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Natural killer cell large granular lymphocyte leukemia

Natural killer cell large granular lymphocyte leukemia
Author:
Thierry Lamy, MD, PhD
Section Editor:
Richard A Larson, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Apr 2025. | This topic last updated: Nov 18, 2024.

INTRODUCTION — 

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+, CD57+, CD56- T cells, representing in vivo antigen-activated cytotoxic effector T cells.

●CD3-, CD56+ 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:

●Viral infections (eg, Epstein-Barr virus [EBV], hepatitis B virus [HBV], hepatitis C virus [HCV], HIV, cytomegalovirus [CMV]), connective tissue disease, immune thrombocytopenia (ITP), non-Hodgkin lymphoma, various skin disorders, and the hemophagocytosis syndrome are the main non-malignant situations that have been associated with reactive T cell LGL expansion (ie, CD3+ cells with T cell receptor genes in germline configuration) [1,3-5].

●The myelodysplastic syndrome and solid tumors are sometimes associated with increased numbers of circulating NK LGL cells [4].

●NK cell proliferative disorders have been found in atomic bomb survivors presenting with neutropenia [6].

LGL DISORDERS — 

A syndrome characterized by the proliferation of LGLs associated with neutropenia was initially reported in 1977 [7]. Since then, several studies of LGL proliferative disorders have appeared [1,3,8-11].

The term LGL leukemia was proposed for this disorder based on demonstration of invasion of bone marrow, spleen, and liver by LGLs and the first proof that such LGLs were clonally expanded [12]. A subsequent French-American-British (FAB) classification recognized LGL leukemia as one of four subgroups of chronic T cell lymphoid leukemias and, in 1993, it was proposed that LGL leukemias could be classified into T cell and NK cell types, depending on the cell lineage of the leukemic cells [1]. The revised European-American classification of lymphoid neoplasms (REAL) categorized LGL leukemia as a distinct entity classified under peripheral T cell and NK cell neoplasms [13].

The 2016 World Health Organization (WHO) classification of mature T and NK cell neoplasms continues to distinguish T cell LGL leukemia (T-LGL leukemia) from aggressive NK cell leukemia based on their unique molecular and clinical features [14]. A provisional entity of chronic lymphoproliferative disorder of NK cells (also known as chronic NK cell lymphocytosis) distinguishes it from much more aggressive NK cell leukemia [14,15].

Contemporary classification schemes differ in their labels for LGL leukemias. The 5th edition of the World Health Organization classification of Haematolymphoid Tumours Neoplasms (WHO5) includes T cell LGL leukemia and NK cell LGL leukemia as distinct entities, while the International Consensus Classification (ICC) includes T cell LGL leukemia and chronic lymphoproliferative disorder of NK cells [16].

As described above, the NK cell is usually associated with a CD3-/CD56+ phenotype. About 15 percent of patients with LGL proliferation have this phenotype [1]. In our opinion, the term chronic NK lymphocytosis should be discarded. We have developed an NK clonality score to separate NK-phenotyped LGL leukemia from reactional NK-LGL proliferation, based on phenotype, NK LGL cell count, and molecular profile [17].

NK CELL LGL LEUKEMIA

Etiology and pathogenesis — Activated intracellular signaling is detected in NK cell lymphocytosis [11]. Constitutive activation of the Ras/MEK/ERK pathway was reported in 13 of 13 patients with NK cell lymphoproliferative disease of large granular lymphocytes (LGLs; 12 with chronic and 1 with aggressive disease) [18]. Exposure of these cells to inhibitors of MEK or Ras resulted in apoptosis of patient NK cells. Activating mutations in STAT3 were reported in one-third of these patients [19].

A retroviral antigen or a cellular protein with homology to a viral antigen may contribute to the pathogenesis of this disorder. Sera from patients with chronic NK lymphocytosis react to the BA21 epitope of the human T cell lymphotropic virus (HTLV) I/II transmembrane envelope protein [20]. An Italian series reported evidence of viral infection in 13 of 18 patients [21], but a French series of 27 patients reported no evidence of Epstein-Barr virus infection [22] or HTLV I/II [23]. Similar findings have been noted in T cell LGL leukemia [24].

It is not clear whether NK cell LGL leukemia remains an indolent disease over time. Follow-up studies in patients with chronic NK LGL proliferations occasionally demonstrate clonal progression via the presence of new chromosomal abnormalities during a transformation into a more acute NK cell LGL leukemia [25].

There is skewed NK receptor expression on NK cells in patients with the natural killer (NK) type of lymphoproliferative disease of granular lymphocytes, with an increased activating-to-inhibitory killer-cell Ig-like inhibitory receptor (KIR) ratio [26]. This altered ratio might induce inappropriate lysis or cytokine production and affect disease pathogenesis.

Clinical features and prognosis — Approximately 10 percent of all patients with LGL expansion have NK LGL leukemia.

The clinical features are similar to those of CD3+ T cell LGL leukemia [11,27]. The median age is 60 years with a male to female ratio of 3.2. It is a chronic disease with two-thirds of patients alive at 10 years. No deaths were reported in a series of 10 patients [28]. Affected patients do not have lymphadenopathy; splenomegaly and hepatomegaly are rare. Vasculitis, including acute glomerulonephritis, urticarial vasculitis, and cutaneous polyarteritis nodosa, has been reported [28]. Pure red cell aplasia, aplastic anemia, and mild thrombocytopenia have also been observed.

Compared with T cell LGL, patients with NK LGL leukemia are significantly less symptomatic and the association with rheumatoid arthritis is more rarely observed [11]. Conversely, autoimmune cytopenias are more frequent in NK lymphocytosis.

Laboratory findings — The severity of neutropenia is less than in T cell LGL leukemia. The median absolute number of NK cells is 2.3 x 109/L (2300/microL). The vast majority of NK LGL leukemia cases harbored a cytotoxic CD2+/CD3-/CD4-/CD8-/CD16high CD56low CD57+/- profile. CD57 is usually weakly expressed [17].

●Immunophenotype

NK LGL leukemia expresses CD94 lectin with inhibitory NKG2A, forming the CD94/NKG2A heterodimer, with a markedly higher MFI (mean fluorescence intensity) than that observed in normal or reactive NK cells. To a lesser extent, underexpression of CD161 and natural cytotoxicity receptors , in particular NKp30 and NKp44, is more often found in NK LGL leukemia than in NK LGL reactive proliferations [29-31].

Different antigens expressed on NK cell subsets belonging to the 58 Kd molecular family have been described. Using the monoclonal antibodies EB6 and GL183, it is possible to distinguish four subsets of normal NK cells. Most patients with NK cell lymphocytosis have a restricted NK phenotype, with the NK expansion representing one of these four subsets [9].

●Molecular findings

STAT3 gain-of-function mutations are found in 27 to 33 percent of NK cell LGL leukemia [11]. The STAT3 mutations are located in the SH2 domain within exons 20 and 21, with Y640F and D661V accounting for two-thirds of mutations [32]. TET2 mutation is identified in 28 to 34 percent of cases of NK cell LGL leukemia, and this is a valuable diagnostic marker [17,33].

TET2 and STAT3 mutations are generally mutually exclusive and appear to be associated with two different NK phenotypic and functional profiles: the STAT3 mutation is more often found in CD16high/CD57low, or cytotoxic memory NK LGL leukemias, while the TET2 mutation is more commonly associated with the CD16low, or regulatory cytokine profile. The two groups also have distinct transcriptome expression profiles.

Mutations in the CCL22 gene have been described in 20 percent of NK cell LGL leukemias and are specific to the NK subtype in contrast to other mutations, and exclusive of other mutations, especially STAT3 mutation [34]. The CCL2 mutation induces in vitro increased CCL2 chemotaxis and decreased internalization of its Th2 T cell receptor, CCR4. CCL2-mutated NK LGLs show higher CD56 expression than nonmutated ones.

Diagnosis — NK LGL leukemia is suspected in a patient with clinically indolent disease and persistent peripheral blood lymphocytosis, in whom LGLs are seen on examination of the peripheral blood smear (picture 1). The great majority show a CD3-, CD4-, CD8-, CD16+, CD56+, CD57- phenotype (algorithm 1).

The differential diagnosis of NK LGL leukemia includes other causes of lymphocytosis. In particular, it must be differentiated from reactive LGL expansions, T cell LGL leukemia, and aggressive NK cell leukemia (algorithm 1). If lymphocytosis is persistent, then flow cytometry should be performed to determine the phenotype of the circulating lymphocytes. (See "Approach to the child with lymphocytosis or lymphocytopenia".)

●If these lymphocytes have the phenotype of cytotoxic T cells (CD3+, CD57+), then the diagnosis of the T cell form of LGL leukemia should be considered and further evaluated. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia".)

●If the circulating lymphocytes are NK cells (CD3-, CD56+), then chronic NK cell lymphocytosis needs to be distinguished from the clinically aggressive NK cell LGL leukemia. (See 'Diagnosis' below.)

Treatment — Since NK LGL leukemia is an indolent disease, most patients can be followed without treatment, but over the long term, more than one-half will benefit from specific treatment. For patients with severe neutropenia, we suggest treatment with agents similar to those used in T cell LGL leukemia (eg, prednisone plus cyclophosphamide, cyclophosphamide alone, or methotrexate) [2]. We have also had encouraging results with cyclophosphamide used as first-line therapy in a series of 45 patients [35].

Experience with other agents is limited. One patient with symptomatic NK LGL leukemia responded to treatment with the anti-CD52 monoclonal antibody, alemtuzumab [36]. The farnesyltransferase inhibitor tipifarnib achieved no objective responses among eight patients with T cell or NK cell LGL leukemia, but pulmonary hypertension improved in one patient with NK LGL leukemia [37]. Targeted agents, such as inhibitors of PI3K, JAK 2/3, and STAT3, will be evaluated as other treatment options [38]. (See "Treatment of large granular lymphocyte leukemia", section on 'Initial treatment'.)

AGGRESSIVE NK CELL LEUKEMIA

Pathogenesis — Epstein-Barr virus (EBV) may be directly involved in large granular lymphocyte (LGL) cell transformation. Infection with EBV has been implicated in more than 50 percent of the cases of NK cell LGL leukemia reported in Japan [39]. In situ hybridization analyses have shown EBV RNA within the LGLs; EBV nuclear antigen 1 (EBNA1) and EBER-1 can be detected in leukemic cells [40-42]. (See "Virology of Epstein-Barr virus".)

Clinical presentation — The clinical presentation of NK cell LGL leukemia is more aggressive than that of T cell LGL leukemia and chronic NK cell lymphocytosis (table 1) [43]. A retrospective series of 113 patients from China reported a peak incidence in patients 21 to 30 years old [44]. Initial presentation includes "B" symptoms (fever, night sweats, weight loss) and the presence of considerable, often massive, hepatosplenomegaly. Involvement of the gastrointestinal tract is present in many patients, and infiltration of LGLs into the cerebrospinal [45] and peritoneal fluids, with clinical ascites, has been reported [46]. Rheumatoid arthritis has not been observed in this type of LGL leukemia [1,47]. (See "Large granular lymphocyte leukemia in rheumatoid arthritis".)

Laboratory findings — Anemia (100 percent) and thrombocytopenia are more frequent than in T cell LGL leukemia [1]. In contrast, severe neutropenia is less common, being present in about 18 percent of patients with NK cell LGL leukemia. Bone marrow infiltration is seen in the majority of the patients, occasionally with marrow fibrosis.

Absolute LGL counts are higher than in T cell LGL leukemia, often exceeding 10,000/microL. The usual phenotype is CD3-, TCRab-, TCRgd-, CD4-, CD8+, CD16+, CD56+; CD57 is variably expressed [48].

Unlike CD3+ T cell LGL, CD3- NK cell LGLs do not express the T cell receptor (TCR), and thus clonality cannot be demonstrated by showing rearrangement of TCR genes [49]. However, cases described in Asia have been associated with nonrandom clonal cytogenetic abnormalities, including duplication of 1q, rearrangement at 3q, loss of chromosomes Y, 13, or 10, and trisomy 8 [25,49,50].

Diagnosis — Aggressive NK cell leukemia is suspected in a patient with aggressive clinical disease, neutropenia and/or anemia along with persistent peripheral blood lymphocytosis, in whom LGLs are seen on examination of the peripheral blood smear (picture 1). The great majority of aggressive NK cell leukemias show a CD3-, CD4-, CD8+, CD16+, CD56+ phenotype (algorithm 1).

Differential diagnosis — The differential diagnosis of aggressive NK cell leukemia includes a number of uncommon lymphomatous and leukemic conditions [14,43,51,52]. An algorithmic approach has been suggested to establish the diagnosis (algorithm 1).

Extranodal NK/T cell lymphoma, nasal type — Extranodal NK/T cell lymphoma, nasal type is a heterogeneous disease. Most of the cases have been described in Asia, involve the nasopharynx, and are related to infection with EBV. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal NK/T cell lymphoma, nasal type".)

Blastic plasmacytoid dendritic cell neoplasm — Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive neoplasm arising from precursors of the type 2 or plasmacytoid dendritic cells. Most patients present with cutaneous lesions with or without bone marrow involvement and leukemic dissemination. The tumor cells typically express CD4 and CD56. In addition, expression of one or more plasmacytoid dendritic cell specific antigens (CD123, BCDA-2, TCL1, SPIB) is present. (See "Blastic plasmacytoid dendritic cell neoplasm".)

Blastic NK cell lymphoma — Sporadic cases without nasal involvement unrelated to EBV have been described in Asia as well as Europe and North America [53-55]. These cases have been termed blastic NK cell lymphoma or precursor NK cell lymphoblastic leukemia/lymphoma; they may represent a malignancy of plasmacytoid dendritic cells [56,57], although the precise lineage of this malignancy has not been resolved [58,59].

The phenotype is variable but is usually CD3-/CD4+/CD56+ [54,56,58,60-62]. The cells display intermediate or large sizes with features of pleomorphic cell lymphoma. The diagnosis of blastic NK cell lymphoma should be made in the absence of commitment to the T cell or myeloid lineages, and thus blasts should be negative for CD3, CD33, and myeloperoxidase, and the T cell receptor should be germline [58]. Gene expression profiling has been able to separate these cases from cutaneous myelomonocytic leukemia and to demonstrate high expression of various plasmacytoid dendritic cell related genes [63].

Median overall survival is approximately 12 months, and is longer in those with localized disease, especially the skin, than in patients with involvement of multiple organ systems [64]. Radiation therapy is associated with a high initial complete remission rate, although local, regional, and systemic failure rates are also high [65]. While complete responses to combination chemotherapy were described in 18 of 23 patients in one series, relapse has been common [56,66]. Long-term survival has been described following allogeneic hematopoietic cell transplantation [55,56,67-69].

Prognosis — Most patients with NK cell LGL leukemia have a severe and refractory clinical course. In our review, 9 of 11 patients died within two months after diagnosis [1]. Multiorgan failure associated with coagulopathy was the main cause of death. Combination chemotherapy has been ineffective, and long-term remission has been obtained only rarely. The MDR phenotype may be implicated in drug resistance in these cases.

Treatment — Thus far, no treatment has been found to be effective for this disorder. Accordingly, we suggest that patients with this disorder be enrolled in a well-designed experimental treatment program, if available.

There are isolated reports of success following allogeneic hematopoietic cell transplantation, which we suggest be pursued in patients with a suitable donor who are able to tolerate this procedure [70].

CLINICAL TRIALS — 

Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Large granular lymphocyte leukemia".)

SUMMARY AND RECOMMENDATIONS

●Description – The large granular lymphocyte (LGL) is a morphologically distinct lymphoid subset comprising 10 to 15 percent of normal peripheral blood mononuclear cells (picture 1). LGLs can arise from a T cell or natural killer (NK) cell lineage. (See 'The large granular lymphocyte' above.)

●LGL disorders – Increased levels of circulating LGLs can be caused by reactive (multiclonal, secondary to other disorders) or malignant (clonal) processes. We distinguish malignant LGL disorders according to immunophenotype (NK cell versus T cell). (See 'LGL disorders' above.)

●NK cell LGL leukemia – This indolent disorder is characterized by persistent lymphocytosis, with LGLs on the blood smear (picture 1). (See 'NK cell LGL leukemia' above.)

•Diagnosis – NK cell LGL leukemia is suspected in a patient with neutropenia and/or anemia and persistent LGLs on a peripheral blood smear. Most cases show a CD3-, CD4-, CD8-, CD16+, CD56+, CD57- phenotype (algorithm 1). (See 'Diagnosis' above.)

The differential diagnosis includes reactive LGL expansions, T cell LGL leukemia, and aggressive NK cell leukemia (table 2).

●Aggressive NK cell leukemia – This is an aggressive disease that may be associated with multiorgan failure and coagulopathy.

•Diagnosis – Absolute LGL counts are often >10,000/microL. The usual phenotype is CD3-, TCRab-, TCRgd-, CD4-, CD8+, CD16+, CD56+; CD57 is variably expressed. Anemia is universal (100 percent), thrombocytopenia is often present, but neutropenia is uncommon. (See 'Diagnosis' above.)

The differential diagnosis includes aggressive disorders such as extranodal NK/T cell lymphoma, nasal type; blastic plasmacytoid dendritic cell neoplasm (BPDCN); and blastic NK cell lymphoma.

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Thomas P Loughran, Jr, MD, who contributed to earlier versions of this topic review.

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  66. 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.
  67. 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.
  68. 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.
  69. 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.
  70. 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.
Topic 4538 Version 16.0

References

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2 : Clinical features of large granular lymphocyte leukemia.

3 : Granular lymphocyte proliferative disorders: report of 12 cases and review of the literature.

4 : Spectrum of diseases associated with increased proportions or absolute numbers of peripheral blood natural killer cells.

5 : Haemophagocytic lymphohistiocytosis in association with granular lymphocyte proliferative disorders in early childhood: characteristic bone marrow morphology.

6 : Neutropenia among survivors of atomic bomb explosion.

7 : Chronic lymphoproliferative disorder with unusual clinical, morphologic, ultrastructural and membrane surface marker characteristics.

8 : Clinical spectrum of clonal proliferations of T-large granular lymphocytes: a T-cell clonopathy of undetermined significance?

9 : Phenotypic diversity of natural killer (NK) populations in patients with NK-type lymphoproliferative disease of granular lymphocytes.

10 : The lymphoproliferative disease of granular lymphocytes. A heterogeneous disorder ranging from indolent to aggressive conditions.

11 : Toward a Better Classification System for NK-LGL Disorders.

12 : Leukemia of large granular lymphocytes: association with clonal chromosomal abnormalities and autoimmune neutropenia, thrombocytopenia, and hemolytic anemia.

13 : A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group.

14 : The 2016 revision of the World Health Organization classification of lymphoid neoplasms.

15 : Commentary on the 2008 WHO classification of mature T- and NK-cell neoplasms.

16 : The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms.

17 : Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells.

18 : ERK couples chronic survival of NK cells to constitutively activated Ras in lymphoproliferative disease of granular lymphocytes (LDGL).

19 : STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia.

20 : Seroreactivity to an envelope protein of human T-cell leukemia/lymphoma virus in patients with CD3- (natural killer) lymphoproliferative disease of granular lymphocytes.

21 : Serologic and molecular evidence for a possible pathogenetic role of viral infection in CD3-negative natural killer-type lymphoproliferative disease of granular lymphocytes.

22 : Failure to detect Epstein-Barr virus DNA in peripheral blood mononuclear cells of most patients with large granular lymphocyte leukemia.

23 : 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.

24 : Epitope mapping of HTLV envelope seroreactivity in LGL leukaemia.

25 : Acute transformation of chronic large granular lymphocyte leukemia associated with additional chromosome abnormality.

26 : Dysregulated NK receptor expression in patients with lymphoproliferative disease of granular lymphocytes.

27 : Chronic natural killer lymphoproliferative disorders: characteristics of an international cohort of 70 patients.

28 : A long-term study of patients with chronic natural killer cell lymphocytosis.

29 : The immunophenotypic attributes of NK cells and NK-cell lineage lymphoproliferative disorders.

30 : Expression and function of KIR and natural cytotoxicity receptors in NK-type lymphoproliferative diseases of granular lymphocytes.

31 : Phenotypic profile of expanded NK cells in chronic lymphoproliferative disorders: a surrogate marker for NK-cell clonality.

32 : Somatic STAT3 mutations in large granular lymphocytic leukemia.

33 : Frequent somatic TET2 mutations in chronic NK-LGL leukemia with distinct patterns of cytopenias.

34 : CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk.

35 : Cyclophosphamide as a first-line therapy in LGL leukemia.

36 : Chronic natural killer-cell lymphocytosis successfully treated with alemtuzumab.

37 : Clinical improvement by farnesyltransferase inhibition in NK large granular lymphocyte leukemia associated with imbalanced NK receptor signaling.

38 : A modern view of LGL leukemia.

39 : CD3-negative lymphoproliferative disease of granular lymphocytes containing Epstein-Barr viral DNA.

40 : Epstein-Barr viral DNA in acute large granular lymphocyte (natural killer) leukemic cells.

41 : Chronic persistent Epstein-Barr virus infection of natural killer cells and B cells associated with granular lymphocytes expansion.

42 : Epstein-Barr virus-associated natural killer-large granular lymphocyte leukemia.

43 : Large Granular Lymphocyte Leukemia.

44 : Aggressive NK-cell leukemia: clinical subtypes, molecular features, and treatment outcomes.

45 : Fulminant clonal expansion of large granular lymphocytes. Characterization of their morphology, phenotype, genotype, and function.

46 : Leukemia of non-T lineage natural killer cells.

47 : Aggressive natural killer cell leukemia in an adult with establishment of an NK cell line.

48 : Demonstration of aberrant T-cell and natural killer-cell antigen expression in all cases of granular lymphocytic leukaemia.

49 : The detection of clonal proliferation in granular lymphocyte-proliferative disorders of natural killer cell lineage.

50 : Clonal disease of natural killer large granular lymphocytes in Taiwan.

51 : Natural killer cell neoplasms: a distinctive group of highly aggressive lymphomas/leukemias.

52 : Classification of cytotoxic T-cell and natural killer cell lymphomas.

53 : Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm.

54 : Acute agranular CD4-positive natural killer cell leukemia. Comprehensive clinicopathologic studies including virologic and in vitro culture with inducing agents.

55 : CD3- CD56+ non-Hodgkin's lymphomas with an aggressive behavior related to multidrug resistance.

56 : Clinical and biologic features of CD4(+)CD56(+) malignancies.

57 : Plasmacytoid dendritic cell leukaemia/lymphoma: towards a well defined entity?

58 : Plasmacytoid dendritic cell leukaemia/lymphoma: towards a well defined entity?

59 : Plasmacytoid dendritic cells: from the plasmacytoid T-cell to type 2 dendritic cells CD4+CD56+ malignancies.

60 : Differentiation stage of natural killer cell-lineage lymphoproliferative disorders based on phenotypic analysis.

61 : 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.

62 : Cytotoxic/natural killer cell cutaneous lymphomas. Report of EORTC Cutaneous Lymphoma Task Force Workshop.

63 : Gene-expression profiling and array-based CGH classify CD4+CD56+ hematodermic neoplasm and cutaneous myelomonocytic leukemia as distinct disease entities.

64 : Blastic natural killer cell lymphoma/leukemia (CD56-positive blastic tumor): prognostication and categorization according to anatomic sites of involvement.

65 : Angiocentric T-cell and NK/T-cell lymphomas: radiotherapeutic viewpoints.

66 : Complete remission in advanced blastic NK-cell lymphoma/leukemia in elderly patients using the hyper-CVAD regimen.

67 : Killer T-cell induction in patients with blastic natural killer cell lymphoma/leukaemia: implications for successful treatment and possible therapeutic strategies.

68 : Malignancies of natural killer (NK) cell precursor: myeloid/NK cell precursor acute leukemia and blastic NK cell lymphoma/leukemia.

69 : Allogeneic haematopoietic stem cell transplantation as a promising treatment for natural killer-cell neoplasms.

70 : Successful treatment of Epstein-Barr virus-associated natural killer cell large granular lymphocytic leukaemia using allogeneic peripheral blood stem cell transplantation.