The vast majority of bladder cancers in the UK are transitional cell tumours. Adenocarcinoma accounts for approximately 2%.¹ Squamous cell tumours usually follow chronic inflammation from stones or indwelling catheters.¹ Small cell carcinomas arise from neuroendocrine stem cells.² Leiomyosarcoma is the most common sarcoma of the bladder whilst rhabdomyosarcoma is most common in children.³ Rare tumours include carcinosarcoma (a mixed tumour) and primary lymphoma.⁴ In developed countries, about 90% of bladder tumours are transitional cell carcinoma with 5% squamous cell carcinoma; however, in developing countries, 75% are squamous cell carcinoma, mostly due to schistosomiasis.⁵

Cancer arising from the transitional cells of the mucosal urothelium may present as a non-invasive, papillary tumour protruding from the mucosal surface, or as a solid, non-papillary tumour that invades the bladder wall and has a high propensity for metastasis. The non-papillary tumours originate from in situ dysplasia. Bladder carcinogenesis appears to be related to clonal expansion of genetically altered but histologically normal cells that cover broad expanses of the mucosa.⁶

In 1973 the World Health Organization (WHO) classified bladder tumours with respect to the degree of anaplasia:⁷

• Grade 1: well differentiated tumour.
• Grade 2: moderately differentiated tumour.
• Grade 3: poorly differentiated tumour.

Epidemiology⁸

• Bladder cancer is a common cancer in the UK. It is the most frequently occurring tumour of the urinary system and accounts for around 1 in every 30 new cases of cancer each year in the UK. Bladder cancer is the 4th most common cancer in men and the 11th most common in women.
• The overall incidence in the UK is 11.4 per 100,000 population.
• The median age at diagnosis is 68. Men outnumber women by 3:1 but women tend to have a poorer prognosis.¹

Risk factors

• About half of bladder cancers are caused by smoking.
• Other risk factors include industrial exposure to aromatic amines in dyes, paints, solvents, leather dust, inks, combustion products, rubber and textiles.
• Environmental pollution, e.g. arsenic-contaminated wells, has been identified as a factor.⁹
• There may be a genetic predisposition.⁶
• Radiation to the pelvis and cyclophosphamide are risks.
• Suggestions of risk from artificial sweeteners have not been substantiated.¹⁰
• Coffee may increase the risk of bladder cancer by 20% but the meta-analysis was unable to establish a dose-related risk.¹¹
• There is a tenuous link between chronic infection and bladder cancer, e.g. HIV and herpes simplex, but further research is required to confirm this.⁵
• There is no increased risk in those who dye their hair.¹²

Presentation

• The presenting feature is painless haematuria that is gross in 80-90%. There is usually no abnormality on standard physical examination. Painless haematuria must be treated as malignancy of the urinary tract until proved otherwise.
• Advanced disease may cause voiding symptoms, although these can even be produced by carcinoma in situ (CIS).
• At diagnosis, only about 5% of patients have metastatic disease, usually to lymph nodes, lung, liver, bone and central nervous system. Around 25% have involvement of the muscle layer. The remaining 70% have superficial disease, of which 10% is CIS.¹

Differential diagnosis¹

• Haemorrhagic cystitis
• Nephrolithiasis
• Renal cell carcinoma
• Urethral trauma
• Urinary tract infection

Investigations¹

The diagnosis mainly depends on the cystoscopic examination of the bladder, biopsy, and urine cytology:⁷

• Urinalysis including culture should be performed to exclude infection.
• FBC should be arranged to exclude anaemia.
• Renal function tests and electrolytes should be arranged.
• Urine cytology may be helpful but negative results do not exclude disease.
• Intravenous pyelogram (IVP) may show a filling defect.
• CT and ultrasound scans are used but they may miss small tumours.
• Cystoscopy permits direct inspection of the bladder and biopsy of suspicious lesions.

The diagnosis of Tis (see 'Staging, below) is based on the histology of biopsies from the bladder wall. Fluorescence cystoscopy improves the detection rate of Tis. Urine cytology is important in the diagnosis and follow-up of Tis because of its high sensitivity and specificity (over 90%).⁷

Investigations for staging the tumour

• T-staging: either MR imaging with fast dynamic contrast-enhancement or CT with contrast enhancement are recommended for patients considered suitable for radical treatment.
• For patients with confirmed muscle-invasive bladder cancer, CT of the chest, abdomen and pelvis is the optimal form of staging, including CT urography for complete examination of the upper urinary tracts.

Staging

The tumour, node and metastasis (TNM) classification is as follows:⁷

• T - primary tumour.
  • Ta: non-invasive papillary carcinoma.
  • Tis: carcinoma in situ (CIS); 'flat tumour'.
  • T1: tumour invades subepithelial connective tissue.
  • T2: tumour invades muscularis.
    • T2a: superficial muscle (inner half).
    • T2b: deep muscle (outer half).
  • T3: tumour invades perivesical tissue (beyond muscularis).
    • T3a: microscopically.
    • T3b: macroscopically (extravesical mass).
  • T4: tumour invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall.
    • T4a: prostate, uterus, or vagina.
    • T4b: pelvic wall or abdominal wall.
• N - lymph nodes.
  • NX: regional lymph nodes cannot be assessed.
  • N0: no regional lymph node metastases.
  • N1: metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac, or presacral).
  • N2: metastases in multiple lymph nodes in the true pelvis (hypogastric, obturator, external iliac, or presacral).
  • N3: metastasis in a common iliac lymph node(s).
• M - distant metastasis.
  • MX: metastasis not assessed.
  • M0: no distant metastasis.
  • M1: distant metastasis.

Some studies suggest that evaluating lymph node density (the ratio of positive lymph nodes to the total number of lymph nodes removed) may be more accurate than TNM classification in predicting disease-specific survival.¹³

Management

Non-invasive tumours⁷

• The standard initial therapy for Ta and T1 papillary bladder tumours is complete macroscopic transurethral resection (TUR) including a part of the underlying muscle. A second TUR should be considered if there is a suspicion that the initial resection was incomplete.
• Adjuvant treatment:
  • There is considerable risk for recurrence and progression of tumours after TUR and so adjuvant intravesical therapy is recommended for all stages (Ta, T1, and Tis).
  • All patients should receive an immediate postoperative instillation of chemotherapy within six hours after TUR, except in cases of bladder perforation or severe bleeding. The choice of drug (mitomycin C, epirubicin, or doxorubicin) is optional.
  • The choice of further intravesical adjuvant therapy depends on the patient's risk of recurrence and progression. Patients with multiple tumours, large tumours (>3 cm), and highly recurrent tumours (>1 recurrence/year) are at the highest risk of recurrence.
  • Patients with stage T1 tumours, high-grade tumours, and Tis have the highest risk of progression.
  • Intravesical chemotherapy reduces the risk of recurrence but not progression and is associated with minor side-effects.
  • Intravesical immunotherapy with BCG (induction and maintenance) is superior to intravesical chemotherapy in reducing recurrences and in preventing or delaying progression to muscle-invasive bladder cancer. However intravesical BCG is more toxic.
  • Cystectomy is indicated in all T1 patients failing intravesical therapy.
• Tis: Tis cannot be eradicated by TUR and further treatment is essential. Close monitoring and repeated intravesical BCG is the treatment of choice. Radical cystectomy may be considered for patients not responding to BCG treatment.

Invasive tumours¹⁴

• TUR in one piece for small tumours (<1 cm), plus a deep resection with part from the underlying bladder muscle. TUR in fractions (including muscle tissue) for larger tumours.
• Cystectomy:
  • Cystectomy is the preferred curative treatment for localised bladder neoplasms. Radical cystectomy includes removal of regional lymph nodes. The terminal ileum and colon are the intestinal segments of choice for urinary diversion.
  • Radical cystectomy is recommended in T2-T4a, N0 M0, and high-risk non-muscle-invasive bladder cancer.
  • Intraoperative red blood cell salvage is an effective technique for blood replacement during radical cystectomy.¹⁵
  • Laparoscopic cystectomy is recommended by the National Institute for Health and Clinical Excellence (NICE) as an alternative to radical cystectomy by open surgery.¹⁶
• An orthotopic bladder substitute should be offered to male and female patients lacking any contra-indications and who have no tumour in the urethra and at the level of urethral dissection.
• Neoadjuvant cisplatin-containing combination chemotherapy improves overall survival by 5-7% at five years, irrespective of the type of definitive treatment. However, neoadjuvant chemotherapy is not recommended in patients with poor performance status and impaired renal function.
• For patients with inoperable locally advanced tumours (T4b), primary radical cystectomy is not a curative option but a palliative cystectomy may be indicated for symptom relief.

Bladder-sparing treatments

• External beam radiotherapy alone should only be considered when the patient is unfit for cystectomy. Radiotherapy can also be used to stop bleeding from the tumour.
• Although cisplatin-based chemotherapy (as primary therapy for locally advanced tumours in highly selected patients) has led to complete and partial local responses, the long-term success rate is low.

Metastatic disease¹⁴

• First-line treatment for 'fit' patients: use cisplatin-containing combination chemotherapy. Carboplatin and non-platinum combination chemotherapy is not recommended.
• First-line treatment in patients ineligible ('unfit') for cisplatin: use carboplatin combination chemotherapy or single agents, preferably with gemcitabine/carboplatin.
• In patients progressing after platinum-based combination chemotherapy for metastatic disease, vinflunine should be offered.

Surveillance for recurrent bladder cancer

Because of the risk of recurrence of bladder tumours, follow-up cystoscopy is recommended. The American Urological Association recommends surveillance every 3-6 months for three years and at least yearly after that.¹⁷

Complications

• Urinary tract infection.
• Urinary retention.
• Hydronephrosis.
• Recurrence of tumour.
• Increased risk of urethral transitional cell carcinoma.
• Complications of surgery include bowel obstruction, obstruction of the ureter, pyelonephritis and infection of the wound.
• Radical cystectomy damages the S2,3,4 outlet and causes complete erectile dysfunction, although a nerve-sparing approach can reduce this to about half.
• Orthotopic bladders have a risk of urinary incontinence.

Prognosis¹

• The recurrence rate for superficial transitional cell cancer of the bladder is high (70% within five years). As many as 80% of patients have at least one recurrence.
• Patients with tumour recurrences within two years have an aggressive tumour and an increased risk of disease progression (especially with recurrences within 3-6 months).
• The most significant prognostic factors for bladder cancer are grade, depth of invasion, and the presence of carcinoma in situ (CIS).
• Patients with superficial tumours have an excellent prognosis with five-year survival rates between 80-90%.⁸
• Patients with muscle-invasive bladder cancer have five-year survival rates of less than 50%.⁸
• Prognosis for metastatic cancer is poor, with only 5-10% of patients living two years after diagnosis.
• CIS alone, or in association with Ta or T1 papillary tumour, carries a poorer prognosis and a recurrence rate of 63-92%. 78% of patients with diffuse CIS progressed to muscle-invasive disease in one study.

Prevention

• One study found that the role of smoking in the development of bladder cancer is poorly understood and healthcare professionals should do more to publicise the link.¹⁸
• Stopping smoking reduces the risk of recurrence.¹⁹
• People should be encouraged to eat more fruit and vegetables and eat less animal fat.²⁰
• The cost-effectiveness of national bladder cancer screening programmes is currently being evaluated.²¹

Document references

1. Steinberg G et al, Bladder Cancer, Medscape, Aug 2011
2. Cheng L, Jones TD, McCarthy RP, et al; Molecular genetic evidence for a common clonal origin of urinary bladder small cell carcinoma and coexisting urothelial carcinoma. Am J Pathol. 2005 May;166(5):1533-9. [abstract]
3. Childhood Rhabdomyosarcoma; US National Cancer Institute 2007
4. Power RE, Kay EW, O'Connell F, et al; Primary lymphoma of the bladder: a report of three cases. Ir J Med Sci. 2001 Jul-Sep;170(3):196-7. [abstract]
5. Abol-Enein H; Infection: is it a cause of bladder cancer? Scand J Urol Nephrol Suppl. 2008 Sep;(218):79-84. [abstract]
6. Crawford JM; The origins of bladder cancer. Lab Invest. 2008 Jul;88(7):686-93. Epub 2008 May 12. [abstract]
7. Guidelines on Non-muscle invasive Bladder Cancer (TaT1 and CIS), European Association of Urology (2011)
8. Cancer Statistics, Cancer Research UK
9. Nieder AM, MacKinnon JA, Fleming LE, et al; Bladder cancer clusters in Florida: identifying populations at risk. J Urol. 2009 Jul;182(1):46-50; discussion 51. Epub 2009 May 17. [abstract]
10. Weihrauch MR, Diehl V; Artificial sweeteners--do they bear a carcinogenic risk? Ann Oncol. 2004 Oct;15(10):1460-5. [abstract]
11. Zeegers MP, Dorant E, Goldbohm RA, et al; Are coffee, tea, and total fluid consumption associated with bladder cancer risk? Results from the Netherlands Cohort Study. Cancer Causes Control. 2001 Apr;12(3):231-8. [abstract]
12. Takkouche B, Etminan M, Montes-Martinez A; Personal use of hair dyes and risk of cancer: a meta-analysis. JAMA. 2005 May 25;293(20):2516-25. [abstract]
13. Kassouf W, Agarwal PK, Herr HW, et al; Lymph node density is superior to TNM nodal status in predicting disease-specific survival after radical cystectomy for bladder cancer: analysis of pooled data from MDACC and MSKCC. J Clin Oncol. 2008 Jan 1;26(1):121-6. [abstract]
14. Guidelines on Bladder Cancer Muscle-invasive and Metastatic, European Association of Urology (2011)
15. Intraoperative red blood cell salvage during radical prostatectomy or radical cystectomy, NICE Interventional Procedure Guideline (April 2008)
16. Laparoscopic cystectomy, NICE Interventional Procedure Guideline (February 2009)
17. Levy DA et al, Surveillance for Recurrent Bladder Cancer, Medscape, Mar 2011
18. Anastasiou I, Mygdalis V, Mihalakis A, et al; Patient awareness of smoking as a risk factor for bladder cancer. Int Urol Nephrol. 2009 Jul 10. [abstract]
19. Chen CH, Shun CT, Huang KH, et al; Stopping smoking might reduce tumour recurrence in nonmuscle-invasive bladder cancer. BJU Int. 2007 Apr 5;. [abstract]
20. Management of transitional cell carcinoma of the bladder, Scottish Intercollegiate Guidelines Network - SIGN (2005)
21. Svatek RS, Lotan Y; Is there a rationale for bladder cancer screening? Curr Urol Rep. 2008 Sep;9(5):339-41. [abstract]

Internet and further reading

• Improving outcomes in urological cancers, NICE Cancer Service Guidance (2002)