The Muscle-Invasive and Metastatic Bladder Cancer (MIBC) Modern Diagnosis and Treatment

Semir A. S. Al Samarrai

1) Epidemiology:

Bladder Cancer (BC) is the most common malignancy of the urinary tract and seventh most common cancer in men and the 17th in woman (1). Incidence varies between regions and countries (2). The world global age standardized mortality rate is 3 for men versus 1 per 100,000 for women (1). The incidence of BC has decreased in some registries possibly reflecting decreased impact of causative agents, mainly smoking and occupational exposure (4).

The mortality of BC has also decreased possibly reflecting increased standard of care (5).

Approximately 75% of patients with BC present with a disease that confined to the mucosa (Stage Ta, CIS) or submucosa (Stage 1). These categories are grouped as non-muscle-invasive bladder cancer (NMIBC). Non-muscle invasive BC has a high prevalence due to low progression rates and long-term survival in many cases. Patients with muscle-invasive bladder cancer (MIBC) are at higher risk of cancer-specific mortality (3). The prevalence of BC is among the highest of all urological malignancies (1).

2) Risk Factors:

Increasing evidence suggests that genetic predisposition has a significant influence on bladder cancer incidence especially via its impact on susceptibility to other risk factors (3, 6). Tobacco smoking is the most important risk factor for BC, accounting for ?50% of cases (3, 7). Tobacco smoke contains aromatic amines and polycyclic aromatic hydrocarbons, which are renally excreted. Occupational exposure to aromatic amines, polycyclic aromatic hydrocarbons and chlorinated hydrocarbons is the second most important risk factor for BC, accounting in the modern era for ?10% of all cases. Such occupational exposure occurs mainly in industrial branches processing paints, dye, metal and petroleum products (3, 8-10).

The relation between the personal hair dye use and BC risk remains uncertain; increased risk has been suggested in users of permanent hair dyes with NAT2 slow acetylation phenotype (12, 13).


A papillary Bladder tumour confined to the interior layer (Mucosa) is classified as stage (Ta) according to the tumor, Node, Metastasis (TNM) classification system. Tumours that have invaded the inner layer (lamina propia) once classified as Stage T1. Ta and T1 tumours can be removed by transurethral resection (TUR), and therefore they are grouped under the heading of Non-Muscle-Invasive Bladder Cancer (NMIBC) for therapeutic purposes. Also included under this heading are flat, high-grade tumours that are confined to the interior layer (mucosa), and classified as CIS (Tis). However, molecular biology techniques and clinical experience have demonstrated the highly malignant potential of CIS and T1 lesions. Therefore, the terms NMIBC and superficial BC are suboptimal descriptions.

The tumour stage and grade should be used for therapeutic purposes.

The histological grading of all bladder urothelial carcinomas was proposed and published by the WHO in 2004 (15, 16), this classification includes the flat lesions as urothelial hyperplasia, reactive urothelial atypia, dysplasia and CIS. Among Non-Invasive papillary urothelial lesions, the 2004 WHO grading differentiates between papillary urothelial neoplasm of low malignant potential (PUNLMP) and low-grade and high-grade urothelial carcinomas.

Papillary urothelial neoplasm of low malignant potential (PUNLMP) are defined as lesions that do not have cytological features of malignancy but show normal urothelial cells in papillary configuration. Although they have a negligible risk for progression, they are not completely benign and still have a tendency to recur. 3) Diagnosis:

A. Patient history should be taken and recorded for all important information with possible connection to Bladder Tumour; including risk factors and history of suspect symptoms.

B. Symptoms: Hematuria is the most common finding in NMIBC. Ta, T1 tumours do not cause bladder pain and rarely present with lower tract symptoms (LUTS). In patients who do complain of these symptoms particularly in these with irritative LUTS refractory to symptomatic treatment, CIS might be suspected.

C. Physical Examination: the physical examination does not reveal NMIBC but only huge urothelial tumour invades the bladderwall and another organs.

D. Imaging:

a) Intravenous Urography (IVU): Large exophytic tumours maybe seen as filling defects in the bladder

b) Computed Tomography (CT): This investigation give more information than IVU does (including status of lymph nodes and neighboring organs)

c) Ultrasonography (US): The US is often used as the initial tool to assess the urinary tract. The transabdominal US permits characterization of renal mass, detection of hydronephrosis, and visualization of intraluminal masses in the bladder. It can be as accurate as IVU for diagnosis of upper urinary tract obstruction (17).

US is therefore a useful tool for detection of obstruction in patients with haematuria, however, it cannot exclude the presence of upper tract tumours.

CIS cannot be diagnosed with imaging methods (IVU, CT urography or US).

d) Urinary Cytology: Examination of voided urine or bladder-washing specimens for exfoliated cells has high sensitivity in low-grade-tumour. As a result of loss of cell cohesion in the epithelial lining of the bladder in CIS, there is a larger number of floating cells in the urine, as well as a high degree of anaplasia. The sensitivity of cytology for CIS detection in 28-100% (18).

Cytology is thus useful when a high-grade malignancy or CIS is present. Positive voided urinary cytology can indicate a urothelial tumour anywhere in the urinary tract, from the calyx to the ureters, bladder, and proximal urethra.

Negative cytology, however, does not exclude the presence of a tumour in the urinary tract.

e) Urinary molecular marker test: Driven by the low sensitivity of urine cytology, extensive laboratory research has developed numerous urinary tests for BC detection (19-25).

Considering the frequency of cystoscopy for follow-up, markers for recurrent urothelial cancer would be especially useful.

Microsatellite analysis is the most promising of the methods listed in the Table below (26-28).

g) Transurethral resection of Ta, T1 bladder tumours: The goal of the TURB in Ta, T1 BC is to make the correct diagnosis and remove all visible lesions.

It is crucial procedure in the diagnosis and treatment of BC.

The strategy of resection depends on the size of the lesion. Small tumours (<1cm) can be resected en bloc, which includes the entire tumour and part of the underlying bladder wall. Larger tumours should be resected separately in fractions, including the exophytic part of the tumour, the underlying bladder wall with the Bladderwall (detrusor) muscle, and the edges of the resection area. This approach provides good information about the vertical and horizontal extent of the tumour and helps to improve resection completeness (32).

Deep resection is not necessary in small, apparently low-grade lesions with previous history of low-grade Ta (GI) tumour.

The specimens from different biopsies and resection fractions must be referred to the pathologist in separate containers and labeled separately, to enable him/her to make a correct diagnosis. Complete and correct TURB is essential to achieve a good prognosis (33). It has been confirmed that absence of detrusor muscle in the specimen is associated with a significantly higher risk of residual disease and early recurrence (34).

h) New TURB techniques: Compared to monopolar resection, the bipolar electrocautery system may reduce the risk of complications (e.g., bladder perforation � due to obturator nerve stimulation) (35).

i) New methods of tumour visualization: As a standard procedure, cystoscopy and TUR are performed using white light. However, the use of white light can lead to missing lesions that are present but not visible, which is why new techniques are being developed.

Photodynamic diagnosis (fluorescence cystoscopy)

Photodynamic diagnosis (PDD) is performed using violet light after intravesical instillation of 5-amino-laevulinic acid (ALA) or hexaminolaevulinic acid (HAL). It has been confirmed that fluorescence-guided biopsy and resection are more sensitive than conventional procedures for detection of malignant tumour, particularly for CIS (36, 37).

In summary, PDD improves tumour detection rate, particularly in CIS. HAL but not ALA fluorescence-guided TURB was shown to have a beneficial effect on disease recurrence rate.

j) Second resection: The significant risk of residual tumour after initial TURB of Ta, T1 lesions has been demonstrated (33, 38). Persist disease after resection of T1 tumours has been observed in 33-53% of patients (38-43). Moreover, the tumour is often understaged by initial resection. The likelihood that a T1 tumour has been understaged and muscle-invasive disease detected by second resection ranges from 4 to 25%.

There is no consensus about the strategy and timing of second TURB. Most authors recommend resection at 2-6 weeks after initial TURB. The procedure should include resection of the primary tumour sites.

Adjuvant Treatment

Although state-of-the-art TUR by itself can eradicate a Ta, T1 tumour (NMIBC) completely, these tumours commonly recur and can progress to Muscle-Invasive Bladder Tumour (MIBC). The high variability in the 3-month recurrence rate indicate that TUR is incomplete on provokes recurrences in a high percentage of patients (33). It is therefore necessary to consider adjuvant therapy in all patients.

The Intravesical Bacillus Calmette-Guerin (BCG) immunotherapy

Five meta-analysis has confirmed that BCG after TUR is superior to TUR alone or TUR and chemotherapy for prevention of recurrence of non-muscle-invasive tumours (46, 47-50).

Induction BCG instillations are classically given according the empirical 6-weekly schedule that was introduced by Morales in 1976 (51). For optimal efficacy, BCG must be given in a maintenance schedule (44-46, 50). Many different maintenance schedules have been used, ranging from total of 10 instillations given in 18-weeks, to 27 over 3 years.


1. Ferlay J, S.H., Bray F, Forman D, et al. Globocan 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 2010, International Agency for Research on Cancer: Lyon, France
2. Ploeg M, Aben KKH, Kiemeney LA. The present and future burden of urinary bladder cancer in the world. World J Urol 2009 Jun;27(3): 289-93.
3. Burger M, Catto JW, Dalbagni G, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol 2013 Feb;63(2): 234-41.
4. Bosetti C, et al. Trends in mortality from urologic cancers in Europe, 1970-2008. Eur Urol, 2011. 60(1): p. 1-15.
5. Ferlay J., Randi G, Bosetti C, et al., Declining mortality from bladder cancer in Europe. BJU Int 2008 Jan. 101(1):11-9.
6. Rafnar T, Vermeulen SH, Sulem P, et al. European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene. Hum Mol Genet 2011 Nov 1;20(21):4268-81.
7. Freedman ND, Silverman DT, Hollenbeck AR, et al. Association between smoking and risk of bladder cancer among men and women. JAMA 2011 Aug 17;306(7):737-45.
8. Rushton L, Bagga S, Bevan R, et al. Occupation and cancer in Britain. Br J Cancer 2010 Apr 27;102(9):1428-37.
9. Rushton L, Hucthings SJ, Fortunato L, et al. Occupational cancer burden in Great Britain. Br J Cancer 2012 Jun 19;107 Suppl 1:S3-S7.
10. Samanic CM, Kogevinas M, Silverman DT, et al. Occupation and bladder cancer in a hospital-based case-control study in Spain. Occup Environ Med 2008 May;65(5):347-53.
12. Koutros S, Silverman DT, Baris D, et al. Hair dye use and risk of bladder cancer in the New England bladder cancer study. Int J Cancer 2011 Dec 15;129(12):2894-904.
13. Ros MM, Gago-Dominguez M, Aben KK, et al. Personal Hair dye use and the risk of bladder cancer: a case-control study from The Netherlands. Cancer Causes Control 2012 Jul;23(7):1139-48.
15. Epstein JI, Amin MB, Reuter VR, et al. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Am J Surg Pathol 1998 Dec;22(12):1435-48.
16. Sauter G, Algaba F, Amin M, et al. Tumours of the urinary system: non-invasive urothelial neoplasias. In: Eble JN, Sauter G, Eipsten JI, Sesterhenn I, eds. WHO classification of classification of tumours of the urinary system and male genital organs. Lyon: IARCC Press, 2004, pp. 29-34.
17. Goessl C, Knispel HH, Millar K, et al. Is routine excretory urography necessary at first diagnosis of bladder cancer? J Urol 1997 Feb;157(2):480-1.
18. T�tu B. Diagnosis of urothelial carcinoma from urine. Mod Pathol 2009 Jun;22 Suppl 2:S53-9.
19. Lokeshwar VB, Habuchi T, Grossman HB, et al. Bladder tumour markers beyond cytology: international consensus panel on bladder tumour markers. Urology 2005 Dec;66(6 Suppl 1):35-63.
20. Glas AS, Roos D, Deutekom M, et al. Tumour markers in the diagnosis of primary bladder cancer. A systemic review. J Urol 2003 Jun;169(6):1975-82.
21. Lotan Y, Roehrborn CG. Sensitivity and specificity of commonly available bladder tumour markers versus cytology: results of a comprehensive literature review and meta-analysis. Urology 2003 Jan;61(1):109-18.
22. Van Rhijn BW, van der Poel HG, van der Kwast TH. Urine markers for bladder cancer surveillance: a systemic review. Eur Urol 2005 Jun;47(6):736-48.
23. Vrooman OPJ, Witjes JA. Urinary markers in bladder cancer. Eur Urol 2008 May;53(5):909-16.
24. Lotan Y, Shariat SF, Schmitz-Drager BJ, et al. Considerations on implementing diagnostic markers into clinical decision making in bladder cancer. Urol Oncol 2010 Jul-Aug;28(4):441-8.
25. Van Rhijn BWG, van der Poel HG, van der Kwast HG. Cytology and urinary markers for the diagnosis of bladder cancer. Eur Urol Suppl 2009;8:536-41.
26. Van der Aa MN, Zwarthoff EC, Steyerberg EW, et al. Microsatellite Analysis of Voided-Urine Samples for Surveillance of Low-Grade Non-Muscle-Invasive Urothelial Carcinoma: Feasibility and Clinical Utility in a Prospective Multicenter Study (Cost-Effectiveness of Follow-up of Urinary Bladder Cancer Trial (CEFUB)). Eur Urol 2009 Mar;55(3):659-67.
27. De Bekker-Grob EW, van der Aa MN, Zwarthoff EC, et al. Non-muscle-invasive bladder cancer surveillance for which cystoscopy is partly replaced by microsatellite analysis of urine: a cost-effective alternative? BJU Int 2009 Jul; 104(1):41-7.
28. Roupr�t M, Hupertan V, Yates DR, et al. A comparison of the performance of microsatellite and methylation urine analysis for predicting the recurrence of urothelial cell carcinoma, and definition of a set of markers by Bayesian network analysis. BJU Int 2008 Jun;101(11):1448-53.
29. Kurth KH, Schellhammer PF, Okajima E, et al. Current methods of assessing and treating carcinoma in situ of the bladder with or without involvement of the prostatic urethra. Int J Urol 1995 Jun;2(Suppl 2):8-22.
30. Aaronson DS, Walsh TJ, Smith JF, et al. Meta-analysis: does lidocaine gel before flexible cystoscopy provide pain relief? BJU Int 2009 Aug;104(4):506-9; discussion 509-10.
31. Blick CG, Nazir SA, Mallett S, et al. Evaluation of diagnostic strategies for bladder cancer using computed tomography (CT) urography, flexible cystoscopy and voided urine cytology: results for 778 patients from a hospital haematuria clinic. BJU Int 2012 Jul;110(1):84-94.
32. Richterstetter M, Wullich B, Amann K, et al. The value of extended transurethral resection of bladder tumour (TURBT) in the treatment of bladder cancer. BJU Int 2012 Jul;110(2 Pt 2):E76-9.
33. Brausi M, Collette L, Kurth K, et al; EORTC Genito-Urinary Tract Cancer Collaborative Group. Variability in the recurrence Rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies . Eur Urol 2002 May;41(5):523-31.
34. Mariappan P, Zachou A, Grigor KM. Detrusor muscle in the first, apparently complete transurethral resection of bladder tumour specimen is a surrogate marker of resection quality, predicts risk of early recurrence, and is dependent on operator experience. Eur Urol 2010 May;57(5):843-9.
35. Gupta NP, Nayyar R, Hemal AK, et al. Outcome analysis of robotic pyeloplasty: a large single-centre experience. BJU Int 2010 Apr;105(7):980-3.
36. Kausch I, Sommerauer M, Montorsi F, et al. Photodynamic diagnosis in non-muscle-invasive bladder cancer: a systemic review and cumulative analysis of prospective studies. Eur Urol 2010 Apr;57(4):595-606.
37. Mowatt G, N�Dow J, Vale L, et al; Aberdeen technology Assessment Review (TAR) Group. Photodynamic diagnosis of bladder cancer compared with white light cystoscopy: saystemic review and meta-analysis. Int J Technol Assess Health Care 2011 Jan;27(1):3-10.
38. Miladi M, Peyromaure M, Zerbib M, et al. The value of a second transurethral resection in evaluating patients with bladder tumours. Eur Urol 2003 Mar;43(3):241-5.
39. Brauers A, Buettner R, Jakse G. Second resection and prognosis of primary bladder cancer: is cystectomy often too early? J Urol 2001 Mar;165(3):808-10.
40. Schips L, Augustin H, Zigeuner RE, et al. Is repeated transurethral resection justified in patients with newly diagnosed superficial bladder cancer? Urology 2002 Feb;59(2):220-3.
41. Grimm M-O, Steinhoff Ch, Simon X, et al. Effect of routine repeat transurethral resection for superficial bladder cancer: a long-term observational study. J Urol 2003 Aug;170(2 Pt 1):433-7.
42. Divrik RT, Yildirim ?, Zorlu F, et al. The effect of repeat transurethral resection on recurrence and progression artes in patients with T1 tumours of the bladder who received intravesical mitomycin: a prospective, randomized clinical trial. J Urol 2006 May;175(5):1641-4.
43. Jahnson S, Wiklund F, Duchek M, et al. Results of second-look resection after primary resection of T1 tumourof the urinary bladder. Scand J Urol Nephrol 2005;39(3):206-10.
44. B?hle A, Bock PR. Intravesical bacillus Calmette-Guerin versus mitomycin C in superficial bladder cancer: formal meta-analysis of comparative studies on tumour progression. Urology 2004 Apr;63(4):682-6. Discussion 686-7.
45. Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol 2002 Nov;168(5):1964-70.
46. Malmstr?m P-U, Sylvester RJ, Crawford DE, et al. An individual patient data meta-analysis of the long-term outcome of randomized studies comparing intravesical mitomycin C versus bacillus Calmette-Gu�rin for non-muscle-invasive bladder cancer. Eur Urol 2009 Aug;56(2):247-56.
47. Shelley MD, Kynaston H, Court J, et al. A systematic review of intravesical bacillus Calmette-Gu�rin plus transurethral resection vs transurethral resection alone in Ta and T1 bladder cancer. BJU Int 2001 Aug;88(3):209-16.
48. Han RF, pan JG. Can intravesical bacillus Calmette-Gu�rin reduce recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology 2006 Jun;67(6):1216-23.
49. Shelley MD, Wilt TJ, Court J, et al. Intravesical bacillus Calmette-Gu�rin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a metaanalysis of randomized trials. BJU Int 2004 Mar;93(4):485-90.
50. B?hle A, Jocham D, Bock PR. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol 2003 Jan;169(1):90-5.
51. Morales, A, Eidinger D, Bruce AW. Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol 1976 Aug;116(2):180-3.


Professor Doctor of Medicine-Urosurgery, Andrology, and Male Infertility
Dubai Healthcare City, Dubai, United Arab Emirates.
Mailing Address: Dubai Healthcare City, Bldg. No. 64, Al Razi building, Block D,
2nd floor, Dubai, United Arab Emirates, PO box 13576