Characteristics and outcomes of rhabdomyosarcoma patients with isolated lung metastases from IRS-IV

Purpose

To better understand outcomes in children with rhabdomyosarcoma (RMS) and lung-only metastatic disease, the authors reviewed the experience from Intergroup Rhabdomyosarcoma Studies IV Pilot and IV.

Methods

Patients with lung-only (n = 46) vs other sites of metastatic disease (n = 234) were reviewed using patient charts and the database of Children's Oncology Group (COG).

Results

Sixteen percent of patients with RMS and metastatic disease had isolated lung metastases. Thirty-one (67%) had more than 5 metastatic lung lesions. These were bilateral in 34 (74%). Only 6 patients were biopsied at diagnosis. Sixteen children (35%) did not receive any lung radiotherapy. Patients that received lung radiotherapy had fewer lung recurrences (P = .04), although this has no significant impact on overall survival (OAS, 47% radiotherapy vs 31% no radiotherapy). Compared with patients with other sites of metastatic disease, patients with lung-only metastases have a greater proportion of favorable histology (67% vs 39%, P = .0017), negative nodal involvement (67% vs 32%, P = .0013), and parameningeal primaries (39% vs 12%) and a smaller proportion of extremity primaries (20% vs 33%, P = .0005 for site of primary tumor). Overall survival at 4 years for lung-only metastases was not significantly different from other single-site metastasis (42% vs 34%). Survival was not improved for unilateral disease or fewer than 5 metastatic lesions. Factors associated with diminished OAS include unfavorable histology (P = .0001) and age >10 years (P = .015).

Conclusions

Children with RMS and lung-only metastases usually present with extensive bilateral disease that is frequently not biopsied nor given protocol-recommended radiotherapy (XRT). However, outcome is comparable, although slightly better, than patients with other single-site metastasis.     

Hypertrophic osteoarthropathy in primary liver rhabdomyosarcoma

Hypertrophic osteoarthropathy is a well-documented paraneoplastic phenomenon in adults. It is a rare, but important finding in children with malignant disease as it can indicate prognosis. We present a case of hypertrophic osteoarthropathy associated with primary liver rhabdomyosarcoma in a 14-year-old boy.     

P53 gene mutations in pleuropulmonary blastomas

Pleuropulmonary blastoma (PPB) is rarechildhoodtumororiginating fromeitherlung orpleura. Although several cytogenetic changes, such as trisomy 2, trisomy 8, and loss of 17p material, have been reported, evidence of gene mutations is still lacking. Pathologically, PPB shares similarities with rhabdomyosarcoma in which p53 mutations are frequently detected. Possible implication of p53 mutations in PPB was investigated. PPBs of 3 patients were analyzed for occurrence of p53 mutations by using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method, and the nature of mutations was confirmed by direct sequencing. Two PPBs were confirmed to harbor p53 mutations. One was a Val to Leu substitution at codon 173, and another was a ArgArg to TrpCys substitution at codons 282 and 283. In each tumor, only the mutated allele was detected, suggesting inactivation of p53. Both patients with mutations had fatal outcome, while the remaining patient in whom no mutation was detected is disease free for 3 years after completion of treatment. The results raise the possibility that p53 inactivation can occur as a nonrandom genetic change involving the pathogenesis and outcome of PPB. Further studies in a larger series are necessary to clarify these matters.     

RHABDOMYOSARCOMA WITH BONE MARROW METASTASIS SIMULATING ACUTE LEUKEMIA

Rhabdomyosarcoma manifested as a systemic disease is very rare and cases showing diffuse metastasis in the bone marrow are most unusual. Recently we encountered two cases of rhabdomyosarcoma with diffuse bone marrow metastasis which were clinically manifested as acute leukemia. The first patient was a 15-year-old female, who was admitted in 1982 with pancytopenia and many large primitive cells in bone marrow aspirates, hematological malignancy being diagnosed. Thereafter the bilateral breasts showed rapid swelling and a biopsy specimen revealed the histological features of typical alveolar rhabdomyosarcoma. The primary site of the neoplasm remained undetermined during the course. At autopsy, it was disclosed that the neoplasm originated from the left thigh and showed generalized metastasis. The second patient was a 38-year-old man, who was admitted in 1986 because of a nasal polyp obstructing the nasal cavity, and persistent nasal bleeding. Peripheral blood samples showed leucoerythroblastosis and thrombocytopenia, and large primitive cells were found In bone marrow aspirates, so that hematological malignancy was initially diagnosed. A biopsy specimen of the nasal polyp showed proliferation of large round cells and electron microscopy demonstrated the ultrastructural features of rhabdomyosarcoma.     

儿童横纹肌肉瘤"上海儿童医学中心Rs-99方案"临床报告

目的　改善儿童横纹肌肉瘤、生殖细胞性肿瘤、Ewing’s肉瘤等恶性实体瘤预后。 方法　对 1998年10月至 2 0 0 1年 10月明确诊断的横纹肌肉瘤及其它软组织肉瘤、生殖细胞性肿瘤、Ewing’s肉瘤患儿共 17例 ,采用上海儿童医学中心Rs 99方案 ,即外科手术、内科化疗、选择性放疗、病理科与影像学科协作诊断、综合治疗。按方案中条件根据危险因素进行分组 ,并按分组给予分级治疗。结果　 17例恶性实体瘤患儿中 4例自行终止治疗并失访 ,12例获完全缓解 ,1例部分缓解 6个月后进展死亡。随访至 2 0 0 2年 9月 ,12例获缓解者中 1例 2 2个月时复发后死亡 ;1例 2 4个月时复发带病生存至今 35个月。另 10例持续缓解 15～ 4 6个月 ,平均为 2 8个月 ,其中 9例已停药平均 17个月。结论　Rs 99方案诊断及治疗对横纹肌肉瘤、生殖细胞性肿瘤、Ewing’s肉瘤有效。     

肿瘤坏死因子凋亡诱导配体联合顺铂对人横纹肌肉瘤细胞株凋亡的影响

目的探讨肿瘤坏死因子相关凋亡诱导配体（TRAIL）蛋白及TRAIL基因和顺铂联合应用对人横纹肌肉瘤细胞生长抑制和诱导凋亡作用，并分析细胞线粒体膜电位和细胞内cFLIPmRNA表达的改变对凋亡的的影响。方法将TRAIL蛋白、TRAIL基因和顺铂作用于培养的人横纹肌肉瘤细胞，通过MTT比色法、流式细胞仪（FCM）检测细胞凋亡和线粒体跨膜电位的改变、RT-PCR检测cFLIPmRNA表达，观察和分析TRAIL蛋白及TRAIL基因单独对横纹肌肉瘤细胞的作用及和顺铂联合作用的效果和机制。结果TRAIL基因和100μg／L的TRAIL蛋白对横纹肌肉瘤细胞的生长抑制率分别为52．5％和43．5％，凋亡诱导率为12．95％和10．26％，联合应用顺铂，生长抑制率和凋亡诱导率均显著高于单独应用，FCM分析显示联合应用降低了线粒体跨膜电位，RT—PCR显示cFLIPmRNA表达下降，与联合应用细胞凋亡率增加相一致。结论TRAIL蛋白和TRAIL基因能有效诱导横纹肌肉瘤细胞的凋亡从而抑制横纹肌肉瘤细胞的生长，联合应用顺铂可显著提高疗效。     

儿童横纹肌肉瘤的临床特征及其疗效研究

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：RMS Ⅰ、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(χ²＝8.889,P＝0.003;χ²＝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(χ²＝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。     

Multidrug Resistance Phenotype in the RMS-GR Human Rhabdomyosarcoma Cell Line Obtained after Polychemotherapy

Classical cytotoxic treatment of rhabdomyosarcoma (RMS), the most common soft tissue malignancy in children, is often accompanied by significant morbidity and poor response. Chemotherapy may induce multidrug resistance (MDR) associated with the expression of P-glycoprotein, a drug efflux pump which modifies the sensitivity of tumoral cells to drugs. To analyze MDR in RMS we used the RMS-GR cell line, obtained from an embryonal rhabdomyosarcoma treated in vivo with polychemotherapy. The RMS-GR cells showed cross-resistance to vincristine, doxorubicin and actinomycin D, the drugs of choice in the conventional treatment of RMS. Polymerase chain reaction (PCR) analysis showed that these RMS cells overexpressed mdr1 /P-glycoprotein. The pattern of resistance and the level of P-glycoprotein expression were similar to those found in the resistant RMS TE.32.7.DAC cell line obtained in vitro . Southern blot analysis showed that mdr1 overexpression was not due to amplification of the gene. Our results showed that the in vivo treatment of embryonal RMS may induce an MDR phenotype mediated by mdr1 /P-glycoprotein in RMS cells.     

鼻部胚胎型横纹肌肉瘤13例临床分析

目的:提高临床对鼻部胚胎型横纹肌肉瘤(ERMS)的诊疗水平.方法:回顾性分析13例鼻部ERMS患者的病史资料并复习文献.结果:鼻部ERMS男性多发.Ⅰ期1例,Ⅱ期4例,Ⅲ期7例,Ⅳ期1例.单纯手术治疗2例,手术加放、化疗9例,手术加放疗1例,放疗加化疗1例.2年生存率为69.2%(9/13),3年生存率为30.8%(5/13).结论:鼻部ERMS生长较为隐蔽,对可疑患者应及时做病理活检及免疫组织化学确诊.早期诊断、综合治疗将有利于其预后.手术联合放、化疗是治疗鼻部ERMS的有效手段.