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

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)-〈β+ 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.