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Editorial: Transitional Cell Carcinoma—Tantalizing Issues of Tumor Biology
0022-5347/96/1563-0961$03.00/0
THEJOURNAL
OF
UROLOGY
Copyright 0 1996 by AMERICAN UROL~CICAL ASSOCIATION, INC.
Vol. 156,961,September 1996 Printed in U.S.A.
EDITORIAL: TRANSITIONAL CELL CARCINOMA-TANTALIZING ISSUES OF TUMOR BIOLOGY Transitional cell carcinoma is distinguished by its widely normal cells, it is not surprising that direct analysis of tumor variegated clinical presentation. In its most benign form as a tissue resulted in generally larger aneuploid values. Increassolitary low grade papilloma (stage Ta, grade 1)it presents ing stage and grade were associated with a greater percent of little more than a nuisance that requires periodic cystoscopic aneuploid cells. Automated image analysis was comparable observation and resection. However, in its aggressive form as to flow cytometry in assessing aneuploidy from direct tissue a muscle invasive, high grade lesion (for example stage T2, samples and, thus, either method appears acceptable for grade 3) it is a life threatening disease. A fundamental goal clinical use. Although not the direct purpose of this study, the fundaof transitional cell carcinoma research is to determine the mental underpinning of this and other ploidy based studies is biological and genetic basis for these observed differences. In this issue of the Journal 3 articles highlight transitional that aneuploidy reflects abnormal tumor cell DNA. That cell carcinoma biology from distinct vantage points. Eder et gross nonphysiological changes in tumor cell DNA content a1 (page 953) examine the ability of a serum marker, trans- may be associated with worsening clinical stage and grade forming growth factor-p, to distinguish muscle invasive from makes not only intuitive sense but is strongly supported by noninvasive transitional cell carcinoma. Goulandris et a1 molecular studies showing stepwise DNA mutations during (page 958) reexamine the methodology of deoxyribonucleic carcinogenesis and the development of intrinsic genomic inacid (DNA) ploidy across the spectrum of tumor stage and stability. However, since all dividing cells pass through a grade. Finally, Kiemeney and Schoenberg (page 867) provide period of noninteger DNA content during the required S an epidemiological basis for the existence of a heritable germ phase of DNA replication, aneuploidy by itself does not define line alteration for certain cases of transitional cell carcinoma. a cell with quantitatively or qualitatively abnormal DNA. Together these articles not only provide new insights but also Thus, 20% of grade 1 tumor samples in the study of raise new questions about the origin and behavior of this Goulandris et a1 derived either directly from tumors or from bladder washings contaminated with normal cells demonmalignancy. Two of the most important unfavorable prognostic features strated aneuploidy that must have been at least partly due to of clinical transitional cell carcinoma are high grade and replicative cells with grossly normal DNA. The future chalmuscle invasion. The data of Eder et a1 encompassing 57 lenge for those using ploidy technology will be to distinguish patients with transitional cell carcinoma show a clear and truly replicative from structural aneuploidy, and to deterstatistically significant increase in serum transforming mine the use for each type in predicting clinical tumor begrowth factor-pl in patients who have tumors with these havior. The recent development of whole chromosome specific features. The source of this elevated serum protein cannot be paints may facilitate such analysis. Are there 1 or more transitional cell carcinoma genes? determined from this study but, given the fact that similar increases are observed in patients with other malignancies, Kiemeney and Schoenberg address this issue through a comtransforming growth factor-pl is probably derived from host prehensive review of the available case reports and epidemisources. Is this a consequence of the invasive event, which ological studies pertaining to familial transitional cell carcimay include associated tissue remodeling, or a function of the noma. At least 2 familiar family cancer syndromes, the Lynch advanced cancer state? From this study it only can be deter- type I1 and Muir-Torre syndromes, are associated with transmined that metastatic disease is not a prerequisite for trans- itional cell carcinoma, and case reports of other familial forming growth factor-pl elevation but a relationship to tu- clustering suggest that further unique entities may exist. Furthermore, a composite analysis of the relatively few well mor burden may still exist. Acknowledging the known controlledepidemiologicalstudies suggests an increased transbiological characteristics of transforming growth factor-pl, itional cell carcinoma susceptibility risk of 1.5 to 2.5 for a the authors speculate that transforming growth factor- first degree relative. P l might have a direct role in promoting tumor growth, Proof of a heritable pattern of transitional cell carcinoma enhancing tumor angiogenesis andor impeding immune sur- acquisition has far-reaching clinical and research conseveillance. Thus, the biological host response to the tumor quences. Already investigation of individual pedigrees for could actually be viewed as counterproductive or self- other cancer syndromes has yielded tremendous insight into destructive. However, given the current inability to distin- specific tumor biology. Well-known cases include identificaguish the biologically active and inactive forms of transform- tion of the von Hippel-Lindau tumor suppressor gene in von ing growth factor-pl, it is equally plausible that the observed Hippel-Lindau disease and sporadic renal cell carcinoma, the elevation of transforming growth factor-pl has no intrinsic adenomatous polyposis coli gene in hereditary and sporadic biological function but is simply a marker of the invasive colon cancer, and most recently 2 genes associated with hedisease process. Regardless of its actual role, the potential reditary breast cancer, BRCA 1 and 2. ability of serum transforming growth factor-pl to detect paMuch further work must be done to define the molecular tients and classify them into a poor risk disease category basis for transitional cell carcinoma development and evoluappears sound. Its clinical use will ultimately require pro- tion. Regardless of the vantage point taken, whether epidespective testing, and direct comparison with existing hag- miological, tumor intrinsic or host response, these tantaliznostic and staging modalities. ing early leads into transitional cell carcinoma biology must In keeping with this same desire to classify and predict be rigorously evaluated and ultimately judged against the transitional cell carcinoma behavior, Goulandris et d reeval- yardstick of clinical behavior. uated the methodology of DNA ploidy analysis. They comMichael A. ODonnell pared tissue source (bladder wash versus tumor tissue) and Division of Urology ploidy analysis technique (flowcytometry versus image analBeth Israel Hospital ysis). Since percent of aneuploidy in a bladder wash clearly Boston, Massachusetts depends on the relative number of shed tumor cells versus 961
THEJOURNAL
OF
UROLOGY
Copyright 0 1996 by AMERICAN UROL~CICAL ASSOCIATION, INC.
Vol. 156,961,September 1996 Printed in U.S.A.
EDITORIAL: TRANSITIONAL CELL CARCINOMA-TANTALIZING ISSUES OF TUMOR BIOLOGY Transitional cell carcinoma is distinguished by its widely normal cells, it is not surprising that direct analysis of tumor variegated clinical presentation. In its most benign form as a tissue resulted in generally larger aneuploid values. Increassolitary low grade papilloma (stage Ta, grade 1)it presents ing stage and grade were associated with a greater percent of little more than a nuisance that requires periodic cystoscopic aneuploid cells. Automated image analysis was comparable observation and resection. However, in its aggressive form as to flow cytometry in assessing aneuploidy from direct tissue a muscle invasive, high grade lesion (for example stage T2, samples and, thus, either method appears acceptable for grade 3) it is a life threatening disease. A fundamental goal clinical use. Although not the direct purpose of this study, the fundaof transitional cell carcinoma research is to determine the mental underpinning of this and other ploidy based studies is biological and genetic basis for these observed differences. In this issue of the Journal 3 articles highlight transitional that aneuploidy reflects abnormal tumor cell DNA. That cell carcinoma biology from distinct vantage points. Eder et gross nonphysiological changes in tumor cell DNA content a1 (page 953) examine the ability of a serum marker, trans- may be associated with worsening clinical stage and grade forming growth factor-p, to distinguish muscle invasive from makes not only intuitive sense but is strongly supported by noninvasive transitional cell carcinoma. Goulandris et a1 molecular studies showing stepwise DNA mutations during (page 958) reexamine the methodology of deoxyribonucleic carcinogenesis and the development of intrinsic genomic inacid (DNA) ploidy across the spectrum of tumor stage and stability. However, since all dividing cells pass through a grade. Finally, Kiemeney and Schoenberg (page 867) provide period of noninteger DNA content during the required S an epidemiological basis for the existence of a heritable germ phase of DNA replication, aneuploidy by itself does not define line alteration for certain cases of transitional cell carcinoma. a cell with quantitatively or qualitatively abnormal DNA. Together these articles not only provide new insights but also Thus, 20% of grade 1 tumor samples in the study of raise new questions about the origin and behavior of this Goulandris et a1 derived either directly from tumors or from bladder washings contaminated with normal cells demonmalignancy. Two of the most important unfavorable prognostic features strated aneuploidy that must have been at least partly due to of clinical transitional cell carcinoma are high grade and replicative cells with grossly normal DNA. The future chalmuscle invasion. The data of Eder et a1 encompassing 57 lenge for those using ploidy technology will be to distinguish patients with transitional cell carcinoma show a clear and truly replicative from structural aneuploidy, and to deterstatistically significant increase in serum transforming mine the use for each type in predicting clinical tumor begrowth factor-pl in patients who have tumors with these havior. The recent development of whole chromosome specific features. The source of this elevated serum protein cannot be paints may facilitate such analysis. Are there 1 or more transitional cell carcinoma genes? determined from this study but, given the fact that similar increases are observed in patients with other malignancies, Kiemeney and Schoenberg address this issue through a comtransforming growth factor-pl is probably derived from host prehensive review of the available case reports and epidemisources. Is this a consequence of the invasive event, which ological studies pertaining to familial transitional cell carcimay include associated tissue remodeling, or a function of the noma. At least 2 familiar family cancer syndromes, the Lynch advanced cancer state? From this study it only can be deter- type I1 and Muir-Torre syndromes, are associated with transmined that metastatic disease is not a prerequisite for trans- itional cell carcinoma, and case reports of other familial forming growth factor-pl elevation but a relationship to tu- clustering suggest that further unique entities may exist. Furthermore, a composite analysis of the relatively few well mor burden may still exist. Acknowledging the known controlledepidemiologicalstudies suggests an increased transbiological characteristics of transforming growth factor-pl, itional cell carcinoma susceptibility risk of 1.5 to 2.5 for a the authors speculate that transforming growth factor- first degree relative. P l might have a direct role in promoting tumor growth, Proof of a heritable pattern of transitional cell carcinoma enhancing tumor angiogenesis andor impeding immune sur- acquisition has far-reaching clinical and research conseveillance. Thus, the biological host response to the tumor quences. Already investigation of individual pedigrees for could actually be viewed as counterproductive or self- other cancer syndromes has yielded tremendous insight into destructive. However, given the current inability to distin- specific tumor biology. Well-known cases include identificaguish the biologically active and inactive forms of transform- tion of the von Hippel-Lindau tumor suppressor gene in von ing growth factor-pl, it is equally plausible that the observed Hippel-Lindau disease and sporadic renal cell carcinoma, the elevation of transforming growth factor-pl has no intrinsic adenomatous polyposis coli gene in hereditary and sporadic biological function but is simply a marker of the invasive colon cancer, and most recently 2 genes associated with hedisease process. Regardless of its actual role, the potential reditary breast cancer, BRCA 1 and 2. ability of serum transforming growth factor-pl to detect paMuch further work must be done to define the molecular tients and classify them into a poor risk disease category basis for transitional cell carcinoma development and evoluappears sound. Its clinical use will ultimately require pro- tion. Regardless of the vantage point taken, whether epidespective testing, and direct comparison with existing hag- miological, tumor intrinsic or host response, these tantaliznostic and staging modalities. ing early leads into transitional cell carcinoma biology must In keeping with this same desire to classify and predict be rigorously evaluated and ultimately judged against the transitional cell carcinoma behavior, Goulandris et d reeval- yardstick of clinical behavior. uated the methodology of DNA ploidy analysis. They comMichael A. ODonnell pared tissue source (bladder wash versus tumor tissue) and Division of Urology ploidy analysis technique (flowcytometry versus image analBeth Israel Hospital ysis). Since percent of aneuploidy in a bladder wash clearly Boston, Massachusetts depends on the relative number of shed tumor cells versus 961