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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e31827bd0ec
Review Articles

Molecular Basis of Urinary Bladder Cancer

Al Hussain, Turki O. MD; Akhtar, Mohammed MD, FCAP, FRCPA, FRCPath

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Author Information

Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

The authors have no funding or conflicts of interest to disclose.

Reprints: Mohammed Akhtar, MD, FCAP, FRCPA, FRCPath, Department of Pathology & Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Kingdom of Saudi Arabia (e-mail: makhtar69@kfshrc.edu.sa).

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Abstract

Bladder cancer is a relatively common and potentially life-threatening neoplasm. The diagnosis of urothelial carcinoma usually entails a lifelong surveillance to detect recurrent disease. In recent years, significant progress has been made in understanding the molecular mechanisms of carcinogenesis in urinary bladder. An early step in the process of carcinoma development is establishment of a premalignant abnormal urothelial patch that may give rise to various types of urothelial carcinoma and may provide a fertile ground for development of multifocal synchronous and metachronous tumors. Two distinct molecular pathways are involved. Low-grade papillary carcinoma is associated with mutation in the FGFR3 or in some cases mutations in RAS genes. High-grade in situ/muscle-invasive carcinoma on the other hand is characterized by alteration of p53 and pRB. Loss of function of these key genes, which play a crucial role in the control of cell cycle, leads to accumulation of additional mutations and deletions of genes resulting in an aggressive phenotype. It is hoped that a thorough understanding of the molecular basis of urothelial cancer will facilitate early diagnosis and will lead to development of new modalities for the management and treatment of these carcinomas.

Bladder cancer is the fifth most commonly diagnosed noncutaneous solid malignancy and the second most frequently diagnosed genitourinary tumor after prostate cancer. Approximately 357,000 individuals are diagnosed worldwide with bladder carcinoma each year, with about 145,000 people dying from the disease. It is estimated that there were approximately 71,000 new cases of urothelial carcinoma (UC) and 14,300 deaths in the United States in 2009 as a result of the disease.1–3 In Saudi Arabia, according to the tumor registry figures at King Faisal Specialist Hospital in Riyadh, bladder cancer is the fourth most common malignant neoplasm in men.4

The incidence of bladder cancer rises with age, peaking between age 50 and 70 years and is 3 times more common in men than in women.1–3 As the final recipient and reservoir of urine, the urothelium is inevitably exposed to carcinogens, which can create a large cancer field in this tissue. A large number of risk factors for UC have been identified. Use of tobacco is considered to be the most important factor, contributing to approximately 50% of all bladder cancers. Other possible causative agents include industrial chemicals, ingestion of arsenic-laced water, radiation therapy to organs adjacent to the bladder, therapeutic use of alkylating agents in chemotherapy regimens, and infection with Schistosoma haematobium.1–13 The latter risk factor is closely associated with squamous cell carcinoma of the bladder but may also cause UC. Occupations with increased exposure to aromatic amines and other potential bladder carcinogens, include those in the painting and leather industries, and other group such as autoworkers, truck drivers, metalworkers, paper and rubber manufacturers, foundry workers, dry cleaners, dental technicians, hairdressers, and marine engineer. Bladder cancer from occupational exposures often occurs after 30 to 50 years after exposure. There is no strong evidence to indicate that coffee, alcohol, and artificial sweeteners are potential bladder carcinogens.5–10

The most important step for reducing the risk of bladder cancer is to give up smoking, which generally reduces the relative risk of dying of bladder cancer from 3 to 2.6–8 Increased fluid intake may be associated with a lower risk of bladder cancer and has been proposed as a dietary modification for patients with bladder cancer. Increasing urine output may decrease the contact time of carcinogens with the urothelium and dilute their relative concentration. This beneficial effect of fluid intake has been demonstrated by some studies; however, others have failed to confirm these findings. The consumption of fruits and vegetables has also been suggested to have a protective effect, but it remains to be proven.4–12,14

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UROTHELIUM AND CARCINOMA

Urinary bladder is a hollow organ with a thick muscular wall. It is lined by a special type of multilayered epithelium, the urothelium (previously called transitional epithelium). The urothelium is composed of 4 to 7 layers of cells, including a layer of basal cells, followed by 2 to 4 layers of intermediate cells and a surface layer of large cells with abundant cytoplasm termed as umbrella cells.15 The most common histologic type of bladder cancer is UC, which was formerly called “transitional cell carcinomas.”1,2 Squamous cell carcinoma of the bladder is common in some geographic areas with endemic infection with S. haematobium.13 Adenocarcinoma, small cell carcinoma, and other rare subtypes constitute a small proportion of the bladder cancer.16

UCs present as a heterogenous group of diseases that consist of 2 main phenotypic variants, low-grade papillary carcinoma (LGPC) and high-grade muscle-invasive carcinoma (MIC), which have drastically different behaviors and prognoses. Approximately 80% of patients with UC present with LGPC, which are morphologically well differentiated with uniform nuclei and only minimal loss of cell polarity. LGPCs are successfully treated by endoscopic resection; however, approximately 70% of the patients have 1 or more recurrences within 5 years, and in 15% cases the carcinoma progresses to high grade with invasive disease. Because of high rate of recurrence and a significant risk of progression, the patients with this type of carcinoma require close follow-up for life, with periodic cystoscopic examination.1,2,7,14,15 High-grade MICs in contrast are poorly differentiated with nuclear pleomorphism, increased mitotic activity, and loss of cell polarity. Most of the MIC starts as a flat intramucosal lesion with high-grade dysplasia/carcinoma in situ (CIS) (stage Tis). After a variable interval, many of these lesions become invasive and clinically present as MIC (stages 2 to 4). Muscle-invasive UCs are commonly treated with a radical cystectomy or chemoradiotherapy. Despite aggressive treatment, approximately 50% of these patients develop subsequent metastatic disease, with most succumbing usually within 2 years of diagnosis.1,2

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FIELD CANCERIZATION

Normal urothelium maintains a strict control of cell proliferation and restricts the thickness of the epithelium to 4 to 7 layers, allowing only limited and controlled proliferation in order to replace the damaged cells and the cells that are normally sloughed off from the surface of the epithelium. Most of the proliferation in the urothelium takes place in the basal layer.15 Intermediate cells gradually exit the proliferation cycle, as they undergo differentiation and maturation. The umbrella cells, located on the luminal surface of the urothelium, are terminally differentiated and seem to have permanently exited the proliferation cycle.

An important physiological function of epithelia such as urothelium is their protective role that inevitably exposes them to environmental substances, including carcinogens. These can create vast areas of genetically altered precancerous fields. Epithelial cells frequently self renew and can undergo abnormal proliferation. Hyperplastic epithelia could form the basis of neoplastic transformation leading to the formation of the most common types of cancers of the human body.14,15

Changes of field cancerization have been documented for several epithelial tumors including those of the head and neck, esophagus, stomach, lungs, skin, cervix, vulva, bladder, colon, breast, ovary, pancreas, and possibly prostate. The idea of field cancerization was conceived by Slaughter et al in 1953.17 In a an extensive histopathologic review of 783 oral cancer patients, Slaughter and colleagues used the term field cancerization to describe the existence of generalized carcinogen-induced early genetic changes in the epithelium from which multiple independent lesions occur, leading to the development of multifocal tumors. It was also observed that normal-appearing cells in close proximity to malignant cells were part of the transformed cells in a particular tumor field and consequently were responsible for the occurrence of local tumor recurrences.18–20

Several recent studies have addressed the molecular basis of the process of cancer development, and genetic progression models have been proposed for various tumor types. It is now well established that an accumulation of genetic alterations forms the basis for the progression from a normal cell to a cancer cell, referred to as the process of multistep carcinogenesis. The process of field cancerization can be defined in molecular terms, and its position in the process of multistep carcinogenesis can be delineated. Several lines of evidence indicate that the presence of a field lesion with genetically altered cells is a distinct biological stage in epithelial carcinogenesis with important clinical implications.18–20

There are 2 major theories pertaining to the sources of such precancerous fields in the urinary bladder. According to 1 concept the cancer field effect is produced by intraepithelial migration of cancer cells (the tumor-first-field-later mode). According to this concept, neoplastic cells from urothelial cancer spread laterally replacing the adjacent normal urothelium for a variable distance. These displaced cancer cells remain dormant for variable length of time and are responsible for multifocal synchronous and metachronous tumors. The spread of carcinoma cells may also occur through the urine so that these cells may implant within the urothelium at a considerable distant from the original source (Fig. 1A). According to the alternative view point, the field cancerization is caused by nonmalignant cells with preneoplastic genetic changes. These cells proliferate and replace large parts the urothelium (clonal expansion), which, with passage of time and after acquisition of additional genetic abnormalities, may lead to cancer (clonal evolution) (Fig. 1B). According to this theory, additional synchronous and metachronous tumors may develop in a background of genetically altered preneoplastic urothelium (the field-first-cancer-later mode).21

Figure 1
Figure 1
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STEM CELLS AND CANCER

Cancer stem cells (CSC) comprise usually 1% to 4% of the viable cell population in a malignant neoplasm. These cells proliferate through asymmetric differentiation. After cell division, one daughter cell retains the capacity to divide again, whereas the other daughter cell is able to diversify into heterogenous cancer cell lineages. When tumors arise from CSCs or progenitor cells, a specific set of genomic, epigenomic, and/or microenvironmental niche alterations is essential for continued clonal expansion.19 According to the cancer progression model, several events are required for the progression from normal epithelium to carcinoma. Because of their extended life span, stem cells would represent the most likely target for the accumulation of these genetic events, but this has not been formally proven for most of solid cancers. Even more importantly, CSCs seem to harbor mechanisms protecting them from standard cytotoxic therapy.21

Although purified bladder CSCs have not yet been isolated, many studies have observed putative stem cell–like cell populations in bladder cancer. These bladder stem cells appear to be present in UC and can be identified by their properties of colony formation, self-renewal, high proliferation rate, and expression of stem cell–related genes.22–26

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UROTHELIUM IS A MOSAIC

Clonality studies, based on X chromosome inactivation in females, have revealed that urothelium is a mosaic composed of numerous patches each one of which contains a monoclonal cell population derived from a single founding cell or a stem cell. These patches of urothelium measure about 120 mm2 with an average population of 2×106 cells. It has been estimated that the urothelium in each bladder is composed of 200 to 300 such patches. It seems that these patches are responsible for maintaining the integrity of the cell layers by replacing damaged cells and that these patches to some extent behave independently.27,28

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PRENEOPLASTIC UROTHELIAL PLAQUE (PUP)

The process of bladder carcinogenesis starts when a stem cell in one of the normal patches in the urothelium acquires mutations in one of the tumor suppressor genes. The resulting cell population has a slight proliferation advantage as compared with the normal cells in the urothelium, so that, at least partly, these cells are free from the strict control of cell division maintained by the normal urothelium. As the cells in the resulting PUP have a higher proliferation rate, the plaque slowly expands replacing variable numbers of adjacent normal patches of urothelium (Fig. 2). The abnormal plaque may expand over several months and years, ultimately replacing a major segment of the urothelium. This abnormal plaque is monoclonal, because it is populated by progenies of the mutated stem cell.21 The concept of normal/hyperplastic urothelium in a PUP sharing early preneoplastic genetic changes with UC has been supported by numerous studies, which reveal clonal and oligoclonal cell populations within the PUP.21,29–36

Figure 2
Figure 2
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The genetic abnormality responsible for the formation of the PUP is, in most cases, loss of heterozygosity of chromosome 9. Detailed mapping studies of chromosome 9 have revealed that the region between 9p12 and 9q34.1 contains several potential tumor suppressor genes, including TSC1 (tuberous sclerosis 1), DBC1 (deleted in bladder cancer gene 1), PTCH1 (patched homolog 1), MSSE (multiple self-healing squamous epithelioma), and CDKN1B [encoding P27, a cyclin-dependent kinase inhibitor (CDKI) protein] (Fig. 3). Loss of these genes results in a higher proliferation rate within the PUP, although it is not sufficient for producing a carcinomatous lesion, which requires additional genetic events.7,14,15,21

The PUP may be histologically indistinguishable from normal urothelium. However, because the cells in the plaque have slightly higher rate of proliferation as compared with normal urothelium, several types of hyperplastic lesions (such as flat and papillary hyperplasia) may be recognized. Because of increased cellular proliferation rate, the cells in the PUP are at higher risk for developing additional mutations, which may ultimately lead to development of UC. The type of the carcinoma (high-grade vs. low-grade) developing in a PUP, however, depends on the nature of these additional genetic abnormalities.

Figure 3
Figure 3
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LOW-GRADE PAPILLARY UROTHELIAL CARCINOMA

In approximately 80% of the cases the carcinoma arising in the urothelium is noninvasive low-grade papillary type. The epithelium in this carcinoma is essentially similar to that of normal urothelium, except for increased thickness (>7 layers of cells), variable nuclear pleomorphism, and a papillary growth pattern. These LGPCs are the result of abnormal and excessive activation of transduction signals from cell surface receptors to the nucleus for transcription. Abnormalities in the transduction pathways due to gene mutations result in deregulation of cellular homeostasis leading to increased cellular proliferation. In LGPC, the Ras-MAPK signaling cascades are an important signal transduction pathway. Mutations in the fibroblast growth factor receptor 3 gene (FGFR3) gene result in an abnormal receptor capable of constitutive dimerization and activation without binding to the growth factor ligand, resulting in activation of the Ras-MAPK transduction pathway. FGFR3 mutations are encountered in approximately 70% of low-grade papillary UCs. The presence of such mutations, have been associated with genetic stability in a majority of cases. In approximately 15% of the cases there may be overexpression of FGFR3 without any demonstrable gene mutation. Harvey rat sarcoma viral oncogene homolog gene (H-RAS) mutations have been identified in about 10% of the LGPC. FGFR3 and H-RAS mutations seem to be mutually exclusive, because both activate the RAS-MEK-ERK signaling pathway.7,14,15,37,38

FGFR3 is a member of 4 highly conserved and structurally related tyrosine kinase receptor genes. It is located at chromosome 4p16.3 and is composed of 19 exons spanning 16.5 kb. It encodes an 806–amino acid protein belonging to the fibroblast growth factor receptor family. The receptor consists of an extracellular region, composed of 3 immunoglobulin-like domains, a single hydrophobic transmembrane segment, and a cytoplasmic tyrosine kinase domain (Fig. 4). The extracellular portion of the protein interacts with fibroblast growth factors and initiates cascades of downstream signals, ultimately influencing cell growth, migration, differentiation, and angiogenesis. The signal transduction pathways for FGFR3 receptors are shared by many receptor tyrosine kinases. FGFR3 mutations are most commonly seen in exon 5 accounting for 50% to 80% of all mutations. Mutations affecting exon 10 (representing transmembrane domain) account for 15% to 40%. Approximately 5% to 10% of the mutations are encountered in tyrosine kinase 2 domain represented by exon 15. FGFR3 activation triggers several downstream kinase pathways.7,14,15,37–40 The most important of these pathways is the RAS cell cycle regulation pathway, which induces mitogenic signals and plays a central role in the proliferation and renewal of epithelial cells. Activated FGFR3 may also trigger activation of additional transduction pathways including the phosphatidylinositol 3-kinase (PI3-K), and the signal transducer and activator of transcription (STAT) pathway.

Figure 4
Figure 4
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The human RAS genes represent a family of cellular transforming oncogenes; H-RAS mutations being originally identified in the human urothelial cancer cell line T24. Two mechanisms have been reported for gene transformation: mutations that affect the enzymatic activity of the encoded Ras protein and internal splicing within the last intron. It has been reported that a glycine to valine substitution at codon 12 of the H-RAS occurs in approximately 30% of urothelial malignancies.37,41

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HIGH-GRADE (NONPAPILLARY) UROTHELIAL CARCINOMA

The second type of carcinoma possibly arising from the PUP is high-grade UC, which usually starts as a flat UC, also called urothelial carcinoma in situ (UCIS). The genetic abnormalities in UCIS comprise of mutations of potent tumor suppressors, including p53 and retinoblastoma susceptibility gene RB, both of which play crucial role in control of normal cell cycle, inhibiting progression at the G1-S transition. P53 induces the transcription of p21WAF1/CIP1, which encodes for p21, a CDKI.15,38 Cyclin-dependent kinases play a crucial role in phosphorylation of pRB leading to release E2F, which facilitates transcription of proteins necessary for S phase of the cell cycle (Fig. 5).

Figure 5
Figure 5
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Alterations of the p53 tumor suppressor gene play a crucial role in the carcinogenesis of many tumors, including bladder urothelial cancers. The p53 gene, located at the short arm of chromosome 17 (17p13.1), spans 19.2 kb and is composed of 11 exons. P53 encodes a 393–amino acid protein (p53) that regulates the cell cycle, DNA repair, and apoptosis. The N-terminus of p53 contains several functional domains. The activation domain 1 (amino acids 1 to 42) activates transcription of downstream factors. Activation domain 2 (amino acids 43 to 63) regulates apoptotic activity. The proline-rich domain (amino acids 80 to 94) is also important in apoptosis. The DNA-binding domain (amino acids 100 to 300) activates downstream transactivation of other genes. The nuclear localization signaling domain (amino acids 316 to 325) and the homooligomerization domain (amino acids 307 to 355) are essential for the structure and homing of p53. P53 also induces the transcription of p21WAF1/CIP1, which encodes for p21, a CDKI.15,38

P53 mutations in cancers are usually missense, loss-of-function mutations occurring in the DNA-binding domain. These impair the binding of p53 to its target DNA, further affecting transcriptional activation of downstream genes. Mutant forms of p53 can also dimerize with wild-type p53, blocking its function. P53 mutations induce a series of downstream effects, including decreased expression of p21. This important downstream target of p53 is downregulated in the majority of UC. Mutations involved in the p53 protein dysfunction occur in 2 phases: initially one allele is affected, followed by loss of second, wild-type allele with TP53 mutations. Numerous studies have indicated that p53 mutations are strongly associated with high tumor grade, invasive behavior, risk of recurrence, and adverse clinical outcome.15,38

The retinoblastoma (RB) susceptibility gene encodes a nuclear phosphoprotein (pRB), which functions as a negative cell cycle regulator. The active dephosphorylated Rb binds to and inhibits E2F. In its phosphorylated state, Rb releases E2F that in turn is able to induce gene transcription for DNA synthesis. Mutations in the RB gene that inactivate Rb have been found in bladder cancer. This is postulated to occur through Rb hyperphosphorylation owing to loss of expression of the CDKI p16 and/or cyclin D1 overexpression. RB inactivation is linked with genetic instability, based on the increased activity of E2F and its transactivation of the MAD2 gene, critical in controlling the mitotic spindle and chromosome segregation, thus producing an “aneuploid” phenotype. The genetic instability and antiapoptotic phenotype produced by such mutations generate loss of critical physiological functions and command the accumulation of multiple genetic aberrations.15,38

Urothelial tumors with alterations in both p53 and Rb expression had increased rates of recurrence and progression and worse survival than tumors harboring defects of either gene. In addition, studies in transgenic mice with functionally inactivated p53 and Rb proteins develop exclusively high-grade CIS lesions that progress to muscle-invasive disease. Therefore, it may be suggested that p53 and RB act as tumor suppressors and may have a synergistic role in preventing evolution of high-grade urothelial tumors.42

MDM2 is another gene that may be involved in the development of UCIS. Mdm2 degrades p53 after upregulation of the MDM2 promoter by elevated p53 levels. MDM2 amplification has been documented in bladder cancer and has been shown to be more frequent in high-stage and high-grade tumors. A single-nucleotide polymorphism in the MDM2 promoter, SNP309, is a frequent event in bladder cancer.15,38

Loss of PTEN has been shown to collaborate with p53 to promote a muscle-invasive phenotype. Other pathway defects, including activation of PI3 kinase and/or AKT1 may also play important roles, but their relationships to CIS and the muscle-invasive phenotypes are not as clear.15

Approximately 15% of the LGPC undergo progression to high-grade carcinomas, many of which subsequently progress to MIC. This progression from a low-grade and indolent carcinoma to a high-grade and potentially aggressive carcinoma usually follows development of additional mutations in P53 and/or pRB. Thus, papillary carcinomas that progress from low-grade to high-grade carcinoma will have mutations usually encountered in LGPC (FGFR3 or RAS mutations) with superimposed mutations characteristic of high-grade carcinomas.

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ROLE OF PRENEOPLASTIC UROTHELIAL PLAQUE IN TUMOR RECURRENCE

One of the key challenges in the management of UC is the high frequency of recurrences, necessitating long-term follow-up. LGPCs are generally treated by endoscopic removal followed by close follow-up with cystoscopic examination for many years. There is no treatment modality currently available to delineate and remove the PUP, which persists and probably continues to expand and serve as a potent source for initiation of new tumor foci.21 This concept of expanded fields of preneoplastic cells that may potentially function as a fertile ground for new tumor foci has important clinical consequences. Significant improvements in recurrence-free survival have been achieved by combining transurethral resection with intravesical chemotherapy or immunotherapy, which is expected to eradicate any tumor cells missed by cystoscopic removal. However, an important potential source for recurrences will remain: an abnormal plaque of urothelium in a preneoplastic state with capacity to transform into an overt tumor. There are no studies evaluating the efficacy of adjuvant therapy in modifying or eliminating the persistent PUP. This is partly because of the fact that there are no reliable techniques currently available to visualize and delineate these abnormal fields within the urinary bladder.21

Fluorescence cystoscopy has been investigated as a tool to enhance visualization of UCIS, dysplasia, and other preneoplastic lesions. Intravesical porphyrin-based fluorescence cystoscopy involves instilling a photosensitizing agent such as 5-aminolevulinic acid or its hexyl ester, hexaminolevulinate 5-aminolevulinic acid, into the bladder. It induces preferential accumulation of fluorescent-photoactive-endogenous porphyrins in abnormal epithelial cells as opposed to normal cells of urothelial origin. Under subsequent blue-light illumination, neoplastic lesions fluoresce red, enabling visualization of tumors and other related lesions. Overall, blue-light cystoscopy shows a statistically significant superiority over the usual white-light cystoscopy (WLC) regarding sensitivity for the detection of various abnormal urothelial lesions. Several studies have compared the efficacy of fluorescence cystoscopy with WLC. Many of these studies showed that patients having a resection under fluorescence cystoscopy have significantly less residual tumor and a longer recurrence-free survival. This technique also highlights hyperplasic and inflammatory lesions, but there is no clear evidence that it can outline a PUP within the urinary bladder.43,44 Other studies have shown no significant advantage in the recurrence-free survival in patients treated with fluorescence cystoscopy as compared with those managed with conventional WLC.45

The UroVysion test (Abbott Molecular, Des Plaines, IL) is a multitarget multicolor fluorescent in situ hybridization assay, which takes advantage of the high occurrence of specific chromosomal abnormalities in urothelial cancers. The test is performed on exfoliated cells from urine using centromeric fluorescent probes for chromosome 3, 7, 17, and the locus-specific identifier probe for 9p21. The sensitivity of UroVysion ranges from 39% to 97% (average 74%) but is significantly lower for low-grade and low-stage tumors. The specificity is, however, high (89% to 100%). The test is particularly useful at predicting tumor recurrence. In 1 study, 27% of patients under bladder carcinoma surveillance without immediate evidence of tumor recurrence had a positive UroVysion and 65% of these patients had recurrent UC within 29 months. Furthermore, 85% of patients with atypical cytology and positive fluorescent in situ hybridization developed a biopsy-proven UC within 12 months.46 The sensitivity of this technique does not seem to be influenced by prior Bacillus Calmette-Guerin treatment.46,47 These findings indicate that UroVysion has the capability to detect preneoplastic lesions, which on follow-up may evolve into UC.46,47 In a review paper, Caraway and Katz concluded that that the technique is useful, but urine cytopathology is still preferred because of low cost.48

The real question, however, is: what can be done in these cases to eliminate the PUP or to forestall its progression into overt carcinoma? It is hoped that as the pathogenesis and molecular basis of these lesions is thoroughly understood, appropriate treatment modalities for their management and possible elimination will also become available.

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SUMMARY

In recent decades, there is an exponential accumulation of information on molecular basis of UCs. As the molecular mechanisms and biological pathways that lead to urothelial tumor genesis are increasingly understood, it is hoped that it will lead to enhanced diagnostic capabilities and will provide the impetuous for development of improved therapeutic modalities targeting specific molecular pathways.

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Keywords:

bladder; urothelium; carcinoma; genes; mutations; preneoplastic; plaque; molecular; fluorescent in situ hybridization

© 2013 Lippincott Williams & Wilkins, Inc.

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