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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.