【作者】 刘晓；

【导师】 张明智；

【作者基本信息】 郑州大学 ， 肿瘤学（专业学位）， 2019， 硕士

【摘要】 背景目的外周T细胞淋巴瘤(Peripheral T cell lymphomas,PTCLs)被定义为由一群成熟T细胞或自然杀伤(natural killer cell,NK)细胞引起的非均质性淋巴增生性疾病。成熟T细胞淋巴瘤具有胸腺T淋巴细胞的免疫原性,可被分为αβT细胞和γδT细胞,约占恶性淋巴瘤的10%-15%。大多数PTCLs的预后均不良。除ALK阳性间变性大细胞淋巴瘤外,PTCLs患者5年生存率约30%。国际预后指数(IPI)是目前被广泛使用的PTCLs预后评分系统,除IPI中的各项指标外,还有一些与PTCLs预后相关的分子指标近年也越来越多地被发现。而细胞毒颗粒蛋白(cytotoxic molecule,CM)是存在于细胞毒性细胞的嗜天青颗粒中的细胞凋亡诱导分子,主要分布于NK细胞和细胞毒性T淋巴细胞。来源于细胞毒性细胞的PTCLs可能因释放大量CM而更具侵袭性或对获得常规化疗方案的耐药性从而使得预后更差。为此,我们进行了一项回顾性研究,以探究CM阳性表达对PTCLs的预后有无消极影响,进而对临床治疗发挥一定指导作用。资料与方法1.一般资料:我们回顾了2010年12月至2017年11月在我院诊断为PTCLs的94名患者的医疗记录。病理诊断根据2016年的WHO造血与淋巴组织肿瘤诊断标准进行。诊断为外周T细胞淋巴瘤-非特指型((peripheral T-cell lymphoma,not otherwise specified,ALCL),PTCL-NOS)、间变大细胞淋巴瘤(anaplastic large cell lymphoma,ALCL,包括ALK阳性和ALK阴性)、血管免疫母细胞性淋巴瘤(angioimmunoblastic T cell lymphoma,AITL)、肝脾T细胞淋巴瘤(Hepatosplenic T-cell lymphoma,HSTCL)、皮下脂膜炎样T细胞淋巴瘤(Subcutaneous panniculitis-like T-cell lymphoma,SPTCL)和肠病相关T细胞淋巴瘤(enteropathy-associated T-cell lymphoma,EATL)的患者均被包括在内。由病理科进行病理诊断和免疫组化检测,免疫组化中TIA-1、perforin或GrB任一一种表达阳性均判定为CM表达阳性。临床数据来自对患者记录的回顾,包括年龄、性别、临床分期(临床分期根据Ann Arbor分期进行)、IPI评分、骨髓受累情况、血液异常指标、治疗方案、疾病应答情况和患者的生存结局。所有患者均有化疗前可在影像中观察到的临床病变。94例患者的一线化疗方案为CHOP或GDPT方案,化疗4周期后进行疗效评价,评价为疾病稳定和疾病进展的患者更换化疗方案。所有患者至少经过6周期化疗方案的应用。本研究按照赫尔辛基宣言的原则进行,不包含任何对动物的研究。2.疗效判断标准:根据非霍奇金淋巴瘤国际疗效判断标准(Cheson标准)进行疗效评价。完全缓解(complete remission,CR)定义为该疾病的所有临床证据消失以及在开始治疗之前被认为是异常的所有实验室指标和放射学检查结果转为正常,部分缓解(partial remission,PR)定义为可测量病灶减少超过50%,疾病进展(progressive disease,PD)定义为出现新病灶或原病灶增大(在治疗评估之前由于进展或与治疗相关毒性反应的任何原因导致的死亡均包括在PD中),除此之外的表现均属于疾病稳定(stable disease,SD)。疾病客观缓解率(objective response rate,ORR)为CR和PR的总和。总生存期(overall survival,OS)为从诊断日期到死亡或最近随访的时间。无进展生存期(progression free survival,PFS)仅适用于达到CR的患者,记为从一线治疗结束至复发的时间。3.统计学处理:所有数据均使用SPSS软件20.0版本进行分析。采用χ~2检验分析两组临床特征之间的相关性,使用Kaplan-Meier方法估计存活曲线,并且通过Cox比例风险回归模型在多变量分析中鉴定与预后相关的独立因子。所有P值均为双侧,如果P<0.05,则认为值具有统计学意义。结果1.患者特征及分组:94例研究对象的年龄从17岁到74岁不等,平均年龄为48岁。其中,PTCL-NOS患者27例,AITL患者22例,ALCL患者32例(ALK阳性患者17例,ALK阴性患者15例),SPTCL患者6例,EATL患者5例,HSTCL患者2例。男性患者在总人群中稍占优势,男女比例为1.76。94例患者中,10例患者(10.6%)疾病处于I期,12例患者(12.8%)处于II期,22例患者(23.4%)处于III期,50例患者(54.9%)处于IV期。近一半的患者出现全身症状(45例,49.5%),41例患者(40.1%)表达细胞毒颗粒蛋白,其中23例患者仅表达一种毒颗粒蛋白(主要为TIA-1或GrB),剩余18例至少表达2种毒颗粒蛋白。94例患者中,有91例患者(96.8%)的临床记录可得出IPI评分,其中,37例患者(40.6%)为0-1分,28例患者(30.8%)为2分,17例患者(18.7%)为3分,9例患者(9.9%)为4-5分。6例患者(6.38%)初始即有骨髓侵犯,42例患者(44.7%)初始乳酸脱氢酶(LDH)值高于正常范围,17例患者(18.1%)开始治疗时人类疱疹病毒(EBV)抗体筛查为阳性。CM阳性组(41例)与CM阴性组(53例)患者临床特点均衡,P>0.05,无统计学差异。2.近期疗效及远期生存:本研究随访日期截至2018年6月,中位随访时间为28.1(2.1-74.0)个月。94例患者中,在经过一线治疗后,33例患者(35.1%)达到CR,29例患者(30.9%)达到PR,SD和PD的患者为32例患者(34.0%)。总有效率(ORR)为66.0%。其中,CHOP方案组CRR为32.7%,GDPT方案组CRR为38.1%;CHOP方案组ORR为65.4%,GDPT方案ORR为66.7%,两组P值均大于0.05,无统计学差异。按CM的表达情况分组,CM阳性组完全缓解率(CRR)为29.3%,CM阴性组CRR为39.6%,P>0.05;CM阳性组ORR为48.8%,CM阴性组ORR为79.2%,P<0.05。94例患者中有40例(42.5%)死亡,3年的累计生存率为63.4%。中位OS为17.5个月(CM表达阳性组为15个月,CM表达阴性组为20个月),中位PFS为12个月(CM表达阳性组为12.7个月,CM表达阴性组为12个月)。CM表达阳性的患者3年OS率为48.3%,CM表达阴性的患者3年OS率为76.7%,两组差异有统计学意义(P<0.05)。3.预后分析:单因素分析中结果显示,疾病分期晚(P=0.007)、IPI得分高(P=0.002)、骨髓受累(P=0.004)及细胞毒颗粒蛋白阳性表达(P=0.022)是PTCLs预后的不利因素。采用COX回归模型进行多因素生存分析,结果显示IPI得分高、骨髓受累和细胞毒颗粒蛋白阳性表达为独立的预后风险因素(P<0.05)。结论1.疾病分期晚、IPI得分高、骨髓受累及细胞毒颗粒蛋白阳性表达的外周T细胞淋巴瘤患者可能预后较差。2.细胞毒颗粒蛋白是外周T细胞淋巴瘤独立的预后影响因子。更多还原

【Abstract】 ObjectivePeripheral T-cell lymphomas(PTCLs)are defined as a heterogeneous group of lymphoproliferative disorders originating from mature T-cells or nature killer(NK)cells.Mature T-cell lymphomas manifest the immunophenotypic features of post-thymic T lymphocytes,which are derived from both αβ T-cells and γδ T-cells.Mature T-cell constitute approximately 10–15% of lymphoid malignancies.Most prognosis of patients diagnosed with PTCLs is dismal.For instance,the 5-year overall survival(OS)rate of patients diagnosed with PTCLs except for those with ALK-positive ALCL,is approximately 30%.The International Prognostic Index(IPI)is generally used in prognosis of PTCLs,In addition to the indicators in IPI,however,there are other prognostic factors associating with the outcome of patients diagnosed with PTCLs.Cytotoxic molecules(CM)are apoptosis-inducing molecules that are present in the azurophilic cytoplasmic granules of cytotoxic cells,which defend individuals against neoplastic processes and viral infections.PTCLs derived from cytotoxic cells may be more aggressive or acquire resistance to conventional chemotherapy regimens due to the release of a large number of CM,resulting in a worse prognosis.We conducted a retrospective study to investigate the relationship between the expression of CM and the prognosis of patients diagnosed with PTCLs,and try to provide some guidance for clinical treatment.Methods1.General information: We reviewed the medical records of 94 consecutive patients diagnosed with PTCLs from December 2010 to November 2017 in our hospital.The pathological diagnosis was made according to WHO 2016classification guidelines.Patients diagnosed with PTCL-NOS,ALCL(both ALK-positive and ALK-negative),AITL,HSTCL,subcutaneous panniculitis-like T-cell lymphoma(SPTCL)and enteropathy-associated T-cell lymphoma(EATL)were included in the cohort.Pathological diagnosis and immunohistochemical examination were performed by the pathology department.In the immunohistochemistry,either TIA-1,perforin or Gr B with positive expression was identified as CM positive.Clinical data,which included age,sex,clinical stage(performed according to Ann Arbor classification guidelines),IPI score,bone marrow involvement,abnormality in blood,treatment regimen,disease response and outcome,were derived from the patient records.All patients had clinical lesions that could be observed by CT before chemotherapy.They were treated with CHOP and GDPT approaches as the first-line a respectively,and the efficacy was evaluated after 4 cycles of chemotherapy.The chemotherapy regimen was changed for patients whose diseases were in stable or prgressed.All patients underwent at least 6 cycles of chemotherapy.This study was conducted in accordance with the principles of the Declaration of Helsinki.The study protocol was approved by the ethics committee of The First Affiliated Hospital of Zhengzhou University.This article does not contain any studies with animals performed by any of the authors.2.Assessment of adverse effects and response criteria: Treatment responses were classified according to International Harmonization Project criteria.Complete remission(CR)was defined as the disappearance of all clinical evidence of the disease,as well as the normalization of all laboratory values and radiologic findings1 that had been considered abnormal before starting the treatment.Partial remission(PR)was defined as a ≥50% reduction in the tumor size.Progressive disease(PD)was defined as the presence of new lesions or enlargement of primary lesions(all deaths due to progression or treatment-related toxicities before treatment evaluation are included in PD).Stable disease(SD)was definedas any response that did not fall into the previously defined.The objective response rate(ORR)is the sum of CR and PR.OS rate was calculated from the date of diagnosis to the date of death or the latest follow-up.The progression-free survival(RFS)rate was applied only to patients attaining in CR.It was calculated from the end of first-line therapy to relapse.3.Statistical analysis: All data were analyzed using the Statistical Package for the Social Sciences(SPSS).The correlation between clinical characteristics of the two groups was analyzed by chi-square test.The OS curves were estimated using the Kaplan--Meier method.The factors independently associating with the OS were identified by multivariate analysis using the Cox proportional hazards regression model.All P--values were two sided,and values were regarded statistically significant at P≤0.05.Results1.Clinical characteristics: The characteristics of the 94 patients diagnosed with PTCL are summarized in Table 1.The patient age ranged from 17 to 74 years,with a median age of 48 years.Among all patients,27 cases were PTCL-NOS,22 cases were AITL,32 cases were ALCL(17 cases of ALK+ and 15 cases of ALK-),6 cases were SPTCL,5 cases were EATL and 2 cases were HSTCL.There was a slight male preponderance,with a male-to-female ratio of 1.76.Of the 94 patients,10patients(10.6%)were in stage I,12 patients(12.8%)were in stage II,22patients(23.4%)were in stage III,and 50 patients(54.9%)were in stage IV.Forty-five out of 91(49.5%)patients presented with systemic symptoms,and 41 out of 91(40.1%)patients expressed at least one CM.Among them,23 patients expressed only one kind of CM(mainly TIA-1 or Gr B),and the remaining 18 patients expressed at least two kinds of CM.The IPI score was available for 91 out of 94(96.8%)patients,Specifically,37 out of 91(40.6%)patients were classified as low risk,28(30.8%)as intermediate--low,17(18.7%)as intermediate—high risk,9(9.9%)as high risk.Bone marrow involvement was found initially in 6 patients(6.38%),initial lactate dehydrogenase(LDH)values were higher than normal in 42 patients(44.7%),and human herpes virus(EBV)antibody was positive in 17 patients(18.1%).The clinical characteristics of the patients in the CM positive group(41 cases)and the CM negative group(53 cases)were balanced,with no statistical difference.2.Response and outcomes: After a mean follow-up of 28.1 months(range from2.1 to 74.0 months),the CR rate was 35.1%(33 out of 94 patients),the PR rate was30.9%(29 out of 94 patients),the PR and SD rate was 34.0%(32 out of 94 patients),and the ORR was 66.0%.Among them,the complete response rate(CRR)of CHOP group and GDPT group was 32.7% vs 38.1%,the ORR of CHOP group and GDPT group was 65.4% vs 66.7%.P values of both groups were higher than 0.05,showing no statistical difference.According to the expression of CM,the CRR was 29.3% in the CM positive group and 39.6% in the CM negative group,P > 0.05.The ORR in the negative CM expression group was higher than in the positive CM expression group(ORR:79.2% vs.48.8%,P<0.05).40(42.5%)patients died,and the cumulative probability of survival at 3 years was 63.4%.The median OS was 17.5 months(15 months for positive CM expression and 20 months for negative CM expression).The median PFS was 12 months(12.7months for positive CM expression and 12 months for negative CM expression).Respectively,the 3-year OS rate of patients with positive CM expression was 48.3%,and the 3-year OS rant of patients with negative CM expression was 76.7%.3.Survival analysis: The univariate analysis suggested that four factors significantly affected and shortened OS,namely,advanced stage(P=0.007),a high IPI score(P=0.002),bone marrow involvement(P=0.004)and CM expression(P=0.022).Multivariate analysis showed that high IPI score,bone marrow involvement and positive CM expression were the independent risk factors.Conclusions1.PTCLs patients with advanced stage,a high IPI score,bone marrow involvementand CM expression always have poor prognosis.2.CM expression is an independent prognostic factor of PTCLs.更多还原