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 ...