结外NK/T细胞淋巴瘤的免疫靶向治疗进展

结外NK/T细胞淋巴瘤（extranodal NK/T-cell lymphoma,ENKTCL）是一种高度侵袭性的非霍奇金淋巴瘤,对以门冬酰胺酶为基础的化疗方案较敏感,但仍有部分患者预后不佳。近年来,随着对ENKTCL发病机制的进一步了解,认为免疫靶向治疗在初治或复发难治ENKTCL患者治疗中具有重要的临床价值。本文就单克隆抗体类药物、靶向细胞信号传导通路的小分子抑制剂、表观遗传学药物、免疫调节剂、EBV特异性细胞毒性T细胞及嵌合抗原受体修饰的T细胞治疗在ENKTCL中的临床前研究及临床试验等研究进展进行综述。     

18F-FDG PET/CT在结外NK/T细胞淋巴瘤中的预后价值

结外NK/T细胞淋巴瘤（extranodal natural killer/T-cell lymphoma,ENKTL）是一种与EB病毒（epstein-barr virus,EBV）相关的侵袭性非霍奇金淋巴瘤（non-Hodgkin's lymphoma,NHL）,好发于亚洲和南美洲,其病程进展较快、病死率较高、预后不佳。目前应用的预后模型主要包括国际预后指数（international prognostic index,IPI）、韩国预后指数（Korean prognostic index,KPI）、NK细胞淋巴瘤预后指数（prognostic index of natural killer cell lymphoma,PINK）及包含EBV DNA的NK细胞淋巴瘤预后指数（prognostic index of natural killer cell lymphoma with epstein-barr virus DNA,PINK-E）,尚存在一定的局限性。正电子发射断层显像融合计算机断层扫描（positron emission tomography/computed tomography,PET/CT）是一种将解剖结构成像和代谢功能成像相结合的影像技术,具有高敏感性、高特异性的优势,在多种恶性淋巴瘤的诊断、分期、疗效评价和预后评估等方面发挥重要的作用,但其对于ENKTL的预后价值仍存争议。因此,本文针对治疗前、治疗中期和治疗结束后PET/CT对于ENKTL的预后价值进行综述。      

结外NK/T细胞淋巴瘤检测EB病毒与疗效关系的研究*

目的:探讨血浆中EB病毒阳性在评价结外NK/T细胞淋巴瘤近期疗效和远期疗效中的临床意义。方法:收集2011年1 月至2014年4 月郑州大学第一附属医院经病理及免疫组化确诊为结外NK/T细胞淋巴瘤的患者109 例,应用qRT-PCR方法检测其血浆中EBV-DNA拷贝数,比较EBV 阴性和EBV 阳性患者对治疗疗效与预后的差异。结果:109 例结外NK/T细胞淋巴瘤患者,53例阳性患者中有34例（64.2%）为晚期（Ⅲ～Ⅳ期）,56例阴性患者中22例（39.3%）为晚期（Ⅲ～Ⅳ期）,EBV 阳性组中伴有B 症状33例（62.3%）,阴性组患者21例（37.5%）,EBV 阴性患者与EBV 阳性患者在分期及B 症状方面均具有统计学意义（P<0.05）。 34例（60.7%）EBV 阴性结外NK/T细胞淋巴瘤患者达到客观缓解率,显著高于EBV 阳性患者的客观缓解率（22例,41.5%）（P<0.05）。EBV 阴性组与EBV 阳性组相比,其2 年无进展生存期更高（P<0.05）。 结论:检测结外NK/T细胞淋巴瘤患者血浆中EB病毒对评价其近期疗效及2 年无进展生存期具有重要的临床意义。      

鼻型NK/T细胞淋巴瘤26例临床病理分析

目的：研究鼻型NK/T细胞淋巴瘤（ENKL）的免疫表型、病理特点、临床特点。方法：回顾性分析26例ENKL的临床表现、病理组织学特点,采用免疫组化SP法检测LCA、CD3、UCHL1、CD20、CD79a、CD56、TIA-1、Granzyme B、perforin,原位杂交方法检测EBER在ENKL中的表达情况。结果：NK/T细胞淋巴瘤发生在鼻腔占80.77%（21/26）,伴坏死、溃疡、鼻出血者100%（26/26）,肿瘤细胞嗜血管现象占46.15%（12/26）,伴＂鳞状细胞癌样反应＂占20.08%（6/26）。CD3、CD56、TIA-1、Granzyme B、perforin及EBER阳性表达率达100%。结论：临床及病理形态复杂多样性是NK/T细胞淋巴瘤的特点。病理诊断中须注意与炎症或高分化鳞状细胞癌鉴别。ENKL根据典型的临床表现、病理形态学改变、免疫表型特点及EBER原位杂交阳性能准确诊断。     

NK/T细胞淋巴瘤发病机制研究进展

NK/T细胞淋巴瘤(NK/T cell lymphoma, NKTCL)属高度侵袭性肿瘤, 预后差, 目前尚无明确有效的治疗方案。除了组织形态改变及EBV相关, 该病也存在染色体异常、基因突变、信号通路及蛋白表达的异常。国内外学者由此出发, 对其发病机制进行了持续的深入研究。本文就NKTCL发病机制的研究进展作一综述。      

抑制EBNA1表达对NK/T细胞淋巴瘤细胞增殖的影响

目的 研究抑制EBV阳性NK/T细胞淋巴瘤细胞系HANK1细胞EBV核抗原1的表达对细胞增殖和周期分布的影响,探讨抑制EBV感染治疗EBV相关性NK/T细胞淋巴瘤的潜在应用价值。方法 用RNA干扰（RNA interference,RNAi）方法抑制HANK1细胞EBNA1表达,Western blot检测EBNA1蛋白表达,流式细胞仪检测细胞周期分布和细胞凋亡。结果EBNA1-shRNA表达载体明显抑制EBNA1表达,细胞周期G₁期停滞,凋亡细胞增多,细胞增殖受抑。结论 根治EBV感染可能是治疗EBV相关性NK/T细胞淋巴瘤的好方法。     

EB病毒及EB病毒感染相关淋巴瘤发病机制的研究进展

EB病毒（Epstein-Barr virus,EBV）是一个已知与人类肿瘤相关的病毒。在多种上皮、间叶和淋巴造血肿瘤中可检测到EBV的存在,与淋巴瘤关系尤为密切,特别是与Burkitt淋巴瘤（Burkitt’s lymphoma,BL）、霍奇金淋巴瘤（Hodgkin's lymphoma,HL）、弥漫性大Ｂ细胞淋巴瘤（diffuse large B-cell lymphoma,DLBCL）、移植后淋巴组织增殖性疾病（post-transplant lymphoproliferative disorders,PTLD）及NK/T细胞淋巴瘤等疾病的发生、发展、预后相关。大量的研究报道以及临床数据表明,EBV及其编码的蛋白、微小RNA在诱导淋巴细胞恶性转化的过程中发挥极其重要又复杂的作用,包括促进其增殖、抑制凋亡在内的多种信号通路中的蛋白。本文就近些年来EBV及EBV感染密切相关淋巴瘤发病机制的研究进展进行综述,旨在为进一步了解EBV感染与其导致淋巴瘤的机制提供一定的理论基础。      

血管免疫母细胞性T细胞淋巴瘤的不良预后因素研究进展

血管免疫母细胞性T细胞淋巴瘤（angioimmunoblastic T-cell lymphoma，AITL）是外周T细胞淋巴瘤（peripheral T-cell lymphoma，PTCL）的主要亚型，在国际T细胞淋巴瘤项目中占全部T细胞和NK细胞淋巴瘤的18.5%。AITL临床表现不佳，疾病进展迅速，预后差。由于疾病早期症状不明显，患者诊断时处于临床Ⅲ/Ⅳ期较多。人们对AITL进行不断的研究，也取得一定的进展。在此主要对C反应蛋白、干扰素调节因子-4/多发性骨髓瘤癌基因-1、白细胞介素-10等AITL近年来报道的不良预后因素进行综述。     

鼻腔鼻窦非霍奇金淋巴瘤免疫表型及其与EB病毒感染的关系

背景与目的:鼻腔鼻窦非霍奇金淋巴瘤(non-Hodgkin's lymphoma,NHL)的患病率和免疫表型组成具有地域性差异.本研究探讨中国广州地区57例鼻腔鼻窦NHL免疫表型及其与EB病毒(Epstein-Barr virus,EBV)感染的关系.方法:收集2000年4月1日至2006年10月31日中山大学肿瘤防治中心病理科57例鼻腔鼻窦NHL标本.免疫组化染色确定免疫表型,EBER原位杂交及PCR检测EBV感染情况.结果:在同期诊断的1 412例NHL中,71例(5.03%)发生于鼻腔鼻窦,其中仅有57例适用于本研究.57例鼻腔鼻窦NHL患者中,男性38例,女性19例,年龄3～75岁,中位年龄50岁;44例(77.19%)为鼻型NK/T细胞淋巴瘤,其中37例(84.09%)为EBV /CD56 NK细胞肿瘤,7例(15.91%)为EBV /CD56-细胞毒性T细胞表型;11例(19.30%)为B细胞淋巴瘤,其中6例为弥漫大B表型,2例为Burkitt(Burkitt样)淋巴瘤(EBV ),1例为髓外浆细胞瘤(EBV ),1例为MALT淋巴瘤(EBV-),1例为小淋巴细胞性淋巴瘤(EBV-);2例(3.51%)为外周T细胞淋巴瘤(EBV-).37例适用DNA检测的病例中,25例(67.57%)感染缺失型LMP1(del-LMP1)EBV株,12例(32.43%)感染野生型LMP1(wt-LMP1)EBV株.结论:鼻腔鼻窦NHL最常见的类型为鼻型NK/T细胞淋巴瘤,可进一步分为EBV /CD56 NK细胞及EBV /CD56-细胞毒性T细胞表型.NK/T细胞淋巴瘤均感染了EBV,EBV株主要为del-LMP1型.     

NK/T细胞淋巴瘤基因组中EBV DNA整合检测及分析

  目的  明确NK/T细胞淋巴瘤（NK/T cell lymphoma,NKTCL）基因组中是否存在EB病毒（Epstein-Barr virus,EBV）DNA整合,初步分析NKTCL细胞系基因组中EBV DNA整合信息。  方法  利用PCR法扩增EBV DNA和原位杂交法检测EBER表达,验证由郑州大学第一附属医院生物样本库提供的5例EBV（+）及4例EBV（-）NK/T样本EBV感染情况。测序全基因组DNA样本并进行生物信息学分析。利用全基因组序列比对捕获EBV整合序列;使用Blast比对样本EBV fasta文件与EBV fasta库。采用CREST软件提取softclip reads,过滤paired reads并对过滤后的reads进行染色体分布的统计。使用IGV比对染色体部分区域reads分布情况,采用PCR法扩增EBV DNA高频整合区域并行sanger测序。  结果  5例EBV（+）NK/T样本中均检测出EBV DNA和EBER表达,4例EBV（-）NK/T样本则未能检出。样本的测序深度、覆盖深度、覆盖率和比对率均满足后续研究要求。比对结果显示捕获的序列为病毒序列。EBV（+）NKTCL细胞系SNK、YTS和EBV（+）鼻腔NTKCL组织的reads数目最多,且在2号染色体上呈非随机性富集。chr2:30234084-30234483 400 bp区域存在EBV DNA整合,并导致chr2p23.1位点的插入缺失。  结论  EBV（+）NKTCL细胞在chr2p23.1位点存在EBV DNA的高频整合,提示可能影响相关基因表达。      

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.     

Primary nasal lymphoma,NK/T‐cell type: Report of two cases with similar presentation but different outcome

Two cases of natural killer (NK)/T‐cell primary nasal lymphoma with similar clinical presentations are reported, for comparison and contrast, to highlight the clinical issues and challenges posed by this unusual disease, its aggressiveness being matched only by its rarity. Presenting as a lesion in the nasal cavity with histological features of malignant lymphoma, primary nasal lymphoma is an uncommon extranodal lymphoma, which poses problems in both diagnosis and management. In people of oriental descent, the common cell subtype is NK/T‐cell. Although it is generally thought that combination treatment with chemotherapy and radiation is the best management for early stage non‐Hodgkin's lymphoma (NHL), there is still debate as to whether combined therapy is optimal treatment for this particular subtype of NHL, given that it responds less well to conventional chemotherapy. Herein we report two patients to illustrate these controversies.     

结外鼻型NK/T细胞淋巴瘤27例临床分析

 目的　分析结外鼻型NK／T细胞淋巴瘤（ENKL）的临床特征、不同治疗方法的疗效及影响预后的因素。方法　回顾性分析27例ENKL患者,予单纯放疗3例,单纯化疗9例,其余15例采用放化疗联合治疗,其中3例患者行自体造血干细胞移植（auto-HSCT）。对B组症状、乳酸脱氢酶（LDH）、一般状况评分、国际预后指数评分、Ann Arbor分期、治疗模式和近期疗效进行单因素分析。单因素分析采用 Kaplan-Meier法。结果　全组平均生存时间为32（2～42）个月。1、2、3年的总体生存（OS）率分别为79.5 %、71.6 %、53.7 %。早期（Ⅰ期+Ⅱ期）及晚期（Ⅲ期+Ⅳ期）患者2年生存率分别为83.3 %、62.3 %（P＝0.368）,早期患者单纯放疗或化疗4例均获总有效（OR）（CR+PR）,化疗联合放疗10例,OR 9例。晚期患者单纯化疗8例,OR 2例;化疗联合放疗5例,OR 2例。单因素分析显示,年龄及近期疗效是影响生存率的主要因素（P＜0.05）。结论　对于ENKL早期患者,放疗或化疗可取得较好的疗效,放化疗联合治疗及auto-HSCT是治疗晚期ENKL的重要方法。年龄及近期疗效可作为判断ENKL预后的参考因素。     

NK/T Cell Lymphoma: Updates in Therapy

Purpose of Review

Extranodal NK/T cell lymphoma (ENKL), nasal type, is a highly aggressive lymphoma which used to show a poor clinical outcome. Expression of P-glycoprotein on lymphoma cells of ENKL is a major reason for the refractoriness to conventional chemotherapy containing anthracycline. However, recent innovative approaches have improved the outcome and prognosis of ENKL. The purpose of this review is to summarize the proceedings of treatment.

Recent Findings

Concurrent chemoradiotherapy containing platinum and several drugs including L-asparaginase, methotrexate, and alkylators shows excellent outcomes for the limited-stage ENKL. SMILE (steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide) or other L-asparaginase-containing therapy is promising for advanced-stage ENKL, followed by either autologous or allogeneic hematopoietic stem cell transplantation. Anti-PD-1 or other immunological checkpoint inhibitors are recently reported to be effective for relapsed/refractory ENKL thought to be due to EBV-driven upregulation of PD-L1 expression.

Summary

The prognosis of ENKL is therefore improving by the introduction of these strategies. The 5-year overall survival (OS) rate of limited stage was 63.2% [95% confidence interval (CI), 55.3 to 70.0%] before 2010, but was 79.4% (95% CI, 66.9 to 87.6%) in 2010 or after. However, there still exists a room for improvement, particularly for advanced-stage patients. The 2-year OS of advanced ENKL was 30.3% (95% CI, 19.5 to 41.7%) before 2010, but was 40.5% (95% CI, 24.8 to 55.8%) in 2010 or after. Optimal treatment scheme should further be explored.

     

NK/T-Cell Lymphomas: Pathobiology, Prognosis and Treatment Paradigm

The current World Health Organization (WHO) classification includes two types of natural killer (NK)-cell lymphomas: extranodal NK/T-cell lymphoma, nasal type (ENKL), and aggressive NK-cell leukemia (ANKL). These diseases are mostly endemic to East Asia and Latin America. The Epstein-Barr virus (EBV) is usually detected in tumor cells, suggesting that EBV plays an important role in lymphomagenesis. At the site of origin, ENKL can be divided into two major subtypes: nasal and extranasal diseases. The advanced disease presentation, highly aggressive clinical course, and poor prognosis of the latter are analogous to ANKL. It is well known that P-glycoprotein, which is a product of the multi-drug resistance (MDR1) gene, is expressed on neoplastic cells of ENKL or ANKL. This is a major cause of the refractoriness of malignant lymphoma to conventional chemotherapeutic regimens containing anthracycline. Recent studies, however, have identified that L-asparaginase-containing regimens, such as SMILE (steroid, methotrexate, ifosfamide, L-asparaginase and etoposide), are effective for ENKL. Considering the myelotoxicity of SMILE, its use in the treatment of ANKL needs some modifications, but this treatment scheme is promising in improving the prognosis of NK-cell lymphomas.     

鼻型NK/T细胞淋巴瘤26例临床病理分析

目的:研究鼻型NK/T细胞淋巴瘤(ENKL)的免疫表型、病理特点、临床特点。方法:回顾性分析26例ENKL的临床表现、病理组织学特点,采用免疫组化SP法检测LCA、CD3、UCHL1、CD20、CD79a、CD56、TIA-1、Granzyme B、perforin,原位杂交方法检测EBER在ENKL中的表达情况。结果:NK/T细胞淋巴瘤发生在鼻腔占80.77%(21/26),伴坏死、溃疡、鼻出血者100%(26/26),肿瘤细胞嗜血管现象占46.15%(12/26),伴"鳞状细胞癌样反应"占20.08%(6/26)。CD3、CD56、TIA-1、Granzyme B、perforin及EBER阳性表达率达100%。结论:临床及病理形态复杂多样性是NK/T细胞淋巴瘤的特点。病理诊断中须注意与炎症或高分化鳞状细胞癌鉴别。ENKL根据典型的临床表现、病理形态学改变、免疫表型特点及EBER原位杂交阳性能准确诊断。     

Efficient recruitment of c‐FLIPL to the death‐inducing signaling complex leads to Fas resistance in natural killer‐cell lymphoma

Activation‐induced cell death (AICD) mediated by the Fas/Fas ligand (FasL) system plays a key role in regulating immune response. Although normal natural killer (NK) cells use this system for their homeostasis, malignant NK cells seem to disrupt the process. Extranodal NK/T‐cell lymphoma, nasal type (ENKL) is a rare but fatal disease, for which novel therapeutic targets need to be identified. We confirmed that ENKL‐derived NK cell lines NK‐YS and Hank1, and primary lymphoma cells expressed procaspase‐8/FADD‐like interleukin‐1β‐converting enzyme (FLICE) modulator and cellular FLICE‐inhibitory protein (c‐FLIP), along with Fas and FasL. Compared with Fas‐sensitive Jurkat cells, NK‐YS and Hank1 showed resistance to Fas‐mediated apoptosis in spite of the same expression levels of c‐FLIP and the death‐inducing signaling complex (DISC) formation. Unexpectedly, the long isoform of c‐FLIP (c‐FLIP_L) was coimmunoprecipitated with Fas predominantly in both ENKL‐derived NK cell lines after Fas ligation. Indeed, c‐FLIP_L was more sufficiently recruited to the DISC in both ENKL‐derived NK cell lines than in Jurkat cells after Fas ligation. Knockdown of c‐FLIP_L per se enhanced autonomous cell death and restored the sensitivity to Fas in both NK‐YS and Hank1 cells. Although ENKL cells are primed for AICD, they constitutively express and efficiently utilize c‐FLIP_L, which prevents their Fas‐mediated apoptosis. Our results show that c‐FLIP_L could be a promising therapeutic target against ENKL.     

7例原发性鼻腔NK/T细胞淋巴瘤的临床分析

目的探讨原发性鼻腔NK/T细胞非霍奇金淋巴瘤的临床特点及治疗方法。方法回顾性分析7例鼻腔NK/T细胞淋巴瘤的临床资料,其中5例采用化、放疗联合治疗,1例采用单纯化疗,1例采用单纯放疗,化疗方案为CHOP方案或EPOCH方案。结果单一放疗或化疗效果差,采用EPOCH方案化疗联合局部侵犯野放疗的效果较好。结论对原发性鼻腔NK/T细胞淋巴瘤,采用CHOP方案化疗疗效差,采用EPOCH方案化疗联合放疗预后较好。     

原发鼻腔非霍奇金淋巴瘤的治疗

关于原发鼻腔非霍奇金淋巴瘤的最佳治疗方案存在较大争议,不同治疗方式的效果差别很大.近年来的研究表明,放疗正逐渐成为治疗早期鼻腔自然杀伤(NK)-T细胞淋巴瘤的主要方式;但对于晚期患者,放化疔的效果均很差,应考虑新的有效的全身治疗方案.     

鼻NK／T细胞淋巴瘤相关噬血细胞综合征

 【摘要】　目的　探讨鼻NK／T细胞淋巴瘤并发噬血细胞综合征（HPS）的临床特征、治疗方法及预后。方法　对3例鼻NK／T细胞淋巴瘤并发HPS患者的临床资料进行回顾性分析。结果　3例鼻NK／T细胞淋巴瘤患者符合HPS诊断标准,初诊时具有多项淋巴瘤相关不良预后因素,1例以HPS为首发症状,2例发生HPS时处于疾病进展期,骨髓检查均发现淋巴瘤细胞浸润。并发HPS后患者病情进展迅速,最明显症状是发热、血象进行性下降、纤维蛋白原降低、血清铁蛋白升高及骨髓中出现噬血现象。给予以HLH-2004为基础的方案联合化疗后,HPS均有不同程度改善,但由于原发病无法控制,HPS很快复发,患者并发肝功能异常、凝血异常或弥散性血管内凝血,最终死亡。结论　鼻NK／T细胞淋巴瘤并发HPS时预后差,常发生在淋巴瘤进展期或终末阶段。以HLH-2004为基础的方案联合化疗有望逆转病情,延缓疾病进展,为原发病治疗创造机会。