On the Origin of Syn- and Metachronous Urothelial Carcinomas Mattias Höglund  European Urology  Volume 51, Issue 5, Pages 1185-1193 (May 2007) DOI: 10.1016/j.eururo.2006.11.025 Copyright © 2006 European Association of Urology Terms and Conditions

Fig. 1 Schematic representation of the origin of clonally related tumors. Three urothelial carcinomas A, B, and C, showing the indicated mutated genes. Arrows indicates possible developmental routs from a common progenitor cell. Jagged arrow indicates a possible origin of tumor B from tumor A. Boxes contains two X chromosomes, one of which is inactivated by methylation (gray shaded). European Urology 2007 51, 1185-1193DOI: (10.1016/j.eururo.2006.11.025) Copyright © 2006 European Association of Urology Terms and Conditions

Fig. 2 An outline of the field-first-tumor-later model. (a) Normal urothelium is organized in monoclonal patches as described by Tsai et al [39]. (b) A first mutation occurs in a progenitor cell from which daughter cells spread and occupy the monoclonal patch (indicated by light orange). (c) Cells in the first patch invade neighboring patches. (d) In some patches further mutations occurs and the mutated cells spread into further neighbouring patches (indicated by orange). (e) Further mutations occur (indicated by dark orange), and cells spread to further neighboring patches, with the urothelium eventually reaching a state of criticality. (f) Local critical genetic events result in the development of an overt tumor (indicated by a star). (g) The same bladder after resection of the primary tumor in (g). (h) A second critical genetic event occurs in a patch of modified cells that was present already when the primary tumor was resected. European Urology 2007 51, 1185-1193DOI: (10.1016/j.eururo.2006.11.025) Copyright © 2006 European Association of Urology Terms and Conditions