What we could do now: molecular pathology of bladder cancer.(Statistical Data Included)

Abstract

There is much information on the genetic alterations that contribute to the development of bladder cancer. Because it is hypothesised that the genotype of the cancer cell plays a major role in determining phenotype, this genetic information should impact on clinical practice. To date however, this has not happened. Some of the alterations identified in bladder cancer have clear associations with outcome--for example, mutational inactivation of the cell cycle regulator proteins p53 and the retinoblastoma protein (Rb). However, as single markers, these events have insufficient predictive power to be applied in the management of individual patients. The use of panels of markers is a potential solution to this problem. Examples of suitable panels include those genes/proteins with known impact on specific cell cycle checkpoints or with impact on cellular phenotypes, such as immortalisation, invasion, or metastasis. To evaluate such marker panels, large tumour series will be needed--for example, archival samples fr om completed clinical trials. The use of these valuable resources will require coordination of sample provision. This might involve central collection and distribution of tissue blocks, sections, or tissue arrays and the provision of patient follow up information to laboratories participating in a study. With the availability of microarray technologies, including cDNA and comparative genomic hybridisation arrays, the transcriptome and genome of transitional cell carcinomas of different phenotypes can be compared and will undoubtedly provide a wealth of information with potential diagnostic and prognostic uses. Although these studies can be initiated using small local tissue collections, high quality collection of fresh tissues from new clinical trials will be crucial for proper evaluation of associations with clinical outcome. Funding for molecular pathological studies to date has been poor. To begin to translate molecular information from the laboratory to the clinic and to make maximum use of valuable urolo gical patient resources in the UK, adequate funding and scientific energy are required. Whereas the latter is not in doubt, present funding for this type of translational research is inadequate.

(J Clin Pathol: Mol Pathol 200 1;54:215-221)

Keywords: bladder cancer; molecular pathology

A great deal of information has accumulated on the genetics of transitional cell carcinoma (TCC) in recent years. Numerous genes and genetic changes involved in tumour development have been identified and the literature abounds with papers that show clear associations of specific genetic changes or gene mutations with clinical parameters. Therefore, one might predict that this must have generated novel laboratory tests (for screening, diagnosis, prediction of prognosis, etc) or some prospective studies or clinical trials. However, not only is little of this information currently being applied in the clinical setting but also, on closer examination of the data, it is clear that additional information will be needed before relevant applications emerge. This review examines the crucial clinical issues involved in the management of TCC, presents a summary of the current state of knowledge of molecular genetic alterations in bladder cancer, describes attempts made to apply genetic markers in the clinic, and then c onsiders the way forward both in terms of what could be applied now and what further information is needed.

Problems in clinical management of TCC What are the questions relating to the clinical management of this disease that might be dealt with by the application of novel molecular genetic markers? There are several situations during the diagnosis and selection of appropriate treatment for TCC where objective markers could potentially transform clinical practice. Because it is postulated that the genetic changes that contribute to the development of these tumours collectively determine tumour phenotype, markers based on genetic changes should provide robust diagnostic and predictive power.

Urothelial tumours can be classified into two groups based on histopathology and clinical behaviour. At presentation, more than 80% of bladder tumours are non-muscle invasive papillary tumours (pTa or pT1). Patients with such superficial tumours frequently develop recurrences (approximately 70%), often over the course of many years, but progression to muscle invasion occurs in only 10-20% of cases. The tumours that do progress are usually those that show superficial invasion (pT1) at diagnosis. In contrast, the 20% of tumours that show muscle invasion at the time of diagnosis have a much less favourable prognosis and often progress rapidly.

Superficial papillary and invasive bladder tumours are widely believed to have different natural histories, based both on histopathological and genetic information. Most invasive bladder tumours have no known papillary precursor, are solid invasive lesions, and are commonly associated with carcinoma in situ (CIS) elsewhere in the bladder. The proposed progression pathway for these lesions is therefore urothelial atypia [right arrow] dysplasia [right arrow] CIS [right arrow] invasive TCC. Genetic analyses have shown that CIS contains a spectrum of genetic alterations (such as TP53 mutation and loss of heterozygosity (LOH) of 3p, 8p, 13q, and l7p), similar to that seen in invasive TCC and very distinct from that seen in low grade papillary TCC, where only LOH of chromosome 9 is common. The proposed pathway for development of this last category of tumours is urothelial hyperplasia [right arrow] urothelial atypia (G1-3) [right arrow] low grade papillary TCC.

For superficial bladder cancer, identification of tumours that will progress has long been perceived as a potential application of genetic studies. If such patients could be identified at presentation, more aggressive treatment might result in a cure. The debate about choice of cystectomy, particularly for pT1 rumours, has raged for many years and, although it is clear that this can achieve complete cure, the associated morbidity cautions against this approach except where a very high probability of progression is predicted. Therefore, the identification of such patients is a priority. Markers that show very strong association with progression will also be useful at diagnosis, with the potential to identify those rumours that are invasive but for which an inadequate tissue sample failed to show invasion. For many pTa rumours, most of which are classified as carcinoma rather than papilloma, …