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Urinary Bladder Carcinogenesis
PRINCIPLES OF ONCOLOGY, AND TUMORS OF BLADDER, PENIS AND URETHRA
Expression of Immunohistochemical Markers (PCNA, Ki-67,486p and p53) on Paraffin Sections and Their Relation to the Recurrence Rate of Superficial Bladder Tumors
R. VORREUTHER, R. HAKE, P. BORCHMA", S. LUKOWSKY, J. THIELE AND U. ENGELMANN, Department of Urology and Institute of Pathology, University of Cologne, Cologne, Germany Urol. Int., 59 88-94, 1997 Permission to Publish Abstract Not Granted
Editorial Comment: The authors analyzed the presence of a number of proliferation and progression markers in stages pTa and pT1 urothelial cancers. An association between the expression of these markers and grade with tumor recurrence was demonstrated. Recurrence within grade also indicated increased expression of these markers, which have been found in association with several aspects of DNA replication. Of further interest is the inverse of this association, namely a substantial number of tumors in each category did not appear to express these markers. Therefore, their usefulness in indicating the likelihood of recurrence and possibly of progression, may be somewhat limited when assessed in an individual. Further studies are needed not only to validate the usefulness of these markers individually or in aggregate to determine clinical prognosis, but also in possibly understanding the significance of their expression regarding the biological mechanisms underlying distinctions between these various forms of bladder cancer. Michael J. Droller, M.D.
Immunohistochemical Studies of Proliferating Cell Nuclear Antigen and Cathepsin D in Transitional Cell Carcinoma of the Urinary Bladder
T. ILZUMI, T. ILYAMA, W. TANAKA, E. OKADA, Y. KAMIYAMA, Y. OKANO,S. SATO, T. YAZAKI,T. UMEDA AND T. IMAMURA, Departments of Urology and Surgical Pathology, Teikyo University School of Medicine, Tokyo, Japan Urol. Int., 5 9 81-87, 1997 Permission to Publish Abstract Not Granted Editorial Comment: The proliferating cell nuclear antigen is an indicator of DNA synthesis and has been associated with histological grade and recurrence. Cathepsin D is an enzyme associated in other tumor systems with the invasive potential of malignant cells and a potentially more ominous prognosis. Of interest in this study was the unexpected finding that expression of cathepsin D was high in normal samples and grade 1tumors but low or negative in the majority of grade 3 tumors. A similar association was noted between an increased expression of cathepsin D and superficial tumors versus no expression in the majority of invasive tumors. Expression of proliferating cell nuclear antigen was the opposite, that is high expression in high grade invasive cancer and low expression in low grade tumors. Loss of cathepsin D was suggested to reflect deletion of the short arm of chromosome 11where the gene for cathepsin D is located. However, this finding would not necessarily explain the biological capability of higher grade cancer cells to infiltrate, a process requiring the activated form of several cathepsins. Although neither the proliferating cell nuclear antigen index nor cathepsin expression was an independent prognostic factor in this investigation, further assessment of the expression of various enzymes presumably necessary for the process of invasion and metastases seems indicated. Michael J. Droller, M.D.
Urinary Bladder Carcinogenesis
S. M. COHEN,Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska Toxicol. Path., 2 6 121-127, 1998 Urinary bladder carcinogenesisin rodents bears numerous similaritiesto the diseases in humans. In rats, the process progresses through the morphologic stages of simple hyperplasia, papillary and nodular hyperplasia, papilloma, noninvasive, and invasive carcinoma. In mice, the pathogenesis can be similar or can follow a sequence of marked dysplasia with or without hyperplasia, leading to carcinoma in situ and ultimately to high-gradeinvasive carcinoma.Although the papillary and nonpapillarydiseases appear to be
717
7 18
PRINCIPLES OF ONCOLOGY, AND TUMORS OF BLADDER, PENIS AND URETHRA
related in rodents and in humans, they are distinct morphologically, biologically, and molecularly. Numerous classes of genotoxic chemicals have been identified as bladder carcinogens in rodents, and some of these have also been identified as carcinogenic in humans, most notably, aromatic amines, nitrosamines, and cyclophosphamide. In contrast, nongenotoxic chemicals appear to be highly specific with respect to species, strain, diet, agent, dose, and mechanism. For some, it is unclear whether the results a t high doses in rodents can be extrapolated to low doses or to humans, e.g., chemicals that cause bladder cancer only at high doses related to the formation of calculi. Numerous observations in rodents can assist in identifying possible mechanisms involved for these nongenotoxic chemicals and therefore can be important for a rational evaluation of human risk.
Editorial Comment: The author reviews bladder carcinogenesis, and the distinction between genotoxic and nongenotoxic mechanisms by which bladder cancers may be induced. Genotoxic substances induce bladder cancer by inducing errors in deoxyribouucleic acid (DNA)while nongenotoxic substances produce this effect indirectly by inducing cell replication, which increases the possibility that DNA mutations may occur. Animal models, in which various substances have been determined to induce bladder cancer, are examined on the basis of their species specific reactions to various substances, depending on their ability to detoxify potential carcinogens or their susceptibility to the potential carcinogenic effect of these substances. In humans the dose response relationship between the most commonly accepted bladder carcinogens (aromatic amines) and the development of bladder tumors is sigmoid rather than linear, although the formation of DNA adducts is linear. This relationship may reflect the need to produce adequate numbers of DNA replicative events (cell hyperplasia) to induce a detectable incidence of bladder tumors. Thus, cell proliferation may be important if interactions with genotoxic substances are to result in bladder cancer development. It may also be important to consider that different genetic events may be necessary in the development of different types of bladder cancer. Thus, variable susceptibility of a particular host to different substances as well as specific interactions of various substances in a unique manner with a particular host urothelium may account for the different types of bladder cancer. Predictability of these events remains unclear. Equally unclear is the question as to whether certain types of tumor with low malignant potential may ultimately give rise to tumors with greater malignant potential. Issues of clonality versus field effects, mutational cascades and variability in phenotypic expression in host-tumor-treatment interactions remain to be clarified. Michael J. Droller, M.D.
Prospective Pathologic Analysis of Female Cystectomy Specimens: Risk Factors for Orthotopic Diversion in Women J. P. STEIN, D. ESRIG, J. A. FREEMAN, G. D. GROSSFELD, D. A. GINSBERG, R. J. COTE,S. GROSHEN, S. D. BOYD, G. LIESKOVSKY AND D. G. SKINNER, Departments of Urology and Pathology, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles and Departments of Urology, University of San Francisco, San Francisco, California, and University of North Carolina, Chapel Hill, North Carolina U r ~ l o g51: ~ , 951-955,1998 Objectives. To prospectively evaluate our previously established pathologic risk factors in women undergoing cystectomy for bladder cancer and to determine if these criteria identify appropriate female candidates for orthotopic diversion. Methods. Prospective pathologic evaluation was performed on 7 1 consecutive female cystectomy specimens removed for primary transitional cell carcinoma of the bladder. The histologic grade, pathologic stage, presence of carcinoma in situ, number, and location of tumors were determined. In addition, final pathologic analysis of the bladder neck and proximal urethra was performed and compared with the intraoperative frozen-section analysis of the distal margin (proximal urethra). Results. Tumor at the bladder neck and proximal urethra was seen in 14 (19%)and 5 (7%) cystectomy specimens, respectively. Bladder neck tumor involvement was found to be the most significant risk factor for tumor involving the urethra (P < 0.001).All patients with urethral tumors demonstrated concomitant bladder neck tumors. However, more than 6 0 8 of patients with bladder neck tumors had a normal (tumor-free) proximal urethra. Furthermore, no patient with a normal bladder neck demonstrated tumor involvement of the urethra. Intraoperative frozen-section analysis of the distal surgical margin was performed on 47 patients: 45 without evidence of tumor and 2 patients with urethral tumor involvement. In all cases, the intraoperative frozen-section analysis was correctly confirmed by final permanent section. Conclusions. We prospectively demonstrate that bladder neck tumor involvement is a significant risk factor for urethral tumor involvement in women. However, despite bladder neck tumor involvement, a
Expression of Immunohistochemical Markers (PCNA, Ki-67,486p and p53) on Paraffin Sections and Their Relation to the Recurrence Rate of Superficial Bladder Tumors
R. VORREUTHER, R. HAKE, P. BORCHMA", S. LUKOWSKY, J. THIELE AND U. ENGELMANN, Department of Urology and Institute of Pathology, University of Cologne, Cologne, Germany Urol. Int., 59 88-94, 1997 Permission to Publish Abstract Not Granted
Editorial Comment: The authors analyzed the presence of a number of proliferation and progression markers in stages pTa and pT1 urothelial cancers. An association between the expression of these markers and grade with tumor recurrence was demonstrated. Recurrence within grade also indicated increased expression of these markers, which have been found in association with several aspects of DNA replication. Of further interest is the inverse of this association, namely a substantial number of tumors in each category did not appear to express these markers. Therefore, their usefulness in indicating the likelihood of recurrence and possibly of progression, may be somewhat limited when assessed in an individual. Further studies are needed not only to validate the usefulness of these markers individually or in aggregate to determine clinical prognosis, but also in possibly understanding the significance of their expression regarding the biological mechanisms underlying distinctions between these various forms of bladder cancer. Michael J. Droller, M.D.
Immunohistochemical Studies of Proliferating Cell Nuclear Antigen and Cathepsin D in Transitional Cell Carcinoma of the Urinary Bladder
T. ILZUMI, T. ILYAMA, W. TANAKA, E. OKADA, Y. KAMIYAMA, Y. OKANO,S. SATO, T. YAZAKI,T. UMEDA AND T. IMAMURA, Departments of Urology and Surgical Pathology, Teikyo University School of Medicine, Tokyo, Japan Urol. Int., 5 9 81-87, 1997 Permission to Publish Abstract Not Granted Editorial Comment: The proliferating cell nuclear antigen is an indicator of DNA synthesis and has been associated with histological grade and recurrence. Cathepsin D is an enzyme associated in other tumor systems with the invasive potential of malignant cells and a potentially more ominous prognosis. Of interest in this study was the unexpected finding that expression of cathepsin D was high in normal samples and grade 1tumors but low or negative in the majority of grade 3 tumors. A similar association was noted between an increased expression of cathepsin D and superficial tumors versus no expression in the majority of invasive tumors. Expression of proliferating cell nuclear antigen was the opposite, that is high expression in high grade invasive cancer and low expression in low grade tumors. Loss of cathepsin D was suggested to reflect deletion of the short arm of chromosome 11where the gene for cathepsin D is located. However, this finding would not necessarily explain the biological capability of higher grade cancer cells to infiltrate, a process requiring the activated form of several cathepsins. Although neither the proliferating cell nuclear antigen index nor cathepsin expression was an independent prognostic factor in this investigation, further assessment of the expression of various enzymes presumably necessary for the process of invasion and metastases seems indicated. Michael J. Droller, M.D.
Urinary Bladder Carcinogenesis
S. M. COHEN,Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska Toxicol. Path., 2 6 121-127, 1998 Urinary bladder carcinogenesisin rodents bears numerous similaritiesto the diseases in humans. In rats, the process progresses through the morphologic stages of simple hyperplasia, papillary and nodular hyperplasia, papilloma, noninvasive, and invasive carcinoma. In mice, the pathogenesis can be similar or can follow a sequence of marked dysplasia with or without hyperplasia, leading to carcinoma in situ and ultimately to high-gradeinvasive carcinoma.Although the papillary and nonpapillarydiseases appear to be
717
7 18
PRINCIPLES OF ONCOLOGY, AND TUMORS OF BLADDER, PENIS AND URETHRA
related in rodents and in humans, they are distinct morphologically, biologically, and molecularly. Numerous classes of genotoxic chemicals have been identified as bladder carcinogens in rodents, and some of these have also been identified as carcinogenic in humans, most notably, aromatic amines, nitrosamines, and cyclophosphamide. In contrast, nongenotoxic chemicals appear to be highly specific with respect to species, strain, diet, agent, dose, and mechanism. For some, it is unclear whether the results a t high doses in rodents can be extrapolated to low doses or to humans, e.g., chemicals that cause bladder cancer only at high doses related to the formation of calculi. Numerous observations in rodents can assist in identifying possible mechanisms involved for these nongenotoxic chemicals and therefore can be important for a rational evaluation of human risk.
Editorial Comment: The author reviews bladder carcinogenesis, and the distinction between genotoxic and nongenotoxic mechanisms by which bladder cancers may be induced. Genotoxic substances induce bladder cancer by inducing errors in deoxyribouucleic acid (DNA)while nongenotoxic substances produce this effect indirectly by inducing cell replication, which increases the possibility that DNA mutations may occur. Animal models, in which various substances have been determined to induce bladder cancer, are examined on the basis of their species specific reactions to various substances, depending on their ability to detoxify potential carcinogens or their susceptibility to the potential carcinogenic effect of these substances. In humans the dose response relationship between the most commonly accepted bladder carcinogens (aromatic amines) and the development of bladder tumors is sigmoid rather than linear, although the formation of DNA adducts is linear. This relationship may reflect the need to produce adequate numbers of DNA replicative events (cell hyperplasia) to induce a detectable incidence of bladder tumors. Thus, cell proliferation may be important if interactions with genotoxic substances are to result in bladder cancer development. It may also be important to consider that different genetic events may be necessary in the development of different types of bladder cancer. Thus, variable susceptibility of a particular host to different substances as well as specific interactions of various substances in a unique manner with a particular host urothelium may account for the different types of bladder cancer. Predictability of these events remains unclear. Equally unclear is the question as to whether certain types of tumor with low malignant potential may ultimately give rise to tumors with greater malignant potential. Issues of clonality versus field effects, mutational cascades and variability in phenotypic expression in host-tumor-treatment interactions remain to be clarified. Michael J. Droller, M.D.
Prospective Pathologic Analysis of Female Cystectomy Specimens: Risk Factors for Orthotopic Diversion in Women J. P. STEIN, D. ESRIG, J. A. FREEMAN, G. D. GROSSFELD, D. A. GINSBERG, R. J. COTE,S. GROSHEN, S. D. BOYD, G. LIESKOVSKY AND D. G. SKINNER, Departments of Urology and Pathology, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles and Departments of Urology, University of San Francisco, San Francisco, California, and University of North Carolina, Chapel Hill, North Carolina U r ~ l o g51: ~ , 951-955,1998 Objectives. To prospectively evaluate our previously established pathologic risk factors in women undergoing cystectomy for bladder cancer and to determine if these criteria identify appropriate female candidates for orthotopic diversion. Methods. Prospective pathologic evaluation was performed on 7 1 consecutive female cystectomy specimens removed for primary transitional cell carcinoma of the bladder. The histologic grade, pathologic stage, presence of carcinoma in situ, number, and location of tumors were determined. In addition, final pathologic analysis of the bladder neck and proximal urethra was performed and compared with the intraoperative frozen-section analysis of the distal margin (proximal urethra). Results. Tumor at the bladder neck and proximal urethra was seen in 14 (19%)and 5 (7%) cystectomy specimens, respectively. Bladder neck tumor involvement was found to be the most significant risk factor for tumor involving the urethra (P < 0.001).All patients with urethral tumors demonstrated concomitant bladder neck tumors. However, more than 6 0 8 of patients with bladder neck tumors had a normal (tumor-free) proximal urethra. Furthermore, no patient with a normal bladder neck demonstrated tumor involvement of the urethra. Intraoperative frozen-section analysis of the distal surgical margin was performed on 47 patients: 45 without evidence of tumor and 2 patients with urethral tumor involvement. In all cases, the intraoperative frozen-section analysis was correctly confirmed by final permanent section. Conclusions. We prospectively demonstrate that bladder neck tumor involvement is a significant risk factor for urethral tumor involvement in women. However, despite bladder neck tumor involvement, a