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 (LGL) 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. + T-LGL LEUKEMIA Download Section PDF Listen +++ +++ Etiology and Pathogenesis ++ 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. Epstein-Barr virus implicated in some cases of NK-LGL. Leukemic cells have features of antigen-activated cytotoxic T lymphocytes (CTL), suggesting 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 (e.g., neutropenia, rheumatoid arthritis). +++ Clinical Features ++ About half of patients have palpable splenomegaly. About one-third of patients have recurrent bacterial infections and/or "B symptoms" (e.g., low-grade fevers, night sweats, and/or weight loss) (aggressive variant) (see Table 58–1). About one-quarter of patients have rheumatoid arthritis, often with features of "Felty syndrome." Less than 10 percent of patients have lymphadenopathy. ++Table Graphic Jump LocationTABLE 58–1COMPARATIVE FEATURES OF LARGE GRANULAR LYMPHOCYTIC LEUKEMIAView Table||Download (.pdf) TABLE 58–1 COMPARATIVE FEATURES OF LARGE GRANULAR LYMPHOCYTIC LEUKEMIA Variable T-cell LGL Leukemia (Indolent type) T-cell LGL leukemia (Aggressive type) NK-LGL leukemia (Aggressive type) Chronic NK Lymphocytosis (Indolent type) Median age (years) 60 40 40 60 Male:female ratio 1 2 1 7 Phenotype CD3+CD16+CD57+Clonal TCRαβ rearrangement CD3+CD16+CD56+Clonal TCRαβ rearrangement CD3–CD16+CD56+ CD3–CD16+ CD56+ Clinical features One-third asymptomatic Two-thirds symptomatic Cytopenias, splenomegaly, rheumatoid arthritis (~25% of patients). Symptomatic, usually with B symptoms (fever, sweats, weight loss) Lymphadenopathy, hepatosplenomegaly. Symptomatic, usually with B symptoms (fever, sweats, weight loss) Lymphadenopathy, hepatosplenomegaly Most patients are asymptomatic; about 40% with signs (cytopenias, vasculitis, neuropathy, splenomegaly) Treatment approach Observation or immunosuppressive therapy, if required Acute lymphoblastic leukemia-type therapy Acute lymphoblastic leukemia-type therapy Observation or immunosuppressive therapy if required Prognosis Relatively Good Poor Very Poor Relatively Good Source: Williams Hematology, 8th ed, Chap. 96, Table 96–3, p. 1495 +++ Laboratory Features ++ Immunophenotype of LGL cells in blood and marrow: CD3+CD8+CD16+ CD57+ CD4-CD56-, and, often, HLA-DR+. Patients have clonal T-cell–receptor gene rearrangement(s), usually involving α and β chains. Nearly 85 percent of patients have neutropenia, often less than 0.5 × 109/L. 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. About one-quarter 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) (Fig. 58–1). More than 90 percent 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. Patients commonly have elevated levels of certain autoantibodies and other serologic abnormalities (Table 58–2). ++ FIGURE 58–1 Blood film. Four large granular lymphocytes with azurophilic granules in cytoplasm. (Reproduced with permission from Bruce Cheson.) (Source: Williams Hematology, 8th ed, Chap. 96, Fig. 96–1, p. 1494.) Graphic Jump LocationView Full Size||Download Slide (.ppt) ++Table Graphic Jump LocationTABLE 58–2SEROLOGIC FINDINGS IN CD3+ LGL LEUKEMIAView Table||Download (.pdf) TABLE 58–2 SEROLOGIC FINDINGS IN CD3+ LGL LEUKEMIA Feature Percent of Patients Rheumatoid factor ~60 Circulating immune complexes ~50 Antinuclear antibody ~40 Antineutrophil antibody ~40 Polyclonal hypergammaglobulinemia ~25 Positive antiglobulin (Coombs) test ~15 Monoclonal gammopathy ~8 Source: Williams Hematology, 8th ed, Chap. 96, Table 96–2, p. 1494. +++ Differential Diagnosis ++ T-LGL leukemia should be considered in patients with increased blood LGL counts and — 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 (Table 58–1). +++ Therapy, Course, and Prognosis ++ Chronic. Unusual cases that coexpress CD3 and CD56 may have a more aggressive clinical course. Significant morbidity/mortality from infections. Low-dose methotrexate 10 mg/m2 orally once weekly or cyclophosphamide 100 mg PO daily, or cyclosporine may be effective in alleviating neutropenia/anemia. Coexisting B-cell neoplasms (e.g., essential monoclonal gammopathy or chronic lymphocytic leukemia) occur in 25 percent of patients. + NK-LGL LEUKEMIA Download Section PDF Listen +++ +++ Etiology and Pathogenesis ++ Epstein-Barr virus infection implicated in the pathogenesis. +++ Clinical Features ++ Fever, night sweats, weight loss are common (see Table 58–1). Massive hepatosplenomegaly typical. Lymphadenopathy and gastrointestinal tract involvement are common. Patients tend to be of younger age than those with CD3+ LGL leukemia. +++ Laboratory Features ++ LGL lack expression of CD3 and clonal T-cell receptor rearrangements. NK-leukemic LGL is usually CD4+CD16+CD56+CD8–CD57-. LGL counts are generally high and may exceed 50 × 109/L. Severe neutropenia (e.g., < 0.5 × 109/L) is observed in less than one-fifth of patients. Anemia and thrombocytopenia very common. Coagulopathy frequently occurs. Clonal cytogenetics may be present. Serologic abnormalities listed in Table 58–2 are uncommon in NK-LGL leukemia. +++ Therapy, Course, and Prognosis ++ Acute presentation and aggressive course is common. Patients with chronic NK lymphocytosis may not require treatment. Effective combination chemotherapy has not been reported. Patients with NK-LGL usually die a few months after diagnosis despite aggressive multidrug chemotherapy. ++ For a more detailed discussion, see Thomas P. Loughran, Marshall E. Kadin: Large Granular Lymphocytic Leukemia. Chap. 96, p. 1493 in Williams Hematology, 8th ed.