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

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.

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