Large granular lymphocytic leukemia (LGLL) was initially described in the 1970s,^1,2 and further characterized in 1985,³ as a clonal disorder of cytotoxic cluster of differentiation (CD)8+ T-cells involving blood, marrow, liver, and spleen, and clinically manifesting as an indolent proliferation of large granular lymphocytes (LGLs). Normally LGLs comprise 10 to 15 percent of blood mononuclear cells and may be either surface 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 × 10⁹/L. According to the 2008 World Health Organization (WHO) Classification of Tumors of the Hematopoietic and Lymphoid Tissues, T-cell large granular lymphocytic leukemia (T-LGLL) is defined as a persistent (>6 months) and usually clonal expansion of surface CD3 (sCD3+) LGL without a clearly identifiable cause.⁴ The corresponding NK cell type of LGLL (sCD3–, CD16+), referred to as chronic lymphoproliferative disorders of NK cells (CLPD-NK), was included as a provisional diagnosis in the 2008 WHO classification and is similarly defined.⁵ LGLL represent 2 to 3 percent of mature lymphocytic leukemias.⁴ CLPD-NK should be distinguished from the acute and often fulminant aggressive NK cell leukemia (ANKL),⁶ which is associated with Epstein-Barr virus (EBV) infection of the neoplastic NK cells. In contrast to ANKL, both T-LGLL and CLPD-NK are clinically indolent and have a low risk of transformation into an aggressive malignancy. The main impact of LGLL on patients’ lives, and the most common indication for therapy, derives from the occurrence and severity of single lineage or multilineage cytopenias and by the resultant infections and transfusion requirement.

The etiologies of T-LGLL and CLPD-NK are not definitively established. It has been postulated, based on the analysis of T-cell receptor (TCR) complementarity determining region 3 (CDR3) patterns and Vβ family usage, that chronic antigenic stimulation results in the proliferation and/or increased survival of LGLs. Moreover, leukemic T-LGL show characteristics of antigen-activated cytotoxic T lymphocytes (CTLs), suggesting that an initial step in T-LGLL could be an antigen-driven clonal expansion.^7,8,9 Clonal drift in the T-cell repertoire with a change in the dominant clone occurs in approximately one-third of cases during the course of the disease,¹⁰ implying that a dynamic process of clonal 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.¹¹ Some evidence implicates cytomegalovirus (CMV) as the 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 LGL survival and expansion and, therefore, contribute to the pathogenesis of LGLL. Patients with T-LGLL frequently have humoral immune abnormalities, including positive tests for rheumatoid factor (RF)—with or without clinical arthrosynovitis–antinuclear antibodies, antineutrophil cytoplasmic antibodies, polyclonal hypergammaglobulinemia, hypogammaglobulinemia, and circulating immune complexes (Table 94–1).¹³ The high incidence of autoimmunity in patients with LGLL and the fact that the autoimmune manifestations often precede the occurrence of LGL expansions suggest that sustained immune activation may contribute to the pathogenesis of LGLL. However, because the detection of asymptomatic expansions of LGL in the blood requires examination of a blood film or flow cytometry, this temporal association should be interpreted with caution.

Normal CTL homeostasis is maintained, in part, through activation-induced cell death (AICD). Leukemic T-LGL constitutively express high levels of Fas (CD95) and Fas ligand (CD178), yet are resistant to Fas-mediated death.¹⁴ Some disease manifestations, such as neutropenia, are associated, at least in part, with circulating CD178 in these patients.¹⁵ High levels of proinflammatory or prosurvival cytokines associated with sustained immune activation could account for at least part of the mechanism driving LGL leukemias.^16,17,18,19 Likewise, constitutive activation of survival signaling pathways could represent a central pathogenetic mechanism in LGLL. Evidence for the importance of signal transducer and activator of transcription (STAT)-3/Mcl-1, phosphatidylinositol 3′-kinase (PI3K)/AKT, and sphingolipid signaling leading to apoptotic resistance have all been demonstrated.^20,21,22 Mutations in STAT3 were identified in approximately 40 percent of T-LGLL and in CLPD-NK, and STAT5b mutations have also been detected in T-LGLL.^23,24,25,26 Using a network modeling approach, it was also found that interleukin (IL)-15 and platelet-derived growth factor (PDGF) are the two key mediators controlling interactions amongst these survival pathways.²⁷ In a transgenic mouse model resulting in constitutive murine IL-15 production, there is clonal expansion of LGLs that show overlapping features with human LGLL diseases.^28,29

Targeting of normal tissue by leukemic LGL may also play a role in disease pathogenesis. Lysis of endothelial cells resulting from activation of NK receptors via signaling partners DAP10 and DAP12 could explain development of pulmonary hypertension observed in some patients with LGL leukemia.³⁰

The marrow biopsy in T-LGLL may be hypo-, normo-, or hypercellular, with often preserved trilineage hematopoiesis. There may be occasional nodules of reactive CD4+ and B lymphocytes as well as scattered LGL, which are better seen in the aspirate. The presence of interstitial and/or intrasinusoidal clusters of at least eight CD8+ and/or TIA-1+ LGLs or at least six granzyme B+ LGLs has been correlated with marrow involvement by LGLL.³¹ Various superimposed findings may reflect secondary immune diseases such as granulocyte maturation arrest and absence of red cell precursors (red cell aplasia). T-LGL leukemia invariably affects the spleen, where the major findings are leukemic cell infiltration of the red pulp cords and sinuses, plasma cell hyperplasia, and prominent germinal centers (Fig. 94–1).^3,32 Hepatic sinusoids and portal areas are infiltrated by LGL. Lymph nodes usually are not involved but can have expanded paracortical areas containing plasma cells and LGLs.

T-LGLL and CLPD-NK share overlapping immunophenotypic features in that both often express the NK-associated markers CD16 and CD57. Aberrant expression of NKp46 (CD335), which is normally selectively expressed by NK cells, occurs in T-LGLL.³³ CD56, which is constitutively expressed by circulating NK cells in healthy individuals, may be downregulated in CLPD-NK, and its expression in T-LGLL may be associated with a less-favorable clinical course.³⁴ T-leukemic LGLs usually are CD3+, CD4–, CD8+, CD16+, CD56–, CD57+, and often human leukocyte antigen (HLA)-DR+. Less commonly, leukemic LGLs express CD4 with variable CD8 expression.³⁵ Leukemic T-LGL usually express the TCR αβ+ heterodimer, although cases with similar clinical features have been described that express the γδ TCR heterodimer.³⁶ In contrast to normal LGL of T-cell origin, leukemic LGL express significantly lower levels of CD5 and show abnormal killer immunoglobulin-like receptor (KIR) expression.³⁷ The neoplastic NK cells often demonstrate abnormal KIR expression with either complete absence of surface KIR or restricted KIR expression indicating outgrowth of a clonal population.³⁸