Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + DEFINITION Download Section PDF Listen +++ ++ T-cell large-granular lymphocytic (T-LGL) leukemia results from the clonal expansion of large granular lymphocytes (LGLs) with a T-cell (CD3+) phenotype and a clonal T-cell receptor gene rearrangement(s). Natural killer (NK)-LGL leukemia is a clonal expansion of LGL with a NK cell (CD3–) phenotype. It lacks convenient markers to determine clonality, such as antigen receptor rearrangements. (See Chap. 66.) + T-LGL LEUKEMIA Download Section PDF Listen +++ +++ Etiology and Pathogenesis ++ There is suggestive evidence of a role for human T lymphotropic virus (HTLV) retroviral infection in some patients. Most patients are not infected with either HTLV-I or HTLV-II. Cytomegalovirus implicated in rare cases of CD4+ T-LGL. Leukemic cells have features of antigen-activated cytotoxic T lymphocytes, suggesting a role for antigen in initial LGL expansion. Constitutive overexpression of the Fas ligand (CD178), which also is found at high levels in patients’ sera, may be a factor in many disease manifestations (eg, neutropenia, rheumatoid arthritis). +++ Clinical Features ++ About half of patients have palpable splenomegaly. (Table 57–1) About one-third of patients have recurrent bacterial infections. “B symptoms” (eg, low-grade fevers, night sweats, and/or weight loss) (aggressive variant) are very infrequent. About one-fourth of patients have rheumatoid arthritis, often with features of “Felty syndrome.” Less than one-tenth of patients have lymphadenopathy. ++Table Graphic Jump LocationTABLE 57–1CLINICAL FEATURES OF T-CELL LARGE GRANULAR LYMPHOCYTIC LEUKEMIAView Table||Download (.pdf) TABLE 57–1CLINICAL FEATURES OF T-CELL LARGE GRANULAR LYMPHOCYTIC LEUKEMIA Pandolfi (1990) Loughran (1993) Dhodapkar (1994) Semenzato (1997) Neben (2003) Bareau (2010) Number of patients 151 129 68 162 44 201 Median age 55 57 61 59 63 59 Male/Female 1.3 0.8 1 0.8 1.0 0.8 Symptomatic 72% – 69% – 73% 82% Splenomegaly 50% 50% 19% 50% 35% 24% Hepatomegaly 34% 23% 1% 32% – 10% Adenopathy 13% 1% 3% 13% 5% 6% B symptoms – – 12% – – 7% Infections 38% 39% 15% 56% – 23% Rheumatoid arthritis 12% 28% 26% 36% 20% 17% Rheumatoid factor – 57% 61% 43% 48% 41% Antinuclear antibodies – 38% 44% 38% 48% 48% Autoimmune cytopenias – – 7% 9% 5% 7% Lymphocytosis 29% LGL > 4 × 109/L 52% 52% – – – 14% LGL 1–4 × 109/L 38% 40% – – – 50% LGL < 1 × 109/L 10% 8% – 7% – 36% Neutropenia Moderate (< 1.5 × 109/L) 64% 84% 74% – 52% 61% Severe (0.5 × 109/L) 7% 48% 40% 37% 41% 26% Anemia Any severity 25% 49% 51% 26% 89% 24% Severe (Hgb < 8 g/dL) 37% – 19% – 36% 7% Thrombocytopenia 9% 19% 20% 29% 36% 19% LGL marrow infiltration 67% 88% – 76% 83% 72% Hypergammaglobulinemia – 45% 5% 43% – 35% Monoclonal gammopathy – 45% 8% – – 10% Need for treatment 30% 73% 69% 33% 80% 44% LGLL-related death 14% 36% 8% 27% – 7% Hgb, hemoglobin; LGL, large granular lymphocyte; LGLL, large granular lymphocytic leukemia.Modified with permission from Bareau B, Rey J, Hamidou M, et al. Analysis of a French cohort of patients with large granular lymphocyte leukemia: A report on 229 cases. Haematologica. 2010;95(9):1534–1541.Source: Williams Hematology, 9th ed, Chap. 94, Table 94–1. +++ Laboratory Features ++ Approximately half of the patients have anemia, often caused by pure red cell aplasia and/or autoimmune hemolytic anemia. Approximately one-fifth of patients have thrombocytopenia. Nearly three-fourths of patients have neutropenia, often less than 0.5 × 109/L. About one-fourth of patients do not have increased blood total lymphocyte counts. The median LGL count in patients is 4.0 × 109/L (normal mean: 0.3 × 109/L) (Figure 57–1). Immunophenotype of LGL cells in blood and marrow: CD3+CD8+CD16+CD57+CD4–CD56–, and, often, HLA-DR+. LGL cells have clonal T-cell–receptor gene rearrangement(s), usually involving α and β chains. Patients commonly have elevated levels of certain autoantibodies and other serologic abnormalities (see Table 57–1). More than 90% of patients have LGL infiltration of the marrow and splenic red pulp. Marrow infiltration may be nodular or interstitial. If interstitial, it may be difficult to appreciate involvement without staining for neoplastic cells using immunocytochemistry (Figure 57–2). ++ FIGURE 57–1Buffy coat blood film. High magnification image of two large granular lymphocytes (LGLs) displaying larger size than characteristic blood small lymphocytes and with more cytoplasm. Cytoplasmic granules are conspicuous in both LGLs. (Reproduced with permission from Lichtman’s Atlas of Hematology, www.accessmedicine.com.) Graphic Jump LocationView Full Size||Download Slide (.ppt) ++ FIGURE 57–2Morphology and immunohistochemical analysis of T-cell large-granular lymphocytic (T-LGL) leukemia in peripheral blood (PB) and bone marrow (BM). Upper panels show high-power images of circulating large granular lymphocytes (LGLs) from a patient with T-LGL leukemia (original magnification = 500×). Note for comparison the small lymphocyte next to the LGL in the right panel. LGLs are slightly larger than other lymphocytes, and they have more nuclear membrane irregularity, moderate amounts of pale blue cytoplasm, and fine cytoplasmic granules. The lower panels show foci of atypical clusters of CD8+ (left) and granzyme B+ (right) lymphocytes in the bone marrow of a patient with T-LGL leukemia (original magnification = 500×). The identification of atypical clusters of at least eight CD8+ and/or at least six granzyme B+ lymphocytes supports the diagnosis of LGL leukemia in the appropriate clinical setting. (Source: Williams Hematology, 9th ed, Chap. 94, Fig, 94–1.) Graphic Jump LocationView Full Size||Download Slide (.ppt) +++ Differential Diagnosis ++ T-LGL leukemia should be considered in patients with increased blood LGL counts and the following: — Chronic or cyclic neutropenia — Pure red cell aplasia — Rheumatoid arthritis T-LGL leukemia can be distinguished from NK-LGL leukemia by immunophenotype and clonal T-cell–receptor gene rearrangement. NK-LGL leukemia is a much more aggressive disease. Hepatosplenic T-cell lymphoma typically occurs in young men and follows a more aggressive course. (See Chap. 66). +++ Therapy, Course, and Prognosis ++ This disease is usually chronic, and treatment is not always indicated. Unusual cases that coexpress CD3 and CD56 may have a more aggressive clinical course. Significant morbidity/mortality from infections occurs. Indications for therapy include (1) severe neutropenia or moderate neutropenia and infection, (2) transfusion-dependent anemia, (3) platelet count < 50 × 109/L, and (4) coincident autoimmune diseases requiring therapy. Low-dose methotrexate 10 mg/m2, orally, once weekly or cyclophosphamide 100 mg, orally, daily, or cyclosporine may be effective in alleviating neutropenia/anemia. ++ For a more detailed discussion, see Pierluigi Porcu and Ahron G. Freud: Large Granular Lymphocytic Leukemia, Chap. 94 in Williams Hematology, 9th ed.
For a more detailed discussion, see Pierluigi Porcu and Ahron G. Freud: Large Granular Lymphocytic Leukemia, Chap. 94 in Williams Hematology, 9th ed.