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european urology supplements 7 (2008) 618–626 available at www.sciencedirect.com journal homepage: www.europeanurology.com Epidemiology, Staging, Grading, and Risk Stratification of Bladder Cancer Marc Colombel a,*, Mark Soloway b, Hideyuki Akaza c, Andreas Böhle d, Joan Palou e, Roger Buckley f, Donald Lamm g, Maurizio Brausi h, J. Alfred Witjes i, Raj Persad j a Department of Urology, Claude Bernard University, Hôpital Edouard Herriot, Lyon, France Department of Urology, University of Miami School of Medicine, Miami, Florida, USA c Department of Urology, University of Tsukuba, Tsukuba, Japan d Department of Urology, HELIOS Agnes Karll Hospital, Bad Schwartau, Germany e Department of Urology, Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain f Department of Urology, North York General Hospital, Toronto, Ontario, Canada g Department of Surgery, University of Arizona; BCG Oncology, Phoenix, Arizona, USA h Department of Urology, AUSL Modena Estense and B Ramazzini Hospitals, Modena, Italy i Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands j Department of Urology/Surgery, Bristol Royal Infirmary and Bristol Urological Institute, Bristol, United Kingdom b Article info Abstract Keywords: Bladder cancer risk factors Epidemiology Grading Non–muscle invasive bladder cancer Risk stratification Staging Context: Understanding the epidemiology and risk factors for non–muscle invasive bladder cancer (NMIBC) can assist in the prevention and early detection of the disease. Furthermore, staging, grading, and risk stratification are critical for determining the most appropriate management strategies for NMIBC based on risk of recurrence and progression. Objective: To provide community urologists with an overview of the epidemiology of NMIBC as well as current approaches to staging, grading, and risk stratification. Evidence acquisition: A committee of internationally renowned leaders in bladder cancer management, known as the International Bladder Cancer Group (IBCG), identified current key influencing guidelines and published English-language literature related to the epidemiology, staging, and grading of NMIBC available as of March 2008. The IBCG met on four occasions to review the main findings of the identified literature and the current clinical practice guidelines of the European Association of Urology (EAU), the First International Consultation on Bladder Tumors (FICBT), the National Comprehensive Cancer Network (NCCN), and the American Urological Association (AUA). Evidence synthesis: Based on this review, the IBCG provided a summary on the epidemiology of NMIBC and recommendations for the staging, grading, and risk stratification of the disease. Conclusions: Urologists should record the smoking habits of patients and monitor for possible occupational exposure to urothelial carcinogens. The tumour-node-metastases (TNM) classification for tumour staging and both the World Health Organization (WHO) 1973 and 2004 grading systems should be applied for appropriate staging and grading of NMIBC. Urologists should also consider the use of the European Organisation for Research and Treatment of Cancer (EORTC) risk tables for risk stratification of NMIBC based on risk of disease recurrence and progression. # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. Please visit www.eu-acme.org/ europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically. * Corresponding author. Service D’Urologie – CHU Edouard Herriot, 5 place d’Arsonval, cedex 03, 69437 Lyon, France. Tel. +33 472 11 62 89; Fax: +33 472 11 05 82. E-mail address: [email protected] (M. Colombel). 1569-9056/$ – see front matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eursup.2008.08.002 european urology supplements 7 (2008) 618–626 1. Introduction A thorough understanding of the epidemiology of bladder cancer can assist in the prevention and early detection of the disease. In addition, staging, grading, and risk stratification are essential for determining the most appropriate management strategies for non–muscle invasive bladder cancer (NMIBC) based on risk of recurrence and progression. Therefore, a committee of internationally renowned leaders in bladder cancer management, known as the International Bladder Cancer Group (IBCG), identified current key influencing guidelines and published Englishlanguage literature related to the epidemiology, staging, and grading of NMIBC available as of March 2008. The IBCG met on four occasions to review the main findings of the identified literature and the current clinical practice guidelines of the European Association of Urology (EAU), the First International Consultation on Bladder Tumors (FICBT), the National Comprehensive Cancer Network (NCCN), and the American Urological Association (AUA). This article provides a summary of the epidemiology of NMIBC and the IBCG’s recommendations for staging, grading, and risk stratification of the disease based on currently available guidelines and evidence. 2. Incidence Bladder cancer ranks ninth in worldwide cancer incidence. It is the 7th most common cancer in men and the 17th most common cancer in women [1]. Globally, the incidence of bladder cancer varies significantly, with Egypt, Western Europe, and North America having the highest incidence rates, and Asian countries the lowest rates (see Fig. 1) [2]. Although the disease may occur in young persons, >90% of new cases occur in persons 55 yr of age [3]. 3. Risk factors The two most well-established risk factors for bladder tumours are cigarette smoking and occupational exposure to urothelial carcinogens [4,5]. Cigarette smoking is the most important risk factor, accounting for 50% of cases in men and 35% in women [5]. In fact, cigarette smokers have a 2- to 4-fold increased risk of bladder cancer compared to non-smokers [6], and the risk increases with increasing intensity and/or duration of smoking [7]. Upon cessation of cigarette smoking, the risk of bladder cancer falls >30% after 1–4 yr and >60% after 25 yr [7,8] but never returns to the level of risk of non-smokers. 619 Occupational exposure to urothelial carcinogens is the second most important risk factor, accounting for 5–20% of all bladder cancers [9,10]. The relative risk of occupational exposure to carcinogens is likely underestimated and varies from country to country. Current or historical exposure to aromatic amines (eg, benzidine, 2-naphthylamine, 4-aminobiphenyl, o-toluidine, and 4-chloro-o-toluidine) used in the chemical, rubber, and dye industries [11–13] and polycyclic aromatic hydrocarbons (PAHs) used in the aluminum, coal, and roofing industries [14] have all been associated with the development of bladder cancer. An increased risk of bladder cancer has also been reported in painters, varnishers, and hairdressers [15]. Other environmental exposures that have been associated with bladder cancer include chronic urinary tract infections [16], cyclophosphamide use [17], and exposure to radiotherapy [18]. Recently, the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) group found an increased incidence of bladder cancer in men with prostate cancer treated with radiotherapy [19]. Inadequate consumption of fruits, vegetables, and certain vitamins may also play a role in the development of bladder cancer. A meta-analysis by Steinmaus et al [20] found that increased risks of bladder cancer were associated with diets low in fruit intake (relative risk [RR], 1.40; 95% confidence interval [CI], 1.08–1.83), and slightly increased risks were associated with diets low in vegetable intake (RR, 1.16; 95% CI, 1.01–1.34). Evidence also suggests that garlic [21] and vitamin A [22] have chemoprotective effects in bladder cancer. Furthermore, a small randomised study of 65 patients with transitional cell carcinoma (TCC) of the bladder found that megadoses of vitamins A, B6, C, and E plus zinc decreased bladder tumour recurrence in patients receiving bacillus Calmette-Guérin (BCG) immunotherapy [23]. Large-scale prospective, randomised trials are required to clarify the role of vitamins in bladder cancer prevention. Although it has been suggested that coffee consumption and artificial sweeteners may be associated with an increased risk of bladder cancer, results from epidemiologic studies investigating these agents have been inconclusive. A major problem in evaluating the independent effect of coffee consumption on the development of bladder cancer is its relationship to cigarette smoking [1]. To avoid the residual confounding effect of cigarette smoking, a pooled analysis of studies examining nonsmokers in Europe was performed. Although the study was limited by bias in control selection, the investigators observed a significant increased risk of 620 european urology supplements 7 (2008) 618–626 Fig. 1 – Worldwide age-standardised incidence rates (per 100 000) for bladder cancer in (a) males and (b) females [2].* * Reprinted from Ferlay et al [2]. bladder cancer only in subjects consuming 10 cups of coffee per day (odds ratio [OR], 1.8; 95% CI, 1.0–3.3) [24]. Furthermore, most epidemiologic studies have failed to show any evidence of bladder carcinogenicity with saccharin and other sweeteners [1]. In 1999, the International Agency for Research on Cancer (IARC) concluded that saccharin and its salts were not classifiable as carcinogenic in humans, despite evidence suggesting that sodium saccharin causes urothelial bladder tumours in experimental animals [25]. Familial bladder cancer is rare compared to the familial occurrence of cancer in other tumour sites. However, there does appear to be an increased risk european urology supplements 7 (2008) 618–626 of bladder cancer in individuals with a family history of cancer, particularly in those with first-degree relatives who developed bladder cancer at age 60 yr or earlier [26]. A population-based, family casecontrol study by Aben et al [27] found an almost 2-fold increased risk among first-degree relatives of patients with urothelial cell carcinoma, which could not be explained by smoking. A segregation analysis of >1100 families could not find strong evidence of inheritance of bladder cancer through a single major gene. However, the investigators could not exclude the possibility of an inherited subtype of bladder cancer. A major gene may segregate in some families, but this effect may have been masked in a background of high sporadic incidence [28]. 4. Major pathologic subtypes TCC is the most common primary pathologic subtype of bladder cancer and is observed in >90% of tumours [29]. Squamous cell carcinoma and adenocarcinoma are less common and occur in approximately 5% and 1% of bladder cancers, respectively [30,31]. Secondary carcinomas can appear in the colon, uterus, ovaries, and prostate, as well as lymphomas. In certain regions of the world where schistosomiasis (also known as bilharziasis) infection is endemic, squamous cell carcinoma can account for up to 75% of bladder cancers [32,33]. Schistosomiasis is a parasitic disease caused by various species of flatworm. It typically affects agricultural communities, particularly those dependent upon irrigation to support their agriculture. Areas with a high prevalence of schistosomiasis include Africa, the Caribbean, South America, East Asia, and the Middle East. Recently, variants of TCC (nested and micropapillary) have been noted that may have prognostic and therapeutic significance [34,35]. Results from a recent study suggest that intravesical therapy may be ineffective in patients with the micropapillary variant, and that radical cystectomy may be the preferred treatment option for patients with this form of TCC [36]. However, Gaya et al [37] recently noted good results with intravesical BCG in patients with a micropapillary pattern and without concomitant carcinoma in situ (CIS). are critical for the appropriate treatment and management of NMIBC. 5.1. Staging The most widely used and universally accepted staging system is the tumour-node-metastases (TNM) system shown in Table 1 [38]. Under this system, NMIBC includes (1) papillary tumours confined to the epithelial mucosa (stage Ta); (2) tumours invading the subepithelial tissue (ie, lamina propria; T1); and (3) Tis (CIS). 5.2. Grading Traditionally, bladder carcinomas have been graded according to the World Health Organization (WHO) 1973 grading of urothelial papilloma: well differentiated (G1), moderately differentiated (G2), or poorly differentiated (G3). In 2004, the WHO and Table 1 – 2002 TNM classification of urinary bladder cancer [38] T: Primary tumour TX T0 Ta Tis T1 T2 T3 T4 N: Lymph nodes NX N0 N1 N2 N3 5. Staging and grading Stage and grade are significant prognostic factors for recurrence, progression, and survival and, therefore, 621 M: Distant metastasis MX M0 M1 Primary tumour cannot be assessed No evidence of primary tumour Non-invasive papillary carcinoma Carcinoma in situ: ‘‘flat tumour’’ Tumour invades subepithelial connective tissue Tumour invades muscle T2a: Tumour invades superficial muscle (inner half) T2b: Tumour invades deep muscle (outer half) Tumour invades perivesical tissue: T3a: Microscopically T3b: Macroscopically Tumour invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall T4a: Tumour invades prostate, uterus, or vagina T4b: Tumour invades pelvic wall or abdominal wall Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis in a single lymph node 2 cm in greatest dimension Metastasis in a single lymph node >2 cm but not >5 cm in greatest dimension, or multiple lymph nodes, none >5 cm in greatest dimension Metastasis in a lymph node >5 cm in greatest dimension Distant metastasis cannot be assessed No distant metastasis Distant metastasis 622 european urology supplements 7 (2008) 618–626 Table 2 – World Health Organization (WHO) grading of urinary tumours in 1973 and 2004 [39,40] WHO 1973 Urothelial papilloma Grade 1: well differentiated Grade 2: moderately differentiated Grade 3: poorly differentiated WHO 2004 Urothelial papilloma PUNLMP Low-grade papillary urothelial carcinoma High-grade papillary urothelial carcinoma PUNLMP = papillary urothelial neoplasms of low malignant potential. the International Society of Urological Pathology (ISUP) published a new grading system that employs specific cytologic and architectural criteria [39,40]. The new WHO/ISUP classification differentiates between papillary urothelial neoplasms of low malignant potential (PUNLMP) and low-grade and high-grade urothelial carcinomas. Comparisons of the 1973 and 2004 classification systems are shown in Table 2 and Fig. 2 [41]. Use of the 2004 WHO/ISUP classification should result in more uniform diagnoses of tumours that are better stratified according to risk potential. However, according to the EAU guidelines for non– muscle invasive disease, both the 1973 and 2004 WHO classifications should be used for tumour grading until the 2004 grading system is validated in more clinical trials [42,43]. Evidence suggests that the WHO/ISUP 2004 classification does not increase the inter-observer reproducibility of non–muscle invasive tumours compared to the 1973 WHO classification. Reproducibility is particularly low for the 2004 PUNLMP classification (50%). However, differentiation between low-grade and high-grade urothelial carcinoma using the 2004 classification does have a high inter-observer reproducibility (84–90%) [44–46]. Urologists should interact with their pathologists to determine which grading system they are using. Regardless of the grading method utilised, it is important that the urologist review the pathology slides with the pathologist. 6. Risk stratification and progression Approximately 75–80% of bladder tumours present as non–muscle invasive disease and the remainder present as muscle-invasive disease [47]. In NMIBC, approximately 70% present as Ta lesions, 20% as T1 lesions and 10% present as CIS or Tis lesions [6]. NMIBC represents a heterogeneous group of tumours with completely different oncologic outcomes. Low-grade tumours, for example, have a modest recurrence rate but are at low risk for progression. High-grade tumours, on the other hand, are associated with significant recurrence, progression, and mortality rates. This heterogeneity in bladder tumours complicates the ability to compare the efficacy of different treatment modalities and thereby establish unified treatment recommendations. Therefore, risk stratification is imperative for classifying patients with similar risks of recurrence and progression, and it helps to determine the appropriate management strategies for each risk category. To date, the European Organisation for Research and Treatment of Cancer (EORTC) risk tables are considered the most reliable tools for estimating progression and/or recurrence of NMIBC. The EORTC scoring system combines data on previous tumour recurrence rate, number of tumours, tumour dia- Fig. 2 – Comparison of the 1973 and 2004 World Health Organization (WHO) grading systems. Some 1973 WHO grade 1 carcinomas are reassigned to the papillary urothelial neoplasm of low malignant potential (PUNLMP) category and others to the 2004 WHO low-grade carcinoma category. Similarly, 1973 WHO grade 2 carcinomas are reassigned, some to the low-grade carcinoma category and others to the high-grade carcinoma category. All 1973 WHO grade 3 tumours are assigned to the 2004 WHO high-grade carcinoma category. TCC = transitional cell carcinoma. Reprinted with permission from Elsevier Inc [41]. 623 european urology supplements 7 (2008) 618–626 Table 3 – European Organisation for Research and Treatment of Cancer weighting used to calculate recurrence and progression scoresa Factor Recurrence Progression Number of tumours Single 2–7 >8 0 3 6 0 3 3 Tumour diameter <3 cm 3 cm 0 3 0 3 Prior recurrence rate Primary 1 recurrence per year >1 recurrence per year 0 2 4 0 2 2 Category Ta T1 0 1 0 4 Carcinoma in situ No Yes 0 1 0 4 Grade (1973 WHO) G1 G2 G3 0 1 2 0 0 5 0–17 0–23 Total score Note: This table is based on results from patients treated primarily with older chemotherapeutic regimens and, therefore, may not be predictive of results with improved chemotherapy protocols and, more importantly, with bacillus Calmette-Guérin immunotherapy. a Reprinted with permission from Elsevier Inc [48]. meter, T category and WHO grade, and the presence or absence of concomitant CIS to estimate the risk of recurrence and progression [48]. The EORTC scoring system is shown in Table 3, and the EORTC risk tables are shown in Table 4. The Web-based EORTC risk calculator based on these tables can be downloaded from the EORTC’s Web site [49] and may be used by urologists to determine the most appropriate treatment strategies based on risk of progression and/or recurrence. A simple, office-based risk calculator that categorises patients into low-, intermediate-, and high-risk groups is also available [50]. New models of risk stratification based on tumour biology, particularly the use of chromosomal aberrations, appear promising but require validation and further study [51]. The main limitation of the EORTC risk tables is that the risk groups were based on patients who, for the most part, were treated with older intravesical chemotherapy regimens. Therefore, the use of a single, immediate chemotherapeutic instillation, induction and maintenance BCG, and repeat transurethral resection of the bladder tumour (TURBT) were not considered in the development of these risk tables. Improvements in chemotherapy administration, in addition to the increased use of BCG, may reduce the predictability of these tables. In addition, very few cases of CIS were included in the studies used as the basis for this scoring system and, hence, the EORTC tables may not accurately predict recurrence and progression in these patients. Furthermore, external validation of these risk tables is still required. The validation of prediction tables on external, contemporary data sets is important for judging their applicability and performance in patients currently undergoing treatment. Clinical trial patients are not a random sample of all patients, and changes do occur over time with respect to diagnostic procedures, staging, and grading classification systems, as well as treatment recommendations, all of which can affect therapeutic outcomes and prognosis [52]. The EORTC is in the process of reviewing and updating the current tables to reflect a larger sample of patients with NMIBC. Table 4 – Probability of recurrence and progression according to scorea Recurrence score 0 1–4 5–9 10–17 Progression score 0 2–6 7–13 14–23 Probability of recurrence at 1 yr (95% CI) 15% 24% 38% 61% (10%, (21%, (35%, (55%, 19%) 26%) 41%) 67%) Probability of progression at 1 yr (95% CI) 0.2% (0%, 0.7%) 1% (0.4%, 1.6%) 5% (4%, 7%) 17% (10%, 24%) Probability of recurrence at 5 yr (95% CI) 31% 46% 62% 78% (24%, (42%, (58%, (73%, 37%) 49%) 65%) 84%) Probability of progression at 5 yr (95% CI) 0.8% (0%, 1.7%) 6% (5%, 8%) 17% (14%, 20%) 45% (35%, 55%) Note: This table is based on results from patients treated primarily with older chemotherapeutic regimens and, therefore, may not be predictive of results with improved chemotherapy protocols and, more importantly, with bacillus Calmette-Guérin immunotherapy. a Reprinted with permission from Elsevier Inc [48]. 624 european urology supplements 7 (2008) 618–626 NMIBC is further classified into low-, intermediate-, or high-risk disease depending on the patient’s risk of recurrence and progression. However, there are differences among current guidelines on the exact definitions and management strategies for each of these risk levels. A more detailed discussion of these risk categories is provided in the article entitled Current Approaches to the Management of Non– Muscle Invasive Bladder Cancer: Comparison of Current Guidelines and Recommendations in this supplement. 7. International Bladder Cancer Group recommendations Based on review of the epidemiology, risk factors, staging, grading, and risk stratification of bladder cancer, the IBCG proposes the following recommendations: Record the smoking habits of patients presenting with bladder cancer. Encourage smoking cessation and refer patients to smoking cessation programs or services. Monitor for possible occupational exposure to urothelial carcinogens. If occupational exposure is suspected, identify the causative agent, implement preventative measures, and advise the patient to discuss this with the occupational health department at his or her place of employment. Use the TNM classification for tumour staging. Use both the WHO 1973 and 2004 grading systems until the 2004 classification is validated in further clinical trials. Consider use of the EORTC risk tables for risk stratification based on disease recurrence and progression. Urologists should interact with pathologists to understand the grading system they are using. Urologists should review pathology slides with the pathologist. An understanding of the epidemiology and risk factors for NMIBC can assist in the prevention and early detection of the disease. Furthermore, staging and grading are critical for determining the most appropriate management strategies for NMIBC. Risk-stratification tools, such as the EORTC risk tables, can assist the urologist in selecting optimal strategies based on risk of recurrence and progression. Financial disclosures: All conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Professor Marc Colombel has consulted on educational programs on bladder cancer for sanofi pasteur. Professor Joan Palou has received honoraria from sanofi pasteur, Lilly, and Amgen. Dr. Roger Buckley has received grants/funding from GlaxoSmithKline and has participated in consultancies and provided expert testimony for sanofi pasteur; he has also received honoraria from Pfizer and MSD. Dr. Donald Lamm has received grants/funding from Bioniche, TAP Pharmaceutical Products, Cell Genesys, Biocancell, Schering Plough, and Mission Pharmacal; he has participated in consultancies for sanofi pasteur and has received honoraria from sanofi pasteur. Professor Maurizio Brausi has participated in advisory board meetings on non–muscle invasive bladder cancer and has received honoraria for his participation in these meetings from sanofi pasteur. Professor JA Witjes has been an investigator for MEL/Amsterdam, Spectrum Pharma, and PhotoCure/ Oslo; he has been a lecturer for Spectrum Pharma, sanofi pasteur, PhotoCure/Oslo, GE, and Matritech, and he has received honoraria for his participation as lecturer; he has also been an advisor for MEL/Amsterdam, Spectrum Pharma, sanofi pasteur, Teva Pharmaceutical Industries, Astellas, Telormedix, and GE. Dr. Raj Persad has been a member of an advisory board for sanofi pasteur. Professor Andreas Böhle has participated in consultancies for Lilly and sanofi pasteur; he has also received honoraria for his role as lecturer for Apogepha and CytoChemia. The following authors have nothing to disclose: Dr. Hideyuki Akaza, Dr. Mark Soloway. Funding/Support and role of the sponsor: Administrative and medical writing support were made possible through an unrestricted educational grant from sanofi pasteur. Acknowledgment statement: The authors acknowledge Sue Tattersall and Julie Tasso from Complete Medical Communications for their administrative and medical writing support. References [1] Murta-Nascimento C, Schmitz-Dräger BJ, Zeegers MP, et al. Epidemiology of urinary bladder cancer: from tumour development to patient’s death. World J Urol 2007;25:285–95. [2] Ferlay J, Bray F, Pisani P, Parkin DM., GLOBOCAN 2002: cancer incidence, mortality and prevalence worldwide. IARC CancerBase no. 5, version 2.0. Lyon, France: IARC Press; 2004. http://www-dep.iarc.fr. 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