Development and progression of urothelial carcinoma

Abstract

Urothelial carcinomas are well known to feature multifocal development in the urinary tract, both synchronously and asynchronously. This phenomenon can be explained by either seeding of cancer cells in the urinary tract or field cancerization. As there are two characteristic morphological patterns of urothelial carinomas, papillary and nodular, published papers were here reviewed to understand the development and progression of urothelial carcinoma regarding multifocality due to seeding or field changes with reference to the type of urothelial carcinoma. From animal experiments using rats, mice and dogs treated with N-butyl-N-(4-hydoroxybutyl) nitrosamine, and from pathological observation of human cystectomy specimens on step-sectioning and molecular analysis, nodular carcinomas appear to either develop via papillary carcinomas or de novo. Clinical aspects of multifocal tumor development are outside of the scope of this review, although an understanding of the mechanisms underlying multifocality and the papillary/nodular morphological relationship is important to determine follow-up strategies for patients treated for primary urothelial carcinomas and for reconstruction of the urinary tract after cystectomy.

Figure 1

Clinical findings indicating multifocal tumor development in the urinary tract. Black lesions are original tumors and red lesions are recurrent tumors.

Figure 2

A case of renal pelvic, ureteral and vesical carcinomas who underwent right nephroureterocystectomy.

Figure 3

Histogenesis and progession of papillary carcinomas in rats. (Reproduced with permission from Medical view Co., T. Kakizoe, Development and Progression of Bladder Cancer, 1995.)

Figure 4

Histogenesis and progression of nodular invasive carcinoma in mice. (Reproduced with permission from Medical view Co., T. Kakizoe, Development and Progression of Bladder Cancer, 1995.)

Figure 5

Development and progression of papillary and nodular carcinomas depending on the concentration and period of administration of N‐butyl‐N‐(4‐hydroxybutyl) nitrosamine (BHBN) in female dogs.^{( 34 )} (Reproduced with permission from Medical view Co., T. Kakizoe, Development and Progression of Bladder Cancer, 1995.)

Figure 6

Conceptual progression routes of papillary (P), papillonodular (PN) and nodular (N) carcinoma, and carcinoma in situ (C), in 186 cystectomized specimens examined by step‐sectioning.^{( 35 )}

Figure 7

Cases of pT3 cystectomized specimens indicating coexistence of papillary (P; blue), papillonodular (PN; yellow) and nodular (N; red) carcinoma together with oblique line area (C) and shaded area (dysplasia).^{( 35 )}

Figure 8

Eleven cases of cystectomized specimens having histories of multiple transurethral resection for papillary recurrent carcinomas showing variety of stages and morphology in a single bladder.^{( 35 )}

Figure 9

Presumed molecular pathways of development of papillary and nodular carcinoma. (Modified from Wu.^{( 38 )}) CIS, carcinoma in situ; FGFR3, fibroblast growth factor receptor 3; MMPS, matrix metal proteinases; RB, retinoblastoma gene; VEGF, vascular endothelial growth factor.