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. Author manuscript; available in PMC: 2011 Jul 1.
Published in final edited form as: Urol Oncol. 2010 Jul–Aug;28(4):429–440. doi: 10.1016/j.urolonc.2010.04.008

Figure 1. Dual-track concept of bladder carcinogenesis.

Figure 1

The expansion of a preneoplastic clone which shows minimal phenotypic deviation from the normal urothelium, is the incipient event in bladder carcinogenesis referred to as LGIN. In this phase, the loss of FR genes function provides growth advantage associated with the expansion of proliferating compartment. The proliferating cells expressing normal RB protein are seen in the entire thickness of LGIN. In contrast, normal urothelium contains only scattered proliferating cells expressing RB protein located in its basal layer. The continuous growth of LGIN leads to the development of low grade superficial papillary TCC. In the non-papillary pathway, clonal evolution results in the establishment of a successor clone with microscopic features of HGIN which often shows a loss of major tumor suppressors such as RB1 and has a high propensity for progression to an invasive high grade non papillary TCC. a, Normal urothelium (upper panel). Expression of Ki67 in proliferating basal cells of normal urothelium (lower panel, left). Expression of RB protein in peribasal cells of normal urothelium (lower panel, right). b, Urothelial hyperplasia with mild atypia referred to as LGIN (upper panel). Expression of Ki67 in the entire thickness of LGIN (lower panel, left); expression of RB protein in the entire thickness of LGIN (lower panel, right). c, Low-grade superficial TCC retaining normal expression of the RB protein: insets to c show low and high power photomicrographs illustrating the expression of normal RB protein in low grade papillary TCC. d, Severe intraurothelial dysplasia/carcinoma in situ (HGIN) (upper panel). Loss of RB protein expression in HGIN (lower panel). e, High-grade invasive nonpapillary carcinoma (upper panel). Loss of RB protein expression in high grade invasive nonpapillary TCC. Arrow shows expression of RB protein in endothelial cells adjacent to tumor which serve as an internal positive control (lower panel). f, Severe intraurothelial dysplasia/carcinoma in situ developing in bladder mucosa adjacent to a low-grade papillary tumor. It is responsible for switching the pathway and progression of some low-grade papillary tumors to high-grade invasive cancers. (Modified and reprinted with permission from T. Majewski et al. Lab Invest 88:694–721, 2008).