Bladder Cancer COE Articles

FDA ALERT: RE: Label Updates in Clinical Trials for Some Patients Taking Pembrolizumab or Atezolizumab as Monotherapy to Treat Urothelial Cancer with Low Expression of PD-L1

FDA Breakthrough Therapy Designation for Erdafitinib in the Treatment of Metastatic Urothelial Cancer

TURBT More Important Than Ever

[Concurrent renal cell carcinoma and urothelial carcinoma: long-term follow-up study of 24 cases].

A Care Bundle to Improve Perioperative Mitomycin Use in Non-Muscle-Invasive Bladder Cancer – Beyond the Abstract

A Golden Age of Bladder Cancer Drug Development

Written by: Noah M. Hahn, MD

References:

1. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507:315-22, 2014
2. Bellmunt J, de Wit R, Vaughn DJ, et al: Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 376:1015-1026, 2017
3. Patel MR, Ellerton J, Infante JR, et al: Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol 19:51-64, 2018
4. Powles T, O'Donnell PH, Massard C, et al: Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: Updated results from a phase 1/2 open-label study. JAMA Oncology 3:e172411, 2017
5. Rosenberg JE, Hoffman-Censits J, Powles T, et al: Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. The Lancet 387:1909-1920, 2016
6. Sharma P, Retz M, Siefker-Radtke A, et al: Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. The Lancet Oncology 18:312-322, 2017
7. Rosenberg JE, Sridhar SS, Zhang J, et al: Updated results from the enfortumab vedotin phase 1 (EV-101) study in patients with metastatic urothelial cancer (mUC). Journal of Clinical Oncology 36:4504-4504, 2018
8. Siefker-Radtke AO, Necchi A, Park SH, et al: First results from the primary analysis population of the phase 2 study of erdafitinib (ERDA; JNJ-42756493) in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRalt). J Clin Oncol 36, 2018

ASCO GU 2018: Lessons Learned From New Guidelines and How They Have Changed Management of Muscle-Invasive Bladder Cancer

ASCO GU 2019: Genomic Insights and Biomarkers for Treatment Selection in Muscle-Invasive and Non-Muscle-Invasive Bladder Cancer

ASCO GU 2019: Multimodality Treatment in Challenging Cases of Urothelial Carcinoma: Case Panel Discussion

ASCO GU 2019: PIVOT-02 Study of NKTR-214 with Nivolumab in Metastatic Urothelial Carcinoma

ASCO GU 2019: Sacituzumab Govitecan (IMMU-132) in Patients with Previously Treated Metastatic Urothelial Cancer

Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial

Atezolizumab as First-line Treatment in Cisplatin-ineligible Patients with Locally Advanced and Metastatic Urothelial Carcinoma: A Single-arm, Multicentre, Phase 2 Trial

BCG-Unresponsive Nonmuscle Invasive Bladder Cancer: Developing Drugs and Biologics for Treatment Guidance for Industry

Bladder Cancer BioMarkers: Optimal Utilization for Diagnosis and Recurrence: EVERYDAY UROLOGY- Full text article

Published in Everyday Urology - Oncology Insights: Volume 1, Issue 3

Bladder Cancer Immunotherapy: Establishing a Clinic of Excellence

Published in Everyday Urology - Oncology Insights: Volume 3, Issue 1

Bladder Cancer Outcomes in Women Vary over Time - Expert Commentary

Bladder Cancer: New Insights Into its Molecular Pathology - Beyond the Abstract

Blue Light Cystoscopy: Insights on Recurrence, Progression, and Clinical Management

Published in Everyday Urology - Oncology Insights: Volume 3, Issue 3

Brief Q&A for Patients by the International Bladder Cancer Group on the BCG Shortage

Carcinoma In Situ of the Bladder with Plasmacytoid Features - Expert Commentary

Clinical impact of postoperative loss in psoas major muscle and nutrition index after radical cystectomy for patients with urothelial carcinoma of the bladder.

Clinical Outcomes in Patients with Micropapillary Urothelial Carcinoma of the Bladder - Expert Commentary

Clinical Outcomes in Patients with Panurothelial Carcinoma Treated with Radical Nephroureterectomy Following Cystectomy for Metachronous Recurrence.

Conditional Reprogramming of Patient-derived Bladder Cancer Cells for Personalized Treatment Strategies – Expert Commentary

Contemporary treatment patterns and outcomes of sarcomatoid bladder cancer: Beyond the Abstract

CUOS 2019: Bladder Preservation for Invasive Bladder Cancer: Lessons Learned and Future Perspectives

CUOS 2019: Five-Year Outlook in the Management of Metastatic Urothelial Carcinoma

Diagnosing Bladder Cancer using Urinary Cell-Free microRNA - Expert Commentary

Diagnosis and Pathology of Bladder Cancer

Diagnosis:

Clinical Presentation

There are no reliable screening tests available for detecting bladder cancer; hence the diagnosis is usually made based on clinical signs and symptoms. Painless hematuria – microscopic or gross – is the most common presentation and a hematuria investigation in an otherwise asymptomatic patient detects bladder neoplasm in roughly 20% of gross and 5% of microscopic cases.^1,2 Irritative voiding (frequency, urgency, and/or dysuria) is usually ascribed to benign urinary tract disorders but has been associated with carcinoma in situ. Other symptoms are often a signal of more advanced disease, such as flank pain caused by ureteral obstruction or pelvic pain from extravesical invasion of surrounding structures.  

Cystoscopy

Cystoscopy is a mainstay for the diagnosis and treatment of bladder cancer, allowing for direct access to a tumor for biopsy, fulguration, and/or resection. Low grade (LG), papillary (Ta) tumors can be reliably eradicated with one treatment but more advanced disease (high grade and/or T1) often requires repeat resection for complete eradication. Following an initial diagnosis of HG Ta or T1, between 40% and 78% of re-TUR specimens may contain residual disease, with muscle invasion present in 2% and 14%, respectively.^3-6 Hence the AUA and EAU guidelines recommend repeat TURBT within 6 weeks from the index procedure to confirm tumor stage, ensure complete visual tumor clearance, and optimize response to subsequent intravesical therapy.^7,8 

Recent technological advances promise improved detection over white light cystoscopy (WLC) alone, theoretically allowing for a more complete endoscopic tumor removal. Blue light cystoscopy (BLC) has been approved for over a decade in Europe and the US based on numerous studies showing improvement in detection of bladder tumors as well as lengthening the time to recurrence by as much as 7 months (9.4 months vs 16.4 months). The improvement in tumor detection estimated to be 20% greater with BLC compared to WLC, and up to 40% specifically for CIS, however, the beneficial effect on disease recurrence and/or progression has not been universally reported in all studies.^9-12 Narrow band imaging (NBI) also offers better detection than WLC but does not require a pre-operative medication instillation like BLC. Specialized optical equipment emits light in two specific wavelengths (415 nm and 540 nm) that are more readily absorbed by hemoglobin, thereby enhancing submucosal vascularity associated with malignancy.¹³ In a recent systematic review of five RCTs comparing WLC to NBI, the authors found statistically significant reduction in NMIBC recurrence at 3 months (RR 0.39), 1 year (RR 0.52), and 2 years (RR 0.60).¹⁴ No matter the technique, enhanced cystoscopy improves detection but whether the added time and expense translate into improved patient outcomes is still not entirely clear. 

Urinary Markers

The urothelium is particularly well suited anatomically for assessment of potential biomarkers that can be obtained with little to no need for invasive procedures. Cells and cellular molecules (proteins, RNA, etc.) shed into the urine as it passes through the upper and lower urinary tract; they can be collected and purified from voided or catheterized specimens. The information gathered can then be used for screening, diagnosis, treatment response, and/or surveillance. The most well-known and widely used technique is urinary cytology, by which the cellular component of a urine specimen is microscopically assessed for features typically associated with high-grade malignancy (mitotic figures, condensed chromatin, enlarged nucleoli, etc.). Interpretation and reporting by cytopathologists has contributed to confusion surrounding urinary cytology with the use of terms like “suspicious, atypical, or indeterminate. The Paris Reporting System for Urinary Cytology has standardized the cytopathologic nomenclature while providing an estimated risk of malignancy based on associated literature (Table 1).¹⁵ While specificity has historically been very high (>99%), the poor sensitivity of urinary cytology, especially for papillary tumors (4-31%), make it far from ideal for either screening or surveillance.^16-19 More contemporary data has been less robust, placing specificity at a more modest 82-88% and highlighting the need for more advanced markers.²⁰

There are now five FDA-approved tests available (Table 2) in addition to many more potential biomarkers (i.e. DNA methylation, cell free DNA, histone modification) in various stages of development.^21,22 The UroVysion test uses fluorescence in situhybridization (FISH) to detect common chromosomal aberrations associated with bladder cancer and outperforms urinary cytology in terms of sensitivity, though this is almost entirely attributable to better detection of Ta tumors.²³ The ImmunoCyt (uCyt+) assay was designed to complement cytology and increases the sensitivity to 59% for grade 1 tumors and up to 90% for grade 3 by using monoclonal antibodies directed against common urothelial surface markers.²⁴ Nuclear matrix protein-22 (NMP-22) is involved in normal chromatin maintenance during mitosis but is greatly overexpressed in bladder carcinoma cells. Despite a reported sensitivity of 73% and specificity of 80%, the test has not gained widespread acceptance due to variability in accuracy between institutions and a high rate of false positive tests.^25,26 The newest test to gain FDA-approval is the RNA based CxBladder test which measures the relative levels of 5 different mRNA transcripts within the urine (4 associated with malignancy and 1 with benign conditions) to produce an impressive combination of sensitivity and specificity at 82% and 85%, respectively.^27,28 

To date, none of the available data supports the use of urinary biomarkers as the sole method of bladder cancer detection, diagnosis, or follow-up, as stated by both the EAU and AUA in their respective NMIBC guidelines, however, they may offer useful information when assessing treatment response and during long-term surveillance as an adjunct to cystoscopy.^7,8 Initial enthusiasm for these tests in the early to mid-2000s has waned, whereas use of urinary cytology has remained constant despite its shortcomings.²⁹ The use of markers in prognostication and prediction of response to therapy is discussed in the next section on management of NMIBC.

Imaging

A complete diagnostic evaluation includes imaging of the entire urinary tract to assess for abnormalities of the urothelium normally out of view from cystoscopy. Upper tract urothelial tumors are uncommon, present in only 1.5% of patients with NMIBC, but certain features (multifocality, trigonal lesions, and/or CIS) raise this risk to more than 7%.^30,31 The best combination of sensitivity (67-100%) and specificity (93-99%) is offered by computed tomographic urography (CTU) because of high soft tissue special resolution and contrast enhanced assessment of the urothelial surfaces and this has replaced intravenous urography in most centers in North America.^32-35 Magnetic resonance imaging can be used as a substitute for CTU if the patient has an allergy to iodinated contrast or low GFR.³⁶ In an effort to standardize MRI reporting and improve diagnostic accuracy, the multiparametric MRI based Vesical Imaging-Reporting and Data System (VI-RADS) was introduced in early 2018 with a 5 tiered system designed to predict likelihood of finding muscle invasion on TURBT, though it has not been validated in the clinical setting as of yet.³⁷ Ultrasonography with retrograde pyelography is reserved for circumstances where both CT and MRI cannot be performed.

Pathology:

Urothelial carcinoma is the most common bladder cancer histology (~90%) diagnosed in the US, followed by squamous (2-5%), adenocarcinoma (2%), neuroendocrine (1%), and other rare tumors (<1%).³⁸ The urothelium is the epithelial lining of the urinary tract and has a thickness in the bladder of approximately 5 to 7 cell layers overlying the lamina propria. Tumors that are confined to the bladder and do not invade the muscularis propria are considered non-muscle invasive bladder cancer (NMIBC) comprised of stages Ta, T1, and carcinoma in situ (CIS). Invasion of the muscularis propria – so called muscle invasive bladder cancer (MIBC,T2)“ represents an advanced stage with life threatening consequences requiring surgical management (i.e. radical cystectomy). 

Tumor Grading

Tumor grade is an important prognostic feature of bladder cancer but there is a lack of consensus internationally regarding the classification system. The extreme ends of the spectrum (highly aggressive and low malignant potential) are easy to identify but the middle ground has proved more elusive. In the World Health Organization 1973 grading system, there are 3 tiers of tumor grade (1, 2, and 3), though a majority of tumors end up as the intermediate grade 2 as a diagnosis of exclusion. The International Society of Urologic Pathologists (ISUP)/WHO 2004 grading system includes only high or low grade and exhibits better prognostic ability over the WHO 1973 system, at the expense of upward stage migration.^39,40 Enrichment of the grade 3 group via inclusion of borderline grade 2 cases only leaves more indolent disease in the LG category and exposes those patients to overtreatment. The final version released as the ISUP/WHO 2004 grading system (now updated with minor revisions as the 2016 system) has been adopted throughout North America but the 1973 version is still in widespread use across Europe (Figure 1).⁴¹ 

Divergent Differentiation and Histologic Variants

The ability of the urothelium to exhibit divergent differentiation is well known and may occur in a pure or mixed form (Table 3).^42,43 When certain subtypes are present without elements of usual urothelial carcinoma, the tumor is referred to in terms of its pure histology (i.e. squamous cell carcinoma [SCC] of the bladder, adenocarcinoma of the bladder), in contrast to variant histology discussed below.⁴¹ Adenocarcinoma has a typical glandular (intestinal) appearance and tends to be more aggressive than UC.⁴⁴ As such, complete early resection with radical cystectomy is advocated, even for T1 tumors, to achieve the best clinical outcomes.⁴⁵ Pure SCC is more common in regions with endemic Bilhazrial infections and has been associated with a favorable clinical course, however, the non-infectious form is a distinct entity with a worse prognosis warranting similar management as adenocarcinoma.⁴⁶ Small cell carcinoma is a neuroendocrine tumor with a very high propensity for distant spread at presentation and should be treated with upfront chemotherapy followed by surgery if free of detectable metastasis.⁴⁷

The impact of mixed histologic variants is less clear owing to multiple factors including low recognition historically among pathologists and tumor under-sampling during resection.^48,49 In one study, repeat pathologic review of more than 1,200 bladder cancers diagnosed as pure UC between 1980 and 2005 found that 1/3^rd actually contained a variant component.⁵⁰ The sarcomatoid subtype is characterized by a mesenchymal and spindle-cell like appearance and exhibits a propensity for aggressive growth.⁵¹ These tumors present with extravesical invasion (T3-4) in about 1/3^rd of cases.⁵² Micropapillary histologic architecture has been described in other malignancies and is typically associated with poor prognosis.⁵³ Higher stage on presentation and increased likelihood for bladder invasion have been noted when even small regions of micropapillary differentiation are present (~10%), but the optimal treatment approach (neoadjuvant chemotherapy versus immediate RC) is still a topic for debate.^54,55 Plasmacytoid variant is locally aggressive and frequently under-staged as evidenced by an 80% upstaging rate of clinical T1 to pathologic after cystectomy.^56,57 The pattern of spread of plasmacytoid is particularly unusual for bladder cancer given its predilection for peritoneal implantation.⁵⁸ The histologic appearance of nested subtype is similar to von Brunn nests, but unlike the benign nature of the latter, nested variant carries significant probability of muscle invasion (70%) and/or lymph node positivity (67%).⁵⁹ Squamous and glandular differentiation are associated with a higher stage at initial diagnosis, however, clinical outcomes are no different than conventional urothelial carcinoma and standard treatment pathways should be sufficient.^60,61 The AUA NMIBC guidelines direct the clinician to consider upfront radical cystectomy in T1 patients with any variant histology, citing the association of variant histology with a high rate of under-staging, however, the EAU guidelines limit their recommendation to only micropapillary histology.^7,8,55,62

Molecular Classification

The accumulation of DNA damage necessary to produce bladder cancer requires several decades to occur, and as a result, MIBC exhibits a very high mutational burden and chromosomal instability. Concurrent genomic studies from several international research groups produced a range of intrinsic MIBC molecular subtypes with similar expressional profiles but different nomenclature. It is generally accepted that there are 2 major subtypes, luminal and basal, with better prognosis among the former. These tumors tend to be enriched for FGFR3 mutations associated with hyperproliferation and found at high frequency in non-invasive tumor. Despite the poor prognosis of the basal subtype, characterized by p53 mutations and alterations of DNA-damage repair pathways, these tumors are more responsive to platinum-based neoadjuvant chemotherapy than any other group.⁶³ Low-grade tumors are genetically far more stable than MIBC, with highly conserved alterations in FGFR3 (79%), KDM6A (53%), and PIK3CA (52%).^64,65 NMIBC has also been classified according to a molecular profiling schema, though it is less robust than what is available for MIBC. The major take-home point from this work thus far is the similarity between HG NMIBC and MIBC, pointing to a common pathway for progression.^64,66,67

Written by: Justin T. Matulay, MD and Ashish Kamat, MD, MBBS

References: 1. Khadra MH, Pickard RS, Charlton M, et al. A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice. J Urol. 2000;163(2):524-527.
2. Mishriki SF, Nabi G, Cohen NP. Diagnosis of urologic malignancies in patients with asymptomatic dipstick hematuria: prospective study with 13 years' follow-up. Urology. 2008;71(1):13-16.
3. Divrik RT, Yildirim U, Zorlu F, et al. The effect of repeat transurethral resection on recurrence and progression rates in patients with T1 tumors of the bladder who received intravesical mitomycin: a prospective, randomized clinical trial. J Urol. 2006;175(5):1641-1644.
4. Gendy R, Delprado W, Brenner P, et al. Repeat transurethral resection for non-muscle-invasive bladder cancer: a contemporary series. BJU Int. 2016;117 Suppl 4:54-59.
5. Lazica DA, Roth S, Brandt AS, et al. Second transurethral resection after Ta high-grade bladder tumor: a 4.5-year period at a single university center. Urol Int. 2014;92(2):131-135.
6. Cumberbatch MGK, Foerster B, Catto JWF, et al. Repeat Transurethral Resection in Non-muscle-invasive Bladder Cancer: A Systematic Review. Eur Urol. 2018.
7. Babjuk M, Bohle A, Burger M, et al. EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol. 2017;71(3):447-461.
8. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J Urol. 2016;196(4):1021-1029.
9. Chang TC, Marcq G, Kiss B, et al. Image-Guided Transurethral Resection of Bladder Tumors - Current Practice and Future Outlooks. Bladder Cancer. 2017;3(3):149-159.
10. O'Brien T, Ray E, Chatterton K, et al. Prospective randomized trial of hexylaminolevulinate photodynamic-assisted transurethral resection of bladder tumour (TURBT) plus single-shot intravesical mitomycin C vs conventional white-light TURBT plus mitomycin C in newly presenting non-muscle-invasive bladder cancer. BJU Int. 2013;112(8):1096-1104.
11. Schumacher MC, Holmang S, Davidsson T, et al. Transurethral resection of non-muscle-invasive bladder transitional cell cancers with or without 5-aminolevulinic Acid under visible and fluorescent light: results of a prospective, randomised, multicentre study. Eur Urol. 2010;57(2):293-299.
12. Yuan H, Qiu J, Liu L, et al. Therapeutic outcome of fluorescence cystoscopy guided transurethral resection in patients with non-muscle invasive bladder cancer: a meta-analysis of randomized controlled trials. PLoS One. 2013;8(9):e74142.
13. Herr HH. Narrow band imaging cystoscopy. Urol Oncol. 2011;29(4):353-357.
14. Kang W, Cui Z, Chen Q, et al. Narrow band imaging-assisted transurethral resection reduces the recurrence risk of non-muscle invasive bladder cancer: A systematic review and meta-analysis. Oncotarget. 2017;8(14):23880-23890.
15. Barkan GA, Wojcik EM, Nayar R, et al. The Paris System for Reporting Urinary Cytology: The Quest to Develop a Standardized Terminology. Adv Anat Pathol. 2016;23(4):193-201.
16. Lotan Y, Roehrborn CG. Sensitivity and specificity of commonly available bladder tumor markers versus cytology: results of a comprehensive literature review and meta-analyses. Urology. 2003;61(1):109-118; discussion 118.
17. Schmitz-Drager BJ, Droller M, Lokeshwar VB, et al. Molecular markers for bladder cancer screening, early diagnosis, and surveillance: the WHO/ICUD consensus. Urol Int. 2015;94(1):1-24.
18. Xylinas E, Kluth LA, Rieken M, et al. Urine markers for detection and surveillance of bladder cancer. Urol Oncol. 2014;32(3):222-229.
19. Zuiverloon TCM, de Jong FC, Theodorescu D. Clinical Decision Making in Surveillance of Non-Muscle-Invasive Bladder Cancer: The Evolving Roles of Urinary Cytology and Molecular Markers. Oncology (Williston Park). 2017;31(12):855-862.
20. Yafi FA, Brimo F, Auger M, et al. Is the performance of urinary cytology as high as reported historically? A contemporary analysis in the detection and surveillance of bladder cancer. Urol Oncol. 2014;32(1):27 e21-26.
21. Chou R, Gore JL, Buckley D, et al. Urinary Biomarkers for Diagnosis of Bladder Cancer: A Systematic Review and Meta-analysis. Ann Intern Med. 2015;163(12):922-931.
22. Santoni G, Morelli MB, Amantini C, et al. Urinary Markers in Bladder Cancer: An Update. Front Oncol. 2018;8:362.
23. Hajdinjak T. UroVysion FISH test for detecting urothelial cancers: meta-analysis of diagnostic accuracy and comparison with urinary cytology testing. Urol Oncol. 2008;26(6):646-651.
24. Comploj E, Mian C, Ambrosini-Spaltro A, et al. uCyt+/ImmunoCyt and cytology in the detection of urothelial carcinoma: an update on 7422 analyses. Cancer Cytopathol. 2013;121(7):392-397.
25. Shariat SF, Marberger MJ, Lotan Y, et al. Variability in the performance of nuclear matrix protein 22 for the detection of bladder cancer. J Urol. 2006;176(3):919-926; discussion 926.
26. Poulakis V, Witzsch U, De Vries R, et al. A comparison of urinary nuclear matrix protein-22 and bladder tumour antigen tests with voided urinary cytology in detecting and following bladder cancer: the prognostic value of false-positive results. BJU Int. 2001;88(7):692-701.
27. Kavalieris L, O'Sullivan PJ, Suttie JM, et al. A segregation index combining phenotypic (clinical characteristics) and genotypic (gene expression) biomarkers from a urine sample to triage out patients presenting with hematuria who have a low probability of urothelial carcinoma. BMC urology. 2015;15:23.
28. O'Sullivan P, Sharples K, Dalphin M, et al. A multigene urine test for the detection and stratification of bladder cancer in patients presenting with hematuria. J Urol. 2012;188(3):741-747.
29. Narayan VM, Adejoro O, Schwartz I, et al. The Prevalence and Impact of Urinary Marker Testing in Patients with Bladder Cancer. J Urol. 2018;199(1):74-80.
30. Palou J, Rodriguez-Rubio F, Huguet J, et al. Multivariate analysis of clinical parameters of synchronous primary superficial bladder cancer and upper urinary tract tumor. J Urol. 2005;174(3):859-861; discussion 861.
31. Millan-Rodriguez F, Chechile-Toniolo G, Salvador-Bayarri J, et al. Upper urinary tract tumors after primary superficial bladder tumors: prognostic factors and risk groups. J Urol. 2000;164(4):1183-1187.
32. Chlapoutakis K, Theocharopoulos N, Yarmenitis S, et al. Performance of computed tomographic urography in diagnosis of upper urinary tract urothelial carcinoma, in patients presenting with hematuria: Systematic review and meta-analysis. Eur J Radiol. 2010;73(2):334-338.
33. Cowan NC, Turney BW, Taylor NJ, et al. Multidetector computed tomography urography for diagnosing upper urinary tract urothelial tumour. BJU Int. 2007;99(6):1363-1370.
34. Froemming A, Potretzke T, Takahashi N, et al. Upper tract urothelial cancer. Eur J Radiol. 2018;98:50-60.
35. Roupret M, Babjuk M, Comperat E, et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2017 Update. Eur Urol. 2018;73(1):111-122.
36. Takahashi N, Glockner JF, Hartman RP, et al. Gadolinium enhanced magnetic resonance urography for upper urinary tract malignancy. J Urol. 2010;183(4):1330-1365.
37. Panebianco V, Narumi Y, Altun E, et al. Multiparametric Magnetic Resonance Imaging for Bladder Cancer: Development of VI-RADS (Vesical Imaging-Reporting And Data System). Eur Urol. 2018;74(3):294-306.
38. Hansel DE, Amin MB, Comperat E, et al. A contemporary update on pathology standards for bladder cancer: transurethral resection and radical cystectomy specimens. Eur Urol. 2013;63(2):321-332.
39. Cao D, Vollmer RT, Luly J, et al. Comparison of 2004 and 1973 World Health Organization Grading Systems and Their Relationship to Pathologic Staging for Predicting Long-term Prognosis in Patients With Urothelial Carcinoma. Urology. 2010;76(3):593-599.
40. Lokeshwar SD, Ruiz-Cordero R, Hupe MC, et al. Impact of 2004 ISUP/WHO classification on bladder cancer grading. World Journal of Urology. 2015;33(12):1929-1936.
41. Humphrey PA, Moch H, Cubilla AL, et al. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part B: Prostate and Bladder Tumours. Eur Urol. 2016;70(1):106-119.
42. Lopez-Beltran A, Cheng L. Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications. Hum Pathol. 2006;37(11):1371-1388.
43. Shanks JH, Iczkowski KA. Divergent differentiation in urothelial carcinoma and other bladder cancer subtypes with selected mimics. Histopathology. 2009;54(7):885-900.
44. Wright JL, Porter MP, Li CI, et al. Differences in survival among patients with urachal and nonurachal adenocarcinomas of the bladder. Cancer. 2006;107(4):721-728.
45. Zaghloul MS, Nouh A, Nazmy M, et al. Long-term results of primary adenocarcinoma of the urinary bladder: a report on 192 patients. Urol Oncol. 2006;24(1):13-20.
46. Ehdaie B, Maschino A, Shariat SF, et al. Comparative outcomes of pure squamous cell carcinoma and urothelial carcinoma with squamous differentiation in patients treated with radical cystectomy. J Urol. 2012;187(1):74-79.
47. Lynch SP, Shen Y, Kamat A, et al. Neoadjuvant chemotherapy in small cell urothelial cancer improves pathologic downstaging and long-term outcomes: results from a retrospective study at the MD Anderson Cancer Center. Eur Urol. 2013;64(2):307-313.
48. Willis D, Kamat AM. Nonurothelial bladder cancer and rare variant histologies. Hematol Oncol Clin North Am. 2015;29(2):237-252, viii.
49. Shah RB, Montgomery JS, Montie JE, et al. Variant (divergent) histologic differentiation in urothelial carcinoma is under-recognized in community practice: Impact of mandatory central pathology review at a large referral hospital. Urol Oncol. 2013;31(8):1650-1655.
50. Linder BJ, Boorjian SA, Cheville JC, et al. The impact of histological reclassification during pathology re-review--evidence of a Will Rogers effect in bladder cancer? J Urol. 2013;190(5):1692-1696.
51. Moch H, Humphrey PA, Ulbright TM, et al. WHO Classification of Tumours of the Urinary System and Male Genital Organs. 4th ed. Lyon, France: International Agency for Research on Cancer; 2016.
52. Sui W, Matulay JT, Onyeji IC, et al. Contemporary treatment patterns and outcomes of sarcomatoid bladder cancer. World J Urol. 2017;35(7):1055-1061.
53. Sui W, Matulay JT, James MB, et al. Micropapillary Bladder Cancer: Insights from the National Cancer Database. Bladder Cancer. 2016;2(4):415-423.
54. Kamat AM, Dinney CP, Gee JR, et al. Micropapillary bladder cancer: a review of the University of Texas M. D. Anderson Cancer Center experience with 100 consecutive patients. Cancer. 2007;110(1):62-67.
55. Meeks JJ, Taylor JM, Matsushita K, et al. Pathological response to neoadjuvant chemotherapy for muscle-invasive micropapillary bladder cancer. BJU Int. 2013;111(8):E325-330.
56. Kaimakliotis HZ, Monn MF, Cary KC, et al. Plasmacytoid variant urothelial bladder cancer: is it time to update the treatment paradigm? Urol Oncol. 2014;32(6):833-838.
57. Keck B, Wach S, Stoehr R, et al. Plasmacytoid variant of bladder cancer defines patients with poor prognosis if treated with cystectomy and adjuvant cisplatin-based chemotherapy. BMC Cancer. 2013;13:71.
58. Ricardo-Gonzalez RR, Nguyen M, Gokden N, et al. Plasmacytoid carcinoma of the bladder: a urothelial carcinoma variant with a predilection for intraperitoneal spread. J Urol. 2012;187(3):852-855.
59. Wasco MJ, Daignault S, Bradley D, et al. Nested variant of urothelial carcinoma: a clinicopathologic and immunohistochemical study of 30 pure and mixed cases. Hum Pathol. 2010;41(2):163-171.
60. Amin MB. Histological variants of urothelial carcinoma: diagnostic, therapeutic and prognostic implications. Mod Pathol. 2009;22 Suppl 2:S96-S118.
61. Mitra AP, Bartsch CC, Bartsch G, Jr., et al. Does presence of squamous and glandular differentiation in urothelial carcinoma of the bladder at cystectomy portend poor prognosis? An intensive case-control analysis. Urol Oncol. 2014;32(2):117-127.
62. Vetterlein MW, Wankowicz SAM, Seisen T, et al. Neoadjuvant chemotherapy prior to radical cystectomy for muscle-invasive bladder cancer with variant histology. Cancer. 2017;123(22):4346-4355.
63. Seiler R, Ashab HA, Erho N, et al. Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy. Eur Urol. 2017.
64. Hurst CD, Alder O, Platt FM, et al. Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency. Cancer Cell. 2017;32(5):701-715 e707
65. Robertson AG, Kim J, Al-Ahmadie H, et al. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell. 2017;171(3):540-556 e525.
66. Hedegaard J, Lamy P, Nordentoft I, et al. Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma. Cancer Cell. 2016;30(1):27-42.
67. Pietzak EJ, Bagrodia A, Cha EK, et al. Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets. Eur Urol. 2017;72(6):952-959.
68. Soloway MS, Briggman V, Carpinito GA, et al. Use of a new tumor marker, urinary NMP22, in the detection of occult or rapidly recurring transitional cell carcinoma of the urinary tract following surgical treatment. J Urol. 1996;156(2 Pt 1):363-367.
69. Irani J, Desgrandchamps F, Millet C, et al. BTA stat and BTA TRAK: A comparative evaluation of urine testing for the diagnosis of transitional cell carcinoma of the bladder. Eur Urol. 1999;35(2):89-92.
70. Fradet Y, Lockhard C. Performance characteristics of a new monoclonal antibody test for bladder cancer: ImmunoCyt trade mark. Can J Urol. 1997;4(3):400-405.
71. Mostofi FK, Sobin LH, Torloni H. Histological typing of urinary bladder tumours. Geneva, Switerland: World Health Organization; 1973.
72. Eble JN, Sauter G, Epstein JI, et al. Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs. Lyon: IARC Press; 2004.

Early Detection of Bladder Urothelial Cell Carcinoma Using Micronuclei, Nucleoplasmic Bridges and Nuclear Buds - Expert Commentary

Early Detection of Relapse using Circulating Tumor DNA in Patients with Urothelial Bladder Carcinoma – Expert Commentary

EAU 2019: Blue Light Flexible Cystoscopy – Improving the Patient Experience

EAU 2019: Primary Results from SAUL: A Prospective, Multinational Single-Arm Study of Atezolizumab for Locally Advanced or Metastatic Urothelial Carcinoma of the Urinary Tract

EAU 2019: TERT Promoter and FGFR3 Mutations – A Highly Sensitive and Non-invasive Tool for Bladder Cancer Recurrence Detection

Enhanced Recovery After Surgery, Radical Cystectomy and Urinary Diversion

Published in Everyday Urology - Oncology Insights: Volume 2, Issue 1

Enhanced Recovery after Urological Surgery: A Contemporary Systematic Review of Outcomes, Key Elements, and Research Needs.

Epidemiology and Etiology of Bladder Cancer

Epidemiology

Bladder cancer is the most common malignancy of the urinary tract and second only to the prostate in the entire genitourinary system. The most updated available global estimate, based on registry data collected through the year 2012, found approximately 430,000 new diagnoses worldwide, making it the 9th most common malignancy overall (6th in men and 17th in women) while being the 13th leading cause of cancer mortality (Figure 1).¹ A more recent estimate available for the United States population based on Surveillance, Epidemiology, and End Results (SEER) data estimates the annual incidence will be 81,000 for the year 2018 corresponding to the 4th and 11th most common cancer among men and women, respectively.² In the decade between 2006 and 2015 the annual incidence of bladder cancer per 100,000 persons has declined by 1.3% annually, however, the mortality rate has remained nearly unchanged.³ By comparison, the mortality rates of the other top malignancies, lung, colon, and prostate, have declined by 2.6%, 2.4%, and 2.9% over the same period of time, respectively.

Figure 1.  Age-standardized rates (ASR) of incidence (gold) and mortality (blue) from the World Health Organization International Agency for Research on Cancer GLOBOCAN 2012 dataset. (A) Worldwide ASR for the top 20 cancers, divided by sex. Bladder cancer incidence is the 6th most common among men and 17th among women. (B) Bladder cancer ASR incidence and mortality by WHO reporting region. More developed regions have 2-3 times higher incidence than less developed regions.

The gender disparity in bladder cancer risk is readily evident considering men represent slightly more than 75% of new diagnoses each year.2 Perhaps the most obvious explanation for this difference is the inequality in exposure to bladder carcinogens, namely tobacco smoke. This topic has undergone close examination but higher rates of smoking and tobacco use among males fails to entirely account for the increased bladder cancer risk.4,5 Sex hormones may play a key role in the development and progression of bladder cancer, with increased androgen receptor expression noted in lower stage/grade tumors while higher stage disease is associated with increased expression of the estrogen receptor β isoform (Figure 2).^6-9 This may point to an explanation for the poorer stage-adjusted cancer-specific mortality in women compared to men (HR 1.17-4.47) in spite of a male to female incidence ratio of 4 to 1.^10-14

 

Internationally, gender differences in bladder cancer mirrors the trends seen in the US population but incidences vary widely from region to region. For instance, the lowest age-standardized rates (ASR) in men are seen in Africa (Uganda ASR = 2.6 per 100,000) while the highest are found in North America (ASR = 19.5 per 100,000) and Europe (ASR = 17.7 per 100,000), including Spain with its ASR of 36.7 per 100,000 men.¹ In an analysis of the WHO cancer databases, Antoni et al. made several notable observations regarding worldwide bladder cancer incidence and mortality.¹⁵ The ASR of more developed regions is approximately 3-times higher than the developing world and is likely explained by the high prevalence of cigarette smoking among the former population during the preceding three to four decades. Case-in-point, nearly 2 in 3 Spanish adult males actively smoked in the late 1970s, and while smoking rates have certainly declined among the developed world, it will take many more years to see the attendant decline in the disease burden of bladder cancer.15-17 Egypt – and the Northern African region as a whole – are worth highlighting given the abnormally high incidence when compared to the continent overall (ASR = 19.0, 15.1, and 6.3 per 100,000, respectively).¹⁵ Endemic parasitic infection with Schistoma haematobiumhas traditionally been associated with the increased prevalence of disease among the Egyptian population, especially squamous cell carcinoma (SCC) which accounted for up to 81% of all bladder cancers diagnosed before the turn of the century.¹⁸ More recently, bilharzial infection rates have fallen and SCC now accounts for less than 30% of bladder cancer pathology, but the overall incidence is holding steady due to smoking rates among the male population that has increased to over 50%.^18,19

Racial disparity among the US population is skewed towards a 2-fold higher incidence of bladder cancer among Caucasian men, however, tumor stage and grade are higher at the presentation in African American men.²⁰ Several researchers have noted worse disease-specific outcomes for African Americans and hypothesize that this is probably due to socioeconomic factors and poor access to healthcare, but a recent evaluation of a Florida cancer registry actually found significantly better overall survival among blacks (HR=0.35, p=0.045) when controlling for patient and disease factors.^21-25

Etiology

Risk Factors

The urothelium is exposed to the outside environment, not unlike the skin or the lung epithelium, making it susceptible to damage from environmental toxins. Once filtered by the kidney and concentrated in the urine, these toxins remain in continuous contact with the urothelium of the bladder until expelled during urination. The result is DNA damage caused by several carcinogenic compounds (aromatic amines, polycyclic aromatic hydrocarbons, etc.) which leads to accumulation of oncogenic mutations over the course of decades and explains why bladder cancer carries one of the highest mutational burdens of all cancers.^26,27

The most strongly attributable risk factor for bladder cancer is cigarette smoking, which causes approximate 50% of cases annually across both sexes.28 Since the overall rate of smoking in the US has dropped in the past several decades, one would expect to see a commensurate decline in the incidence of bladder cancer, but this has not been the case. Instead, it appears that the strength of association between bladder cancer and smoking has increased, likely due to the enrichment of carcinogenic agents found in cigarette tobacco over time – specifically nitrates, which become metabolized into carcinogenic N-nitrosamines.^28,29

E-cigarettes are a popular “safe” alternative to cigarette smoking, but the vaporized liquid, comprised of nicotine and flavoring, contains several carcinogenic compounds found in tobacco smoke, such as polycyclic aromatic hydrocarbons, phenols, nitrosamines, and aldehydes, among others.³⁰ It is too early to make a causal link between e-cigarettes and bladder cancer, however, studies have discovered, while less than cigarette smokers, levels of carcinogenic metabolites in the urine of e-cigarette smokers are significantly higher than non-smoking controls.^31,32 Furthermore, pre-clinical work with mouse models demonstrated DNA damage induced by nitrosamines from e-cigarettes in the murine lungs, heart, and bladder.³³

Other environmental toxins, aside from tobacco smoke, that are known to cause bladder cancer are often found in industrial settings where workers are subjected to repeated daily exposure. In a contemporary analysis of bladder cancer risk from occupational exposures, workers in tobacco, dye, rubber, printing, leather, and hairdressing industries as well as chimney sweeps, firefighters, aluminum workers, and oil workers were at highest risk for bladder cancer secondary to environmental presence of aromatic amines and polycyclic aromatic hydrocarbons (Table).^26,34-37 The inorganic form of arsenic found both naturally and as a contaminant in the environment, has been strongly linked to urothelial malignancy, especially when the concentration in drinking water is over 150-300 µg/L.^38,39

Innumerable dietary risk factors have been associated with cancer risk in general and even a few with particular emphasis on bladder cancer.⁴⁰ Meat consumption at the population level appears to be positively correlated with bladder cancer risk for both red meat and processed meats, but the quality of evidence is generally poor.^41,42 Likewise, artificial sweeteners are a frequent suspect for dietary carcinogenesis while lacking any clear link to cancer of the urinary tract, only conflicting results from case-control studies.^43-45

The most commonly cited hereditary links to bladder cancer are not tumor suppressor or proto-oncogene mutations, but rather related to the manner in which an individual metabolizes the carcinogens from the environment, especially in the form of cigarette smoke. Two isoforms of the N-acetyltransferase enzyme (NAT1 and NAT2) that are responsible for inactivating the carcinogenic aromatic and heterocyclic amine compounds can be associated with an increased risk of developing bladder cancer when certain germline polymorphisms are present that correlate with “slow” enzyme activity.^46,47 Enzymes in the glutathione S-transferase (GST) family also carry a detoxifying function, and bladder cancer risk is increased in the GSTM1-null genotype, however, the effect in this population is more pronounced among never smokers over former or current smokers through an as of yet unknown mechanism.^48,49

Chronic inflammation contributes to bladder cancer formation through a process by which immune cells (neutrophils, monocytes, and macrophages) generate reactive oxygen species that induce DNA damage as well as stimulate cellular proliferation through cell-signaling pathways. ⁵⁰ Urinary tract infections and urothelial irritants, such as calculi and indwelling catheters, are associated with increased risk of bladder cancer overall, as well as an increased proportion of squamous cell carcinoma.^51,52 This is particularly evident among spinal cord injury patients and populations with endemic Schistosomiasis, and though the exact mechanism is unknown, urothelial to squamous metaplasia appears to precede the development of invasive carcinoma in these patients.^50,53

Iatrogenic causes of bladder cancer include systemic agents (i.e. chemotherapy) and pelvic irradiation for other malignancies. The popular class of anti-diabetic medications known as thiazolidinediones (TZD), which includes the specific drugs pioglitazone and rosiglitazone, have been implicated in urothelial carcinoma carcinogenesis via activation of the peroxisome proliferator-activated receptors gamma (PPARγ). Large cohort studies have reported conflicting results regarding an increased incidence of bladder cancer that increases with duration of TZD therapy, especially pioglitazone, prompting the FDA to include a warning label regarding the increased risk and recommend ongoing re-evaluation of the data.^54-58 Bladder cancer risk is also associated with systemic cyclophosphamide chemotherapy, due to either direct effect of toxic metabolites in the urine (acrolein and phosphoramide) or severe urothelial inflammation.^59,60 Radiotherapy of the pelvis may lead to at least 30% increased risk, though this effect is seen only with the external beam but not brachytherapy.⁶¹

Prevention

Given the role of inflammation in carcinogenesis, it makes sense that inhibiting enzymes within the pro-inflammatory pathways (i.e. cyclooxygenase-2 [COX-2] or 3-hydroxy-3-mehylglutaryl-coenzyme A [HMGCoA] reductase) might be useful for disease prevention. Laboratory models of nonsteroidal anti-inflammatories (NSAIDs) have demonstrated promising results related to bladder cancer prevention, however, a randomized controlled trial of the COX-2 inhibitor celecoxib failed significantly reduce NMIBC recurrences in humans.^62-64 Likewise, results from case-control studies suggest that HMGCoA reductase inhibitors do not offer a significant benefit.^65,66

Smoking cessation, on the other hand, can help to erase some of the tobacco-associated bladder cancer risks, especially when the user quits prior to disease onset. The risk of developing bladder cancer in former smokers decreases with time since quitting but they still maintain a higher risk when compared to never smokers, though, this is approximately 50% less than that of current smokers.^37,67-69 Smoking status remains important even after bladder cancer has developed, as former smokers who quit at least 1 year prior to bladder cancer diagnosis appear to have a lower recurrence risk when compared to more recent former smokers and current smokers, but some studies have only found a difference for patients who quit more than 10 years before.^70,71

Cannabis may possess antineoplastic properties based on inhibition of tumor growth and pro-apoptotic effects seen in the laboratory, but supporting clinical data is currently lacking.^72-74  A slightly higher incidence of bladder cancer was noted in non-smokers (neither tobacco nor cannabis) when compared to cannabis users (0.4% v. 0.3%, respectively) in one large cohort study, translating into a relative risk of 0.55 (p=0.048) on multivariate analysis, though only age, race, and BMI were used as co-variables.⁷⁵ Conversely, a much smaller case-control study of Vietnam-era veterans found increased rates of habitual marijuana use among bladder cancer patients (88.5%) when compared to matched controls (69.2%), though tobacco use was equal among both groups.⁷⁶

Proposed dietary factors offering a protective effect include increased fluid intake, fruits, vegetables, vitamin supplements (A, C, & D), selenium, and other antioxidants.⁶⁷ Randomized controlled trials are lacking in this arena and systematic reviews of retrospective, case-control studies have yielded mixed results, so no definitive conclusions can be drawn at this time.^40,77,78

Summary/Conclusions:

• Bladder cancer is a leading malignancy worldwide but incidence is disproportionately higher among more developed nations, including the US.
• The most important recognized risk factor is cigarette smoking, but despite declining rates of smoking, bladder cancer incidence has declined only slightly, owing to the long lead time and potentially increased carcinogenicity of modern tobacco products.
• Men continue to have a 3-4 fold higher lifetime risk even though the gender gap for smoking has narrowed significantly, raising the possibility of a hormonal influence
• Other environmental risks are largely related to occupational exposures to carcinogenic compounds (i.e. aromatic amines).
• Lifestyle factors and chemoprevention may be able to reduce bladder cancer risk but currently available literature is inconclusive
• Smoking cessation substantially lowers lifetime risk, though not reaching the same level as a never smoker.

Written by: Justin T. Matulay, MD, and Ashish Kamat, MD, MBBS

References:

1. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. 2013; http://globocan.iarc.fr. Accessed 8/8, 2018.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30.
3. Surveillance, Epidemiology, and End Results (SEER) Research Data (1973-2015). 2018; https://www.seer.cancer.gov. Accessed 8/10, 2018.
4. Hemelt M, Yamamoto H, Cheng KK, Zeegers MPA. The effect of smoking on the male excess of bladder cancer: A meta-analysis and geographical analyses. International Journal of Cancer. 2009;124(2):412-419.
5. Hartge P, Harvey EB, Linehan WM, et al. Unexplained Excess Risk of Bladder Cancer in Men. JNCI: Journal of the National Cancer Institute. 1990;82(20):1636-1640.
6. Miyamoto H, Yao JL, Chaux A, et al. Expression of androgen and oestrogen receptors and its prognostic significance in urothelial neoplasm of the urinary bladder. BJU International. 2012;109(11):1716-1726.
7. Tuygun C, Kankaya D, Imamoglu A, et al. Sex-specific hormone receptors in urothelial carcinomas of the human urinary bladder: A comparative analysis of clinicopathological features and survival outcomes according to receptor expression. Urologic Oncology: Seminars and Original Investigations. 2011;29(1):43-51.
8. Shen SS, Smith CL, Hsieh J-T, et al. Expression of estrogen receptors-α and -β in bladder cancer cell lines and human bladder tumor tissue. Cancer. 2006;106(12):2610-2616.
9. Boorjian S, Ugras S, Mongan NP, et al. Androgen receptor expression is inversely correlated with pathologic tumor stage in bladder cancer. Urology. 2004;64(2):383-388.
10. Dobruch J, Daneshmand S, Fisch M, et al. Gender and Bladder Cancer: A Collaborative Review of Etiology, Biology, and Outcomes. Eur Urol. 2016;69(2):300-310.
11. Messer JC, Shariat SF, Dinney CP, et al. Female gender is associated with a worse survival after radical cystectomy for urothelial carcinoma of the bladder: A competing risk analysis. Urology. 2014;83(4):863-867.
12. Kluth LA, Rieken M, Xylinas E, et al. Gender-specific Differences in Clinicopathologic Outcomes Following Radical Cystectomy: An International Multi-institutional Study of More Than 8000 Patients. European Urology. 2014;66(5):913-919.
13. Tilki D, Svatek RS, Novara G, et al. Stage pT0 at Radical Cystectomy Confers Improved Survival: An International Study of 4,430 Patients. The Journal of Urology. 2010;184(3):888-894.
14. Tilki D, Reich O, Svatek RS, et al. Characteristics and Outcomes of Patients With Clinical Carcinoma In Situ Only Treated With Radical Cystectomy: An International Study of 243 Patients. The Journal of Urology. 2010;183(5):1757-1763.
15. Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder Cancer Incidence and Mortality: A Global Overview and Recent Trends. Eur Urol. 2017;71(1):96-108.
16. Regidor E, Gutiérrez-Fisac J, De los Santos Ichaso M, Fernández E. Trends in principal cancer risk factors in Spain. Annals of oncology. 2010;21(suppl_3):iii37-iii42.
17. Regidor E, Gutierrez-Fisac JL, Calle ME, Navarro P, Domı́nguez V. Trends in Cigarette Smoking in Spain by Social Class. Preventive Medicine. 2001;33(4):241-248.
18. Salem HK, Mahfouz S. Changing Patterns (Age, Incidence, and Pathologic Types) of Schistosoma-associated Bladder Cancer in Egypt in the Past Decade. Urology. 2012;79(2):379-383.
19. Gouda I, Mokhtar N, Bilal D, El-Bolkainy T, El-Bolkainy NM. Bilharziasis and bladder cancer: a time trend analysis of 9843 patients. Journal of the Egyptian National Cancer Institute. 2007;19(2):158-162.
20. Burger M, Catto JW, Dalbagni G, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013;63(2):234-241.
21. Underwood W, 3rd, Dunn RL, Williams C, Lee CT. Gender and geographic influence on the racial disparity in bladder cancer mortality in the US. J Am Coll Surg. 2006;202(2):284-290.
22. Mallin K, David KA, Carroll PR, Milowsky MI, Nanus DM. Transitional cell carcinoma of the bladder: racial and gender disparities in survival (1993 to 2002), stage and grade (1993 to 2007). J Urol. 2011;185(5):1631-1636.
23. Scosyrev E, Noyes K, Feng C, Messing E. Sex and racial differences in bladder cancer presentation and mortality in the US. Cancer. 2009;115(1):68-74.
24. Yee DS, Ishill NM, Lowrance WT, Herr HW, Elkin EB. Ethnic differences in bladder cancer survival. Urology. 2011;78(3):544-549.
25. DeDeugd C, Miyake M, Palacios DA, Rosser CJ. The Influence of Race on Overall Survival in Patients with Newly Diagnosed Bladder Cancer. J Racial Ethn Health Disparities. 2015;2(1):124-131.
26. Cumberbatch MG, Cox A, Teare D, Catto JW. Contemporary Occupational Carcinogen Exposure and Bladder Cancer: A Systematic Review and Meta-analysis. JAMA Oncol. 2015;1(9):1282-1290.
27. Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502(7471):333-339.
28. Freedman ND, Silverman DT, Hollenbeck AR, Schatzkin A, Abnet CC. Association between smoking and risk of bladder cancer among men and women. Jama. 2011;306(7):737-745.
29. Hoffmann D, Hoffmann I, El-Bayoumy K. The less harmful cigarette: a controversial issue. a tribute to Ernst L. Wynder. Chem Res Toxicol. 2001;14(7):767-790.
30. Cheng T. Chemical evaluation of electronic cigarettes. Tob Control. 2014;23 Suppl 2:ii11-17.
31. Fuller TW, Acharya AP, Meyyappan T, et al. Comparison of Bladder Carcinogens in the Urine of E-cigarette Users Versus Non E-cigarette Using Controls. Sci Rep. 2018;8(1):507.
32. Hecht SS, Carmella SG, Kotandeniya D, et al. Evaluation of toxicant and carcinogen metabolites in the urine of e-cigarette users versus cigarette smokers. Nicotine Tob Res. 2015;17(6):704-709.
33. Lee HW, Park SH, Weng MW, et al. E-cigarette smoke damages DNA and reduces repair activity in mouse lung, heart, and bladder as well as in human lung and bladder cells. Proc Natl Acad Sci U S A. 2018;115(7):E1560-E1569.
34. Bosetti C, Boffetta P, La Vecchia C. Occupational exposures to polycyclic aromatic hydrocarbons, and respiratory and urinary tract cancers: a quantitative review to 2005. Ann Oncol. 2007;18(3):431-446.
35. Letasiova S, Medve'ova A, Sovcikova A, et al. Bladder cancer, a review of the environmental risk factors. Environ Health. 2012;11 Suppl 1:S11.
36. Rota M, Bosetti C, Boccia S, Boffetta P, La Vecchia C. Occupational exposures to polycyclic aromatic hydrocarbons and respiratory and urinary tract cancers: an updated systematic review and a meta-analysis to 2014. Arch Toxicol. 2014;88(8):1479-1490.
37. Zeegers MP, Tan FE, Dorant E, van Den Brandt PA. The impact of characteristics of cigarette smoking on urinary tract cancer risk: a meta-analysis of epidemiologic studies. Cancer. 2000;89(3):630-639.
38. Meliker JR, Nriagu JO. Arsenic in drinking water and bladder cancer: review of epidemiological evidence. Trace Metals Other. 2007;9:551-584.
39. Saint-Jacques N, Parker L, Brown P, Dummer TJ. Arsenic in drinking water and urinary tract cancers: a systematic review of 30 years of epidemiological evidence. Environ Health. 2014;13:44.
40. Al-Zalabani AH, Stewart KF, Wesselius A, Schols AM, Zeegers MP. Modifiable risk factors for the prevention of bladder cancer: a systematic review of meta-analyses. Eur J Epidemiol. 2016;31(9):811-851.
41. Crippa A, Larsson SC, Discacciati A, Wolk A, Orsini N. Red and processed meat consumption and risk of bladder cancer: a dose-response meta-analysis of epidemiological studies. Eur J Nutr. 2018;57(2):689-701.
42. Li F, An S, Hou L, Chen P, Lei C, Tan W. Red and processed meat intake and risk of bladder cancer: a meta-analysis. Int J Clin Exp Med. 2014;7(8):2100-2110.
43. Andreatta MM, Munoz SE, Lantieri MJ, Eynard AR, Navarro A. Artificial sweetener consumption and urinary tract tumors in Cordoba, Argentina. Prev Med. 2008;47(1):136-139.
44. Moller-Jensen O, Knudsen JB, Sorensen BL, Clemmesen J. Artificial sweeteners and absence of bladder cancer risk in Copenhagen. Int J Cancer. 1983;32(5):577-582.
45. Morrison AS, Buring JE. Artificial sweeteners and cancer of the lower urinary tract. N Engl J Med. 1980;302(10):537-541.
46. Garcia-Closas M, Malats N, Silverman D, et al. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet. 2005;366(9486):649-659.
47. Moore LE, Baris DR, Figueroa JD, et al. GSTM1 null and NAT2 slow acetylation genotypes, smoking intensity and bladder cancer risk: results from the New England bladder cancer study and NAT2 meta-analysis. Carcinogenesis. 2011;32(2):182-189.
48. Gu J, Wu X. Genetic susceptibility to bladder cancer risk and outcome. Per Med. 2011;8(3):365-374.
49. Rothman N, Garcia-Closas M, Chatterjee N, et al. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat Genet. 2010;42(11):978-984.
50. Michaud DS. Chronic inflammation and bladder cancer. Urol Oncol. 2007;25(3):260-268.
51. Vermeulen SH, Hanum N, Grotenhuis AJ, et al. Recurrent urinary tract infection and risk of bladder cancer in the Nijmegen bladder cancer study. Br J Cancer. 2015;112(3):594-600.
52. Clouston D, Lawrentschuk N. Metaplastic conditions of the bladder. BJU Int. 2013;112 Suppl 2:27-31.
53. Mostafa MH, Sheweita SA, O'Connor PJ. Relationship between schistosomiasis and bladder cancer. Clin Microbiol Rev. 1999;12(1):97-111.
54. Lewis JD, Habel LA, Quesenberry CP, et al. Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes. JAMA. 2015;314(3):265-277.
55. Tuccori M, Filion KB, Yin H, Yu OH, Platt RW, Azoulay L. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ. 2016;352:i1541.
56. Tang H, Shi W, Fu S, et al. Pioglitazone and bladder cancer risk: a systematic review and meta-analysis. Cancer Med. 2018;7(4):1070-1080.
57. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279-1289.
58. Erdmann E, Harding S, Lam H, Perez A. Ten-year observational follow-up of PROactive: a randomized cardiovascular outcomes trial evaluating pioglitazone in type 2 diabetes. Diabetes Obes Metab. 2016;18(3):266-273.
59. Talar-Williams C, Hijazi YM, Walther MM, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med. 1996;124(5):477-484.
60. Travis LB, Curtis RE, Glimelius B, et al. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma. J Natl Cancer Inst. 1995;87(7):524-530.
61. Wallis CJ, Mahar AL, Choo R, et al. Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis. BMJ. 2016;352:i851.
62. Elwood PC, Gallagher AM, Duthie GG, Mur LA, Morgan G. Aspirin, salicylates, and cancer. Lancet. 2009;373(9671):1301-1309.
63. Nicastro HL, Grubbs CJ, Margaret Juliana M, et al. Preventive effects of NSAIDs, NO-NSAIDs, and NSAIDs plus difluoromethylornithine in a chemically induced urinary bladder cancer model. Cancer Prev Res (Phila). 2014;7(2):246-254.
64. Sabichi AL, Lee JJ, Grossman HB, et al. A randomized controlled trial of celecoxib to prevent recurrence of nonmuscle-invasive bladder cancer. Cancer Prev Res (Phila). 2011;4(10):1580-1589.
65. Cholesterol Treatment Trialists C, Emberson JR, Kearney PM, et al. Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One. 2012;7(1):e29849.
66. Crivelli JJ, Xylinas E, Kluth LA, et al. Effect of statin use on outcomes of non-muscle-invasive bladder cancer. BJU Int. 2013;112(2):E4-12.
67. Kwan ML, Garren B, Nielsen ME, Tang L. Lifestyle and nutritional modifiable factors in the prevention and treatment of bladder cancer. Urol Oncol. 2018.
68. van Osch FH, Jochems SH, van Schooten FJ, Bryan RT, Zeegers MP. Quantified relations between exposure to tobacco smoking and bladder cancer risk: a meta-analysis of 89 observational studies. Int J Epidemiol. 2016;45(3):857-870.
69. Baris D, Karagas MR, Verrill C, et al. A case-control study of smoking and bladder cancer risk: emergent patterns over time. J Natl Cancer Inst. 2009;101(22):1553-1561.
70. Rink M, Furberg H, Zabor EC, et al. Impact of smoking and smoking cessation on oncologic outcomes in primary non-muscle-invasive bladder cancer. Eur Urol. 2013;63(4):724-732.
71. Simonis K, Shariat SF, Rink M, Urothelial Cancer Working Group of the Young Academic Urologists Working Party of the European Association of U. Smoking and smoking cessation effects on oncological outcomes in nonmuscle invasive bladder cancer. Curr Opin Urol. 2014;24(5):492-499.
72. Orellana-Serradell O, Poblete CE, Sanchez C, et al. Proapoptotic effect of endocannabinoids in prostate cancer cells. Oncol Rep. 2015;33(4):1599-1608.
73. Sreevalsan S, Joseph S, Jutooru I, Chadalapaka G, Safe SH. Induction of apoptosis by cannabinoids in prostate and colon cancer cells is phosphatase dependent. Anticancer Res. 2011;31(11):3799-3807.
74. Gasperi V, Evangelista D, Oddi S, et al. Regulation of inflammation and proliferation of human bladder carcinoma cells by type-1 and type-2 cannabinoid receptors. Life Sci. 2015;138:41-51.
75. Thomas AA, Wallner LP, Quinn VP, et al. Association between cannabis use and the risk of bladder cancer: results from the California Men's Health Study. Urology. 2015;85(2):388-392.
76. Chacko JA, Heiner JG, Siu W, Macy M, Terris MK. Association between marijuana use and transitional cell carcinoma. Urology. 2006;67(1):100-104.
77. Liu H, Wang XC, Hu GH, et al. Fruit and vegetable consumption and risk of bladder cancer: an updated meta-analysis of observational studies. Eur J Cancer Prev. 2015;24(6):508-516.
78. 78. Xu C, Zeng XT, Liu TZ, et al. Fruits and vegetables intake and risk of bladder cancer: a PRISMA-compliant systematic review and dose-response meta-analysis of prospective cohort studies. Medicine (Baltimore). 2015;94(17):e759.

Expert Commentary: Adjuvant chemotherapy in patients with urothelial carcinoma and adverse pathologic features receiving prior neoadjuvant chemotherapy and radical cystectomy

Expert Commentary: Multi Receptor Tyrosine Kinase Inhibitor Pazopanib Versus Weekly Paclitaxel In Relapsed Or Progressive Urothelial Cancer

Expert Commentary:Contemporary use trends and survival outcomes in patients undergoing radical cystectomy or bladder-preservation therapy for muscle-invasive bladder cancer

Factors Associated with Recurrence in Primary Carcinoma in situ of the Bladder Treated with Bacillus Calmette-Guérin - Expert Commentary

First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study

FOXA1 and Oncogenic HRAS are Required for Maintenance of Urothelial Hyperplasia - Expert Commentary

Gene Methylation and Urine Cytology to Monitor Bladder Cancer - Expert Commentary

Identification of key pathways and genes influencing prognosis in bladder urothelial carcinoma.

Immune Phenotype of Peripheral Blood Mononuclear Cells in Patients with High-risk Non-muscle Invasive Bladder Cancer - Expert Commentary

Immunohistochemical and molecular characterizations in urothelial carcinoma of bladder in patients less than 45 years.

Impact of divergent differentiation in urothelial carcinoma on oncological outcome in patients with T1 high-grade bladder cancer.

Implications of Micropapillary Urothelial Carcinoma Variant on Prognosis Following Radical Cystectomy: A Multi-Institutional Investigation – Beyond the Abstract