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Natural killer (NK) cell large granular lymphocyte leukemia

Natural killer (NK) cell large granular lymphocyte leukemia
Literature review current through: Sep 2023.
This topic last updated: Aug 11, 2022.

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].

Classification of 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].

As described above, the NK cell is associated with a CD3-/CD56+ phenotype. About 15 percent of patients with LGL proliferation have this phenotype [1]. These patients can be subclassified into two categories: chronic NK cell lymphocytosis and NK cell LGL leukemia [15].

CHRONIC NK CELL LYMPHOCYTOSIS

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) [16]. 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 [17].

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 [18]. An Italian series reported evidence for viral infection in 13 of 18 patients [19], but a French series of 27 patients reported no evidence of Epstein-Barr virus infection [20] or HTLV I/II [21]. Similar findings have been noted in T cell LGL leukemia [22].

It is not clear whether chronic NK lymphocytosis represents a benign disorder or a chronic phase of NK cell LGL leukemia. Follow-up studies in patients with chronic NK lymphocytosis occasionally demonstrate clonal progression via the presence of new chromosomal abnormalities during a transformation into a more acute NK cell LGL leukemia [23].

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 [24]. This altered ratio might induce inappropriate lysis or cytokine production and affect disease pathogenesis.

Clinical features and prognosis — Approximately 5 percent of all patients with LGL expansion have chronic NK cell lymphocytosis. The clinical features are similar to those of CD3+ T cell LGL leukemia [25]. The median age is 60 years with a male to female ratio of 3.2. It is a chronic disease with a median duration of five years; no deaths were reported in a series of 10 patients [26]. Affected patients do not have lymphadenopathy; splenomegaly and hepatomegaly are rare. Vasculitis, including acute glomerulonephritis, urticarial vasculitis, and cutaneous polyarteritis nodosa, has been reported [26]. Pure red cell aplasia, aplastic anemia, and mild thrombocytopenia have also been observed.

Compared with T cell LGL, patients with NK lymphoproliferations are significantly less symptomatic and the association with rheumatoid arthritis is more rarely observed. Conversely, autoimmune cytopenia 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) and the main phenotype is CD2+/CD3-/CD4-/CD8-/CD16+/CD56+. CD57 is usually weakly expressed. Different antigens expressed on NK cells 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].

Diagnosis — Chronic NK cell lymphocytosis 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 chronic NK cell lymphocytosis 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 lymphocytosis is an indolent disease, therapy is usually not needed. 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 [27].

Experience with other agents is limited. One patient with symptomatic chronic NK lymphocytosis responded to treatment with the anti-CD52 monoclonal antibody, alemtuzumab [28]. 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 chronic NK cell lymphocytosis [29]. (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 [30]. 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 [31-33]. (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) [34]. A retrospective series of 113 patients from China reported a peak incidence in patients 21 to 30 years old [35]. 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 [36] and peritoneal fluids, with clinical ascites, has been reported [37]. Rheumatoid arthritis has not been observed in this type of LGL leukemia [1,38]. (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 [39].

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 [40]. 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 [23,40,41].

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 [14,34,42,43]. 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 [44-46]. 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 [47,48], although the precise lineage of this malignancy has not been resolved [49,50].

The phenotype is variable, but is usually CD3-/CD4+/CD56+ [45,47,49,51-53]. The cells display intermediate or large size 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 [49]. 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 [54].

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 [55]. Radiation therapy is associated with a high initial complete remission rate, although local, regional, and systemic failure rates are also high [56]. While complete responses to combination chemotherapy were described in 18 of 23 patients in one series, relapse has been common [47,57]. Long-term survival has been described following allogeneic hematopoietic cell transplantation [46,47,58-60].

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 [61].

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

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 arise from a T cell or natural killer (NK) cell lineage. Increased levels of circulating LGLs can be benign (nonclonal, secondary to other disorders) or malignant (clonal). (See 'The large granular lymphocyte' above.)

The current classification of mature T and NK cell neoplasms distinguishes T cell LGL leukemia from aggressive NK cell leukemia based on their unique molecular and clinical features. Chronic NK cell lymphocytosis is a provisional entity distinguished from the much more aggressive NK cell leukemia. It is not clear whether chronic NK cell lymphocytosis represents a benign disorder or a chronic phase of NK cell LGL leukemia. (See 'Classification of LGL disorders' above.)

Chronic NK cell lymphocytosis 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). (See 'Clinical features and prognosis' above and 'Laboratory findings' above.)

Among newly diagnosed patients with asymptomatic chronic NK cell lymphocytosis, we suggest close observation rather than immediate treatment (Grade 2C). Treatment is reserved for patients with symptoms due to neutropenia, anemia, or thrombocytopenia, and for patients with associated autoimmune conditions requiring therapy. (See 'Treatment' above.)

There is no agreed-upon standard treatment regimen for symptomatic chronic NK cell lymphocytosis, but there is general agreement that immunosuppressive therapy, such as that administered for T cell LGL leukemia, is reasonable. A choice among immunosuppressive treatments is primarily made based on the clinical setting and physician experience. (See 'Treatment' above and "Treatment of large granular lymphocyte leukemia", section on 'Initial treatment'.)

NK cell LGL 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 NK cell LGL leukemias show a CD3-, CD4-, CD8+, CD16+, CD56+ phenotype (algorithm 1). The differential diagnosis of NK cell LGL leukemia includes a number of uncommon lymphomatous and leukemic conditions (table 2). (See 'Clinical presentation' above and 'Laboratory findings' above and 'Differential diagnosis' above.)

Most patients with NK cell LGL leukemia have a severe and refractory clinical course. Multiorgan failure associated with coagulopathy is the main cause of death. Combination chemotherapy has been ineffective, and long-term remission has been obtained only rarely. (See 'Prognosis' above.)

Thus far, no treatment has been found to be effective for NK cell LGL leukemia; although isolated reports suggest a benefit from allogeneic hematopoietic cell transplantation (HCT). For patients with NK cell LGL leukemia, we suggest allogeneic HCT, ideally performed within the context of a clinical trial (Grade 2C). Patients who are not candidates for this approach should be encouraged to enroll in a well-designed experimental treatment program, if available. (See 'Treatment' above.)

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

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