Clonality of multifocal urothelial carcinomas: 10 years of molecular genetic studies

Multifocal occurrence and frequent recurrence are characteristic features of urothelial carcinomas of both the urinary bladder and the upper urinary tract. To describe the clonal nature of these tumors, 2 theories have been proposed. The monoclonality hypothesis describes the multiple tumors as descendants of a single genetically transformed cell spreading throughout the urothelium. In contrast, field cancerization caused by carcinogen exposure of the urothelium may lead to independent development of synchronous or metachronous nonrelated tumors at different sites of the urothelial tract. In the last 10 years, a multitude of molecular genetic studies have investigated the clonality of multifocal urothelial carcinomas. The majority of studies revealed a monoclonal origin of the multiple tumors. However, most of these studies investigated advanced invasive carcinomas. A small but significant proportion of multifocal urothelial carcinomas appear to arise from different clones, supporting the field-cancerization hypothesis. Oligoclonal tumors might be more common in precursor lesions and early tumor stages. The frequent monoclonality found in patients with advanced tumors could be due to outgrowth of 1 tumor cell clone with specific genetic alterations. Two important mechanisms appear to be important for the spread of malignant cells: intraluminal seeding and intraepithelial migration. Investigation of the entire urothelial lining in patients with urothelial tumors should provide further insight into the development of multifocal urothelial carcinomas.