Large granular lymphocyte (LGL) leukemia is characterized by peripheral blood and marrow lymphocytic infiltration with clonal LGLs, splenomegaly, and cytopenias, most commonly neutropenia. LGL leukemia arises most frequently (85 percent) from a T cell lineage or, less commonly (15 percent), from a natural killer (NK) cell lineage [1,2]. The etiology, clinical features, diagnosis, and treatment of natural killer (NK) cell LGL disorders will be discussed here. T cell LGL leukemia is discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia" and "Treatment of large granular lymphocyte leukemia".)
THE LARGE GRANULAR LYMPHOCYTE
The large granular lymphocyte (LGL) is a morphologically distinct lymphoid subset comprising 10 to 15 percent of normal peripheral blood mononuclear cells (picture 1). The absolute number of LGLs in the peripheral blood of normal subjects is 200 to 400/microL. LGLs arise from two major lineages:
- CD3 positive, CD 57 positive, CD56 negative T cells, representing in vivo antigen-activated cytotoxic effector T cells
- CD3-, CD56+ natural killer (NK) cells. It had been postulated that such NK cells mediate non-major histocompatibility complex (MHC)-restricted cytotoxicity. It is now established that NK cells possess specific receptors for MHC class I molecules named "killer-cell Ig-like inhibitory receptor" (KIR) and "killer-cell activating receptor" (KAR). Interactions between these receptors and MHC class I molecules on target cells may inhibit or activate NK cell-mediated cytotoxicity.
Secondary benign (nonclonal) LGL expansions have been reported in the following clinical situations:
- Viral infections (eg, EBV, HBV, HCV, HIV, CMV), connective tissue disease, immune thrombocytopenia (ITP), non-Hodgkin lymphoma, various skin disorders, and the hemophagocytosis syndrome are the main non-malignant situations that have been associated with reactive T cell LGL expansion (ie, CD3+ cells with T cell receptor genes in germline configuration) [1,3-5].
- The myelodysplastic syndrome and solid tumors are sometimes associated with increased numbers of circulating NK LGL cells .
- NK cell proliferative disorders have been found in atomic-bomb survivors presenting with neutropenia .