The Spectrum of T-cell and Natural Killer – Large Granular Lymphocytic Proliferations

European Haematology, 2010;4:65-9

Abstract:

Large 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: estella.matutes@icr.ac.uk

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.
Aetiology
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.
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Keywords: T cells, natural killer, large granular lymphocyte (LGL), apoptosis, immunosuppressive, leukaemia, apoptosis, killer immunoglobulin receptor (KIR), T-cell receptor (TCR)