Superficial Bladder Cancer: An Update on Etiology, Molecular Development, Classification, and Natural History

Treatment Update

RIU0329_03-14.qxd 3/15/08 3:00 AM Page 31 TREATMENT UPDATE Superficial Bladder Cancer: An Update on Etiology, Molecular Development, Classification, and Natural History Erik Pasin, MD,* David Y. Josephson, MD,* Anirban P. Mitra, MBBS,† Richard J. Cote, MD, FRCPath,*,† John P. Stein, MD, FACS* Departments of *Urology and †Pathology, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA Superficial “non–muscle-invasive” bladder tumors represent a heterogeneous group of cancers, including those that are (1) papillary in nature and limited to the mucosa, (2) high grade and flat and confined to the epithelium, and (3) invasive into the submucosa, or lamina propria. The goal of treatment is 2-fold: (1) to reduce tumor recurrence and the subsequent need for additional therapies and the morbidity associated with these treatments and (2) to prevent tumor progression and the subsequent need for more aggressive therapy. This update reviews important contemporary concepts in the etiology, molecular mechanisms, classification, and natural history of superficial bladder cancer. [Rev Urol. 2008;10(1):31-43] © 2008 MedReviews, LLC Key words: Bladder neoplasms • Non–muscle-invasive tumor • Molecular mechanisms • Genitourinary tumors • Transitional cell carcinoma n 2007 it was estimated that 67,160 new patients would be diagnosed with bladder cancer, with 13,750 projected deaths from the disease. The incidence of bladder cancer is nearly 4 times higher in men than in women.1 Histologically, more than 90% of bladder-cancer cases are transitional cell (urothelial) carcinoma, approximately 5% are squamous cell carcinoma, and less than 2% are adenocarcinoma.2 I VOL. 10 NO. 1 2008 REVIEWS IN UROLOGY 31 RIU0329_03-14.qxd 3/15/08 3:00 AM Page 32 Superficial Bladder Cancer continued Transitional cell carcinoma (TCC) of the bladder is the second most common malignancy of the genitourinary tract and the third most common cause of death among people with genitourinary tumors.1 Nearly 80% of patients who initially present with bladder TCC have tumors confined to the mucosa or submucosa—so-called superficial “non–muscle-invasive” bladder cancers.2 Superficial bladder tumors represent a heterogeneous group of cancers that include those that are (1) papillary in nature and limited to the mucosa (Ta), (2) high grade and flat and confined to the epithelium (Tis), and (3) invasive into the submucosa, or lamina propria (T1).3 This article reviews the recent literature concerning important contemporary issues in the management of patients with superficial bladder TCC. A brief overview of all aspects of superficial bladder cancer including the etiology, molecular development, diagnosis, and treatment is presented with a focus on recent advances. Etiology Classically, bladder cancer has been associated with exogenous and environmental risk factors. The 2 best known risk factors for bladder cancer are smoking and occupational exposure. Compared with the general population, smokers are at 2 to 4 times greater risk of bladder cancer, and heavy smokers are at 5 times the risk.4 The exact mechanism by which tobacco causes bladder cancer is not known, but urothelial carcinogens such as acrolein, 4-amino-biphenyl, arylamine, and oxygen-free radicals have been implicated.5-8 Furthermore, increased duration and intensity of tobacco exposure and degree of inhalation contribute significantly to cancer development, whereas smoking cessation has been associated with an almost immediate decline in 32 VOL. 10 NO. 1 2008 risk.9 With established tobacco-associated superficial TCC of the bladder, those who continue to smoke after diagnosis have a worse recurrence-free survival rate than those who quit at the time of diagnosis.10 Occupational exposure to aniline dyes and aromatic amines such as 2naphthylamine and benzidine has been implicated as the second most common risk factor for bladder cancer.11,12 Benzidine, the most carcinogenic aromatic amine, has been primarily used in dye production and as a hardener in the rubber industry. The degree of carcinogenesis due to occupational exposure varies with the failed to establish this relationship.26,27 More recently, large case-control human studies have shown that a dosing association may exist, as “heavy” use of artificial sweeteners ( 1680 mg/day) was related to an increased relative risk of bladder cancer but “low” usage ( 1680 mg/day) was not.28 Molecular Pathogenesis The large fund of molecular knowledge on carcinogenesis, which has expanded remarkably in recent years, has provided evidence and a better understanding of the genetic alterations that lead to the development of bladder cancer. Most superficial blad- Most superficial bladder tumors show a loss of heterozygosity of chromosome 9. In fact, deletions on chromosome 9 are the most common chromosomal abnormalities in transitional cell carcinoma (TCC) and are found in more than 50% of all grades and stages of TCC. degree of industrialization, but in heavily industrialized nations, occupational exposure may account for up to one fourth of all urothelial cancers.13 The latency period between exposure and tumor development is usually prolonged. Occupational bladder cancer has also been observed in gas workers, painters, and hairdressers.14 Other etiologic factors implicated in the development and progression of bladder cancer include analgesic use15; urinary tract infections,16 including bacterial, parasitic,17 fungal, and viral infections18; urinary lithiasis19; pelvic radiation20; and chemotherapeutic agents such as cyclophosphamide.21 Although caffeine ingestion has been implicated as a risk factor for bladder cancer,22,23 risk estimates for this association decrease after controlling for concomitant tobacco use.24 Similarly, saccharincontaining artificial sweeteners have been shown to induce bladder neoplasms in the rat model,25 but previous human epidemiological studies have REVIEWS IN UROLOGY der tumors show a loss of heterozygosity (LOH) of chromosome 9.29 In fact, deletions on chromosome 9 are the most common chromosomal abnormalities in TCC and are found in more than 50% of all grades and stages of TCC.30 LOH of chromosome 9 is considered to be the least divergent event, indicating that this is likely to be an early genetic change, whereas subsequent events occur during independent evolution of different tumor subclones (Figure 1). Critical regions of LOH have been mapped on both 9p and 9q. These include 1 region of loss on 9p (9p21) and 3 regions on 9q (9q22, 9q32-q33, and 9q34).31,32 The region 9p21 contains the cyclin-dependent kinase inhibitors CDKN2A and CDKN2B loci, which contain the genes that encode for the p16, p14 (on CDKN2A), and p15 (on CDKN2B) proteins; 9q22 contains PTCH (Gorlin syndrome gene), 9q32-q33 contains DBC1, and 9q34 contains TSC1 (tuberous sclerosis syndrome gene 1). RIU0329_03-14.qxd 3/15/08 3:00 AM Page 33 Superficial Bladder Cancer Normal Urothelium 9p-/9q- 9p-/9qLikely Progression Less Likely Progression Hyperplasia FGFR3* HRAS* Superficial Carcinoma Dysplasia FGFR3* HRAS* Papillary Low-Grade Noninvasive Papillary High-Grade Noninvasive Recurrence Recurrence p53† p53† p21† p21† p53† Carcinoma in Situ (CIS) Rb† 9p- Invasive Carcinoma Figure 1. Model depicting potential pathways for urothelial tumorigenesis and progression. This model includes some key molecular events that occur during bladder tumorigenesis and demonstrates how the less aggressive papillary carcinomas generally differ in their origin from the more aggressive carcinoma in situ. Most papillary noninvasive carcinomas do not progress to an invasive phenotype but are more prone to recurrences. Those that do, however, usually accumulate more genetic abnormalities. *Activating mutations; †Inactivating mutations; FGFR3, fibroblast growth factor receptor 3; HRAS, transforming protein p21/H-RAS-1 (Harvey murine sarcoma virus oncogene). p16 and p14 are key cell-cycle regulators. The former negatively regulates the retinoblastoma (Rb) pathway, whereas the latter negatively regulates the p53 pathway.33,34 The genes for both proteins are commonly inactivated in bladder cancer by homozygous codeletion. LOH of 9p21 is seen in both low-grade Ta and invasive bladder cancer, and reduced copy number of 9p21 with or without LOH is present in approximately 45% of tumors,35 indicating that haploinsufficiency of p16 and/or p14 may contribute to bladder tumor development. A significant correlation has been shown between the loss of p16 expression and progression in T1 tumors.36 Investigators have shown decreased expression of PTCH mRNA in superfi- cial tumors with LOH in the 9q22 region compared with normal urothelium, with marked fluctuations of levels in tumors without deletion.37 DBC1, the ectopic expression of whose protein product is postulated to induce a type of cell death that does not follow the classical apoptotic pathway,38 has been shown to be silenced by promoter hypermethylation in bladder cancer.39 Located on 9q34, the TSC1 gene encodes for hamartin, which complexes with the TSC2 gene product tuberin in the PI3-kinase pathway to negatively regulate mTOR, a central molecule in the control of protein synthesis and cell growth.40 Mutations of TSC1 are found in approximately 12% of bladder tumors.41 Interestingly, some of these mutations are in tumors that retain heterozygosity for TSC1, again indicating possible haploinsufficiency.41 Thus, loss of 1 chromosome 9 homologue, a common event in superficial bladder tumors, could possibly affect haploinsufficient genes on both 9p and 9q. In addition to LOH of chromosome 9, low-grade papillary tumors generally exhibit a constitutive activation of the receptor tyrosine kinase-Ras pathway, with activating mutations in the HRAS and fibroblast growth factor receptor 3 (FGFR3) genes, found in 30% to 40% and 60% to 70% of cases of the disease, respectively (Figure 1).42 In a recent prospective study reporting the prevalence and distribution of FGFR3 mutations and their association with outcome in 764 patients with non–muscle-invasive urothelial carcinoma, Hernandez and colleagues provided evidence that mutations of this gene are significantly more prevalent among tumors of low stage and grade and less prevalent among high-grade T1 tumors.43 FGFR3 mutations are confined to hot spots in exons 7, 10, and 15, and all are predicted to cause constitutive activation of the kinase activity of the receptor,44 which in turn VOL. 10 NO. 1 2008 REVIEWS IN UROLOGY 33 RIU0329_03-14.qxd 3/15/08 3:00 AM Page 34 Superficial Bladder Cancer continued can activate the mitogen-activated protein kinase (MAPK) pathway—a pathway shared with the Ras family of proteins.42 Interestingly, in a screen of 98 bladder tumors and 31 bladder cancer cell lines for mutations in FGFR3 and the Ras genes (including HRAS), both mutations were found to be absolutely mutually exclusive, suggesting possible biological equivalence.45 This mutual exclusion suggests that FGFR3 and Ras gene mutations may represent alternative means to confer the same phenotype on bladder-can- tract symptoms. Approximately three fourths of patients with bladder cancer present with painless, intermittent hematuria.53 It is estimated that approximately 20% of patients being evaluated for gross hematuria will subsequently be diagnosed with bladder cancer.54,55 Similarly, of patients presenting with microscopic hematuria, up to 10% will be diagnosed with bladder cancer.56 Microscopic hematuria in patients with bladder cancer tends to be unpredictable and inconsistent; therefore, a single negative urinalysis does not exclude the Approximately three fourths of patients with bladder cancer present with painless, intermittent hematuria. It is estimated that approximately 20% of patients being evaluated for gross hematuria will subsequently be diagnosed with bladder cancer. cer cells wherein oncogenic activation of either FGFR3 or HRAS results in stimulation of the MAPK pathway. High-grade and high-stage cancers, on the other hand, are more commonly associated with p53 alterations.46,47 Similarly, abnormal RB gene expression, as detected by immunohistochemical analysis of the Rb protein, has been seen in aggressive, higher stage/grade tumors.48,49 Advanced bladder cancers have also been shown to have decreased expression of p21, a protein that inhibits cell-cycle progression downstream of p53.50,51 In fact, a combined analysis of the expression of p53, p21, and Rb has suggested that with increasing number of alterations of these proteins, the final prognosis of the patient worsens considerably.52 Diagnosis The diagnosis of superficial bladder cancer can be elusive. The presenting symptoms of bladder cancer may mimic those of other common urologic conditions such as urinary tract infection and general lower urinary 34 VOL. 10 NO. 1 2008 possibility of cancer.57 The Best Policy Panel of the American Urological Association has accounted for this in its recommended definition of asymptomatic microscopic hematuria as “three or more red blood cells per high-power field on microscopic evaluation of urinary sediment from two of three properly collected urinalysis specimens.”58 The panel recommended that all patients without risk factors for primary renal disease should have a urologic evaluation including radiographic imaging of the upper urinary tract fol- that are highly specific for TCC include increased cell size and nuclearcytoplasmic ratio, nuclear pleomorphism, and nucleolar prominence. It should be noted that irrigated bladder cytology is more sensitive than voided cytology in diagnosing bladder cancer.59 One fourth of patients with bladder cancer will present with irritative voiding symptoms of urgency, frequency, and dysuria.60 In the primary care setting, these symptoms are frequently misinterpreted as signs of a urinary tract infection but may signify either trigone involvement with tumor or the presence of carcinoma in situ (CIS).61 Although the incidence of metastatic bladder cancer with superficial disease is low,62 patients may present with bone pain or flank pain due to retroperitoneal adenopathy or ureteric obstruction. Patients with ipsilateral hydronephrosis should be considered to have muscle-invasive disease.63 The initial evaluation and management of patients with suspected bladder cancer involves cystoscopic evaluation of the bladder, transurethral resection (TUR) of visible tumor, and assessment of the appearance of the uninvolved bladder and prostatic urethra. When urinary cytology is positive and no grossly visible tumor is apparent on cystoscopy, directed bladder biopsies, including cold-cup biopsies of the prostatic urethra, to Microscopic hematuria in patients with bladder cancer tends to be unpredictable and inconsistent; therefore, a single negative urinalysis does not exclude the possibility of cancer. lowed by cystoscopy. Although urine cytology is best utilized in patients with known bladder cancer, bladder washings should also be sent at the time of cystourethroscopy in patients with significant risk factors or a high index of suspicion for bladder cancer. Characteristic cytologic abnormalities REVIEWS IN UROLOGY evaluate for the presence of CIS are indicated on initial evaluation or during follow-up. Note that the upper urinary tracts must also be evaluated in this situation. In addition, directed bladder biopsies are indicated during TUR of any visible tumor associated with positive RIU0329_03-14.qxd 3/15/08 3:00 AM Page 35 Superficial Bladder Cancer cytology to map the bladder for concomitant CIS, the presence of which imparts a more aggressive pathology and may influence treatment decisions. Prostatic urethral resection biopsy may be indicated when visible abnormalities of the prostatic urothelium exist. Although physical examination rarely delineates any abnormalities, a bimanual examination should be performed at the time of cystoscopy, preferably under general anesthesia. Palpation of a mass is unusual, but a fixed mass typically represents more advanced disease. Small and/or flat lesions suspicious for CIS can be sampled with coldcup biopsy forceps, and larger lesions should be completely resected, if possible, using loop electrocautery. During TUR, attempts also should be made to obtain muscle in the specimen while avoiding bladder perforation. The fact that only 23% of patients classified as having high-grade Ta tumors on local pathology are confirmed by review pathology64,65 and that approximately 30% of patients with T1 tumors are upstaged after repeat TUR and even higher if muscle perforation after TUR that is not apparent cystoscopically may occur more frequently than believed, but fortunately, these do not seem to impose a significant risk for extravesical tumor seeding.68 Radiographic evaluation of the upper urinary tract should also be performed if not done during the initial assessment of hematuria. Clearly, up to 4% of patients with superficial bladder cancer are at risk for synchronous and metachronous tumors of the upper urinary tract.69-71 Patients with a history of CIS, tumors adjacent to the ureteral orifices, or persistently unexplained positive cytologies might be at increased risk for an upper tract tumor and prostatic urethral tumor involvement. Accurate clinical staging is important, because prognosis and therapy are directed by various clinical and histopathologic factors. Classification Normal Histology The normal urothelium consists of 3 to 7 layers of transitional cells resting on a basement membrane composed A well-trained uropathologist may be an important component in the accurate histopathological diagnosis of patients with bladder cancer undergoing transurethral resection (TUR) for superficial disease. The presence of smooth muscle in the pathologic specimen is an important indicator for an adequately performed resection. is not present in the initial TUR specimen, argues that standard repeat TUR should be performed in patients with high-grade Ta or T1 tumors.66,67 In addition, a well-trained uropathologist may be an important component in the accurate histopathological diagnosis of patients with bladder cancer undergoing TUR for superficial disease. The presence of smooth muscle in the pathologic specimen is an important indicator for an adequately performed resection. A small asymptomatic bladder of extracellular matrix. The most superficial layer consists of flat “umbrella” cells. The configuration of these cells varies from flat to cuboidal, depending on distention or contraction of the bladder. Below the basement membrane, the lamina propria, or submucosa, consists of loose connective tissue and can occasionally have scattered smooth muscle fibers (muscularis mucosae). The muscularis propria forms the next layer and comprises the (smooth) muscular wall of the bladder. Its muscle fibers are arranged in 3 bundled layers: middle circular, surrounded by inner and outer longitudinal fibers. Dysplasia The term dysplasia denotes architectural cell crowding and loss of polarity with sparse or absent mitotic figures. These features are usually limited to the basal and intermediate layers of the urothelium and are less pronounced than the changes seen in CIS. Dysplasia is a marker for cancer risk and progression and may be a precursor for invasion.72,73 High-grade dysplasia should be considered CIS. CIS Urothelial CIS, or flat intraepithelial carcinoma, is characterized by flat, disordered proliferation of cells with marked cytologic abnormalities. On cystoscopy, it may appear as a velvety, reddish patch of urothelium in proximity to an exophytic lesion, as a focal lesion in a patient without macroscopic tumors, or be endoscopically invisible. Overall, 50% of patients with CIS have multifocal lesions with a predilection for the trigone, lateral wall, and dome. By definition, CIS is a high-grade tumor and comprises about 10% of all cases of bladder cancer; 20% to 30% occur as an isolated lesion (primary CIS). Additionally, CIS can emerge during follow-up surveillance in the absence of grossly visible tumor (secondary CIS) or present initially or during follow-up associated with concurrent papillary tumors (concomitant CIS).74-78 In general, concomitant CIS is much more difficult to treat than primary CIS. The fact that with CIS, the mucosa may appear entirely unremarkable cystoscopically reinforces the importance of urine cytology in diagnosing this entity.60,79 In addition, fluorescenceguided cystoscopy using hexaminolevulinate (HAL) has been noted to VOL. 10 NO. 1 2008 REVIEWS IN UROLOGY 35 RIU0329_03-14.qxd 3/15/08 3:00 AM Page 36 Superficial Bladder Cancer continued increase the detection rate of CIS.80 In a prospectively controlled trial of 211 patients with superficial bladder cancer, HAL fluorescence detected approximately 30% more cases of CIS than standard white-light cystoscopy alone. Unfortunately, the routine application of fluorescence cystoscopy has yet to gain wide clinical acceptance despite an improvement in the detection rate of CIS.81 The routine clinical use may be limited in part because HAL fluorescence cystoscopy does suffer from the potential for falsepositive results in the setting of inflammatory conditions. Nevertheless, directed bladder mapping of areas contiguous to and remote from the primary tumor areas remains important in the diagnosis and management of patients with CIS. Histological Grading Much controversy surrounds the grading of bladder tumors, and no uniformly accepted grading system exists at present. Arising from the need to develop a commonly accepted classification system that pathologists, urologists, and oncologists could use, a new classification of noninvasive urothelial tumors was proposed at the 1998 World Health Organization (WHO) and the International Society of Urological Pathology (ISUP) consensus meeting.82 This new classification system for grading urothelial neoplasms was subsequently published by the WHO in 2004.83 Unfortunately, the 2004 WHO grading system lacks validation based on long-term follow-up data. Even today, many published reports rely on the older WHO classification from 1973.84,85 Therefore, a histological grading description based on both classification systems will be discussed here. A papillary lesion with little or no variation in nuclear size, shape, or 36 VOL. 10 NO. 1 2008 spacing when compared to normal urothelium is called a papilloma in both classification systems. The urothelium has an intact superficial umbrella layer with no mitotic activity. Patients with urothelial papillomas have a low incidence of recurrence and rarely progress to develop urothelial carcinoma.86 It may be reasonable not to consider this entity as urothelial cancer. Well-differentiated tumors, or grade 1 tumors based on the WHO 1973 classification, have an orderly arrangement of normal cells lining delicate papillae. They have minimal architectural abnormalities with minimal anaplasia or pleomorphism. Mitotic figures are rare or absent. Furthermore, WHO 1973 grade 1 lesions that show no cytologic atypia and merely thickened urothelium with, at most, nuclear enlargement are called papillary urothelial neoplasms of low malignant potential (PUNLMP) in the WHO/ISUP system. However, WHO 1973 grade 1 lesions with definite, yet slight cytologic atypia, would be diagnosed in the WHO/ISUP system as low-grade urothelial carcinomas.83 Moderately differentiated tumors, or WHO 1973 grade 2 lesions, retain some of the orderly appearance and maturation of grade 1 carcinoma but have some focal variation in nuclear appearance. The WHO 1973 grade 2 category is very broad, and most pathologists grade cases of urothelial cancer as WHO 1973 grade 2 by default. In an attempt to avoid using an intermediate category, the WHO/ISUP system classifies bladder papillary urothelial cancers into only 2 categories: low-grade or high-grade papillary urothelial carcinoma. WHO 1973 grade 2 lesions that demonstrate an overall orderly appearance but have minimal variability in architecture and/or cytologic features and are easily recognizable at scanning magnification would be REVIEWS IN UROLOGY considered low-grade urothelial carcinomas in the WHO/ISUP system. When WHO 1973 grade 2 lesions display more of a disorderly appearance because of marked architectural and cytologic abnormalities, recognizable at low magnification, they are considered high-grade urothelial carcinomas. Poorly differentiated tumor lesions called WHO 1973 grade 3 are, by definition, high-grade urothelial carcinomas in the WHO/ISUP system. They demonstrate the most extreme nuclear abnormalities. There is an obvious disorder, loss of polarity, and frequent mitotic activity. Pathologic Staging Pathologic staging is most important regarding risk assessment and in dictating patient management. The current 2002 TNM classification of bladder cancer describes Ta tumors as noninvasive and papillary confined to the mucosa, Tis tumors as flat CIS confined to the mucosa, and T1 tumors as invasive tumors that invade the subepithelial connective tissue.3 Overall, Ta tumors account for approximately 70% of superficial TCC. These tumors are composed of branching fibrovascular cores with more than 8 cell layers that display features of anaplasia. This arrangement provides their morphologic papillary appearance. In general, Ta tumors are low-grade cancers. T1 tumors, by definition, invade the submucosa (also called lamina propria) and account for approximately 30% of all superficial bladder tumors. T1 lesions may have either a papillary or a broad-based appearance and are generally of higher grade than Ta tumors.87 T2 and higher lesions, by definition, are muscle-invasive tumors. The management of muscle-invasive disease is beyond the scope of this manuscript, but it should be mentioned that these patients should be treated with more aggressive options RIU0329_03-14.qxd 3/15/08 3:00 AM Page 37 Superficial Bladder Cancer (ie, radical cystectomy) because they are at an increased risk of lymphnode and distant metastases, as well as death from bladder cancer.88,89 Although the topic is not addressed in the current TNM staging system, several studies have proposed further substaging of T1 lesions.90 Data suggest a significant difference in prognosis and survival based upon the depth of submucosal invasion, with a worse prognosis associated with increasing invasion of the through urethral extension beyond the ducts (T4a proper).95,96 With this in mind, the 2002 TNM classification has recognized TCC of the prostatic urethra as a separate entity.97 Natural History The natural history of superficial bladder cancer is difficult to predict because of tumor heterogeneity. The 2 features that characterize superficial bladder cancer are disease recurrence and disease progression. The risks Data suggest a significant difference in prognosis and survival based upon the depth of submucosal invasion, with a worse prognosis associated with increasing invasion of the submucosa. submucosa.91,92 A T1 substaging has been based on the following system: T1a, invasion of connective tissue superficial to the level of the muscularis mucosae; T1b, invasion to the level of the muscularis mucosae; T1c, invasion through the level of the muscularis mucosae but superficial to the muscularis propria. Opponents of this subclassification argue that it is often difficult to consistently and accurately assess the TUR tissue for the presence and actual depth of invasion because of orientation and artifactual changes. Similarly, it is argued that muscularis mucosae cannot be consistently identified with certainty in all TUR or biopsy specimens.93,94 The precise definition and staging of prostatic involvement with bladder cancer is another topic of considerable debate. In the current TNM staging system, bladder tumors involving the prostate are considered T4a.3 However, it is well documented that the survival rate of patients with superficial TCC of the prostate (urethra or ducts) in the context of superficial bladder cancer is much better than that of those with involvement of the prostatic stroma, either through direct extension through the bladder wall or for both recurrence and tumor progression are related to multiple histopathologic factors including histologic grade, depth of invasion, multiplicity, tumor size, tumor morphology, presence or absence of vascular or lymphatic invasion, and presence or absence of CIS. Although these conventional measures provide some prognostic information, they ultimately fail to clearly evaluate each until death or for at least 20 years (with no adjuvant therapy), provides some insight into the natural history of this disease left untreated. An overall recurrence rate of 80% was reported, and 22% of patients (11% and 30% of Ta and T1 patients, respectively) died from the disease.102 In this study, death was directly related to tumor grade, number of tumors, and volume of recurrences. Grade Several studies have investigated the role of tumor grade on tumor recurrence, progression, and mortality. Most reports have suggested that grade is a better prognostic indicator of progression and mortality than recurrence.102-105 In a cohort analysis of 1529 patients with superficial bladder cancer from Barcelona (Spain), grade did not correlate with tumor recurrence. The main predictor of progression and mortality in this study, however, was the presence of grade 3 disease.103 Similarly, Heney and associates reported tumor progression rates of 2%, 11%, and 45% for grade 1, 2, and 3 disease, respectively.106 Nearly 60% to 90% of patients with superficial disease will have a tumor recurrence if treated by TUR alone. individual tumor’s malignant potential. These shortcomings with traditional clinical and histopathologic features have therefore led to significant efforts to better define a tumor’s true biological potential on a molecular level. 98-100 Unfortunately, molecular markers do not have significant clinical application at present. Nearly 60% to 90% of patients with superficial disease will have a tumor recurrence if treated by TUR alone.101 A retrospective analysis of 176 patients with superficial TCC from Sweden, who were followed up Furthermore, when stratified by stage of disease, tumor grade continued to correlate with patient mortality. In another study, Jakse and associates reported the following 10-year survival rates for patients with initial stage Ta or T1 disease: 95% for TaG1 compared with 84% for TaG3 and 78% for T1G2 compared with 50% for T1G3.107 Stage Because Ta tumors are, by definition, confined to the basement membrane without access to lymphatics and vessels, these lesions tend to remain VOL. 10 NO. 1 2008 REVIEWS IN UROLOGY 37 RIU0329_03-14.qxd 3/15/08 3:00 AM Page 38 Superficial Bladder Cancer continued localized. The National Bladder Cancer Cooperative Group studies of the 1970s have provided some insight into the natural course of superficial bladder cancer with regard to stage following TUR and no adjuvant intravesical therapy. Recurrence with progression to muscle invasion was found within 3 years in only 4% of patients with initial Ta tumors (without associated atypia or CIS) and 11% of patients with Ta tumor with associated atypia.108 Patients with low-grade Ta disease have a propensity for tumor recurrence despite low progression rates. In a long-term follow-up study of 255 patients with low-grade Ta disease, approximately 70% of patients had repeat resections for tumor recurrence, whereas only 2% of patients progressed to muscle-invasive disease.109 When these patients were subclassified on the basis of the new WHO/ISUP classification system; 37% had PUNLMP and 63% had low-grade urothelial carcinomas. As expected, recurrence rates of PUNLMP were significantly lower than those of lowgrade urothelial carcinoma: 35% versus 71%, respectively. The incidence of high-grade Ta lesions is rare and varies between 2% and 9% of all cases of superficial bladder cancer.106,107 Despite the relatively low malignant potential component of being Ta, it is the highgrade component that has significant impact on progression and poses a considerable problem for the clinician. Even with intravesical treatments, nearly 50% recur and 25% of these high-grade tumors progress to muscle-invasive disease.110 A recent review showed that as many as 20% of patients with high-grade Ta lesions may die of bladder cancer.111 Therefore, these lesions should be regarded as malignant and demand vigorous treatment and follow-up. Furthermore, there must be a high index for clini- 38 VOL. 10 NO. 1 2008 cal understaging in patients reportedly having high-grade Ta tumors, and these patients should be considered for repeat TUR to ensure appropriate staging. Most T1 bladder cancers are highgrade lesions with potential for recurrence, progression, and death. These lesions are frequently understaged or misclassified.64,65 van der Meijden and colleagues assessed pathology results from 1400 patients treated in the European Organization for Research and Treatment of Cancer (EORTC) randomized trials, comparing various treatment strategies for superficial bladder cancer.64 In this study, 10% of patients originally staged T1 by local pathologists were found to have evidence of muscle invasion simply on re-review. Furthermore, tumors that lack detrusor smooth muscle in the initial resected specimen are subsequently associated with residual tumor burden or muscle-invasive disease at repeat resection in up to 50% of cases.66,112,113 progress to muscle-invasive disease within 3 years when treated by TUR alone.106,114,115 Furthermore, as mentioned earlier, the depth of submucosal invasion may be prognostically significant. The prognosis of highgrade T1 tumors is variable and multifactorial, based on additional tumor histopathologic characteristics. The presence of concomitant CIS confers a particularly worse prognosis, with up to 80% progressing to muscle-invasive disease.106,116 Clearly, high-grade T1 disease represents a potentially lethal disease class that may warrant early radical cystectomy, particularly when conservative management with intravesical therapy fails. CIS The presence of associated CIS may be ominous, as patients are at increased risk for progression and death from bladder cancer with this pathologic entity. In 1 study, the presence of CIS significantly increased the 3-year risk of disease progression to 31% compared Nearly one half of patients presenting with carcinoma in situ that is either diffuse and symptomatic or associated with superficial papillary lesions of any grade progress to muscle-invasive disease. Patients who present with marked urinary symptoms generally have a shorter interval preceding the development of muscle-invasive cancer. Importantly, a second TUR for T1 tumors is recommended because at least 30% of patients with T1 disease will be upstaged at the time of a second TUR. The percentage will be even higher if no muscle is present in the original TUR specimen. The risk of residual tumor on second TUR is also significant. Therefore, for patients with T1 disease, a second TUR should be performed within 1 to 4 weeks following the initial resection. T1 bladder tumors have a high incidence of progression. Between 35% and 48% of patients with T1 tumors REVIEWS IN UROLOGY with only a 7% progression rate in patients without CIS.73 Nearly one half of patients presenting with CIS that is either diffuse and symptomatic or associated with superficial papillary lesions of any grade progress to muscle-invasive disease.117,118 Patients who present with marked urinary symptoms generally have a shorter interval preceding the development of muscleinvasive cancer. Reliable prognostic factors that predict the course of CIS, unfortunately, do not exist. However, some studies have suggested that response RIU0329_03-14.qxd 3/15/08 3:00 AM Page 39 Superficial Bladder Cancer to intravesical chemotherapy or immunotherapy can be used to predict progression and death from the disease. With bacillus Calmette-Guérin therapy, a complete response rate of about 70% to 80% can be achieved.119 Despite this complete response rate, however, as many as 20% of patients will ultimately die of metastatic disease, and a significant proportion will develop both intravesical and extravesical recurrences.74 This implies that a durable and complete response is not always achieved and underscores the importance of lifelong surveillance in patients with this disease. Although the bladder remains the most common site for recurrence, the upper urinary tract and the prostatic urethra must be closely monitored in patients with CIS. Number The number of tumors is thought to be an important risk factor for recurrence.106,120,121 Recurrences for solitary bladder tumors vary from 18% to 60%, whereas rates for multiple tumors range from 40% to 90%. In a multivariate analysis of prognostic variables, Herr reported in a series that the factor most predictive of recurrence is tumor multifocality, whereas tumor stage and grade correlated to a lesser degree.122 Size Tumor size may be a prognostic factor for superficial bladder cancer. Heney and associates reported that progression to muscle invasion was seen in 35% of patients with superficial tumors larger than 5 cm, compared to only 9% of patients with small bladder tumors.106 Others report that tumor size may influence tumor stage, but not progression.123 First Recurrence/Previous Recurrence Rate The time for the first bladder-cancer recurrence may also be an important variable.120,124 In a group of 414 people with Ta tumors, it was reported that if no recurrence occurred at the first follow-up cystoscopy, 79% of patients had no further recurrence for the remainder of the follow-up period. In patients with a follow-up recurrence at 3 months, however, only 10% were without any recurrence during the remainder of the follow-up period. Thus, in patients with a prior tumor history, previous recurrence rate predicts future recurrences. Specifically, for patients with lowgrade Ta tumors, a previous recurrence rate of more than 1 per year imparts an increased risk of future recurrences. clinical outcomes of superficial disease has also been identified through the use of full-genome expression analysis.129 The prognostic value of the moststudied molecular marker, p53, has been a topic of considerable discussion. Meta-analysis results of more than 3700 patients in 43 trials have shown that p53 correlates with tumor stage and grade, but it is unclear whether this molecular marker has independent prognostic information.130 Despite these scientific advances, the potential application of molecular markers/genes is only beginning in clinical trials and, unfortunately, is not yet ready for clinical practice. Other Prognostic Factors The patient’s age at diagnosis is thought to be associated with prognosis, particularly in patients with primary CIS. In a study of 138 patients with primary CIS from the Mayo Clinic, patients’ age of 65 years or less was a significant predictor for improved progression-free and overall survival.125 In addition, the presence of vascular or lymphatic invasion has been identified as a poor prognostic sign.106,126 Although lymphovascular invasion may be difficult to ascertain because of interobserver variability and the fact that it could be confused with retraction artifact, it has been shown to increase the risk of death to as high as 70% when present.126,127 Lastly, various laboratory parameters have also been evaluated for prognostic significance. Specifically, blood group antigens, tumor-associated antigens, proliferation antigens, oncogenes, peptide growth factors and their receptors, cell adhesion molecules, tumor angiogenesis and angiogenesis inhibitors, and cell cycle regulatory proteins have been identified recently.99,128 Furthermore, an actual gene signature to predict Combined Risk Factors On the basis of previously established data, a risk group classification system combining the aforementioned prognostic factors has been suggested. In a multivariate analysis of 1529 patients with superficial bladder cancer, risk groups were assessed by combining stage and grade. Risk groups were classified as low (grade 1 stage Ta disease and a single grade 1 stage T1 tumor), intermediate (multiple grade 1 stage T1 tumors, grade 2 stage Ta disease, or a single grade 2 stage T1 tumor), and high (multiple grade 2 stage T1 tumors, grade 3 stages Ta or T1 disease, and any stage disease associated with CIS). Recurrence, progression, and overall survival were significantly different among the 3 groups.131 Low-risk and intermediate-risk patients demonstrated 37% and 45% risk of recurrence, respectively, without significant risk for progression or death from bladder cancer. On the contrary, in the highrisk category, the incidence of recurrence, progression, and mortality was 54%, 15%, and 9.5%, respectively (Table 1). Similarly, a combined analysis of about 2600 patients from VOL. 10 NO. 1 2008 REVIEWS IN UROLOGY 39 RIU0329_03-14.qxd 3/15/08 3:00 AM Page 40 Superficial Bladder Cancer continued Table 1 Recurrence, Progression, and Mortality 40 Months After TUR in Patients With Primary, Superficial TCC of the Bladder Recurrence (%) Progression (%) Low risk • Grade 1 stage Ta • Grade 1 stage T1, single tumor 37 0 0 Intermediate risk • Grade 1 stage T1, multiple tumors • Grade 2 stage Ta • Grade 2 stage T1, single tumor 45 1.8 0.7 Risk Group High risk • Grade 2 stage T1, multiple tumors • Grade 3 stage Ta • Grade 3 stage T1 • CIS association 54 Overall 48 Mortality (%) 7 EORTC trials has allowed Sylvester and colleagues to calculate shortand long-term risks of recurrence and progression based on multiple factors including stage, grade, presence of CIS, multifocality, size, and history of prior recurrence.116 It is hoped that these tables will afford the urologist accurate prognostic information based on routinely assessed clinical and pathologic variables in an effort to focus on adjuvant therapy and optimize follow-up protocols. Conclusion 15 7.5 9.5 4.6 TUR, transurethral resection; TCC, transitional cell carcinoma. Adapted from Millan-Rodriguez F et al.131 In this article we have discussed the etiology, molecular mechanisms, classification, and natural history of non–muscle-invasive TCC of the bladder. The natural history of superficial bladder cancer is difficult to predict because of tumor heterogeneity. Main Points • Transitional cell carcinoma (TCC) of the bladder is the second most common malignancy of the genitourinary tract. More than 90% of bladder cancer cases are TCC. • The 2 best established risk factors for development of TCC of the bladder are tobacco use and occupational exposure to aniline dyes and aromatic amines. • Superficial “non-muscle-invasive” bladder tumors represent a heterogeneous group of cancers that include those that are (1) papillary and limited to the mucosa (Ta, approximately 70% of all tumors), (2) high grade and flat and confined to the epithelium (Tis, 5% to 10%), and (3) invasive into the submucosa, or lamina propria (T1, 20% to 25%). • Most superficial bladder tumors exhibit a loss of heterozygosity of chromosome 9 and activating mutations in the HRAS and FGFR3 genes. • Initial evaluation and management for patients with suspected bladder cancer involves cystoscopic evaluation of the bladder, transurethral resection (TUR) of visible tumor, and assessment of the appearance of the uninvolved bladder and prostatic urethra. • Directed bladder biopsies, including cold-cup biopsies of the prostatic urethra, to evaluate for the presence of carcinoma in situ (CIS) are indicated when urinary cytology is positive and no grossly visible tumor is apparent on cystoscopy. The upper urinary tracts must also be evaluated in this situation. • The risks for both recurrence and tumor progression are related to multiple histopathologic factors including grade, depth of invasion, multiplicity, tumor size, tumor morphology, presence or absence of vascular or lymphatic invasion, and presence or absence of CIS. • Between 35% and 48% of patients with T1 bladder tumors progress to muscle-invasive disease within 3 years when treated by TUR alone. 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