Molecular Markers for Diagnosis, Staging, and Prognosis of Bladder Cancer

Several important clinical observations describe the natural history of bladder cancer and dictate its treatment:

• Most invasive bladder cancers present with muscle-invasive tumors.
• Most superficial tumors are noninvasive and stay noninvasive.
• Only 10% to 15% of superficial tumors progress to muscle invasion.

These observations lead to two central and related debates for clinicians who must decide on how to treat an individual patient. In patients with superficial disease, how likely are the tumors to behave aggressively? Should aggressive therapy, such as radical cystectomy, be used as initial treatment? In patients with tumors already known to behave aggressively (ie, those who have failed intravesical therapies or who present with lamina propria or muscle invasion), is radical cystectomy sufficient for cure or should adjuvant or neoadjuvant therapy also be used?

Williams and colleagues describe the current state of knowledge of molecular markers in bladder cancer with an excellent and comprehensive overview. The authors document the wealth of knowledge on the molecular mechanisms by which transitional cell carcinomas originate and progress.

Early cytogenetic work established frequent breakpoints on chromosomes 9p, 13q, and 17p that molecular methods later confirmed to exhibit a high frequency of loss of heterozygosity. Correlation of these observations with tumor grade and stage have suggested a clear molecular pathway for the progression of bladder cancer: Deletions of chromosome 9 are an early event, deletions of chromosome 5q are associated with invasion into the lamina propria, and alterations in p53, Rb, p21, and other genes controlling cell cycling are implicated in muscle invasion and tumor growth. It is also clear that factors regulating angiogenesis play an important role in bladder cancer pathogenesis.

Advances in the Biology of Bladder Cancer

The identification of markers of early tumor growth and progression provided a window of insight into the biology of bladder cancer and also revealed a number of molecular targets for drug development. The exploitation of this information holds real promise for the creation of new, biologically directed therapies to supplement the empiric use of existing cytotoxics and immunologics for this disease.

A major challenge still remaining is the development of these markers as prognostic tools and their incorporation into clinical decision-making. The literature is replete with retrospective immunohistochemical studies of various markers whose presence, absence, or alteration is associated with prognosis. These are important studies that generate hypotheses about biological mechanisms and may identify candidate prognostic markers, but their interpretation and clinical use are limited by differing methodologies that are not always reproducible. Their retrospective nature and heterogeneity in treatment also could affect clinical results.