儿童双侧肾母细胞瘤7例临床病理及分子生物学分析

Clinicopathological and molecular biological profiles of bilateral nephroblastoma in children:a report of 7 cases

目的探讨儿童双侧肾母细胞瘤的临床表现、组织形态学特征、免疫表型及分子生物学特点。方法回顾性分析山西省儿童医院2014年4月至2022年6月收治的7例双侧肾母细胞瘤患儿的临床资料,其中男3例,女4例;平均发病年龄为18个月,范围在7~29个月;5例为同时性发生,2例为异时性发生;6例为家长无意间发现腹部包块,1例为肉眼血尿就诊;3例男童均伴发隐睾,其中1例伴尿道下裂Ⅲ度。患儿均接受肿瘤切除手术,镜下观察其组织形态学特征并分型,对肿瘤组织行免疫组织化学染色,并行荧光原位杂交分子检测。除1例死亡病例外,其余6例患儿的预后情况随访至2023年12月。结果7例患儿肿瘤组织镜下形态表现多种多样,均可见胚芽、上皮及间叶组织,3种成分的占比及分化程度在不同患儿及患儿两侧间各不相同,部分患儿肿瘤组织存在大量横纹肌母细胞及横纹肌细胞,大部分患儿伴灶状出血、坏死,7例均无局灶性间变及弥漫性间变。免疫组织化学结果显示,肿瘤上皮成分AE1/AE3弥漫强阳性,胚芽及早期上皮分化成分WT1、CD56弥漫阳性,Vimentin间叶区域阳性、部分胚芽区域阳性,INI1未缺失,CyclinD1和P53表达以上皮及胚芽区为主,P53呈野生型表达,伴横纹肌分化病例Desmin阳性。荧光原位杂交分子检测结果显示,1例患儿WT1基因缺失,1例患儿SRD(1p36)基因缺失,1例患儿SRD基因缺失、1q21/1q23基因扩增,1例患儿SRD基因缺失、16q22/16q23基因缺失。其余3例患儿分子检测结果呈阴性。1例患儿于术后80个月左侧复发,未行手术,化疗2个疗程后出现肾功能不全,现持续治疗。1例患儿合并智力低下、癫痫,因肾功能衰竭于术后65个月死亡。其余5例患儿术前术后均接受规范性化疗,至今无复发及转移。结论儿童双侧肾母细胞瘤的病理组织类型多属于预后良好型,SRD(1p36)基因缺失为其常见染色体改变,1p和16q杂合性缺失和伴发畸形的患儿预后较差。

Objective To explore the clinical manifestations,histomorphological features,immunophenotypes and molecular biological characteristics of bilateral nephroblastoma in children.Methods From April 2014 to June 2022,the relevant clinical data were retrospectively reviewed for 7 children of bilateral nephroblastoma.There were 3 boys and 4 girls with a mean onset age of 18(7-29)months.Occurrence was synchronous(n=5)and heterochronous(n=2).The presenting symptoms were inadvertent parental detection of abdominal mass(n=6)and gross hematuria(n=1).Among 3 boys of cryptorchidism,one of them had gradeⅢhypospadias.Tumor resection was performed and histomorphologic characteristics were classified under microscope.Immunohistochemical stain of tumor tissues and fluorescent in situ hybridization molecular detection were performed.Except for one death case,the outcomes of the remainders were followed up until December 2023.Results Microscopic morphologies of tumor tissues were varied,including germ,epithelial and mesenchymal tissues.The proportion and differentiation of 3 components varied among different children and between two sides.Numerous rhabdomyoblasts were present in some tumor tissues and most cases were accompanied by focal hemorrhage and necrosis.Immunohistochemical results indicated that epithelial components AE1/AE3 were diffuse and strongly positive;WT1 and CD56 were diffuse and positive in germ and early epithelial differentiation;Vimentin was positive in mesenchymal region and in some germ regions;INI1 was not missing;CyclinD1 and P53 were expressed predominantly in epithelial differentiation and germ region;P53 was wild-type expressed.Desmin was positive in individuals with striated muscle differentiation.The results of fluorescent in situ hybridization molecular detection revealed WT1 gene deletion(n=1),SRD gene deletion(n=1),SRD gene deletion&1q21/1q23 gene amplification(n=1),SRD&16q22/16q23 gene deletions.The molecular test results of the other 3 children were negative.One left-sided lesion recurred at Month 80 postoperatively.Without surgery,renal insufficiency occurred after 2 courses of chemotherapy and treatment continued.One child of mental retardation and epilepsy died due to renal failure at Month 65 postoperatively.The remainders received standardized chemotherapy before and after surgery and there was no recurrence or metastasis.Conclusions Most pathological tissue types of bilateral nephroblastoma are good prognostic type.And SRD gene deletion is the common chromosomal change.The outcomes of children with 1p/16q heterozygosity deletion and associated malformation remain poor.