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Prognostic Significance of Angiogenesis in Transitional Cell Carcinoma of the Human Urinary Bladder
PRINCIPLES OF ONCOLOGY AND IMMUNOLOGY, AND TUMORS OF BLADDER, PENIS AND URETHRA
different pathways of tumor development. Papillary urothelial hyperplasia may be a precursor to low grade papillary neoplasia. Lining cells are cytologically unremarkable and demonstrate an orderly pattern of maturation. Flat urothelial hyperplasia is also an unremarkable urothelium cytologically and is often noted in association with inflammatory disorders but it is also seen with papillary hyperplasia and neoplasia. A distinction between these types of malignancy and intraepithelial flat forms of malignancy is reviewed in the context of the presumed morphological continuum of progressive nuclear abnormalities (dysplasia) that progress to carcinoma in situ and then invasive carcinoma. The authors comment on distinctions in those forms of primary carcinoma in situ generally seen in the absence of concomitant grossly visible disease that may be more indolent and in those forms of aggressive carcinoma in situ associated with the multiplicity of disease, occurrence of microinvasion and failure to respond to therapy. The various criteria by which pathologists assess different types of lesions are reviewed. The ongoing controversies and absence of clearly defined criteria underscore the need to generate molecular profiles that replace histological appearances in facilitating correlations with the biological potential of a cancer diathesis. Michael J. Droller, M.D.
Human Papillomavirus 16 and 18 Infection is Absent in Urinary Bladder Carcinomas &. L. Lu, E.-N. LALANl AND P. ABEL, Departments of Histopathology and Surgery, Royal Postgradunte Medical School I Hammersmith Hospital, London, United Kingdom Eur. Urol., 31: 428-432, 1997 Objective: The role of human papillomavirus (HPV) in the pathogenesis of bladder neoplasia remains controversial. Studies to date have mainly utilized polymerase chain reaction and DNA blot techniques to detect HPV DNA. The detection rates have varied from 0 to 81%. One of the major limitations of these techniques is that they lack topographic information. We have used a highly sensitive in situ hybridization (ISH) technique which detects single copies of viral genome and provides topographic information for investigation of HPV infection in bladder carcinomas. Materials and Methods: Thirty-one samples of formalin-fixed paraffin-embedded bladder carcinomas (4 adenocarcinomas, 5 squamous cell and 22 transitional cell carcinomas) were examined using non-isotopic ISH with biotin-labelled DNA probes of HPV 16 and 18 subtypes. HPV-positive skin and anal carcinoma samples were used as controls. Results and Conclusions: No positive signals for HPV 16 or 18 were detected in any of the bladder carcinoma samples. Given the sensitivity of the technique, the result indicates that HPV 16 and 18 are not implicated in the development of bladder neoplasia compared to certain other epithelial malignancies. The possibility that other subtypes of HPV contribute to bladder epithelial carcinogenesis remains to be clarified. Editorial Comment: Controversies regarding the role of human papilloma virus in carcinogenesis in transitional cell cancer have been suggested to be methodologically based, reflecting contamination or low stringency for interpreting the assays used. The authors applied a particularly sensitive in situ hybridization technique on paraffin embedded tissue sections, exploring the localization of types 16 and 18 human papilloma virus in tumors and normal urothelium. No signals were detected in 30 bladder cancers, squamous metaplasia or dysplasia Hybridization signals for the Y chromosome in samples from men indicated that the absence of signals for human papilloma virus was not due to degradation of deoxyribonucleic acid. The putative role of human papilloma virus in the pathogenesis of some forms of transitional cell cancer or in carcinogenesis thus remains to be proved. Michael J. Droller, M.D.
Prognostic Significance of Angiogenesis in Transitional Cell Carcinoma of the Human Urinary Bladder E. A. PHILP, T.J. STEPHENSON AND M. W. R. REED,Departments of Pathology and Surgery, University of Shefield Medical School, Shefield, United Kingdom Brit. J. Urol., 77: 352357, 1996 Objectives. To quantify tumour angiogenesis in bladder cancer and determine whether it correlates with tumour stage, grade and survival. Patients and methods. Archival samples from a total of 113 patients newly presenting with transitional cell carcinomas of the urinary bladder were graded and staged, and analysed for angiogenic blood vessel density by a double immunohistochemical technique. The findings were correlated with the information obtained during a minimum follow-up of 12 years. Results. Univariate analysis showed that TNM stage (P = 0.02) and mean vessel count (P = 0.01) were significant predictors of death from bladder cancer. Blood vessel density was significantly correlated with tumour stage (P = 0.01) and the presence of vascular invasion (P = 0.007).Trained observers were essential
1767
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PRINCIPLES OF ONCOLOGY AND IMMUNOLOGY, AND TUMORS OF BLADDER, PENIS AND URETHRA
for the accurate counting of blood vessels to prevent excessive inter-observer variability. Multiple regression analysis showed that the combination of mean vessel count and stage was a significant prognostic indicator. Conclusion. Angiogenesis in primary bladder cancer is a predictor of death from the disease. Further work to determine whether it predicts invasion and recurrences in superficial tumours may be valuable. Editorial Comment: An association between angiogenesis and more aggressive behavior has been suggested in several cancers. In the present study the distribution of vessels was heterogeneous within each tumor specimen. Wide variation in mean counts between different tumors was also noted. There was little interobserver or intraobserver variation. Although the stage of disease seemed to be related to mean vessel count, tumor grade did not correlate with mean vessel count. In univariate analysis stage and mean vessel count were significant predictors of death from bladder cancer. However, vessel count did not add to the prognostic information provided by stage alone. The wide variation in vessel counts within a given specimen and between different tumors calls into question the use of highest vessel count as a prognostic indicator. Thus, angiogenesis may not be applicable as a predictor of outcome for a particular transitional cell cancer in an individual. Michael J. Droller, M.D.
Granulocyte Colony-StimulatingFactor Receptor Expression on Human Transitional Cell Carcinoma of the Bladder M. TACHIBANA, A. MNAKAWA, A. UCHIDA, M. MURAI,K. EGUCHI,K. NAKAMURA, A. KUBOAND J.-I. HETA, Departments of Urology, Pulmonary Surgery, Radiology and Pathology, School of Medicine, Kelo Uniuersity, Tokyo, Japan Brit. J. Cancer, 7 5 1489-1496,1997 Receptors for granulocyte colony-stimulating factor (G-CSFRs) have been confirmed on the cell surfaces of several nonhaematopoietic cell types, including bladder cancer cells. This observation has naturally led to the hypothesis that the expression of G-CSFR on these cells may enhance their growth by G-CSF. In this study, the expression of G-CSFR was determined in both established human bladder cancer cell lines and primary bladder cancers. We studied five different human bladder cancer cell lines (KU-1, KU-7, T-24, NBT-2 and KK) and 26 newly diagnosed bladder tumours. G-CSFR mRNA expressions on cultured cell lines were determined using the reverse transcriptase polymerase chain reaction (RT-PCR) method. Furthermore, the G-CSFR binding experiments on the cultured cell lines were conducted using the Na1251-labelled G-CSF ligand-binding assay method. Moreover, the G-CSFR mRNA expressions on primary bladder tumour specimens were assessed using the in situ RT-PCR method. Three out of the five cultured cell lines (KU-1, NBT-2 and KK) exhibited G-CSFR mRNA signals when the RT-PCR method was used. The G-CSFR binding experiments showed an equilibrium dissociation constant (K,J of 490 pm for KU-1, 340 pm for NBT-2 and 103 pm for KK cells. With in situ RT-PCR, the tumour cells of 6 out of 26 primary bladder tumour specimens (23.1%) presented positive G-CSFR mRNA signals. Thus, in this study, G-CSFR expression was frequently observed on bladder cancer cells. Therefore, the clinical use of G-CSF for patients with bladder cancer should be selected with great care.
Editorial Comment: Granulocyte colony-stimulating factor stimulates bone marrow progenitor cell proliferation. The authors documented the presence of receptors for this growth factor on a number of urothelial cancer cell lines, tumor tissue specimens and normal tissue from the same bladders. Several of the cell lines (6 of 26) appeared to demonstrate granulocyte colonystimulating factor binding receptors and also responded to their presence by increased proliferation. However, there was no correlation between those cell lines that suggested expression of receptor by tumor grade or stage. A number of growth factor based paracrine and autocrine loops have been suggested as causing proliferation ofvarious cancer cells. These considerations may be important when growth factors are used to avoid some of the side effects of cytotoxic therapy in the treatment of advanced transitional cell cancer. Michael J. Droller. M.D.
Significance of pi53 Overexpression in Urinary Bladder Transitional Cell Carcinoma In Situ Before and After Bacillus Calmette-Guerin Treatment
K. ICK,M. SCHULTZ, P. STOUT AND K. FAN,Departments of Urology and Pathology, University of Arkansas Medical Sciences Campus and John L. McClellan Memorial Veterans Affairs Hospital, Little Rock, Arkansas Urology, 4 9 541-547, 1997 Objectives. Overexpression of p53, normally secondary to gene mutation, in invasive uroepithelial neoplasms (transitional cell carcinoma) and a high percentage of transitional cell carcinoma in situ (CIS) has
different pathways of tumor development. Papillary urothelial hyperplasia may be a precursor to low grade papillary neoplasia. Lining cells are cytologically unremarkable and demonstrate an orderly pattern of maturation. Flat urothelial hyperplasia is also an unremarkable urothelium cytologically and is often noted in association with inflammatory disorders but it is also seen with papillary hyperplasia and neoplasia. A distinction between these types of malignancy and intraepithelial flat forms of malignancy is reviewed in the context of the presumed morphological continuum of progressive nuclear abnormalities (dysplasia) that progress to carcinoma in situ and then invasive carcinoma. The authors comment on distinctions in those forms of primary carcinoma in situ generally seen in the absence of concomitant grossly visible disease that may be more indolent and in those forms of aggressive carcinoma in situ associated with the multiplicity of disease, occurrence of microinvasion and failure to respond to therapy. The various criteria by which pathologists assess different types of lesions are reviewed. The ongoing controversies and absence of clearly defined criteria underscore the need to generate molecular profiles that replace histological appearances in facilitating correlations with the biological potential of a cancer diathesis. Michael J. Droller, M.D.
Human Papillomavirus 16 and 18 Infection is Absent in Urinary Bladder Carcinomas &. L. Lu, E.-N. LALANl AND P. ABEL, Departments of Histopathology and Surgery, Royal Postgradunte Medical School I Hammersmith Hospital, London, United Kingdom Eur. Urol., 31: 428-432, 1997 Objective: The role of human papillomavirus (HPV) in the pathogenesis of bladder neoplasia remains controversial. Studies to date have mainly utilized polymerase chain reaction and DNA blot techniques to detect HPV DNA. The detection rates have varied from 0 to 81%. One of the major limitations of these techniques is that they lack topographic information. We have used a highly sensitive in situ hybridization (ISH) technique which detects single copies of viral genome and provides topographic information for investigation of HPV infection in bladder carcinomas. Materials and Methods: Thirty-one samples of formalin-fixed paraffin-embedded bladder carcinomas (4 adenocarcinomas, 5 squamous cell and 22 transitional cell carcinomas) were examined using non-isotopic ISH with biotin-labelled DNA probes of HPV 16 and 18 subtypes. HPV-positive skin and anal carcinoma samples were used as controls. Results and Conclusions: No positive signals for HPV 16 or 18 were detected in any of the bladder carcinoma samples. Given the sensitivity of the technique, the result indicates that HPV 16 and 18 are not implicated in the development of bladder neoplasia compared to certain other epithelial malignancies. The possibility that other subtypes of HPV contribute to bladder epithelial carcinogenesis remains to be clarified. Editorial Comment: Controversies regarding the role of human papilloma virus in carcinogenesis in transitional cell cancer have been suggested to be methodologically based, reflecting contamination or low stringency for interpreting the assays used. The authors applied a particularly sensitive in situ hybridization technique on paraffin embedded tissue sections, exploring the localization of types 16 and 18 human papilloma virus in tumors and normal urothelium. No signals were detected in 30 bladder cancers, squamous metaplasia or dysplasia Hybridization signals for the Y chromosome in samples from men indicated that the absence of signals for human papilloma virus was not due to degradation of deoxyribonucleic acid. The putative role of human papilloma virus in the pathogenesis of some forms of transitional cell cancer or in carcinogenesis thus remains to be proved. Michael J. Droller, M.D.
Prognostic Significance of Angiogenesis in Transitional Cell Carcinoma of the Human Urinary Bladder E. A. PHILP, T.J. STEPHENSON AND M. W. R. REED,Departments of Pathology and Surgery, University of Shefield Medical School, Shefield, United Kingdom Brit. J. Urol., 77: 352357, 1996 Objectives. To quantify tumour angiogenesis in bladder cancer and determine whether it correlates with tumour stage, grade and survival. Patients and methods. Archival samples from a total of 113 patients newly presenting with transitional cell carcinomas of the urinary bladder were graded and staged, and analysed for angiogenic blood vessel density by a double immunohistochemical technique. The findings were correlated with the information obtained during a minimum follow-up of 12 years. Results. Univariate analysis showed that TNM stage (P = 0.02) and mean vessel count (P = 0.01) were significant predictors of death from bladder cancer. Blood vessel density was significantly correlated with tumour stage (P = 0.01) and the presence of vascular invasion (P = 0.007).Trained observers were essential
1767
1768
PRINCIPLES OF ONCOLOGY AND IMMUNOLOGY, AND TUMORS OF BLADDER, PENIS AND URETHRA
for the accurate counting of blood vessels to prevent excessive inter-observer variability. Multiple regression analysis showed that the combination of mean vessel count and stage was a significant prognostic indicator. Conclusion. Angiogenesis in primary bladder cancer is a predictor of death from the disease. Further work to determine whether it predicts invasion and recurrences in superficial tumours may be valuable. Editorial Comment: An association between angiogenesis and more aggressive behavior has been suggested in several cancers. In the present study the distribution of vessels was heterogeneous within each tumor specimen. Wide variation in mean counts between different tumors was also noted. There was little interobserver or intraobserver variation. Although the stage of disease seemed to be related to mean vessel count, tumor grade did not correlate with mean vessel count. In univariate analysis stage and mean vessel count were significant predictors of death from bladder cancer. However, vessel count did not add to the prognostic information provided by stage alone. The wide variation in vessel counts within a given specimen and between different tumors calls into question the use of highest vessel count as a prognostic indicator. Thus, angiogenesis may not be applicable as a predictor of outcome for a particular transitional cell cancer in an individual. Michael J. Droller, M.D.
Granulocyte Colony-StimulatingFactor Receptor Expression on Human Transitional Cell Carcinoma of the Bladder M. TACHIBANA, A. MNAKAWA, A. UCHIDA, M. MURAI,K. EGUCHI,K. NAKAMURA, A. KUBOAND J.-I. HETA, Departments of Urology, Pulmonary Surgery, Radiology and Pathology, School of Medicine, Kelo Uniuersity, Tokyo, Japan Brit. J. Cancer, 7 5 1489-1496,1997 Receptors for granulocyte colony-stimulating factor (G-CSFRs) have been confirmed on the cell surfaces of several nonhaematopoietic cell types, including bladder cancer cells. This observation has naturally led to the hypothesis that the expression of G-CSFR on these cells may enhance their growth by G-CSF. In this study, the expression of G-CSFR was determined in both established human bladder cancer cell lines and primary bladder cancers. We studied five different human bladder cancer cell lines (KU-1, KU-7, T-24, NBT-2 and KK) and 26 newly diagnosed bladder tumours. G-CSFR mRNA expressions on cultured cell lines were determined using the reverse transcriptase polymerase chain reaction (RT-PCR) method. Furthermore, the G-CSFR binding experiments on the cultured cell lines were conducted using the Na1251-labelled G-CSF ligand-binding assay method. Moreover, the G-CSFR mRNA expressions on primary bladder tumour specimens were assessed using the in situ RT-PCR method. Three out of the five cultured cell lines (KU-1, NBT-2 and KK) exhibited G-CSFR mRNA signals when the RT-PCR method was used. The G-CSFR binding experiments showed an equilibrium dissociation constant (K,J of 490 pm for KU-1, 340 pm for NBT-2 and 103 pm for KK cells. With in situ RT-PCR, the tumour cells of 6 out of 26 primary bladder tumour specimens (23.1%) presented positive G-CSFR mRNA signals. Thus, in this study, G-CSFR expression was frequently observed on bladder cancer cells. Therefore, the clinical use of G-CSF for patients with bladder cancer should be selected with great care.
Editorial Comment: Granulocyte colony-stimulating factor stimulates bone marrow progenitor cell proliferation. The authors documented the presence of receptors for this growth factor on a number of urothelial cancer cell lines, tumor tissue specimens and normal tissue from the same bladders. Several of the cell lines (6 of 26) appeared to demonstrate granulocyte colonystimulating factor binding receptors and also responded to their presence by increased proliferation. However, there was no correlation between those cell lines that suggested expression of receptor by tumor grade or stage. A number of growth factor based paracrine and autocrine loops have been suggested as causing proliferation ofvarious cancer cells. These considerations may be important when growth factors are used to avoid some of the side effects of cytotoxic therapy in the treatment of advanced transitional cell cancer. Michael J. Droller. M.D.
Significance of pi53 Overexpression in Urinary Bladder Transitional Cell Carcinoma In Situ Before and After Bacillus Calmette-Guerin Treatment
K. ICK,M. SCHULTZ, P. STOUT AND K. FAN,Departments of Urology and Pathology, University of Arkansas Medical Sciences Campus and John L. McClellan Memorial Veterans Affairs Hospital, Little Rock, Arkansas Urology, 4 9 541-547, 1997 Objectives. Overexpression of p53, normally secondary to gene mutation, in invasive uroepithelial neoplasms (transitional cell carcinoma) and a high percentage of transitional cell carcinoma in situ (CIS) has