1Large Granular Lymphocyte Leukemia 作者：Lubomir Sokola, Thomas P. Loughran, Jr.b【关键词】 T-cell,LGL,leukemia,Aggressive,NK-cell,leukemia,Cytopenia,AutoimmunityLEARNING OBJECTIVES After completing this course, the reader will be able to: Discuss the basic principles of molecular and cellular biology of LGL leukemia. Describe distinct clinical entities among disorders of LGLs. Jinchutou.com2Discuss the diagnostic criteria for T-cell LGL leukemia. Discuss the therapeutic algorithm of LGL leukemia. ABSTRACT Clonal disorders of large granular lymphocytes (LGLs) represent a spectrum of biologically distinct lymphoproliferative diseases originating either from mature T cells (CD3+) or natural killer (NK) cells (CD3). Both subtypes, T-cell and NK-cell LGL leukemia, can manifest as indolent or aggressive disorders. The majority of patients with T-cell LGL leukemia have a clinically indolent course with a median survival time 10 years. Immunosuppressive therapy with low-dose methotrexate, cyclophosphamide, or cyclosporine A can control symptoms and cytopenias in more than 50% of patients, but this approach is not curative. Several cases of an aggressive variant (CD3+CD56+) of T-cell LGL leukemia with a poor prognosis have also been reported. Aggressive NK-cell LGL leukemia is usually a rapidly progressive disorder associated with Epstein-Barr virus (EBV), with a higher prevalence in Asia and South America. This disease is usually Jinchutou.com3refractory to conventional chemotherapy, with a median survival time of 2 months. Chronic NK-cell leukemia/lymphocytosis is a rare EBV-negative disorder with an indolent clinical course. The malignant origin of this subtype is uncertain because clonality is difficult to determine in LGLs of NK-cell origin. DEFINITION AND CLASSIFICATION Large granular lymphocytes (LGLs) represent 10%15% of the total peripheral blood mononuclear cells in normal adults 1. The majority of these cells (85%) are derived from the CD3 natural killer (NK)cell lineage, and a minority are derived from the CD3+ T-cell lineage (15%). Cytologically, LGLs are medium to large cells with eccentric nuclei and abundant cytoplasm with coarse azurophilic granules (Fig. 1). T-cell LGLs are post-thymic, antigen-primed cytotoxic CD8+ T lymphocytes. NK-cell LGLs belong to the innate immune system with the capability of non-major histocompatibility complex (MHC)restricted cytotoxicity. LGL leukemia was initially described in 1985 as a clonal Jinchutou.com4disorder involving blood, marrow, and spleen 2. In 1993, we proposed two LGL disorders based on either T-cell or NK-cell lineage, which was subsequently adopted by all pathology classification systems 3. Clonal disorders of LGLs represent a biologically heterogeneous spectrum of lymphoid malignancies (Fig. 2) 4, 5. Both the T-cell and NK-cell subtypes can clinically present as an indolent or aggressive diseases (Table 1). World Health Organization (WHO) classification of lymphoid malignancies includes T-cell LGL leukemia and aggressive NK-cell leukemia as two separate entities among T-cell/NK-cell lymphomas/leukemias 6. Since only rare cases of the aggressive variant of T-cell LGL leukemia have been described 7, this subtype was not given separate status in the WHO classification. Transient (6 month) expansions of LGLs are two benign conditions in the spectrum of disorders of LGLs 8. Transient reactive populations of LGLs have been detected in patients with viral infections, autoimmune diseases, and malignancies, and in patients after solid organ transplantation 913. The reactive LGLs are polyclonal with expression of the T-cell (CD3+) immunophenotype in the majority of cases. LGL count normalizes spontaneously or Jinchutou.com5with therapy of underlying condition, usually within 6 months. Since it is difficult to determine clonality for NK cells, it is uncertain whether chronic NK-cell lymphocytocis represents a chronic NK-cell leukemia. In the absence of a clonal marker, clinical presentation is the most important factor available for the differential diagnosis of these two conditions. Patients with systemic symptoms or infiltration of the spleen, liver, or bone marrow could be appropriately classified in the category of chronic NK-cell leukemia. Asymptomatic patients might be better given a diagnosis of benign chronic NK-cell lymphocytosis. In this review we focus mainly on diseases of LGLs included in the WHO classification. EPIDEMIOLOGY LGL leukemia comprises 2%5% of all T-cell/NK-cell malignancies, with only 400 cases reported in the literature 8. Indolent T-cell LGL leukemia is the most common subtype, representing approximately 85% of all cases diagnosed in Western countries. The male-to-female ratio is approximately equal to one. This entity is more frequently diagnosed in older individuals, with a median age at diagnosis of 60 years Jinchutou.com6(Table 1). The aggressive type of NK-cell LGL