The origins of urothelial carcinoma

Abstract

It is now widely believed that there are two major pathways for urothelial carcinogenesis. One pathway usually involves mutation of FGF receptor 3 and gives rise to low-grade papillary tumors that frequently recur but seldom invade. By contrast, high-grade urothelial malignancies, including high-grade papillary urothelial carcinoma and urothelial carcinoma in situ (CIS) usually exhibit deletions or mutations of TP53. Urothelial CIS is the most likely precursor of high-grade invasive bladder cancer. It is a 'flat lesion' that may be relatively inconspicuous at cystoscopy, or even endoscopically undetectable. The clinical hazards associated with this elusive and biologically dangerous neoplasm have been increasingly well documented since the original studies by Melicow in 1952. Primary or secondary urothelial dysplasia is even more challenging to detect and diagnose than CIS. It is theorized that dysplasia may antedate the onset of CIS, but support for the putative progression of dysplasia to CIS is found in fewer than 20% of cases. Since many benign urothelial changes may resemble CIS at cystoscopy, in biopsies and even with molecular profiling, care must be exercised when making a diagnosis of CIS. For patients whose screening tests are worrisome for the presence of premalignant urothelial disease, newer bladder imaging modalities, including Raman spectral imaging and optical coherence tomography, may enable improved biopsy site selection. In this article, we discuss the above-noted topics, as well as other related issues, such as the possible role of papillary urothelial hyperplasia as a preneoplastic lesion and the roles of cancer stem cells and field cancerization in urothelial carcinogenesis.

Are oncogenes sufficient to cause human cancer?

“…The oligoclonal theory holds that a carcinogen causes independent transformation of cells in different locations within the same tissue, resulting in genetically unrelated tumors. These two theories are not mutually exclusive, and it is possible that both phenomena can occur in the same patient (14). The study by Hafner et al (1) seems to support the monoclonal model of synchronous multifocal tumor origin, although the few cases in which clonality was not identified could represent distinct clones.…”

“…These tumors frequently harbor the same FGFR3 mutations, tend to be genomically stable, and arise in a mulifocal manner (14). Two theories have been proposed to explain multifocality of urothelial cancers.…”

New Directions for Biologic Targets in Urothelial Carcinoma

“…FGFR3 is an attractive therapeutic target in these cancers because 60% of mutations occur at a single hotspot that is amenable to screening. Both tyrosine kinase inhibition with the FGFR TKI dovitinib and shRNA knockdown of S249C (the most common FGFR3 mutation) have shown preclinical inhibition of cell proliferation in low-grade cancers (11,12). In contrast, high-grade tumors (commonly flat tumors, CIS, or occasionally papillary tumors) have increased invasive potential and show inactivation of the tumor suppressor genes retinoblastoma (RB) and p53.…”

“…ddMVAC had comparable toxicity and a shorter delay to definitive surgery. A metaanalysis of 2,688 individual patients treated in 10 randomized neoadjuvant chemotherapy trials showed no benefit from single-agent cisplatin, but combination cisplatin regimens showed a significant OS benefit (HR ¼ 0.87; 95% CI, 0.78-0.98; P ¼ 0.016), a 13% decrease in risk of death, and a 5% absolute OS benefit at 5 years (45%-50%) versus surgery alone (12). A smaller meta-analysis of 2 Nordic trials also showed an OS benefit, which was greater in T3 compared with T2 disease.…”

Bladder Cancer and Schistosomiasis: Is There a Difference for the Association?

“…The second theory, the field-effect theory, explains tumor multifocality as a development secondary to the field cancerization effect. In the last scenario, carcinogens cause independent transforming genetic alterations at different sites in the urothelial lining leading to multiple genetically defective tumors (Cheng et al, 2010). That may highlight the existence of different histopathologies in the same specimen.…”