Castillo-Martin Mireia, Collazo Lorduy Ana, Gladoun Nataliya, Hyun Grace, Cordon-Cardo Carlos
Department of Pathology, Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, New York, NY, USA.
Department of Pathology, Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, New York, NY, USA; Spanish Society of Medical Oncology, Spain.
J Pediatr Urol. 2016 Apr;12(2):91.e1-7. doi: 10.1016/j.jpurol.2015.08.020. Epub 2015 Oct 22.
Urothelial carcinoma (UC) of the bladder is a rare entity in the pediatric population, with an incidence of less than 0.4% in patients younger than 20 years. These patients overwhelmingly present with non-muscle-invasive low-grade disease and an indolent behavior.
The aim was to determine the source of the different natural history between pediatric population and adults; we hypothesized that pediatric bladder cancer may stem from different molecular pathways. Our objective with this descriptive case series was to study the main genes involved in pediatric urothelial bladder carcinoma using immunohistochemical (IHC) and mutational analysis. By studying the genetic alterations and immunophenotype of the most commonly altered genes in bladder urothelial cancer in three pediatric tumors we could gain better understanding of the molecular pathogenesis in this rare disease.
Formalin-fixed paraffin-embedded (FFPE) tissue slides of urothelial bladder tumors from three pediatric patients were retrospectively identified at Columbia University pathology archives (1990-2011) and re-evaluated. FGFR3, H-RAS, and PI3K hotspots mutational analyses were conducted by polymerase chain reaction amplification and Sanger sequencing from the FFPE tissue blocks. IHC analysis was conducted using antibodies against p53, PTEN, RB, EGFR, and HER2. Proliferative rate was assessed by Ki-67 expression.
Two patients had low-grade Ta disease, whereas the other tumor was classified as a papillary urothelial neoplasm of low malignant potential. None of the lesions recurred. Notably, all specimens showed H-RAS G12V mutation, whereas they were characterized by wild-type FGFR3 and PI3K. Nuclear p53 was not detected, whereas PTEN and RB expression were maintained. EGFR was expressed in the three cases and HER2 was negative. The proliferation rate was very low in all cases.
It is difficult to draw strong conclusions from the study of three tumors treated at the same institution and from the same referral population, and a multicentric study should be performed to confirm these preliminary results. However, we propose that H-RAS mutation analysis could be performed on urothelial bladder tumors of pediatric patients. The knowledge in the molecular basis of urothelial bladder tumors in children opens a promising field which could lead us to establish different guidelines for surveillance and follow-up of pediatric urothelial bladder cancer patients.
Pediatric tumors are characterized by a consistent H-RAS mutation status, whereas FGFR3 and p53 pathways are not involved in this tumor initiation. These results may explain the few recurrences seen in this population.
膀胱尿路上皮癌（UC）在儿童群体中是一种罕见疾病，20岁以下患者的发病率低于0.4%。这些患者绝大多数表现为非肌层浸润性低级别疾病且病程进展缓慢。
旨在确定儿童群体与成人不同自然病史的根源；我们推测儿童膀胱癌可能源于不同的分子途径。本描述性病例系列的目的是使用免疫组织化学（IHC）和突变分析研究儿童尿路上皮膀胱癌中涉及的主要基因。通过研究三例儿童肿瘤中膀胱尿路上皮癌最常见改变基因的基因改变和免疫表型，我们可以更好地理解这种罕见疾病的分子发病机制。
在哥伦比亚大学病理档案库（1990 - 2011年）中回顾性鉴定并重新评估了三名儿科患者膀胱尿路上皮肿瘤的福尔马林固定石蜡包埋（FFPE）组织切片。通过聚合酶链反应扩增和来自FFPE组织块的桑格测序进行FGFR3、H-RAS和PI3K热点突变分析。使用针对p53、PTEN、RB、EGFR和HER2的抗体进行IHC分析。通过Ki-67表达评估增殖率。
两名患者患有低级别Ta期疾病，而另一个肿瘤被分类为低恶性潜能的乳头状尿路上皮肿瘤。所有病变均未复发。值得注意的是，所有标本均显示H-RAS G12V突变，而它们的特征是FGFR3和PI3K为野生型。未检测到核p53，而PTEN和RB表达得以维持。三例均表达EGFR，HER2为阴性。所有病例的增殖率都非常低。
从对同一机构治疗的三例肿瘤以及同一转诊人群的研究中很难得出有力结论，应进行多中心研究以证实这些初步结果。然而，我们建议对儿科患者的膀胱尿路上皮肿瘤进行H-RAS突变分析。儿童膀胱尿路上皮肿瘤分子基础的知识开辟了一个有前景的领域，这可能使我们为儿童膀胱尿路上皮癌患者建立不同的监测和随访指南。
儿童肿瘤的特征是H-RAS突变状态一致，而FGFR3和p53途径不参与该肿瘤的发生。这些结果可能解释了该群体中复发较少的现象。
