritis Rheum, 1997;40:624–6.
- Scquizzato E, Teramo A, Miorin M, et al., Genotypic evaluation of Killer immunoglobulin-like receptors in NKtype lymphoproliferative disease of granular lymphocytes, Leukemia, 2007;21:1060–69.
- Zambello R, Facco M, Della Chiesa M, et al., Expression and function of KIR and natural cytotoxicity receptors in NK-type lymphoproliferative disease of granular lymphocytes, Blood, 2003;102:1797–1805.
- Semenzato G, Zambello R, Starkebaum G, et al., The lymphoproliferative disease of granular lymphocytes: updated criteria for diagnosis, Blood, 1997;89:256–60.
- Sabnani I, Tsang P, Are clonal T-cell large granular lymphocytes to blame for unexplained haematological abnormalities?, Br J Haematol, 2006;136:30–37.
- Chen X, Bai F, Sokol L, et al., A critical role for DAP10 and DAP12 in CD8+ T-cell mediated tissue damage in large granular lymphocyte leukemia, Blood, 2009;113:3226–34.
- Lima M, Almeida J, Dos Anjos Teixeira M, et al., TCRalphabeta+/CD4+ large granular lymphocytosis: a new clonal T-cell lymphoproliferative disorder, Am J Pathol, 2003; 163:763–71.
- Osuji N, Beiske K, Randen U, et al., Characteristic appearances of the bone marrow in T-cell large granular lymphocyte leukemia, Histopathology, 2007;50:547–54.
- Osuji N, Matutes E, Catovsky D, et al., Histopathology of the Spleen in T-Cell Large Granular Lymphocyte Leukemia and T-Cell Prolymphocytic Leukemia: A Comparative Review, Am J Surg Pathol, 2005;29:935–41.
- Alekshun TJ, Tao J, Sokol L, Aggressive T-cell large granular lymphocyte leukemia: a case report and review of the literature, Am J Hematol, 2007;82:481–5.
- Bourgault-Rouxel AS, Loughran TP Jr, Zambello R, et al., Clinical spectrum of gammadelta+ T cell LGL leukemia: analysis of 20 cases, Leuk Res, 2008;32:45–8.
- Lima M, Almeida J, Santos AH, et al., Immunophenotypic analysis of the TCR-Vbeta repertoire in 98 persistent expansions of CD3(+)/TCR-alphabeta(+) large granular lymphocytes:utility in assessing clonality and insights into the pathogenesis of the disease, Am J Pathol, 2001;159: 1861–8.
- Morice WG, Kurtin PJ, Leibson PJ, et al., Demonstration of aberrant T-cell and natural killer-cell antigen expression in all cases of granular lymphocytic leukaemia, Br J Haematol, 2003;120:1026–36.
- Fischer L, Hummel M, Burmeister T, et al., Skewed expression of natural-killer (NK)-associated antigens on lymphoproliferations of large granular lymphocytes (LGL), Hematol Oncol, 2006;24:78–85.
- Osuji N, Del Giudice I, Matutes E, et al., CD52 expression in T-cell large granular lymphocyte leukemia – implications for treatment with alemtuzumab, Leuk Lymphoma, 2005;46: 723–7.
- Wong KF, Chan JC, Liu HS, et al., Chromosomal abnormalities in T-cell large granular lymphocyte leukemia: report of two cases and review of the literature, Br J Haematol, 2002;116:598–600.
- Lamy T, Liu JH, Landowski TH, et al., Dysregulation of CD95/CD95 ligand-apoptotic pathway in CD3(+) large granular lymphocyte leukemia, Blood, 1998;92:4771–7.
- Yang J, Epling-Burnette PK, Painter JS, et al., Antigen activation and impaired Fas-induced death-inducing signaling complex formation in T-large granular lymphocyte leukemia, Blood, 2008;111:1610–16.
- Shah MV, Zhang R, Irby R, et al., Molecular profiling of LGL leukemia reveals role of sphingolipid signaling in survival of cytotoxic lymphocytes, Blood, 2008;112:770–81.
- Garrido P, Ruiz-Cabello F, Barcena P, et al., Monoclonal TCR-Vbeta 13.1+/CD4+/NKa+/CD8-/+dim T-LGL lymphocytosis: evidence for an antigen-driven chronic T-cell stimulation origin, Blood, 2007;109:4890–98.
- Handgretinger R, Geiselhart A, Moris A, et al., Pure red-cell aplasia associated with clonal expansion of granular lymphocytes expressing killer-cell inhibitory receptors, N Engl J Med, 1999;340:278–84.
- Osuji N, Matutes E, Tjonnfjord G, et al., T-cell large granular lymphocyte leukemia: A report on the treatment of 29 patients and a review of the literature, Cancer, 2006;107: 570–78.
- Matutes E, Wotherspoon AC, Parker NE, et al., Transformation of T-cell large granular lymphocyte leukemia into a high-grade large T-cell lymphoma, Br J Haematol, 2001;115:801–6.
- Loughran TP Jr, Kidd PG, Starkebaum G, Treatment of large granular lymphocyte leukemia with oral low-dose methotrexate, Blood, 1994;84:2164–70.
- Anoop P, Ravindranathan G, Osuji N, et al., Epstein-Barr virus negative large B-cell lymphoma during long term immunomodulatory therapy for T-cell large granular lymphocytic leukaemia, Br J Haem, 2009 (Epub ahead of print).
- Subbiah V, Viny AD, Rosenblatt S, et al., Outcomes of splenectomy in T-cell large granular lymphocyte leukemia with splenomegaly and cytopenias, Exp Hematol, 2008; 36:1078–83.
- Tsirigotis P, Venetis E, Kapsimali V, et al., 2-deoxycoformycin in the treatment of T-large granular lymphocyte leukemia, Leuk Res, 2003;27:865–7.
- Sternberg A, Eagleton H, Pillai N, et al., Neutropenia and anaemia associated with T-cell large granular lymphocyte leukemia responds to fludarabine with minimal toxicity, Br J Haematol, 2003;120:699–701.
- Tse E, Chan JC, Pang A, et al., Fludarabine, mitoxantrone and dexamethasone as first-line treatment for T-cell large granular lymphocyte leukemia, Leukemia, 2007;21:2225–56.
- Alekshun TJ, Sokol L, Diseases of large granular lymphocytes, Cancer Control, 2007;14:141–50.
- Epling-Burnette PK, Sokol L, Chen X, et al., Clinical improvement by farnesyltransferase inhibition in NK large granular lymphocyte leukemia associated with imbalanced NK receptor signaling, Blood, 2008;112:4694–8.