儿童横纹肌肉瘤的临床特征及其疗效研究

Clinical features and therapeutic efficacy of childhood rhabdomyosarcoma

目的探讨儿童横纹肌肉瘤(RMS)的临床病理学特点、疗效与预后,以期规范临床治疗、改善预后。方法选择2010年8月至2015年9月于四川大学华西第二医院儿科收治的26例RMS患儿的病历资料为研究对象。为了分析与RMS进展或复发相关的危险因素,根据随访终点时的疗效,接受随访的23例患儿(剔除3例失访和放弃治疗患儿)中,持续完全缓解(CR)为12例、部分缓解为2例、RMS进展/复发为9例。剔除2例PR患儿后,分为持续CR组(n=12)与RMS进展/复发组(n=9)。RMS进展/复发组与持续CR组患儿性别构成比及发病中位年龄等比较,差异均无统计学意义(P>0.05)。对收集的26例RMS患儿病理学诊断及分型、免疫组化检测结果、细胞遗传学检查结果、RMS分期与危险度分组及预后等进行分析。采用Kaplan-Meier法计算本组23例(剔除3例失访和放弃治疗患儿)RMS患儿的2年总生存(OS)率和无事件生存(EFS)率,非条件多因素logistic回归分析法分析RMS进展/复发相关危险因素。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本组26例RMS中,男性患儿为17例、女性为9例,中位发病年龄为60.5个月(10~171个月),男、女发病年龄比较,差异无统计学意义(T=0.170,P=0.680)。2本组26例RMS中,胚胎型和腺泡型RMS分别为19例(73.1%)和7例(26.9%)。其中,接受免疫组化检测的24例RMS患儿中,肌细胞生成蛋白和结蛋白阳性表达率分别为100.0%(24/24)和95.8%(23/24)。2013年10月后收治的9例(胚胎型为5例和腺泡型为4例)RMS患儿中,经荧光素原位杂交(FISH)技术检测FOXO1A基因易位的结果发现,仅1例腺泡型检出FOXO1A基因易位。3根据RMS组间研究协作小组(IRS)制定的RMS危险度分组标准,本组患儿化疗前RMS临床分期:RMSⅠ、Ⅱ、Ⅲ和Ⅳ期分别为8、1、9和8例。其中,低、中、高危组分别为8、10、8例。423例术后接受规范化疗患儿中,7例尚完成局部放疗,2例接受外周血自体造血干细胞移植。这23例RMS患儿的CR率为73.9%(17/23)。获得持续CR为12例患儿中,疾病进展为4例,复发为5例;累计死亡为5例。5对本组23例接受规范化疗患儿的中位随访时间为13个月(2~50个月),2年OS率为78%,2年EFS率为52%。发病年龄<10岁患儿的2年OS率和EFS率均显著高于发病年龄≥10岁患儿,并且差异有统计学意义(χ~2=8.889,P=0.003;χ~2=4.201,P=0.04);接受化疗≤4个疗程的CR患儿的2年OS率显著高于非CR患儿,差异亦有统计学意义(χ~2=7.017,P=0.008)。RMS进展/复发组患儿接受化疗>4个疗程仍未达CR患儿的构成比显著高于持续CR组,并且差异亦有统计学意义(P=0.007)。6对RMS进展/复发组患儿的危险因素进行非条件多因素logistic回归分析结果显示,发病年龄≥10岁与接受化疗≤4个疗程仍未达CR,均非RMS进展/复发的独立危险因素(OR=0.255,95%CI:0.012~5.173,P=0.432;OR=0.039,95%CI:0.002~0.975,P=0.058)。结论儿童RMS以胚胎型多见,总体CR率可达70%以上,但RMS进展/复发率仍较高。年长儿和早期治疗反应不良RMS患儿的总体预后不良,需多学科协作治疗提高疗效、改善预后。

Objective To explore the clinical and pathological characteristics, therapeutic efficacy and outcomes of childhood rhabdomyosarcoma （RMS）, aiming to formulate a standardized management approach and to improve long-term prognosis. Methods Clinical data of 26 children with RMS admitted to the Department of Pediatrics, West China Second University Hospital, Sichuan University, from August 2010 to September 2015 was collected and analyzed retrospectively. Among 23 cases of RMS with combination chemotherapy and regular follow-up, there were 12 cases in continuous complete remission （CR） , 2 cases achieving partial remission （PR）, and 9 cases with RMS progression/recurrence. Excluding 2 cases of PR, they were divided into continuous CR group （n= 12） and RMS progression/relapse group （n = 9）. There were no significant differences between two groups in terms of gender proportion and median age at onset （P^0.05）, respectively. The pathology diagnosis and typing, immunohistoehemistry, cytogeneties, stage of RMS and risk and prognosis were analyzed. Kaplan-Meier method was used to calculate and compare rates of 2-year overall survival （OS） and event free survival （EFS） between different factors, while multivariate non- conditional logistic analysis was employed to identify RMS progression/relapse risk 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 （~） There were 17 boys and 9 girls among 26 cases of RMS children, whose median age at onset of RMS was 60.5 months （10-171 months）. There was no significant difference in terms of age at tumor onset between boys and girls （T=0. 170, P=0. 874）. @There were 19 cases with embryonal RMS （73.1%） and 7 cases with alveolar RMS （26.9%）. The FOXO1A fusion gene was detected in only one case with alveolar RMS. Positive expressions of myogenin and desmin were documented in 24 cases （100.0%） and 23 cases （95.8%） out of 24 patients in whom immunohistochemical staining was undertaken. Among 9 cases of RMS （including 5 cases of embryonal RMS and 4 cases of alveolar RMS） who were admitted after October 2013, FOXOIA gene translocation was detected by fluorescence in situ hybridization （FISH） in only one case of alveolar RMS. @RMS stage I , Ⅱ ,Ⅲ and Ⅳ were assigned to 8, 1, 9 and 8 cases, respectively before treatment, as determined by Intergroup Rhabdomyosarcoma Study （ISR） pretreatment staging system. There were 8, 10 and 8 cases stratified to RMS low, intermediate and high-risk groups. Twenty-three cases received combination chemotherapy, with ？ cases receiving additional local radiotherapy and 2 cases with peripheral blood stem cell transplantation. Overall rate of CR was 73.9% （17/23）. Up to the follow-up endpoint, continuous CR and PR were documented in 12 and 2 cases, while tumor progression and tumor relapse were identified in 4 and 5 patients, respectively. Five patients died, including 4 cases with tumor regression and 1 relapsed case. With a median follow-up of 13 months （2-50 months）, the rates of 2-year OS and EFS were 78% and 52%, respectively. The rates of 2-year OS and EFS were significantly higher in children with age at onset % 10 years old than those in children with age at onset ≥ 10 years old （X2 = 8. 889, P = 0. 003 ;x2 = 4. 201, P=0.04）. And the rates of 2-year OS and EFS were significantly higher in patients （13 cases） who achieved CR with 4 or fewer chemotherapy courses than those （ 8 cases） who failed to achieve CR （x2 = 7. 017, P = 0. 008）. Similarly, there were more cases who failed to achieve CR with chemotherapy courses 〉4 in the RMS progression/relapse group than those cases in continuous CR group （P=0. 007）. Nevertheless, both age at onset ~10 years old and CR-targeting chemotherapy courses ≤ 4 were not independent risk factors for the prognosis of RMS in the RMS progression/ relapse group, as revealed by muhivariable logistic regression （OR = 0. 255, 95% CI： 0. 012-5. 173, P=0.432; 0R=-0.039, 95% CI：0.002-0.975, P=0.058）. Conclusions Embryonal RMS is more prevalent in children. Although overall rates of CR could be over 70%, RMS progression and relapse occur in substantial cases. Generally, prognosis remains poor in older patients and those with inadequate early therapeutic responses. Multidiseiplinary cooperative approaches should be adopted in order to improve therapeutic efficacy and long-term outcomes.