Natural killer (NK) cell large granular lymphocyte leukemia
- Thierry Lamy, MD, PhD
Thierry Lamy, MD, PhD
- Professor in Hematology
- University of Rennes, France
- Thomas P Loughran, Jr, MD
Thomas P Loughran, Jr, MD
- Director, University of Virginia Cancer Center
- University of Virginia
Large granular lymphocyte (LGL) leukemia is characterized by peripheral blood and marrow lymphocytic infiltration with clonal LGLs, splenomegaly, and cytopenias, most commonly neutropenia. LGL leukemia arises most frequently from a T cell lineage (85 percent) or, less commonly, from a natural killer (NK) cell lineage (15 percent) [1,2]. The etiology, clinical features, diagnosis, and treatment of NK cell LGL disorders will be discussed here. T cell LGL leukemia is discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia" and "Treatment of large granular lymphocyte leukemia".)
THE LARGE GRANULAR LYMPHOCYTE
The large granular lymphocyte (LGL) is a morphologically distinct lymphoid subset comprising 10 to 15 percent of normal peripheral blood mononuclear cells (picture 1). The absolute number of LGLs in the peripheral blood of normal subjects is 200 to 400/microL. LGLs arise from two major lineages:
●CD3 positive, CD 57 positive, CD56 negative T cells, representing in vivo antigen-activated cytotoxic effector T cells
●CD3-, CD56+ natural killer (NK) cells. It had been postulated that such NK cells mediate non-major histocompatibility complex (MHC)-restricted cytotoxicity. It is now established that NK cells possess specific receptors for MHC class I molecules named "killer-cell Ig-like inhibitory receptor" (KIR) and "killer-cell activating receptor" (KAR). Interactions between these receptors and MHC class I molecules on target cells may inhibit or activate NK cell-mediated cytotoxicity.
Secondary benign (nonclonal) LGL expansions have been reported in the following clinical situations:
- Loughran TP Jr. Clonal diseases of large granular lymphocytes. Blood 1993; 82:1.
- Lamy T, Loughran TP Jr. Clinical features of large granular lymphocyte leukemia. Semin Hematol 2003; 40:185.
- Oshimi K. Granular lymphocyte proliferative disorders: report of 12 cases and review of the literature. Leukemia 1988; 2:617.
- Okuno SH, Tefferi A, Hanson CA, et al. Spectrum of diseases associated with increased proportions or absolute numbers of peripheral blood natural killer cells. Br J Haematol 1996; 93:810.
- Imashuku S, Hibi S, Morinaga S, et al. Haemophagocytic lymphohistiocytosis in association with granular lymphocyte proliferative disorders in early childhood: characteristic bone marrow morphology. Br J Haematol 1997; 96:708.
- Imamura N, Kimura A. Neutropenia among survivors of atomic bomb explosion. Lancet 2000; 355:117.
- McKenna RW, Parkin J, Kersey JH, et al. Chronic lymphoproliferative disorder with unusual clinical, morphologic, ultrastructural and membrane surface marker characteristics. Am J Med 1977; 62:588.
- Dhodapkar MV, Li CY, Lust JA, et al. Clinical spectrum of clonal proliferations of T-large granular lymphocytes: a T-cell clonopathy of undetermined significance? Blood 1994; 84:1620.
- Zambello R, Trentin L, Ciccone E, et al. Phenotypic diversity of natural killer (NK) populations in patients with NK-type lymphoproliferative disease of granular lymphocytes. Blood 1993; 81:2381.
- Semenzato G, Pandolfi F, Chisesi T, et al. The lymphoproliferative disease of granular lymphocytes. A heterogeneous disorder ranging from indolent to aggressive conditions. Cancer 1987; 60:2971.
- Loughran TP Jr, Kadin ME, Starkebaum G, et al. Leukemia of large granular lymphocytes: association with clonal chromosomal abnormalities and autoimmune neutropenia, thrombocytopenia, and hemolytic anemia. Ann Intern Med 1985; 102:169.
- Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84:1361.
- Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016; 127:2375.
- Lim MS, de Leval L, Quintanilla-Martinez L. Commentary on the 2008 WHO classification of mature T- and NK-cell neoplasms. J Hematop 2009; 2:65.
- Zambello R, Loughran TP Jr, Trentin L, et al. Serologic and molecular evidence for a possible pathogenetic role of viral infection in CD3-negative natural killer-type lymphoproliferative disease of granular lymphocytes. Leukemia 1995; 9:1207.
- Loughran TP Jr, Zambello R, Ashley R, et al. Failure to detect Epstein-Barr virus DNA in peripheral blood mononuclear cells of most patients with large granular lymphocyte leukemia. Blood 1993; 81:2723.
- Fouchard N, Flageul B, Bagot M, et al. Lack of evidence of HTLV-I/II infection in T CD8 malignant or reactive lymphoproliferative disorders in France: a serological and/or molecular study of 169 cases. Leukemia 1995; 9:2087.
- Loughran TP Jr, Hadlock KG, Yang Q, et al. Seroreactivity to an envelope protein of human T-cell leukemia/lymphoma virus in patients with CD3- (natural killer) lymphoproliferative disease of granular lymphocytes. Blood 1997; 90:1977.
- Loughran TP Jr, Hadlock KG, Perzova R, et al. Epitope mapping of HTLV envelope seroreactivity in LGL leukaemia. Br J Haematol 1998; 101:318.
- Ohno Y, Amakawa R, Fukuhara S, et al. Acute transformation of chronic large granular lymphocyte leukemia associated with additional chromosome abnormality. Cancer 1989; 64:63.
- Epling-Burnette PK, Painter JS, Chaurasia P, et al. Dysregulated NK receptor expression in patients with lymphoproliferative disease of granular lymphocytes. Blood 2004; 103:3431.
- Epling-Burnette PK, Bai F, Wei S, et al. ERK couples chronic survival of NK cells to constitutively activated Ras in lymphoproliferative disease of granular lymphocytes (LDGL). Oncogene 2004; 23:9220.
- Jerez A, Clemente MJ, Makishima H, et al. STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia. Blood 2012; 120:3048.
- Epling-Burnette PK, Sokol L, Chen X, et al. Clinical improvement by farnesyltransferase inhibition in NK large granular lymphocyte leukemia associated with imbalanced NK receptor signaling. Blood 2008; 112:4694.
- Poullot E, Zambello R, Leblanc F, et al. Chronic natural killer lymphoproliferative disorders: characteristics of an international cohort of 70 patients. Ann Oncol 2014; 25:2030.
- Rabbani GR, Phyliky RL, Tefferi A. A long-term study of patients with chronic natural killer cell lymphocytosis. Br J Haematol 1999; 106:960.
- Moignet A, Hasanali Z, Zambello R, et al. Cyclophosphamide as a first-line therapy in LGL leukemia. Leukemia 2014; 28:1134.
- Chee CE, Warrington KJ, Tefferi A. Chronic natural killer-cell lymphocytosis successfully treated with alemtuzumab. Blood 2009; 114:3500.
- Kawa-Ha K, Ishihara S, Ninomiya T, et al. CD3-negative lymphoproliferative disease of granular lymphocytes containing Epstein-Barr viral DNA. J Clin Invest 1989; 84:51.
- Hart DN, Baker BW, Inglis MJ, et al. Epstein-Barr viral DNA in acute large granular lymphocyte (natural killer) leukemic cells. Blood 1992; 79:2116.
- Kanegane H, Wado T, Nunogami K, et al. Chronic persistent Epstein-Barr virus infection of natural killer cells and B cells associated with granular lymphocytes expansion. Br J Haematol 1996; 95:116.
- Gelb AB, van de Rijn M, Regula DP Jr, et al. Epstein-Barr virus-associated natural killer-large granular lymphocyte leukemia. Hum Pathol 1994; 25:953.
- Lamy T, Loughran TP. Large Granular Lymphocyte Leukemia. Cancer Control 1998; 5:25.
- Ohno T, Kanoh T, Arita Y, et al. Fulminant clonal expansion of large granular lymphocytes. Characterization of their morphology, phenotype, genotype, and function. Cancer 1988; 62:1918.
- Sheridan W, Winton EF, Chan WC, et al. Leukemia of non-T lineage natural killer cells. Blood 1988; 72:1701.
- Fernandez LA, Pope B, Lee C, Zayed E. Aggressive natural killer cell leukemia in an adult with establishment of an NK cell line. Blood 1986; 67:925.
- Morice WG, Kurtin PJ, Leibson PJ, et al. Demonstration of aberrant T-cell and natural killer-cell antigen expression in all cases of granular lymphocytic leukaemia. Br J Haematol 2003; 120:1026.
- Shimodaira S, Ishida F, Kobayashi H, et al. The detection of clonal proliferation in granular lymphocyte-proliferative disorders of natural killer cell lineage. Br J Haematol 1995; 90:578.
- Chou WC, Chiang IP, Tang JL, et al. Clonal disease of natural killer large granular lymphocytes in Taiwan. Br J Haematol 1998; 103:1124.
- Cheung MM, Chan JK, Wong KF. Natural killer cell neoplasms: a distinctive group of highly aggressive lymphomas/leukemias. Semin Hematol 2003; 40:221.
- Jaffe ES, Krenacs L, Raffeld M. Classification of cytotoxic T-cell and natural killer cell lymphomas. Semin Hematol 2003; 40:175.
- Chan JK, Sin VC, Wong KF, et al. Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm. Blood 1997; 89:4501.
- Brody JP, Allen S, Schulman P, et al. Acute agranular CD4-positive natural killer cell leukemia. Comprehensive clinicopathologic studies including virologic and in vitro culture with inducing agents. Cancer 1995; 75:2474.
- Drénou B, Lamy T, Amiot L, et al. CD3- CD56+ non-Hodgkin's lymphomas with an aggressive behavior related to multidrug resistance. Blood 1997; 89:2966.
- Feuillard J, Jacob MC, Valensi F, et al. Clinical and biologic features of CD4(+)CD56(+) malignancies. Blood 2002; 99:1556.
- Garnache-Ottou F, Feuillard J, Saas P. Plasmacytoid dendritic cell leukaemia/lymphoma: towards a well defined entity? Br J Haematol 2007; 136:539.
- Chan JK, Jaffe ES, Ralfkiaer E. Blastic NK-cell lymphoma. In: World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, Jaffe ES, Harris NL, Stein H, Vardiman JW (Eds), IARC Press, Lyon 2001. p.214.
- Béné MC, Feuillard J, Jacob MC, Groupe d'Etude Immunologique des Leucémies. Plasmacytoid dendritic cells: from the plasmacytoid T-cell to type 2 dendritic cells CD4+CD56+ malignancies. Semin Hematol 2003; 40:257.
- Mori KL, Egashira M, Oshimi K. Differentiation stage of natural killer cell-lineage lymphoproliferative disorders based on phenotypic analysis. Br J Haematol 2001; 115:225.
- Leroux D, Mugneret F, Callanan M, et al. CD4(+), CD56(+) DC2 acute leukemia is characterized by recurrent clonal chromosomal changes affecting 6 major targets: a study of 21 cases by the Groupe Français de Cytogénétique Hématologique. Blood 2002; 99:4154.
- Santucci M, Pimpinelli N, Massi D, et al. Cytotoxic/natural killer cell cutaneous lymphomas. Report of EORTC Cutaneous Lymphoma Task Force Workshop. Cancer 2003; 97:610.
- Dijkman R, van Doorn R, Szuhai K, et al. Gene-expression profiling and array-based CGH classify CD4+CD56+ hematodermic neoplasm and cutaneous myelomonocytic leukemia as distinct disease entities. Blood 2007; 109:1720.
- Suzuki R, Nakamura S, Suzumiya J, et al. Blastic natural killer cell lymphoma/leukemia (CD56-positive blastic tumor): prognostication and categorization according to anatomic sites of involvement. Cancer 2005; 104:1022.
- Koom WS, Chung EJ, Yang WI, et al. Angiocentric T-cell and NK/T-cell lymphomas: radiotherapeutic viewpoints. Int J Radiat Oncol Biol Phys 2004; 59:1127.
- Shapiro M, Wasik MA, Junkins-Hopkins JM, et al. Complete remission in advanced blastic NK-cell lymphoma/leukemia in elderly patients using the hyper-CVAD regimen. Am J Hematol 2003; 74:46.
- Yamada O, Ichikawa M, Okamoto T, et al. Killer T-cell induction in patients with blastic natural killer cell lymphoma/leukaemia: implications for successful treatment and possible therapeutic strategies. Br J Haematol 2001; 113:153.
- Suzuki R, Nakamura S. Malignancies of natural killer (NK) cell precursor: myeloid/NK cell precursor acute leukemia and blastic NK cell lymphoma/leukemia. Leuk Res 1999; 23:615.
- Murashige N, Kami M, Kishi Y, et al. Allogeneic haematopoietic stem cell transplantation as a promising treatment for natural killer-cell neoplasms. Br J Haematol 2005; 130:561.
- Takami A, Nakao S, Yachie A, et al. Successful treatment of Epstein-Barr virus-associated natural killer cell large granular lymphocytic leukaemia using allogeneic peripheral blood stem cell transplantation. Bone Marrow Transplant 1998; 21:1279.
- THE LARGE GRANULAR LYMPHOCYTE
- Classification of LGL disorders
- CHRONIC NK CELL LYMPHOCYTOSIS
- Etiology and pathogenesis
- Clinical features and prognosis
- Laboratory findings
- AGGRESSIVE NK CELL LEUKEMIA
- Clinical presentation
- Laboratory findings
- Differential diagnosis
- - Extranodal NK/T cell lymphoma, nasal type
- - Blastic plasmacytoid dendritic cell neoplasm
- - Blastic NK cell lymphoma
- CLINICAL TRIALS
- SUMMARY AND RECOMMENDATIONS