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

Semir A. S. Al Samarrai

Bladder cancer is the ninth most common cancer diagnosis worldwide, with more than 330,000 new cases each year and more than 130,000 deaths per year, with an estimated male-female ration of 3.8:1.0 (1). At any point in time, 2.7 million people have a history of urinary bladder cancer (1). At the initial diagnosis of bladder cancer 70% of cases are diagnosed as non-muscle-invasive bladder cancer (NMIBC) and approximately 30% as muscle-invasive bladder cancer (MIBC).

Among patients treated with radical cystectomy because of MIBC, 57% had muscle invasion at presentation, while 45% were initially diagnosed with NMIBC that progressed despite organ-preserving treatment (2). Approximately one third of patients diagnosed with MIBC have undetected metastasis at the time of treatment for the primary tumour (3), while 25% of patients who undergo radical cystectomy present with lymph node involvement at the time of surgery.

Risk factors for bladder cancer:

Tobacco smoking is the most well-established risk factor for bladder cancer causing 50-55% of male cases and 20-30% female cases (4), occupational exposure to chemicals is the second most important risk factor for bladder cancer, Radiotherapy, Bladder schistosomiasis, chronic urinary tract infection and chemotherapy were mentioned in Part I of Bladder Cancer Review Article as the most common risk factors for bladder cancer.

Differences in the gender prevalence of bladder cancer may be due to other factors besides tobacco and chemical exposure. In a large prospective cohort study, postmenopausal status was associated with an increase in bladder cancer risk even after adjustment for smoking status.

Synchronous and metachronous upper tract tumours. In some case, there is an association between upper tract urothelial carcinoma (UTUC) and bladder cancer. The incidence of UTUC after a diagnosis of NMIBC has been reported to be between 1.7% and 26%. Although synchronous UTUC and NMIBC are uncommon, 46% of UTUC are invasive.


The tumour, node, metastasis classification (TNM) of malignant tumours is the method most widely used to classify the extent of cancer spread.

The 2004 WHO grading differentiates between papilloma, papillary urothelial neoplasms of low malignant potential (PUNLMP), and low-grade and high-grade urothelial carcinomas. Papilloma is composed of a delicate fibrovascular core covered by normal urothelium. PUNLMP is defined as a papillary fibrovascular growth covered with proliferated urothelium, exceeding the normal thickness. Although (PUNLMPs) have a negligible risk of progression, they are not completely benign and have a tendency to recur (5). The low-grade papillary urothelial carcinoma group includes the majority of former grade 1 (WHO 1973), so that tumours should be graded using both the 1973 and the 2004 WHO classification (6).

Diagnosis and Staging:

  1. Primary diagnosis: symptoms are: Painless haematuria is the most common presenting complaint. Others include urgency, dysuria, and increased frequency and, in more advanced tumours, pelvic pain and symptoms related to urinary tract obstruction.
  2. Physical examination: this should include rectal and vaginal bimanual palpation. A palpable pelvic mass can be found in patients with locally advanced tumours.
  3. Bladder Imaging: Patients with a bladder mass identified by any diagnostic imaging technique should undergo cystoscopy, biopsy and or resection for histopathological diagnosis and staging.
  4. Urinary cytology and urinary markers: Examination of a voided urine or bladder-washings of exfoliated cancer cells has high sensitivity in high grade tumours (7).
  5. Cystoscopy: Ultimately, the diagnosis of bladder cancer is made by cystoscopy and histopathological evaluation of resected tissue. Cystoscopy is initially performed in the office using flexible instruments.
  6. Transurethral resection (TUR) of invasive bladder tumours: The goal of TUR is to enable histopathological diagnosis and staging, which requires the inclusion of bladder muscle in the resection biopsies. Bladder tumours are often multifocal and can be accompanied by CIS (Carcinoma in Situ) or dysplasia. The biopsies from normal-looking mucosa of the bladder in patients with invasive bladder tumours, so called random biopsies (R-biopsies) show a low yield (8).
  7. Second TUR: There is significant risk of leaving residual tumour in the bladder after the initial TUR (9, 10). Residual disease is observed in 33-53 % of patients (10-16).
    The tumour may be understaged by the initial TUR. There is a 4-25% probability by that tumours initially staged as non-muscle invasive (NMIBC) and muscle invasive (MIBC) (11, 12).
    A second TUR should always be performed if the initial resection has been incomplete, e.g. when multiple and/or large tumours are present.
    The timing of the second TUR is mostly recommended at 2-6 weeks after the initial TUR, and the procedure should include a resection of the primary tumour site.
  8. Imaging for staging MIBC: The treatment and prognosis for MIBC is determined by tumour stage and grade (17). In clinical practice, CT and MRI are the imaging techniques used. The imaging parameter are the extent of local tumour invasion, tumour spread to lymph nodes and tumour spread to upper urinary tract and other distant organs (liver, lungs, bones, peritoneum, pleura, adrenal glands and others.

Treatment of Muscle invasive bladder cancer:

The standard treatment for patients with MIBC is radical cystectomy. However this �gold standard� only provides 5-years survival in about 50% of patients (18-22). In order to improve these unsatisfactory results, the use of peri-operative chemotherapy has been explored since 1980s. There are many advantages of administering chemotherapy before planned definitive surgery (or radiation therapy) to patients with operable MIBC with clinically negative nodes (cNO).


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 Bldg., Block D, 2nd Floor, Dubai, United Arab Emirates, PO Box 939004


1. Ploeg M, Aben KK, Kiemeney LA. The present and future burden of urinary bladder cancer in the world. World J Urol 2009 Jun;27(3):289-93.
2. Vaidya A, Soloway MS, Hawke C, et al. De novo muscle invasive bladder cancer: is there a change in trend? J Urol 2001 Jan;165(1):47-50.
3. Prout GR Jr, Griffin PP, Shipley WU. Bladder carcinoma as a systemic disease. Cancer 1979 Jun;43(6):2532-9.
4. 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.
5. Pan CC, Chang YH, Chen KK, et al. Prognostic significance of the 2004 WHO/ISUP classification for prediction of recurrence, progression, and cancer-specific mortality of non-muscle-invasive urothelial tumours of the urinary bladder: a clinicopathologic study of 1,515 cases. Am J Clin Pathol 2010 May;133 (5):788-95.
6. Lopez-Beltran A, Montironi R. Non-invasive urothelial neoplasms: according to the most recent WHO classification. Eur Urol 2004 Aug;46(2):170-6.
7. Raitanen M-P, Aine R, Rintala E, et al. FinnBladder Group. Differences between local and review urinary cytology and diagnosis of bladder cancer. An interobserver multicenter analysis. Eur Urol 2002 Mar;41(3):284-9.
8. May F, Treiber U, Hartung R, et al. Significance of random bladder biopsies in superficial bladder cancer. Eur Urol 2003 Jul;44(1):47-50.
9. Brausi M, Colette 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.
10. 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.
11. Jakse G, Algaba F, Malmstr?m PU, et al. A second-look TUR in T1 transitional cell carcinoma: why? Eur Urol 2004 May;45(5):539-46.
12. Brauers A, Buettner R, Jakse G. Second resection and prognosis of primary high risk superficial bladder cancer: is cystectomy often too early? J Urol 2001 Mar;165(3):808-10.
13. 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.
14. Grimm MO, 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.
15. Divrik RT, Yildirim ?, Zorlu F, et al. The effect of repeat transurethral resection on recurrence and progression rates 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.
16. Jahnson S, Wiklund F, Duchek m, et al. Results of Second-look resection after primary resection of T1 tumour of the urinary bladder. Scand J Urol Nephrol 2005;39(3):206-10.
17. Jewett HJ. Proceedings: Cancer of the bladder. Diagnosis and Staging. Cancer 1973 Nov;32(5):1072-4. [no abstract available]
18. Stein JP, Skinner DG. Radical cystectomy for invasive bladder cancer; long-term results of a standard procedure. World J Urol 2006 Aug;24(3):296-304.
19. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer; long-term results in 1,054 patients. J Clin Oncol 2001 Sep;19(3):666-75.
20. Dalbagni G, Genega E, Hashibe M, et al. Cystectomy for bladder cancer: a contemporary series, J Urol 2001 Apr;165(4):1111-6.
21. Bassi P, Ferrante GD, Piazza N, et al. Prognostic factors of outcome after radical cystectomy for bladder cancer: a retrospective study of a homogeneous patient cohort. J Urol 1999 May;161(5):1494-7.
22. Ghoneim MA, el-Mekresh MM, el-Baz MA, et al. Radical cystectomy for carcinoma of the bladder: critical evaluation of the results in 1,026 cases. J Urol 1997 Aug;158(2):393-9.


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