• C Cordon-Cardo.
• Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
• Cancer Surv. 1998 Jan 1; 32: 115-31.

AbstractThe molecular genetic changes reported in bladder tumours can be classified as primary and secondary aberrations. Primary molecular alterations may be defined as those directly related to the genesis of cancer. These are frequently found as the sole abnormality and often associated with particular tumours. We describe primary abnormalities as having a dual nature: those events involved in the production of low grade/well differentiated neoplasms, which would destabilise cellular proliferation but have minimal or no effects on cellular "social" interactions or differentiation or on rate of cell death or apoptosis; and others leading to high grade/poorly differentiated tumours, which would disrupt growth control, including cell cycle and apoptosis regulation and have a major impact on cellular differentiation. There is evidence that a target site(s) for a primary event(s) in low grade papillary superficial bladder tumours may reside on chromosome 9. However, a candidate for the initiation of high grade, flat carcinoma in situ lesions has not been yet elucidated. Novel approaches utilizing tissue microdissection techniques and molecular genetic assays are needed to shed light on this subject. Secondary genetic or epigenetic abnormalities may be fortuitous or may determine the biological behaviour of the tumour. Multiple molecular abnormalities are identified in most human cancers studied, including bladder neoplasms. The accumulation, rather than the order, of these genetic alterations is the critical factor that grants synergetic activity. In this regard, it is noteworthy that most of the altered genes act upon the two recognized critical growth and senescence pathways, TP53 and RB. There is a major requirement for well designed, randomized, prospective trials evaluating the strongest candidate markers in order to validate many reported exploratory studies. Although great enthusiasm exists with the application of various tumour makers in the management of bladder cancer, concrete clinical recommendations must be tempered at this time. As with preneoplastic conditions, the discrepancies that exist between clinical investigators regarding the significance of identifying such morphological changes have imposed crucial limitations. Another drawback has been the confusing nomenclature utilized and the lack of reproducibility in interpretation of morphological criteria. Molecular analyses utilizing well characterized preneoplastic lesions, including dysplasia samples, need to be pursued. This in turn may provide the needed information to realise the clinical relevance of detecting genetic instability, as well as molecular or epigenetic alterations, in otherwise morphologically normal appearing urothelium and preneoplastic lesions. The need now is to translate the newly developed scientific information into diagnostic and prognostic strategies, which in turn will prolong patient survival and quality of life.

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