Natural killer-cell neoplasms

The natural killer (NK)-cell neoplasms are rare, representing less than 1% of non-Hodgkin lymphoma, except in Asia and Latin America, where they represent 3% to 6%. NK-cell neoplasms include immature acute leukemias; a blastic NK-cell lymphoma, which is obsolete because of its plasmacytoid dendritic-cell origin; and mature NK neoplasms, comprising extranodal NK/T-cell lymphoma (ENKL), nasal-type; aggressive NK-cell leukemia; and chronic NK-cell lymphoproliferative disorders, which are often reactive. Epstein-Barr virus is usually detected in tumor cells of ENKL and aggressive NK-cell leukemia. The latter two mature NK neoplasms are relatively chemoresistant because of the frequent expression of P-glycoprotein. Early radiation is advocated for localized nasal ENKL. Stem cell transplantation is recommended for advanced disease, owing to a poor prognosis. Novel agents, including chemotherapy, inhibitors of molecular pathways, and monoclonal antibodies, are under investigation.     

Immunoprofiling of cell lines derived from natural killer-cell and natural killer-like T-cell leukemia-lymphoma

T-cells and natural killer (NK)-cells can be distinguished by their immunophenotype and molecular biological studies though there is overlap in T- and NK-cell antigen expression, function, and malignant diseases. The relatively new cell type of NKT-cells (also termed NK-like T-cells) represents a subpopulation of T-cells that share some characteristics with NK-cells. T- and NKT-cells have their T-cell receptor (TCR) genes rearranged while NK-cells are identified molecularly and immunologically by the absence of TCR gene rearrangements and TCR protein and lack of certain surface antigens. Various continuous malignant cell lines have been derived from patients with T-cell, NK- and NKT-cell neoplasms. These cell lines possess several traits typical of the respective diseases. Characterization of these cell lines which was the objective of this study will facilitate future studies of cell biology and therapeutics for which cell lines are indispensable models. In view of the imprecision of morphological criteria alone, we analyzed a series of seven NK-cell, five NKT-cell and five T-cell lines using functional and immunophenotypic tools. All T-cell lines were negative for the presence of azurophilic granules, NK activity and Epstein-Barr virus (EBV). In contrast, 7/7 NK-cell and 4/5 NKT-cell lines displayed the azurophilic granules but only three of these combined twelve NK/NKT-cell lines showed significant NK activity which may be explained by the functional immaturity of the cells. EBV was found in 5/7 NK-cell and in 1/5 NKT-cell lines. As expected, T-cell lines were commonly positive for T-cell surface antigens and negative for NK-cell markers, and NK-cell lines vice versa; nevertheless, a number of immunomarkers were shared between T- and NK-cell lines. NKT-cell lines express T-cell, NK-cell and markers shared between T- and NK-cells. Sets of markers distinctive for the three types of cell lines are presented. The composite data gained on the present panels of cell lines allow for the operational definition of typical NK- and NKT-cell line profiles. Such cell lines will prove invaluable as informative models for studies of normal and neoplastic NK- and NKT-cell biology.     

CD30 expression in extranodal natural killer/T-cell lymphoma,nasal type among 622cases of mature T-cell and natural killer-cell lymphoma at a single institution in South China

Background: Mature T-cell and natural killer (NK)-cell lymphomas compose a heterogeneous group of non-Hodgkinlymphomas, and extranodal NK/T-cell lymphoma, nasal type (ENKTL) is an aggressive subtype with sporadic CD30expression. However, the significance of CD30 expression in ENKTL is controversial. We aimed to classify a large cohortof patients with mature T-cell and NK-cell lymphomas according to the 2016 World Health Organization (WHO) classificationguidelines and to study the association between CD30 expression and prognosis of patients with ENKTL.Methods: We selected consecutive patients with mature T-cell and NK-cell lymphomas who attended our institutionbetween September 1, 2009 and August 31, 2013. We classified the lymphomas according to the 2016 revision of theWHO classification of lymphoid neoplasms, analyzed the associations between CD30 expression and clinicopathologicfeatures of ENKTL patients, and evaluated the prognostic implications of CD30 expression.Results: We identified 622 consecutive patients with mature T-cell and NK-cell lymphomas, including 317 (51.0%)patients with ENKTL. In addition, CD30 expression was detected in 43 (47.3%) of a subset of 91 patients with ENKTL.No clinicopathologic features were associated with CD30 expression, and CD30 positivity showed no prognosticsignificance in patients with ENKTL.Conclusions: ENKTL is the most common type of mature T-cell and NK-cell lymphoma diagnosed at our institution.CD30 is frequently expressed in ENKTL and represents a therapeutic target; however, it may not be a prognosticmarker.     

Recent developments in the biology and therapy of T-cell and natural killer-cell lymphomas

PURPOSE OF REVIEW: T-cell/natural killer (T/NK)-cell lymphomas represent a group of poor-risk lymphoproliferative disorders that have only recently been recognized as distinct clinicopathologic entities. The average outcome with currently available therapy is substantially inferior to that of aggressive B-cell lymphomas. Significant gaps remain in our knowledge of their origin, diagnosis, and clinical spectrum. This review outlines recent developments in the biology and molecular genetics of these disorders, current diagnostic challenges, and future avenues for therapy. RECENT FINDINGS: Several cancer-prone transgenic mouse models that develop predominantly T/NK-cell lymphomas have been produced in the past 2 to 3 years. These models point to an important role for chronic cytokine stimulation and for disruption of genes involved in the control of chromatin remodeling and maintenance of genome integrity in the pathogenesis of T-cell lymphomas. The recognition of T/NK-cell lymphomas has been greatly facilitated by the broad acceptance of standard diagnostic criteria and by the increasing availability of assays for the analysis of T-cell receptor rearrangement and a more precise definition of functional T/NK-cell subsets. New drugs with potential for use in T/NK-cell lymphomas, including monoclonal antibodies, tyrosine kinase inhibitors, synthetic retinoids, immunoconjugates, and immunosuppressive molecules with novel mechanisms of action are in the early phase of clinical investigation. SUMMARY: Much remains to be learned in the pathogenesis, clinical spectrum, and optimal therapy of T/NK-cell lymphomas. The availability of animal models of disease, new diagnostic tools, and targeted drugs with novel mechanisms of action should lead to rapid progress in this group of malignancies in the near future.     

PTEN and p27 expression in mature T-cell and NK-cell neoplasms

PTEN is a tumor suppressor gene located on chromosome 10q23 and is amongst the most commonly mutated genes in human cancers. The lipid phosphatase activity of Pten enables it to dephosphorylate PIP3, thereby antagonizing growth factor stimulated PI3-kinase signaling mediated by AKT/PKB. The growth inhibition effect of PTEN has been shown to be mediated by p27 which is one of the important effector molecules downstream of the AKT pathway. Recently the importance of the Pten and AKT pathway in the regulation of the immune system and development of hematological malignancies has been shown. Loss of Pten and p27 expressions were examined immunohistochemically in 45 patients with peripheral T- and NK-cell lymphoma. Partial or complete loss of Pten was detected in 66.7% of the cases of anaplastic large cell lymphoma (ALCL) compared to only 12.5% of all other mature T-/NK-cell lymphomas combined. Loss of p27 was identified in 64.9% of cases, which showed a positive correlation with Pten loss. In this study, we showed that loss of Pten is more frequent in ALCL as compared to other mature T-/NK-cell lymphomas, which strongly correlates with the loss of p27 expression. Our findings provide further evidence for the importance of the deregulation of the PI3K-AKT pathway in ALCL.     

自然杀伤细胞恶性肿瘤的研究进展

自然杀伤(NK)细胞肿瘤起源于前体和成熟NK细胞,是临床少见但重要的一组肿瘤.大部分NK肿瘤具有侵袭性,死亡率高.新近研究发现,CD4+CD56+原始NK细胞淋巴瘤来源于浆样树突细胞,因而真正的前体NK细胞肿瘤主要起源于CD4-CD56+NK细胞亚群.髓细胞/前体NK细胞白血病来自前体NK细胞.成熟NK细胞肿瘤中,结外NK/T淋巴瘤相对常见.侵袭性NK细胞白血病罕见,预后差.慢性NK淋巴细胞增多症是外周血成熟NK细胞的长期扩增.本文介绍正常NK细胞的发育和各型NK细胞肿瘤的临床特点和治疗.     

Establishment of the T-cell large granular lymphocyte leukemia cell line MOTN-1 carrying natural killer-cell antigens

A novel interleukin-2 (IL-2) dependent leukemia cell line MOTN-1 was established from the peripheral blood of a 63-year-old woman with T-cell large granular lymphocyte (LGL) leukemia in chronic phase. Primary peripheral blood leukemia cells were CD3+, CD5+, CD7+, CD56+, CD94+, CD161+, TcRalphabeta+, and HLA-DR+. The immunoprofile of the established cell line MOTN-1, however, showed CD3-, CD5-, CD7+, CD56+, CD94+, CD159+, CD161+, TcRalphabeta- and HLA-DR+; the MOTN-1 cells were cytoplasmatically positive for CD3varepsilon and the products of the T-cell receptor (TcR) genes beta and gamma. While the TcRbeta and TcRgamma genes were rearranged, the TcRdelta gene was found to be deleted. DNA fingerprinting and chromosome analysis identifying the t(2;6)(q?23;q?21) and t(12;18)(q13;q?22) alterations demonstrated the authenticity and the malignant nature of the cell line. The scientific significance of MOTN-1 lies in (1) the rarity of this type of leukemia cell lines, (2) the co-expression of various T- and natural killer (NK)-cell-associated markers, and (3) its unique chromosomal aberrations.     

Classification and treatment of rare and aggressive types of peripheral T-cell/natural killer-cell lymphomas of the skin.

BACKGROUND: The classification of cutaneous lymphomas has been contentious. Two major competing classifications were the World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC). The principal authors met for a consensus meeting resulted in a combined classification called WHO-EORTC Classification of Cutaneous Lymphoma. METHODS: We review the classification of "mature" or peripheral T-cell lymphoma (PTCL) with high predilection to the skin as published by the WHO-EORTC. We also highlight new information and changes from the previous classifications of cutaneous PTCL according to the WHO classification or the EORTC classification. Finally, the salient findings are compared with similar-looking nodal PTCLs with a high frequency of skin involvement. RESULTS: This review focuses on a rare group of cutaneous PTCLs other than mycosis fungoides or its variants. Changes from the previous classifications are discussed, and the rare group of nodal PTCLs with high predilection to the skin are presented. The salient findings, diagnostic features, and treatments are included, along with summary tables and clinical-histopathologic images. CONCLUSIONS: This review may serve as a guide for hematologists, oncologists and dermatologists in the diagnosis and management of these rare, aggressive, and often difficult to diagnose lymphomas. Although cutaneous lymphomas are morphologically identical to systemic lymphomas, the former behave differently, require divergent management, and should be recognized as separate entities. The consensus WHO-EORTC classification presents unified terminology and definitions to promote conformity in diagnosing and treating these cases, to foster a multidisciplinary approach to these often-obscure diseases, and to lead to more advances in identifying molecular targets specific to these entities.     

Clinicopathologic features and treatment outcome of mature T-cell and natural killer-cell lymphomas diagnosed according to the World Health Organization classification scheme: a single center experience of 10 years.

BACKGROUND: Data on mature T-cell and natural killer (NK)-cell lymphomas diagnosed with the World Health Organization (WHO) classification scheme are scarce. They are regarded to be more common in Asian populations. METHODS: Consecutive T-cell and NK-cell lymphomas classified according to the WHO scheme within 10 years in a Chinese population were reviewed. RESULTS: There were 148 cases, constituting 16.6% (T-cell, n=90, 10.1%, NK-cell, n=58, 6.5%) of all non-Hodgkin lymphomas in this period. There was a male predominance (male:female = 2.5), young age at diagnosis (median age 50 years, range 8-86) and frequent extranodal presentation. Commonest T-cell lymphomas included anaplastic large cell lymphoma (ALCL, n=25, median age 35 years, nodal 60%, stage I/II 60%), peripheral T-cell lymphoma, unspecified (PTCL, n=24, median age 54 years, nodal 42%, stage I/II 42%), and angioimmunoblastic T-cell lymphoma (AILT, n=19, median age 67 years, nodal 95%, stage I/II 26%). Overall frequencies of T-cell lymphomas were comparable to Western patients. AILT, PTCL and ALCL were aggressive with a poor outcome. NK-cell lymphomas were predominantly extranodal (96%) and aggressive, with a frequency much higher than Western patients. CONCLUSIONS: The apparent high prevalence of T-cell and NK-cell lymphomas in the Chinese was due to more frequent NK-cell but not T-cell lymphomas.     

侵袭性NK细胞白血病九例

 目的　提高对侵袭性NK细胞白血病（ANKL）的认识。方法　回顾分析2004年3月至2007年3月期间收治的9例ANKL患者的临床资料。结果　ANKL患者多有全身症状、肝脾大、淋巴结肿大、肝功能异常、贫血、中性粒细胞减少、血小板减少。大部分骨髓侵犯为轻、中度。肿瘤细胞免疫表型sCD-3、CD+56,可同时表达CD2、CD7、CD8、CD11b。3例患者有细胞遗传学异常,但未发现重现性染色体异常,TCR基因重排均为胚系构型。ANKL病程进展迅速,易发生多器官衰竭,中位生存时间9周。获得和未获得完全缓解（CR）患者生存时间分别为50周和3周。结论　ANKL为来源于成熟NK细胞的恶性肿瘤,具有独特的临床特征和免疫表型。病程呈侵袭性,对化疗不敏感,大部分患者短期内死亡。获得CR患者生存期明显延长,但难免复发,治愈率没有提高。     

FDG-PET in T-cell and NK-cell neoplasms.

BACKGROUND: A growing number of studies demonstrate the utility of (18)fluoro-2-deoxyglucose positron emission tomography (FDG-PET) in the management of malignant lymphoma. The results of FDG-PET, however, have not been studied extensively for T-cell and natural killer (NK)-cell neoplasms. PATIENTS AND METHODS: We retrospectively evaluated pretreatment FDG-PET scans in 41 patients with T/NK-cell neoplasms diagnosed according to the World Health Organization (WHO) classification. Histological subtypes frequently included were peripheral T-cell lymphoma, unspecified (PTCLu, n = 11), extranodal NK/T-cell lymphoma, nasal type (ENKL, n = 8), primary cutaneous anaplastic large cell lymphoma (C-ALCL, n = 5), and angioimmunoblastic T-cell lymphoma (AILT, n = 4). RESULTS: FDG-PET detected a lymphoma lesion in at least one site in 36 out of 41 patients. The positive rate was equally high in most histological subtypes except for cutaneous lymphomas: PTCLu 91%, ENKL 100%, C-ALCL 60%, AILT 100%. All the patients without an FDG-avid lesion had lesions restricted to skin. Among patients who had cutaneous lesions, only 50% had FDG-avid cutaneous lesions, all of which were tumorous. The positive rate of FDG-PET for bone marrow involvement was only 20%. CONCLUSION: T/NK-cell neoplasms incorporated in this study were generally FDG-avid except for cutaneous lesions and bone marrow involvement.     

Relationship of natural killer-cell activity to rhesus antigens in man.

A number of previous studies have shown that the level of natural killer (NK) cell activity in humans is relatively constant for a given individual but varies widely between individuals. The factors which determine this variability are largely unknown, but genetic factors appear to be involved. In the present study it was found that Rh- normal subjects and melanoma patients had significantly higher natural cytotoxicity to target cells than Rh+ patients. This difference did not appear to be due to sensitization against Rh antigens on the target cell and may indicate that genes determining NK-cell activity are associated with those determining the expression of Rh antigens. Analysis of the survival data for Rh- and Rh+ patients did not reveal any increase in survival attributable to the higher natural cytotoxicity in Rh- patients.     

Nasal natural killer-cell lymphoma: a disease with very poor prognosis

Nasal Natural Killer-Cell Lymphoma is an aggressive subtype of NHL even when it presents with localized disease. It is more common in Oriental than Western population. We report the case history of a white Caucasian male patient with this disease who died 5 months from diagnosis despite aggressive treatment with 2 different chemotherapy regimes and radiotherapy. We discuss the diagnosis, presentation, treatment and prognosis of this rare disease.     

Treatment outcome and pattern of failure in 77 patients with sinonasal natural killer/T-cell or T-cell lymphoma

BACKGROUND: Sinonasal natural killer (NK)/T-cell or T-cell lymphoma behaves quite differently from other lymphomas. The objective of this study was to investigate clinical features, treatment outcomes, and failure patterns in patients with this type of sinonasal lymphoma. METHODS: From September, 1977 to December, 2000, 77 patients with sinonasal NK/T-cell lymphoma or T-cell lymphoma who had received radiotherapy (R/T), chemotherapy (C/T), or both (R/T and C/T) were evaluated retrospectively. RESULTS: Fifty-six patients (73%) had locoregional disease only, and 21 patients (27%) had systemic involvement. Forty-four patients (57%) achieved a complete remission (CR). The 5-year overall survival rate was 36% (median follow-up, 89 months). Achievement of CR was the only prognostic factor for survival in multivariate analysis. Among patients with locoregional disease, the CR rate was 63%, and the 5-year overall survival rate was 42%. Combined R/T and C/T or R/T alone resulted in better survival compared with C/T alone (5-year survival rates, 59%, 50%, and 15%, respectively; P = 0.01). Incidences of locoregional and systemic failure were 43% and 30%, respectively. Outcome was dismal for patients with systemic disease, with a CR rate of 43% and a 5-year survival rate of 25%. Only 2 of 21 patients had sustained remissions. The locoregional and systemic failure rates were 57% and 71%, respectively. CONCLUSIONS: Treatment outcomes were unsatisfactory for patients with locoregional and systemic sinonasal NK/T-cell or T-cell lymphoma. R/T could not control locoregional disease satisfactorily, and C/T was unable to eradicate systemic disease in many patients. High-dose therapy may be worth studying in these patients. New treatments should be investigated to increase remission rates, prevent failure, and improve survival.     

Different T-cell receptor gene configurations in T-cell neoplasms and acute lymphoblastic leukemia.

Southern blotting and multiple restriction enzymes were used to analyze T-cell receptor (TCR) and immunoglobulin heavy chain genes in 20 postthymic T-cell neoplasms, ten prethymic and thymic T-cell tumors, and 45 cases of precursor-B acute lymphoblastic leukemia (ALL). Immunoglobulin heavy chain, never rearranged in a postthymic specimen and only once in a prethymic/thymic sample, was rearranged in all but two cases of precursor-B ALL. In contrast, biallelic rearrangement of TCR beta with deletion of the first constant region germline fragment was regularly seen in T-cell neoplasms, but only twice in the 45 precursor-B ALL cases. TCR gamma was rearranged in all but one postthymic sample, in all prethymic/thymic samples, and in approximately half of precursor-B ALL specimens as well. Preferential use of V gamma regions was evident among the various disorders: V8 and V10 in postthymic neoplasms; and V3, V5, V7, and, particularly, V9 in precursor-B ALL. In all the studied conditions, TCR delta was rarely in germline configuration. Extensive biallelic deletion of J delta 1, J delta 2, and C delta, almost always (19 of 20 specimens) present in postthymic neoplasms, was observed in only a minority (14 of 45) of precursor-B ALL samples. In precursor-B ALL, rearranged antigen receptor genes were more frequently found in common acute lymphoblastic leukemia antigen-positive and terminal deoxynucleotidyl transferase-positive specimens. Furthermore, TCR gene rearrangement in that disorder was characterized by a hierarchical pattern: TCR beta was not rearranged without TCR gamma nor TCR gamma without TCR delta. Despite uncertainty of the mechanism, the various disorders can be distinguished on the basis of characteristic antigen receptor gene patterns.     

Low natural killer-cell activity and immunoglobulin levels associated with smoking in human subjects.

Previous studies have shown that smoking is associated with a high incidence of certain malignancies and a high incidence of metastatic spread of melanoma. The purpose of the present study was to examine whether this high incidence of malignancy could be associated with certain aspects of immune function believed to be important in restricting tumour growth. Age-and sex-matched smoking and non-smoking normal subjects and male, smoking and non-smoking melanoma patients, were studied for the natural killing (NK) activity of their blood leukocytes against cultured melanoma and Chang cells. The levels of the various immunoglobulin classes in their sera and the E rosette levels of the normal subjects were also assessed. The results indicate that the NK activity of blood leukocytes from both normal subjects and melanoma patients who smoked was significantly lower against cultured melanoma cells than that of non-smokers. Smokers were also shown to have lower IgG and IgA Immunoglobulin levels in their sera compared to non-smokers but no differences in the percentage of E-rosetting (T) cells was detected. Recent studies provide some basis for the belief that the low NK activity and immunoglobulin levels in smokers may be related. These results further suggest that a closer examination of the effects of this environmental hazard on the immune system and its relation to malignancy is needed.     

鼻型结外NK/T细胞淋巴瘤治疗的研究进展

结外NK/T细胞淋巴瘤,鼻型(ENKTL)是一种侵袭性非霍奇金淋巴瘤.ENKTL目前尚无标准治疗方案,局限期患者可考虑单纯放疗或放化疗联合治疗,多药联合化疗为晚期患者主要治疗手段,以蒽环类药物为主的传统化疗方案对ENKTL的疗效欠佳.近年,一些新的治疗方案在ENKTL中显示出一定的疗效,文章就ENKTL治疗的进展进行综述.