Do multifocal or recurrent urothelial carcinomas originate from a single transformed cell or from multiple transformed cells? What is the clinical significance of this argument?


Currently two hypotheses are being considered for the origin of multifocal or recurrent urothelial carcinomas. The clonogenic hypothesis (hypothesis 1) describes tumors as descendants of a single transformed cell that undergoes further multiple genetic alterations, proliferates, and spreads through the urothelial tract either by intraepithelial migration or intraluminal seeding. The “field changes” hypothesis (hypothesis 2) states that urothelial cells undergo malignant transformation at multiple sites and become the source of multifocal tumors. Based on reports with several available techniques, both hypotheses are viable to account for human bladder carcinogenesis. Hypothesis 1 may apply most of the urothelial carcinomas that result from exposure to the conventional carcinogen source (cigarette smoking). The underlying mechanism responsible for oligoclonal tumor development (hypothesis 2) remains unknown. It would be intriguing to suggest that heavy carcinogen exposure (e.g., aromatic amines, irradiation, heavy smoking) may cause the “field changes.”


Bladder Cancer Bladder Tumor Transitional Cell Carcinoma Urothelial Carcinoma Human Bladder Cancer 
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  1. 1.
    Duggan BJ, Gray SB, McKnight JJ, Watson CJ, Johnston SR, Williamson KE (2004) Oligoclonality in bladder cancer: the implication for molecular therapies. J Urol 171: 419–425.PubMedCrossRefGoogle Scholar
  2. 2.
    Habuchi T (2005) Origin of multifocal carcinomas of the bladder and upper urinary tract: molecular analysis and clinical implication. Int J Urol 12: 709–716.PubMedCrossRefGoogle Scholar
  3. 3.
    Hafner C, Knuechel R, Stoehr R, Hartmann A (2002) Clonality of multifocal urothelial carcinomas: 10 years of molecular genetic studies. Int J Cancer 101: 1–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Garcia SB, Park HS, Novelli M, Wright NA (1999) Field cancerization, clonality, and epithelial stem cells: the spread of mutated clones in epithelial sheets. J Pathol 187: 61–81.PubMedCrossRefGoogle Scholar
  5. 5.
    Denzinger S, Mohren K, Knuechel R, Wild PJ, Burger M, Wieland WF, Hartmann A, Stoehr R (2006) Improved clonality analysis of multifocal bladder tumors by combination of histopathologic organ mapping, loss of heterozygosity, fluorescence in situ hybridization, and p53 analysis. Hum Pathol 37: 143–151.PubMedCrossRefGoogle Scholar
  6. 6.
    Lyon MF (1972) X-chromosome inactivation and developmental patterns in mammals. Biol Rev Camb Philos Soc 47: 1–35.PubMedCrossRefGoogle Scholar
  7. 7.
    Jones PA, Buckley JD (1990) The role of DNA methylation in cancer. Adv Cancer Res 54: 1–23.PubMedCrossRefGoogle Scholar
  8. 8.
    Mutter GL, Boynton KA (1995) PCR bias in amplification of androgen receptor alleles, trinucleotide repeat marker used in clonality studies. Nucleic Acids Res 23: 1411–1418.PubMedCrossRefGoogle Scholar
  9. 9.
    Tsai YC, Simoneau AR, Spruck CH III, Nichols PW, Steven K, Buckley JD, Jones PA (1995) Mosaicism in human epithelium: macroscopic monoclonal patches cover the urothelium. J Urol 153: 1697–1700.PubMedCrossRefGoogle Scholar
  10. 10.
    Sidransky D, Frost P, Von Eschenbach A, Oyasu R, Preisinger AC, Vogelstein B (1992) Clonal origin bladder cancer. N Engl J Med 326: 737–740.PubMedGoogle Scholar
  11. 11.
    Li M, Cannizzaro LA (1999) Identical clonal origin of synchronous and metachronous low-grade, noninvasive papillary transitional cell carcinomas of the urinary tract. Hum Pathol 30: 1197–1200.PubMedCrossRefGoogle Scholar
  12. 12.
    Diaz-Cano SJ, Blanes A, Rubio J, Matilla A, Wolfe HJ (2000) Molecular evolution and intratumor heterogeneity by topographic compartments in muscle invasive transitional cell carcinoma of the urinary bladder. Lab Invest 80: 279–289.PubMedGoogle Scholar
  13. 13.
    Knudson AG (1996) Hereditary cancer: two hits revisited. J Cancer Res Clin Oncol 122: 135–140.PubMedCrossRefGoogle Scholar
  14. 14.
    Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002) Molecular biology of the cell. Garland Science, New York, pp 1313–1362.Google Scholar
  15. 15.
    Mao L, Lee DJ, Tockman MS, Erozan YS, Askin F, Sidransky D (1994) Microsatellite alterations as clonal markers for the detection of human cancer. Proc Natl Acad Sci USA 91: 9871–9875.PubMedCrossRefGoogle Scholar
  16. 16.
    Simoneau AR, Spruck CH III, Gonzalez-Zulueta M, Gonzalgo ML, Chan MF, Tsai YC, Dean M, Steven K, Horn T, Jones PA (1996) Evidence for two tumor suppressor loci associated with proximal chromosome 9p to q and distal chromosome 9q in bladder cancer and the initial screening for GAS1 and PTC mutations. Cancer Res 56: 5039–5043.PubMedGoogle Scholar
  17. 17.
    Keen AJ, Knowles MA (1994) Definition of two regions of deletion on chromosome 9 in carcinoma of the bladder. Oncogene 9: 2083–2088.PubMedGoogle Scholar
  18. 18.
    Stadler WM, Sherman J, Bohlander SK, Roulston D, Dreyling M, Rukstalis D, Olopade OI (1994) Homozygous deletions within chromosomal bands 9p21-22 in bladder cancer. Cancer Res 54: 2060–2063.PubMedGoogle Scholar
  19. 19.
    Takahashi T, Habuchi T, Kakehi Y, Mitsumori K, Akao T, Terachi T, Yoshida O (1998) Clonal and chronological genetic analysis of multifocal cancers of the bladder and upper urinary tract. Cancer Res 58: 5835–5841.PubMedGoogle Scholar
  20. 20.
    Spruck CH, Ohneseit PF, Gonzalez-Zulueta M, Esrig D, Miyao N, Tsai YC, Lerner SP, Schmutte C, Yang AS, Cote R, Dubeau L, Nichols PW, Hermann GG, Steven K, Horn T, Skinner DG, Jones PA (1994) Two molecular pathways to transitional cell carcinoma of the bladder. Cancer Res 54: 784–788.PubMedGoogle Scholar
  21. 21.
    Knowles MA, Elder PA, Williamson M, Cairns JP, Shaw ME, Law MG (1994) Allelotype of human bladder cancer. Cancer Res 54: 531–538.PubMedGoogle Scholar
  22. 22.
    Knowles MA (2001) What we could now: molecular pathology of bladder cancer. Mol Pathol 54: 215–221.PubMedCrossRefGoogle Scholar
  23. 23.
    Richter J, Beffa L, Wagner U, Schraml P, Gasser TC, Moch H, Mihatsch MJ, Sauter G (1998) Patterns of chromosomal imbalances in advanced urinary bladder cancer detected by comparative genomic hybridization. Am J Pathol 153: 1615–1621.PubMedGoogle Scholar
  24. 24.
    Simon R, Burger H, Brinkschmidt C, Bocker W, Hertle L, Terpe HJ (1998) Chromosomal aberrations associated with invasion of papillary superficial bladder cancer. J Pathol 185: 345–351.PubMedCrossRefGoogle Scholar
  25. 25.
    Richter J, Jiang F, Gorog JP, Sartorius G, Egenter C, Gasser TC, Moch H, Mihatsch MJ, Sauter G (1997) Marked genetic differences between stage pTa and stage pT1 papillary bladder cancer detected by comparative genomic hybridization. Cancer Res 57: 2860–2864.PubMedGoogle Scholar
  26. 26.
    Hafner C, Knuechel R, Zanardo L, Dietmaier W, Blaszyk H, Cheville J, Hofstaedter F, Hartmann A (2001) Evidence for oligoclonality and tumor spread by intraluminal seeding in multifocal urothelial carcinomas of the upper and lower urinary tract. Oncogene 20: 4910–4915.PubMedCrossRefGoogle Scholar
  27. 27.
    Orlow I, Lianes P, Lacombe L, Dalbagni G, Reuter VE, Cordon-Cardo C (1994) Chromosome 9 allelic losses and microsatellite alterations in human bladder tumors. Cancer Res 54: 2848–2851.PubMedGoogle Scholar
  28. 28.
    Zhao J, Richter J, Wagner U, Roth B, Schraml P, Zellweger T, Ackermann D, Schmidt U, Moch H, Mihatsch MJ, Gasser TC, Sauter G (1999) Chromosomal imbalances in noninvasive papillary bladder neoplasms (pTa). Cancer Res 59: 4658–4661.PubMedGoogle Scholar
  29. 29.
    Presti JC Jr, Reuter VE, Galan T, Fair WR, Gordon-Cardo C (1991) Molecular genetic alterations in superficial and locally advanced human bladder cancer. Cancer Res 51: 5405–5409.PubMedGoogle Scholar
  30. 30.
    Hovey RM, Chu L, Balasz M, DeVries S, Moore D, Sauter G, Carroll PR, Waldman FM (1999) Genetic alterations in primary bladder cancers and their metastases. Cancer Res 58: 3555–3560.Google Scholar
  31. 31.
    Brinkschmidt C, Christiansen H, Terpe HJ, Simon R, Boecker W, Lampert F, Stoerkel S (1997) Comparative genomic hybridization (GCH) analysis of neuroblastomas: an important methodological approach in paediatric tumour pathology. J Pathol 181: 394–400.PubMedCrossRefGoogle Scholar
  32. 32.
    Simon R, Eltze E, Schafer K-L (2001) Cytogenetic analysis of multifocal bladder cancer supports a monoclonal origin and intraepithelial spread of tumor cells. Cancer Res 61: 355–362.PubMedGoogle Scholar
  33. 33.
    Jain KK (2004) Current status of fluorescent in-situ hybridisation. Med Device Technol 15: 14–17.PubMedGoogle Scholar
  34. 34.
    Xu X, Stower MJ, Reid IN, Garner RC, Burns PA (1996) Molecular screening of multifocal transitional cell carcinoma of the bladder using p53 mutations as biomarkers. Clin Cancer Res 2: 1795–1800.PubMedGoogle Scholar
  35. 35.
    Habuchi T, Takahashi R, Yamada H, Kakehi Y, Sugiyama T, Yoshida O (1993) Metachronous multifocal development of urothelial cancers by intraluminal seeding. Lancet 342: 1087–1088.PubMedCrossRefGoogle Scholar
  36. 36.
    Goto K, Konomoto T, Hayashi K, Kinukawa N, Naito S, Kumazawa J, Tsuneyoshi M (1997) p53 mutation in multiple urothelial carcinomas: a molecular analysis of the development of multiple carcinomas. Mod Pathol 10: 428–437.PubMedGoogle Scholar
  37. 37.
    Yasunaga Y, Nakanishi H, Naka N, Miki T, Tsujimura T, Itatani H, Okuyama A, Aozasa K (1997) Alterations of the p53 gene in occupational bladder cancer in workers exposed to aromatic amines. Lab Invest 77: 677–684.PubMedGoogle Scholar
  38. 38.
    Miyao N, Tsai YC, Lerner SP, Olumi AF, Spruck C III, Gonzalez-Zulueta M, Nichols PW, Skinner DG, Jones PA (1993) Role of chromosome 9 in human bladder cancer. Cancer Res 53: 4066–4070.PubMedGoogle Scholar
  39. 39.
    Habuchi T, Ogawa O, Kakehi Y, Ogura K, Koshiba M, Sugiyama T, Yoshida O (1992) Allelic loss of chromosome 17p in urothelial cancer: strong association with invasive phenotype. J Urol 148: 1595–1599.PubMedGoogle Scholar
  40. 40.
    Fujimoto K, Yamada Y, Okajima E, Kakizoe T, Sasaki H, Sugimura T, Terada M (1992) Frequent association of p53 gene mutation in invasive bladder cancer. Cancer Res 52: 1393–1398.PubMedGoogle Scholar
  41. 41.
    Greene LF, Hanash KA, Farrow GM (1973) Benign papilloma or papillary carcinoma of the bladder? J Urol 110: 205–207.PubMedGoogle Scholar
  42. 42.
    Kakizoe T, Fujita J, Murase T, Matsumoto K, Kishi K (1980) Transitional cell carcinoma of the bladder in patients with renal pelvic and ureteral cancer. Cancer Res 124: 17–19.Google Scholar
  43. 43.
    Takahashi T, Kakehi Y, Mitsumori K, Akao T, Terachi T, Kato T, Ogawa O, Habuchi T (2001) Distinct microsatellite alterations in upper urinary tract tumors and subsequent bladder tumors. J Urol 165: 672–677.PubMedCrossRefGoogle Scholar
  44. 44.
    Yamamoto S, Tatematsu M, Yamamoto M, Fukami H, Fukushima S (1998) Clonal analysis of urothelial carcinomas in C3H/HeN-BALB/c chimeric mice treated with N-butyl-N-(4-hydroxybutyl)nitrosamine. Carcinogenesis 19: 855–860.PubMedCrossRefGoogle Scholar
  45. 45.
    Yamamoto S, Romanenko A, Wei M, Masuda C, Zaparin W, Vinnichenko W, Vozianov A, Lee CCR, Morimura K, Wanibuchi H, Tada M, Fukushima S (1999) Specific p53 gene mutations in urinary bladder epithelium after the Chernobyl accident. Cancer Res 59: 3606–3609.PubMedGoogle Scholar
  46. 46.
    Paiss T, Wohr G, Hautmann RE, Mattfeldt T, Muller M, Haeussler J, Vogel W (2002) Some tumors of the bladder are polyclonal in origin. J Urol 167: 718–723.PubMedCrossRefGoogle Scholar
  47. 47.
    Cheng L, Gu J, Ulbright TM, MacLennan GT, Sweeney CJ, Zhang S, Sanchez K, Koch MO, Eble JN (2002) Precise microdissection of human bladder tumor carcinomas reveals divergent tumor subclones in the same tumor. Cancer 94: 104–110.PubMedCrossRefGoogle Scholar
  48. 48.
    Tomlinson IP, Lambros MB, Roylance RR (2002) Loss of heterozygosity analysis: practically and conceptually flawed? Genes Chromosomes Cancer 34: 349–353.PubMedCrossRefGoogle Scholar
  49. 49.
    Sieben NLG, Ter Haar NT, Cornelisse CJ, Fleuren GJ, Cleton-Jansen A-M (2000) PCR artifacts in LOH and MSI analysis of microdissected tumor cells. Hum Pathol 31: 1414–1419.PubMedCrossRefGoogle Scholar
  50. 50.
    Hartmann A, Moser K, Kriegmair M, Hofstetter A, Hofstaedter F, Knuechel R (1999) Frequent genetic alterations in simple urothelial hyperpasias of the bladder in patients with papillary urothelial carcinoma. Am J Pathol 154: 721–727.PubMedGoogle Scholar

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