儿童神经母细胞性肿瘤的临床特征及预后分析的单中心研究

目的 分析儿童神经母细胞性肿瘤(NT)的临床特征及预后情况,探讨NT预后相关危险因素.方法 选择2010年1月至2016年6月,于四川大学华西第二医院儿童血液肿瘤科收治的34例新发儿童NT患儿的临床病例资料为研究对象.对收集的34例新发儿童NT患儿的一般临床资料、辅助检查结果、肿瘤原发及转移部位、病理分型、MYCN基因扩增检测结果、临床分期与危险度分组、疗效及预后等情况进行回顾性分析.采用Kaplan-Meier法计算本研究34例儿童NT患儿的2年无事件生存(EFS)率和总体生存(OS)率,采用对数秩检验(log-rank test)单因素分析影响其预后的影响因素,并采用Cox比例风险回归模型分析儿童NT预后的独立影响因素.本研究遵循的程序符合四川大学华西第二医院人体试验委员会所制定的伦理学标准,得到该委员会批准.结果 ①本研究34例儿童NT患儿中,男性患儿为13例(38.2％),女性为21例(61.8％);中位发病年龄为40.5个月,发病年龄＞18个月患儿为28例(82.4％);腹部包块(50.0％,17/34),发热(32.3％,11/34)和腹部疼痛(32.3％,11/34)是儿童NT最常见的就诊原因.②本研究34例儿童NT患儿中,原发于腹部患儿为28例(82.4％),原发于非腹部患儿为6例(17.6％);初诊时骨髓转移患儿为16例(47.0％),骨骼转移患儿为10例(29.4％),颈部淋巴结转移(原发于纵隔)患儿为3例(8.8％),脾、肺转移患儿各为1例(2.9％).③血常规检查结果显示,贫血患儿为18例(52.9％);17例儿童NT患儿行血清神经元特异性烯醇化酶(NSE)检测,其血清NSE水平为27.28～370.00 ng/mL.④本研究34例儿童NT患儿中,14例(41.2％)患儿的肿瘤最大直径＞9 cm;影像学检查结果显示,肾上腺区包块患儿为18例(52.9％),腹膜后包块患儿为10例(29.4％),纵隔、颈部和盆腔包块患儿分别为4例(11.8％)、1例(2.9％)和1例(2.9％).⑤病理分型:本研究34例儿童NT患儿中,神经母细胞瘤(NB)患儿为24例(70.6％),节细胞性神经母细胞瘤(GNB)患儿为10例(29.4％).⑥本研究接受MYCN基因扩增检测的30例儿童NT患儿中,MYCN扩增患儿为11例(36.7％,均为Ⅲ～Ⅳ期和高/极高危组),未扩增患儿为19例(63.3％).⑦临床分期:本研究34例儿童NT患儿中,Ⅰ～Ⅳ期的儿童NT患儿分别为2例(5.9％)、4例(11.8％)、10例(29.4％)和18例(52.9％);低、中、高、极高危组患儿分别为3例(8.8％)、6例(17.6％)、10例(29.4％)和15例(44.1％).⑧本研究34例儿童NT患儿中,化疗前接受手术治疗患儿为28例(82.4％),术前化疗3～4个疗程后再行延期手术切除肿瘤患儿为6例(17.6％);本研究儿童NT患儿的2年EFS率为50.0％,2年OS率为67.6％.⑨Ⅲ～Ⅳ期儿童NT、化疗前肿瘤未/不全切除、MYCN扩增、高/极高危组NT分别与Ⅰ～Ⅱ期儿童NT、化疗前肿瘤完全切除、无MYCN扩增及低/中危组的2年EFS率分别比较,差异均有统计学意义(x2=7.697、6.048、5.695、5.125,P=0.006、0.014、0.015、0.025).⑩影响儿童NT预后相关因素的多因素分析结果显示,化疗前肿瘤手术切除程度(OR=3.668,95％CI=1.209～11.133,P=0.022)和危险度分组(OR=46.340,95％CI=2.764～777.065,P=0.008)是儿童NT的独立不良预后因素.结论 儿童NT发病年龄小,初诊时常已为进展期NT,并易于早期发生多部位、多灶性转移.MYCN扩增是儿童NT的不良分子生物学预后因素,多见于进展期和高/极高危患儿,其也是划分患儿危险度分组的重要指标.高/极高危儿童NT患儿病死率高、预后差.

Single center study of clinical features and prognostic analysis of neuroblastic tumor in children

Objective To analyze the clinical features and clinical outcomes of pediatric neuroblastic tumor(NT),and to document prognosis-related risk factors of pediatric NT.Methods From January 2010 to June 2016,clinical data of 34 new-onset pediatric NT patients were enrolled in this study.Their general clinical data,results of auxiliary examination,primary site and metastasis site,pathological type,MYCN amplification test results,clinical stage and risk group,treatment,efficacy and prognosis of patients with pediatric NT were analyzed retrospectively.Two-year event-free survival (EFS) rates and overall survival (OS) rates were calculated by the Kaplan-Merire method.Univariable analysis by log-rank test was undertaken to identify prognosis-related influence factors and multivariable analysis by the Cox proportional hazards regression model was for independent prognosis-related influence factors.The study protocol was approved by the Ethical Review Board of Investigation in Human Being of West China Second University Hospital,Sichuan University.Results ① Among 34 pediatric NT patients,there were 13 male patients (38.2％) and 21 female patients (61.8％).Median age of them at diagnosis was 40.5 months,with 28 cases having age of onset over 18 months.Abdominal mass (50.0％,17/34),fever (32.3％,11/34)and abdominal pain (32.3％,11/34) were the leading causes of seeking medical care.(②) Among 34 pediatric NT patients,28 cases (82.3 ％) were primary abdominal mass,6 cases (17.6 ％) occurred in non-abdomen.At diagnosis,there were 16 cases (47.0％) with bone marrow metastasis,10 cases (29.4％) with skeletal metastasis,3 cases (8.8 ％) with cervical lymph nodes metastasis,while spleen and lung metastasis occurred both in one case (2.9％).③ Routine blood test results showed 18 cases (52.9％) had anemia.Seventeen cases finished serum neuron-specific enolase (NSE) test,whose serum NSE level were 27.28-370.00 ng/mL.④ The maximum diameter of the primary tumors in 14 cases were over 9 centimeters.The imaging examination of the study showed 18 cases (52.9％) had adrenal region masses,10 cases (29.4％)had retroperitoneal cavity masses,4 cases (11.8％) had mediastina masses,one case (2.9％) had neck mass,one case (2.9 ％) had pelvic cavity mass.(⑤ Among 34 pediatric NT patients,pathology diagnosis of 24 cases (70.6％) were neuroblastoma (NB) and 10 cases (29.4％) were ganlioneuroblastoma (GNB).⑥) MYCN amplification was identified in 11 out of 30 cases (36.7％).These 11 patients with MYCN-amplified were exclusively stage Ⅲ-Ⅳ and categorized as high-risk or very-high risk.⑦ Among 34 pediatric NT patients,there were 2 cases (5.9％) at stage Ⅰ,4 cases (11.8％) at stageⅡ,10 cases (29.4％) at stage Ⅲ,18 cases (52.9％) at stage Ⅳ.Three cases (8.8％) were categorized in low-risk group,6 cases (17.6％) in media-risk group,10 cases (29.4％) in high-risk group,15 cases (44.1％) in very-high risk group.⑧ A total of 28 cases (82.4 ％) received surgery before chemotherapy,and 6 cases (17.6 ％) received 3-4 cycles chemotherapy before surgery.The 2-year EFS and 2-year OS rates of the 34 pediatric NT patients were 50.0％ and 67.6％,respectively.(⑨) Univariable analysis results showed,stage Ⅲ-Ⅳ,non-resection or incomplete tumor resection before combination chemotherapy,high-risk and very-high risk group,and MYCN amplification were associated with inferior 2-year EFS rates compared to stage Ⅰ-Ⅱ,complete tumor resection,low-risk and middle-high risk group and non-MYCN-amplified (x2 =7.697,6.048,5.695,5.125;P=0.006,0.014,0.015,0.025).⑩ Multivariable analysis by the Cox proportional hazards regression model disclosed that risk group (OR=46.340,95 ％ CI=2.764-777.065,P=0.008) and extent of surgical excision before chemotherapy (OR=3.668,95％CI=1.209-11.133,P=0.022) were independent adverse prognostic risk factors.Conclusions NT is clinically characterized by tumor onset at early childhood,great tendency of early multisite or multifocal distant metastasis,presenting with advanced tumor stage at diagnosis.MYCN amplification which predominantly seen in advanced stage and high-risk NT,is an adverse biological prognostic risk factor essential to refined risk group of NT.Prognosis remains to be quite poor in high-risk and particularly very-high risk NT,with strikingly high mortality rate in high and very-high risk group.