Carcinoma in Situ of the Bladder
Of transitional cell neoplasms 80% are initially papillary, while 20% arise as nodular growths. Carcinoma in situ is likely the precursor to solid tumors. Carcinoma in situ is a spectrum between preneoplastic or precursor lesions and frank penetration of the basement membrane. Diagnosis is subjective and descriptive only. Preneoplastic lesions can be defined by molecular markers, such as LEx and p53, and are targets for chemo-prevention strategies, just as carcinoma in situ is a suitable target for intravesical therapies. It seems clear that carcinoma in situ may have a long or a short in situ phase before progressing to invasion. The duration of a long in situ phase may be years. However, carcinoma in situ is inexorably progressive and will become invasive in 1 or more areas if uncontrolled and given enough time. Carcinoma in situ does not regress but is characterized by indolent transmural growth involving bladder and eventually extravesical transitional urothelium. To date, no study has attempted to stratify carcinoma in situ patients into high and low risk groups prospectively, nor to recommend treatment options based on clinical or pathological features of carcinoma in situ. Based on our review of the literature, we suggest several studies be used in the diagnosis and monitoring of patients with carcinoma in situ for correlation with subsequent treatment outcome. Patients should undergo bladder mapping studies and be stratified into those with focal (1 site) or diffuse (more than 1 site) involvement, and with or without prostatic urethral disease. DNA ploidy will be determined and patients stratified as to the presence of only 1 or multiple aneuploid cell lines. Monoclonal antibody techniques may prove highly useful in determining the invasive/metastatic potential of carcinoma in situ. Those that appear most promising to date include over expression of p53 gene mutation, cell surface receptors, tumor associated antigens and proliferative antigens. With the information currently available, it appears that 2 forms of carcinoma in situ exist. Our educated guess would be that patients with focal carcinoma in situ, a single aneuploid cell line by DNA histogram, lack of over expression of p53, cell surface receptors, tumor associated or proliferative antigens and expression of normal urothelial antigens would predict a low risk with the best overall prognosis. Responsiveness of low risk carcinoma in situ patients to intravesical agents could proceed with a reasonable assumption of a low risk of metastases even if 1 or more intravesical therapies fail. Monitoring of these parameters during intravesical therapy and detection of a change may predict an increased risk in the malignant potential of carcinoma in situ. Such patients may then be reclassified into the high risk group. High risk factors, such as diffuse carcinoma in situ and prostatic urethral involvement, over expression of p53, cell surface receptors, tumor associated or proliferative antigens, or loss of normally expressed antigens, may predict patients in whom early, aggressive management is necessary. Either immediate cystectomy or a 3-month trial of intravesical BCG therapy followed by prompt cystectomy if BCG proves ineffective would be reasonable for high risk patients with carcinoma in situ. Clinical symptoms do not appear useful for disease stratification, although the severely symptomatic patient may elect early cystectomy to control vesical irritability. We realize that much work must be accomplished before parameters are clearly defined and accepted for classifying carcinoma in situ patients into high and low risk categories but we believe the circumstantial evidence continues to support the theory that carcinoma in situ exists in 2 forms of differing invasive/metastatic potential. We urge our colleagues to stratify patients with carcinoma in situ by these and other new parameters to determine if we can better predict the natural history and most appropriate treatment for the individual with carcinoma in situ. Until these parameters are assessed for usefulness in predicting the likelihood of invasive or metastatic disease, and the interval during which this may occur in the individual with carcinoma in situ, treatment recommendations must remain tentative. The likelihood of invasive disease developing during the initial 6 months after diagnosis is low and it appears safe for the majority of patients to be treated with conservative measures within this period. Of the patients who fail conservative therapies, the majority who suffer muscle invasive disease will do so within 5 years after diagnosis but for some disease persists beyond 10 years. Carcinoma in situ appears to be a lifelong disease and even those cured of the bladder component must be followed indefinitely since they are at risk for the development of extravesical carcinoma. Future efforts must be directed toward identifying risk factors in the individual before the development of invasive or metastatic disease so that appropriate aggressive local therapy and chemo-preventive strategies can be applied effectively. (Figure 1) was provided by Dr. Joel Sheinfeld. © 1995 American Urological Association, Inc.
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