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Clonal diseases of larger granular lymphocytes (LGLs) can arise from either T cells or natural killer (NK) cells. Although T-LGL and NK-LGL cells have a similar morphology, they have distinctive surface antigen phenotypes and represent two discrete diseases with different clinical features and clinical outcomes. T-LGL leukemia is defined as a clonal proliferation of CD3+ LGL; NK-LGL leukemia is defined as a clonal proliferation of CD3– LGL. The clinical presentation of NK-LGL leukemia is different from that of T-LGL leukemia. Patients with NK-LGL leukemia usually are younger, more often have systemic B symptoms, and typically have more massive hepatosplenomegaly. Lymphadenopathy and gastrointestinal tract involvement are common. Examination of the blood film is important in making the diagnosis of T-LGL leukemia because approximately 25 percent of patients do not have an increased total lymphocyte count. Most patients with T-LGL leukemia have chronic neutropenia, and approximately half have neutrophil counts less than 500/μL (0.5 × 109/L). In contrast, less than one-fifth of patients with NK-LGL have severe neutropenia. Anemia is observed in 50 percent and 100 percent of cases of T-LGL and NK-LGL leukemia, respectively. Patients with T-LGL leukemia frequently have humoral immune abnormalities, such as elevated rheumatoid factor, and red cell aplasia may occur. Morbidity and mortality usually result as the consequence of recurrent and sometimes lethal infections secondary to severe chronic neutropenia. In contrast to the chronic course of T-LGL leukemia, NK-LGL leukemia has an acute presentation and poor clinical outcome. Most patients die within 2 months of diagnosis from disseminated disease with multiorgan failure despite aggressive combination chemotherapy.

Acronyms and Abbreviations

Acronyms and abbreviations that appear in this chapter include: CD, cluster of differentiation; CMV, cytomegalovirus; CTL, cytotoxic T lymphocytes; HLA, human leukocyte antigen; HTLV, human T-cell leukemia virus; KIR, killer immunoglobulin-like receptor; LGL, large granular lymphocyte; NK, natural killer cell; NK-LGL, natural killer cell large granular lymphocyte; PI3K, phosphatidylinositol 3′-kinase; STAT, signal transducer and activator of transcription; TCR, T-cell receptor; T-LGL, T-cell large granular lymphocyte.

Large granular lymphocytic (LGL) leukemia was initially described in 1985 as a clonal disorder involving blood, marrow, liver, and spleen.1 LGLs comprise 10 to 15 percent of normal blood mononuclear cells and may be of either CD3– (natural killer [NK] cell) or CD3+ (T-cell) lineage. LGL leukemia is of two types: T-LGL leukemia and NK-LGL leukemia, reflecting different cellular origins.2,3 T-LGL leukemia is defined as a clonal proliferation of CD3+ LGL; NK-LGL leukemia is defined as a clonal proliferation of CD3– LGL. T-cell receptor gene rearrangement studies are useful for confirming the clonality of T-LGL leukemia. NK cell leukemia also is a clonal disease, as demonstrated by cytogenetics.4 However, NK cells and NK cell leukemia lack convenient clonal markers, such as antigen receptor gene rearrangements.

The etiology of T-LGL leukemia is unknown. Infection with human T-cell leukemia virus (HTLV)-II has been detected in two patients.5 However, most patients ...

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