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CHAPTER 94 DEFINITION AND HISTORY

LARGE GRANULAR Large granular lymphocytic leukemia (LGLL) was initially described in
the 1970s, and further characterized in 1985, as a clonal disorder of
1,2
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LYMPHOCYTIC LEUKEMIA cytotoxic cluster of differentiation (CD)8+ T-cells involving blood, mar-
row, liver, and spleen, and clinically manifesting as an indolent prolifer-
ation of large granular lymphocytes (LGLs). Normally LGLs comprise
10 to 15 percent of blood mononuclear cells and may be either surface
Pierluigi Porcu and Aharon G. Freud CD3+ (T-cell) or surface CD3– (natural killer [NK] cell). The absolute
number of LGLs in the blood of normal subjects is 0.2 to 0.4 × 10 /L.
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According to the 2008 World Health Organization (WHO) Classifica-
tion of Tumors of the Hematopoietic and Lymphoid Tissues, T-cell large
SUMMARY granular lymphocytic leukemia (T-LGLL) is defined as a persistent (>6
months) and usually clonal expansion of surface CD3 (sCD3+) LGL
Indolent clonal proliferations of large granular lymphocytes (LGLs) can arise without a clearly identifiable cause. The corresponding NK cell type
4
from either T cells or natural killer (NK) cells. These diseases show overlap- of LGLL (sCD3–, CD16+), referred to as chronic lymphoproliferative
ping clinical, morphologic, immunophenotypic, and genetic features. T-cell disorders of NK cells (CLPD-NK), was included as a provisional diag-
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large granular lymphocytic leukemia (T-LGLL) and the related provisional nosis in the 2008 WHO classification and is similarly defined. LGLL
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2008 World Health Organization entity, chronic lymphoproliferative disor- represent 2 to 3 percent of mature lymphocytic leukemias. CLPD-NK
ders of NK cells (CLPD-NK), are similarly defined as persistent (>6 months) should be distinguished from the acute and often fulminant aggres-
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and clonal expansions in blood LGLs, often without a clearly identifiable sive NK cell leukemia (ANKL), which is associated with Epstein-
Barr virus (EBV) infection of the neoplastic NK cells. In contrast to
cause. These patients are typically older, present with single lineage or ANKL, both T-LGLL and CLPD-NK are clinically indolent and have
multilineage cytopenias, and often have clinical and laboratory features of a low risk of transformation into an aggressive malignancy. The main
autoimmunity or immune dysfunction. Autoimmune neutropenia, throm- impact of LGLL on patients’ lives, and the most common indication for
bocytopenia, hemolytic anemia, and occasionally pure red cell aplasia may therapy, derives from the occurrence and severity of single lineage or
occur. Patients with T-LGLL frequently have elevated rheumatoid factor and multilineage cytopenias and by the resultant infections and transfusion
clinical hallmarks of rheumatoid arthritis. The diagnosis of LGL leukemia requirement.
requires a high degree of suspicion and careful examination of the blood
film, because a significant fraction of patients do not have an absolute ETIOLOGY AND PATHOGENESIS
lymphocytosis, although the proportion of LGLs is usually increased. Most
patients with T-LGLL and fewer with CLPD-NK have chronic neutropenia, The etiologies of T-LGLL and CLPD-NK are not definitively established.
and approximately half of T-LGLL patients have neutrophil counts less than It has been postulated, based on the analysis of T-cell receptor (TCR)
0.5 × 10 /L. Anemia is observed in approximately half of patients with complementarity determining region 3 (CDR3) patterns and Vβ fam-
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T-LGLL. Morbidity and mortality usually result from recurrent infections ily usage, that chronic antigenic stimulation results in the proliferation
and/or increased survival of LGLs. Moreover, leukemic T-LGL show
secondary to chronic neutropenia, transfusion-related iron overload, and characteristics of antigen-activated cytotoxic T lymphocytes (CTLs),
less frequently from disease acceleration and transformation into a more suggesting that an initial step in T-LGLL could be an antigen-driven
aggressive T/NK leukemia or lymphoma. The treatment approach gener- clonal expansion. Clonal drift in the T-cell repertoire with a change in
7–9
ally consists of immune modulatory or immune suppressive drugs, such the dominant clone occurs in approximately one-third of cases during
as weekly oral methotrexate, cyclophosphamide, cyclosporine, prednisone, the course of the disease, implying that a dynamic process of clonal
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and alemtuzumab. expansion exists that may affect more than one T-cell family in the same
patient. Early studies suggested a possible association with human T-cell
leukemia viruses (HTLVs); however, most patients are not infected with
this agent. Some evidence implicates cytomegalovirus (CMV) as the
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inciting antigen in the rare CD4+ subset of LGLL, but its role in patients
with the more typical CD8+ subtype of T-LGLL is not clear. 12
In the absence of an exogenous antigenic drive, chronic immune
dysregulation and aberrant cytokine production may lead to enhanced
Acronyms and Abbreviations: AICD, activation-induced cell death; ANKL, aggres- LGL survival and expansion and, therefore, contribute to the patho-
sive NK cell leukemia; CD, cluster of differentiation; CDR3, complementarity deter- genesis of LGLL. Patients with T-LGLL frequently have humoral
mining region 3; CLPD-NK, chronic lymphoproliferative disorders of NK cells; CMV, immune abnormalities, including positive tests for rheumatoid factor
cytomegalovirus; CTL, cytotoxic T lymphocyte; EBV, Epstein-Barr virus; FS, Felty (RF)—with or without clinical arthrosynovitis–antinuclear antibodies,
syndrome; HLA, human leukocyte antigen; HSTCL, hepatosplenic T-cell lymphoma; antineutrophil cytoplasmic antibodies, polyclonal hypergammaglobu-
HTLV, human T-cell leukemia virus; IL, interleukin; KIR, killer immunoglobulin-like linemia, hypogammaglobulinemia, and circulating immune complexes
receptor; LGL, large granular lymphocyte; LGLL, large granular lymphocytic leuke- (Table 94–1) . The high incidence of autoimmunity in patients with
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mia; NK, natural killer cell; NK-LGL, natural killer cell–large granular lymphocyte; LGLL and the fact that the autoimmune manifestations often precede
PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol 3′-kinase; RF, the occurrence of LGL expansions suggest that sustained immune acti-
rheumatoid factor; STAT, signal transducer and activator of transcription; TCR, T-cell vation may contribute to the pathogenesis of LGLL. However, because
receptor; T-LGLL, T-cell large granular lymphocytic leukemia; WHO, World Health the detection of asymptomatic expansions of LGL in the blood requires
Organization. examination of a blood film or flow cytometry, this temporal associa-
tion should be interpreted with caution.

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