EXPRESSION OF BCL-2 AND BCL-X IN BLADDER CANCER

Purpose

TP53 and RB1 gene mutations in bladder transitional cell carcinoma (TCC) are correlated with grade, stage, recurrence, and survival and may correlate with tumor cell apoptotic potential. Overexpression of the bcl-2 and bcl-X anti-apoptotic genes has been correlated with poor prognosis and chemotherapy resistance in other systems. Similar studies have not been performed in TCC. We thus sought to determine expression of bcl-2 and bcl-X in TCC and correlate these with stage, survival and abnormal pRb or p53 expression.

Materials and Methods

Forty-two TCC samples (19 Ta and 23 locally advanced tumors) and normal urothelial controls were examined. Immunohistochemistry for p53, pRb, bcl-2 and bcl-X was performed on an automated system using indirect streptavidin biotin/horseradish peroxidase staining. Western immunoblot analysis was performed on bladder cancer cell lines to further characterize bcl-X expression. Recurrence-free and disease-specific survival were retrospectively determined. Kaplan-Meier survival curves were compared using the log rank test, and correlation of abnormal staining with stage and p53 or pRb status was determined using Fisher's exact test.

Results

Bcl-2 was expressed in less than 1% of normal urothelial cells, but moderate expression of bcl-x was found in all normal urothelial samples. Only 7.0% of TCC samples (1/19 Ta and 2/23 locally advanced tumors) demonstrated bcl-2 overexpression. Bcl-X overexpression was observed in 45.2% of TCC (8/19 Ta and 11/23 locally advanced tumors). Western blot analysis also revealed that both the long (29 kDa) anti-apoptotic form and short (19 kDa) pro-apoptotic form were overexpressed in bladder cancer cell lines and normal human urothelial cells. Bcl-X overexpression was weakly correlated with normal p53 expression (p = 0.06). There were no correlations of bcl-2 and bcl-X overexpression with abnormal p53, pRb, or tumor stage. There were no differences in recurrence-free or overall survival in patients with abnormal bcl-X staining.

Conclusions

Bcl-2 overexpression is rare in TCC. Bcl-X overexpression is common, likely reflecting its expression pattern in normal urothelium, but is not correlated with stage or abnormal p53 or pRb staining. Within the power limitations of this small study, bcl-X overexpression is not correlated with recurrence or survival.     

IMMUNOSTAINING OF LEWIS X IN CELLS FROM VOIDED URINE, CYTOPATHOLOGY AND ULTRASOUND FOR NONINVASIVE DETECTION OF BLADDER TUMORS

Purpose

We examined the use of immunostaining of the Lewis X antigen in exfoliated cells from voided urine samples, cytopathology and bladder ultrasound for noninvasive detection of bladder tumors as a potential substitute for cystoscopy.

Materials and Methods

A total of 260 patients were included, of whom 80 were evaluated because of irritative symptoms or hematuria and 180 were examined during followup visits after resection of bladder tumors. Voided urine samples were obtained from each patient for immunocytology and cytopathology. Bladder ultrasound and cystoscopy were performed. Biopsies were obtained whenever a bladder tumor was seen or if carcinoma in situ was suspected. Indirect immunoperoxidase staining was done on cytocentrifuge slides, using the P12 monoclonal antibody against the Lewis X antigen.

Results

Cystoscopy and biopsies revealed bladder tumors in 84 patients. Immunocytology of 1 urine sample resulted in a sensitivity of 79.8% and a specificity of 86.4%. The diagnosis of primary carcinoma in situ by immunocytology was correct in 100% of the cases. The examination of 2 consecutive urine samples detected 95.1% of the tumors. False-negative results occurred in a few cases with small, superficial, low grade tumors. Cytopathology and bladder ultrasound resulted in a sensitivity of 47.6 and 66.7%, and a specificity of 97.7 and 97.2%, respectively. The results of immunocytology of 2 urine samples were equivalent to the combination of immunocytology of a single urine sample, cytology and ultrasound.

Conclusions

Immunostaining of the Lewis X antigen is significantly more sensitive than cytopathology for the detection of low grade as well as high grade tumor cells in voided urine. Immunocytological evaluation of 2 consecutive voided urine specimens for the Lewis X antigen is the most sensitive method currently available for noninvasive detection of transitional cell tumors. This assay may replace cystoscopy for detection of bladder cancer.     

Fluorescence in Situ Hybridization Identifies More Aggressive Types of Primarily Noninvasive (Stage pTa) Bladder Cancer

Purpose

We evaluated the genetic changes in cytological specimens of bladder cancer by fluorescence in situ hybridization, and related them to stage and grade of the tumor, ploidy, p53 and Ki-67 expression, and clinical outcome to determine a simple method to identify tumors with a poorer prognosis.

Materials and Methods

Using fluorescence in situ hybridization the numerical aberrations of chromosomes 7, 9 and 17 in barbotages and imprints of 50 patients with transitional cell cancer of the bladder were determined. Of the patients 29 had a primary stage pTa tumor, while 21 with stage pT1 or greater disease formed the control group. Data were compared to ploidy status, and Ki-67 and p53 immunoreactivity.

Results

Repeated monosomy 9 and haploid or diploid status on static ploidy determination were found in patients with primary stage pTa tumors without recurrence. Immunoreactivity of p53 was negative in all of these patients, while there was a low percentage of positive staining for Ki-67. Patients with recurrent and progressive disease had a high incidence of trisomy 7 and 17, aneuploid status and high positivity for both immunological markers. For chromosomes 7 and 17, and ploidy status bivariate analysis showed a significant difference.

Conclusions

The evaluation of chromosomal aberrations in barbotage and imprint specimens clearly establishes a relationship between chromosomal defects and aggressiveness of the tumor. The majority of nonaggressive stage pTa transitional cell carcinomas can be distinguished from potentially lethal cases by fluorescence in situ hybridization at a diagnostic point when the grading is not yet prognostic.     

Clinical Evaluation of Cell Deoxyribonucleic Acid Content Measured by Flow Cytometry in Bladder Cancer

Purpose

We evaluated the clinical value of flow cytometry in bladder cancer.

Materials and Methods

Deoxyribonucleic acid (DNA) content was measured by flow cytometry in 275 untreated patients with bladder tumor followed for 1 to 8 years. Four pathological parameters (stage, grade, observed vascular invasion and associated carcinoma in situ) and 3 flow cytometric parameters (ploidy, number of aneuploid cell lines and DNA index) were defined.

Results

Univariate survival analysis showed that every parameter, when considered separately, was a significant prognostic factor (p less than 0.0001 in all cases). Multivariate analysis showed that stage (p less than 0.0001), DNA index (p less than 0.01) and associated carcinoma in situ (p less than 0.05) were independent, significant prognostic factors. However, ploidy and DNA index enhanced prognostic information above the traditional stage and grade only in patients with a stage pT1, grade 3 tumor (p less than 0.05). Retrospectively, different therapeutic decisions could have been made using DNA content only in 4 percent of cases.

Conclusions

In patients with bladder cancer DNA content is an independent predictor of survival but its clinical usefulness is limited.     

THE MOLECULAR CHARACTERISTICS OF BLADDER CANCER IN YOUNG PATIENTS

Purpose

The molecular characteristics of bladder cancer in children and young adults remain largely undefined. We sought to identify common molecular changes in bladder tumors in young patients using standard immunohistochemical and interphase cytogenetic methods.

Materials and Methods

We retrospectively evaluated 73 bladder tumors removed from patients younger than 30 years for the p53 tumor suppressor gene product using immunohitochemical techniques and numerical aberrations of chromosomes 9, 17, X and Y.

Results

Regardless of stage, immunohistochemical evidence of p53 gene product over expression was found in the majority of tumors studied. Numerical abberations (mosomy) of chromosome 9 were rare. Aneuploidy of chromosome 17 was common, particularly in carcinoma in situ and invasive bladder cancer.

Conclusions

These data suggest that immunohistochemical evidence of p53 gene product over expression is common in bladder cancer in young patients. Further prospective analysis of lesions in this population may help to establish a comprehensive molecular progression model for urothelial neoplasms.     

Cyclophosphamide Associated Bladder Cancer--A Highly Aggressive Disease: Analysis of 12 Cases

Purpose

We gained knowledge of the etiology, treatment and prevention of cyclophosphamide associated urothelial cancer.

Materials and Methods

The medical records of 6 men and 6 women (mean age 55 years) with cyclophosphamide associated bladder cancer were reviewed.

Results

All tumors were grade 3 or 4 transitional cell carcinoma. Of the 5 patients initially treated with endoscopic resection alone only 1 is alive without disease. Of The 6 patients who underwent early cystectomy 4 were alive at 24 to 111 months. The remaining patient with extensive cancer underwent partial cystectomy for palliation and died 3 months later.

Conclusions

Cyclophosphamide associated bladder tumor is an aggressive disease. However, long-term survival is possible when radical cystectomy is performed for bladder tumors with any sign of invasion and for recurrent high grade disease, even when noninvasive.     

Determination of Interferon-alpha Receptors in Urothelial Cancer and in Normal Urothelium

Purpose

We determined and compared the presence and frequency of interferon-alpha 2b receptors in urothelial neoplasms and normal urothelium, since the biological activity of interferons becomes apparent only after they bind to specific receptors.

Materials and Methods

With our method detection of interferon-alpha 2b receptors required a large number of cells, that is more than 1 x 10⁶ cells per ml. We studied 14 patients with relatively large tumors of all stages and grades. Three patients had grade I, 4 grade II and 7 grade III disease. As controls we used biopsies of normal urothelium from 14 patients who underwent transvesical prostatectomy. Interferon-alpha 2b receptors were detected quantitatively through the binding of radiolabeled¹²⁵ iodine human recombinant interferon-alpha 2b in normal and malignant urothelial tissue samples. The interferon-alpha 2b receptors are expressed as receptor sites per cell, and the results were evaluated with Scatchard analysis.

Results

The number of interferon-alpha 2b receptor sites per cell ranged from 43 to 100 (mean plus or minus standard deviation 62 +/− 18) in normal urothelium and from 110 to 210 (mean 174 +/− 25) in malignant epithelium. This difference was statistically significant (p <0.001, Student's t test 13.75). The difference in the number of interferon-alpha 2b receptors in grades I plus II and grade III tumors is suggestive but not statistically significant (p <0.10, Student's t test 2.075). High grade tumors expressed greater numbers of interferon-alpha 2b receptors than low grade tumors.

Conclusions

The method used needs refining so that it will require fewer cells to determine interferon-alpha 2b receptors. Interferon-alpha 2b receptors are detected in bladder urothelium and are abundant in malignant tissue with increasing frequency as tumor grade increases. If we can establish, in the future, a correlation of the number of interferon-alpha 2b receptors with the potential response of patients to intravesical instillation therapy with interferon, we might have an important prognostic method for selecting subgroups of patients with transitional cell carcinomas who will benefit from interferon-alpha 2b instillation.     

DIFFERENTIAL EXPRESSION OF INSULIN-LIKE GROWTH FACTOR BINDING PROTEINS IN HIGH VERSUS LOW GLEASON SCORE PROSTATE CANCER

Purpose

The insulin-like growth factor (IGF) system appears to be important in human prostate cancer biology. Expression of specific IGF binding proteins (IGFBPs) by prostate cancer tissues may modulate IGF cellular actions, and possibly determine both IGF-dependent tumor growth and biological aggressiveness in vivo. The purpose of this study was to examine the differential expression of all six IGFBP genes in benign and malignant prostate tissue samples.

Materials and Methods

Using RNAse protection assays, we examined expression of IGFBPs 1 through 6 in 23 paired benign and neoplastic prostate tissue samples obtained from the same prostatectomy specimen. RNA expression levels on each tissue sample were determined densitometrically and groups compared using standard Student's t test.

Results

We found expression of IGFBPs 2 through 6, but not IGFBP-1, in both malignant and benign tissues. A statistically significant differential expression of IGFBPs 2, 3 and 5 was found between tumors with high Gleason score and those with low scores and benign tissues. Expression of IGFBPs 2 and 5 was higher (p = 0.002 and 0.04, respectively) while that of IGFBP-3 was lower (p = 0.05) in high versus low Gleason score cancer specimens. Expression of IGFBPs 4 and 6 was no different between tumors (p = 0.052 and 0.25, respectively). No significant differences in IGFBP expression were evident between benign and tumor tissues when tumor grade was not considered.

Conclusion

Our results indicate that differential expression of certain IGFBPs in human prostate cancer correlates with tumor Gleason score. Thus, expression of certain IGFBPs in prostate cancer may be used as a surrogate marker of aggressive clinical behavior.     

Transforming Growth Factors-beta 1 and beta 2 in Serum and Urine from Patients with Bladder Carcinoma

Purpose

Transforming growth factors-beta (TGF-beta) are cellular regulators and potent angiogenic factors. We determined serum and urinary levels of TGF-beta 1 and beta 2 in patients with bladder carcinoma to study a correlation with tumor stage, grade and metastatic spread.

Materials and Methods

Using commercial immunoassays TGF-beta 1 and beta 2 were determined in serum and urine samples from 57 bladder cancer patients and 18 healthy controls.

Results

Serum TGF-beta 1 levels were significantly elevated in 21 patients with invasive bladder cancer (61.5 ng./ml.) compared to 18 healthy controls (36.3 ng./ml.), whereas serum TGF-beta 1 levels in 36 patients with superficial bladder tumors were within the normal range (33.4 ng./ml.). Serum TGF-beta 1 was increased in 27 patients with grade 3 tumors (55.7 ng./ml.), compared to 16 with grade 1 and 14 with grade 2 tumors (32.6 and 33.3 ng./ml., respectively). By contrast, serum TGF-beta 2 levels were not different from those of controls. No significant increase in serum TGF-beta 1 and beta 2 could be found in patients with lymph node metastases. In urine specimens there was no significant correlation of TGF-beta 1 and beta 2 with tumor stage.

Conclusions

Our results suggest that elevated serum TGF-beta 1 may be relevant for diagnosis of bladder cancer and further studies are warranted.     

Insulin and insulin-like growth factors in central nervous system tumors. Part V: Production of insulin-like growth factors I and II in vitro.

The authors have previously reported the presence of insulin-like growth factor (IGF) receptors in central nervous system (CNS) tumors and the production of IGF's and their binding proteins by CNS tumors in situ. This study was designed to investigate whether CNS tumor cells are capable of autocrine secretion of IGF-I and IGF-II in vitro. Production of IGF's was studied by specific radioimmunoassay of tumor-cell-conditioned serum-free media from 34 CNS tumors: 12 gliomas, 12 meningiomas, and 10 miscellaneous tumors. Normal human serum and cerebrospinal fluid served as controls. Insulin-like growth factor I was detected in five of 12 meningiomas but in none of the gliomas studied. In contrast, IGF-II was detected in four of 12 gliomas and in six of 11 meningiomas studied. Four miscellaneous tumors produced IGF-I and/or IGF-II. These results suggest that CNS tumors differentially produce IGF-I and IGF-II in vitro. Preferential production of IGF's may be an important marker of the tumor-cell differentiation or malignancy and may be useful as a clinical diagnostic tool. These results add further support to the concept that IGF's may play a role in the regulation of the behavior of CNS tumors.     

Pathologic pattern of invasive bladder carcinoma: Impact of bilharziasis

Objective

To describe the pathologic pattern of invasive bladder carcinoma in cystectomy specimens in relation to bilharziasis.

Patients and Methods

Between April 2002 and October 2006, 148 consecutive patients with invasive bladder cancer were subjected to radical cystectomy and orthotopic sigmoid bladder substitution at Al-Azhar Urology Department, Cairo, Egypt. A retrospective computerized database analysis of the pathologic features of the cystectomy specimens was done focusing on the impact of bilharziasis on the pathology of bladder carcinoma. The tumor cell type, stage, grade and gross features in addition to lymph node involvement were particularly noted.

Results

Bilharzial bladder pathology (lesions or ova) was present in 105 (70.9%) of 148 cystectomy specimens. Tumor histology included transitional cell carcinoma (TCC) in 84 (56.7%), squamous cell carcinoma (SCC) in 51 (34.5%), adenocarcinoma in 9 (6.1%) and anaplastic tumor in 4 (2.7%) of these specimens. Most tumors associated with bilharziasis were bulky and appeared fungating or ulcerative. The pathologic tumor stage was pT2 in 23%, pT3 in 70.9% and pT4a involving the prostate or seminal vesicles in 6.1%. None of these pT4a tumors were SCC. The tumor grade was described as low grade in 72 (48.6%) and high grade in 76 (51.4%) specimens. Regional lymph node involvement was detected in 31 (20.9%) specimens irrespective of bilharzial infestation.

Conclusion

Invasive bladder carcinoma associated with bilharzial pathology is mainly stage pT3, low-grade SCC and commonly appears as an ulcerative, bulky, fungating or verrucous mass. On the other hand, bladder carcinoma not associated with bilharziasis is mainly high-grade TCC and commonly appears as nodular or fungating lesions. Positive surgical margin and lymph node involvement are unrelated to bilharzial infestation.     

Reassessment of Conservative Management for Stage T1N0M0 Transitional Cell Carcinoma of the Bladder

Purpose

We evaluated the outcome of stage T1 transitional cell carcinoma of the bladder treated with local tumor resection and intravesical therapies.

Materials and Methods

Of 42 patients with stage T1 bladder cancer seen at our clinic during a 10-year period 38 were treated conservatively with local tumor resection, intravesical therapy and long-term followup. Bacillus Calmette-Guerin (BCG) was used as the primary intravesical agent since 1986.

Results

Of the 38 patients 15 had initial grade 2 or 2 to 3 tumors, including 9 (60 percent) who had at least 1 or more local recurrences but without disease progression. The remaining 23 patients had grade 3 or grades 3 to 4 stage T1 tumors, with local recurrence in 17 (74 percent) and disease progression in 8 (35 percent). Furthermore, 5 patients (22 percent) died of the metastasis despite salvage therapies.

Conclusions

For patients with initial grade 2 or grades 2 to 3, stage T1 disease the risk of disease progression is low. Current management with local tumor resection and intravesical BCG is appropriate and should be continued. Patients with high grade, stage T1 disease are at particularly high risk for disease progression and BCG does not seem to decrease this risk effectively. Therefore, immediate cystectomy is appropriate and should be recommended.     

Bladder Squamous Cell Carcinomas Express Psoriasin and Externalize it to the Urine

Purpose

To report a single biomarker, psoriasin (Mr 11.0 kd, pI 6.2), a calcium binding protein which is expressed largely by stratified squamous epithelia and is externalized to the urine of bladder squamous cell carcinoma (SCC) bearing patients.

Materials and Methods

Protein expression profiles of SCCs obtained immediately after surgery were analyzed by two-dimensional gel electrophoresis and Coomassie blue staining. Protein identity was determined by microsequencing and immunoblotting. Protein expression in cryosections was studied by immunofluorescence.

Results

Four patients with SCC were identified from 100 samples of patients with suspected transitional cell carcinoma (TCC). The protein profiles of the 4 SCCs (56-1, grade III, T4; 181-1, grade I, T3; 219-1, grade III, T3 and 239-1, grade not determined, T2-4) resembled that of keratinocytes, suggesting that these cells express an early developmental pattern of gene expression. Besides expressing markers characteristic of keratinizing stratified squamous epithelia, the SCCs exhibited psoriasin, a protein externalized to the medium by keratinocytes. Immunohistochemistry of 3 of the SCCs with psoriasin antibodies showed that the positive cells were confined chiefly to the “squamous pearls.” The presence of psoriasin in the urine of the 4 SCC patients was demonstrated by two-dimensional gel immunoblotting. Similar analysis of 43 urines from patients with bladder tumors other than SCC revealed 7 positives, some of which may reflect squamous differentiation. Analysis of the urine of 13 control individuals (12 males matched by age and a 42-year-old female) revealed 2 positives. Immunoblotting of the SCC patients' serum proteins with psoriasin antibodies failed to reveal the protein.

Conclusion

The results point towards psoriasin, alone or as part of a biomarker profile, as a potential marker for the noninvasive follow-up of patients with SCC.     

Binding of insulin-like growth factors to cultured rat calvarial cells with differing biologic responses.

The insulin-like growth factors (IGFs) are considered important regulators of bone metabolism affecting a number of biologic responses in vitro. Primary fetal rat calvarial cells (PRC) and a cloned adult rat calvarial cell line (C3) both exhibit a concentration-dependent IGF stimulation of [3H]thymidine incorporation into DNA, but the C3 cells show a greater sensitivity and magnitude of response. IGF-I and IGF-II were nearly equipotent in PRC cultures, but IGF-I was more than twice as active as IGF-II in the C3 cultures. This effect of the IGFs on DNA synthesis in two bone cell cultures with different culture histories has been correlated with receptor and binding protein profiles. Specific high-affinity IGF binding sites were found in both cell types. In general, the sites present on PRC cells showed a preference for binding IGF-II over IGF-I, but C3 cells displayed two types of relatively specific binding sites. In both cell types [125I]IGF-I bound primarily to a protein with IGF type I receptor characteristics. However, in PRC cells, [125I]IGF-II cross-linked specifically with proteins that had IGF type II receptor characteristics plus several sites unique to these cells; in C3 cells, [125I]IGF-II bound to a 139 kD protein that could be displaced by either IGF-I or IGF-II. Finally, IGF-II-specific 85 and 67 kD proteins were common to both cell types. From these studies, it is apparent that the IGFs bind to a variety of high-affinity binding sites in bone cells and that these sites differ between a highly responsive and a less responsive bone cell population.     

Detection of C-ERBB-2 Amplification in Transitional Cell Bladder Carcinoma Using Competitive PCR Technique

Purpose

We used competitive PCR to verify retrospectively the prognostic significance of c-erbB-2 oncogene amplification in transitional cell bladder carcinomas as a predictive index of patient survival with a maximum follow-up of nine years, and to investigate the variations of c-erbB-2 amplification during bladder carcinoma recurrence and/or progression from superficial to more invasive states.

Materials and Methods

Oncogene amplification was determined by an accurate and sensitive procedure based on competitive PCR. Measurements were performed in DNA extracted from fresh cancers or from formalin-fixed, paraffin-embedded tumor samples.

Results

The overall mean incidence of c-erbB-2 oncogene amplification was 26 percent (24/92), with a significant relationship with tumor grade (p less than 0.001). We did not find any statistical difference in survival probability between subjects with (20 percent) or without (30 percent) oncogene amplification. During tumor progression we observed a limited increase of tumors carrying oncogene amplification (2 of 20) whereas the mean degree of amplification was not affected.

Conclusions

c-erbB-2 amplification seems to be a genetic event related to the degree of bladder tumor differentiation. However the presence and/or the degree of this genetic alteration do not seem predictive of tumor progression, recurrence and survival probability, at least in patients with advanced transitional cell bladder carcinoma. These data seem to indicate that the amplification of c-erbB-2 in bladder carcinoma could be considered as an epiphenomenon, present in a subset of tumors but apparently not related to the clinical outcome.     

The effect of antisense Bcl-2 oligonucleotides on Bcl-2 protein expression and apoptosis in human bladder transitional cell carcinoma

PURPOSE: Bcl-2 is an important determinant of transitional cell carcinoma of the bladder recurrence and progression as well as a factor in patient response to chemotherapy or radiotherapy. We determined Bcl-2 down-regulation after antisense oligonucleotide therapy and synergism with mitomycin C in transitional cell carcinoma of the bladder. MATERIALS AND METHODS: Bcl-2 protein was quantified using flow cytometry and immunohistochemistry in 4 bladder cancer cell lines, in bladder washings from 6 patients with carcinoma in situ and in 16 patient tumor samples. The synergistic effects of antisense oligonucleotides G3139 and 2009, and mitomycin C were investigated in 4 cell lines, while 2009 down-regulation was examined in 20 tumor explants in an ex vivo model. RESULTS: Bcl-2 protein expression was found in all 4 cell lines and in 5 of the 6 cell populations derived from patients with carcinoma in situ. Of the 16 tumors 7 were classified positive by frozen section immunohistochemistry and quantitative flow cytometry. G3139 and 2009 down-regulated Bcl-2 protein expression in all 4 cell lines and 2009 down-regulated Bcl-2 protein expression in half of the Bcl-2 positive tumor specimens. There was only evidence in 1 cell line, T24/83, that Bcl-2 protein expression down-regulation enhanced mitomycin C induced apoptotic cell death. CONCLUSIONS: Bcl-2 was expressed in a significant proportion of bladder tumors and in carcinoma in situ. Therefore, antisense oligonucleotides represent a viable strategy for Bcl-2 protein down-regulation. However, it may not always translate into an increased level of mitomycin C induced apoptosis in transitional cell carcinoma of the bladder.     

Transitional Cell Carcinoma Involving the Prostate with a Proposed Staging Classification for Stromal Invasion

Purpose

We investigated the effect on survival of transitional cell carcinoma of the prostatic urethra, ducts and stroma, and determined the difference between prostatic stromal involvement occurring via direct extension through the bladder wall versus stromal invasion arising intraurethrally.

Materials and Methods

Between August 1971 and December 1989, 489 men underwent radical cystoprostatectomy for transitional cell carcinoma, including 143 (29.2 percent) identified with prostate involvement by transitional cell carcinoma in the cystectomy specimen. Patients were separated into 2 groups: 1–19 in whom the primary bladder tumor extended full thickness through the bladder wall to invade the prostate (classified as P4a) and 2–124 in whom prostate involvement arose from within the prostatic urethra.

Results

Five-year recurrence-free and overall survival rates were 25 and 21 percent, respectively, in group 1 versus 64 and 55 percent, respectively, in group 2. In the 124 patients in group 2 survival rates were similar for those with prostatic urethral tumors or carcinoma in situ and ductal tumors (no stromal invasion). Five-year overall survival rates without and with stromal invasion were 71 and 36 percent, respectively (p less than 0.0001). Transitional cell carcinoma of the prostatic urethra or ducts does not alter survival predicted by primary bladder stage alone. Prostatic stromal invasion arising intraurethrally significantly decreases survival, which varies based on primary bladder stage (64.6 percent in stage P1, 30.8 percent in stages P2/P3a and 13.6 percent in stage P3b, p = 0.0001). P1 bladder tumors with prostatic stromal invasion arising intraurethrally had a significantly higher survival rate than P4a tumors (64.6 versus 21 percent, p = 0.0001). P3b bladder tumors with stromal invasion had a survival rate similar to that of P4a tumors (p = 0.78).

Conclusions

Prostatic urethral or ductal transitional cell carcinoma does not alter survival determined by primary bladder stage alone and it should not be classified as P4a. Prostatic stromal involvement arising intraurethrally significantly decreases survival predicted by primary bladder stage alone. P1 bladder tumors with prostatic stromal invasion arising intraurethrally have a significantly higher survival rate than P4a tumors and they should be separately classified as P1str. Muscle invasive (P2/P3a) bladder tumors with stromal invasion have a higher survival rate than P4a tumors (no statistical significance) and they should be designated separately (that is P2str). P3b bladder tumors with prostatic stromal invasion arising intraurethrally are indistinguishable from P4a tumors.