Bladder Tumours

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.^1,2 Small cell carcinomas arise from neuroendocrine stem cells.³ Leiomyosarcoma is the most common sarcoma of the bladder whilst rhabdomyosarcoma is most common in children.^4,5 Rare tumours include carcinosarcoma (a mixed tumour) and primary lymphoma.^6,7 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.⁸

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.⁹

In 1998 a World Health Organisation (WHO) and International Society of Urological Pathology (ISUP) consensus classified urothelial tumours into four categories:¹⁰

• Papilloma
• Papillary urothelial neoplasm of low malignant potential
• Low-grade carcinoma
• High-grade carcinoma

The median age at diagnosis is 68. Men outnumber women by 3:1 but women tend to have a poorer prognosis. Bladder cancer is the 4th most common cancer in men and the 7th most common in women. Worldwide there are over 300,000 new cases a year.

Risk factors

By and large, bladder cancer is an avoidable disease.¹¹ Identified risk factors are as follows:

• 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.¹²
• There may be a genetic predisposition.⁹
• Radiation to the pelvis and cyclophosphamide are risks.¹³
• Suggestions of risk from artificial sweeteners have not been substantiated.¹⁴
• Coffee may increase the risk of bladder cancer by 20% but the meta-analysis was unable to establish a dose-related risk.¹⁵
• 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.⁸
• There is no increased risk in those who dye their hair.¹⁶
• One meta-analysis found that a diet high in fruit and vegetables and low in fat may reduce the risk of bladder cancer.¹⁷ A later study, however, found no link with fruit and vegetable intake.¹⁸

The presenting feature is painless haematuria that is gross in 80 to 90%. There is usually no abnormality on standard physical examination. Painless haematuria must be treated as malignancy of the urinary tract until proved otherwise. This includes clear cell carcinoma of the kidney. Advanced disease may cause voiding symptoms, although these can even be produced by carcinoma in situ.

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

• Urinalysis including culture should be performed to exclude infection.
• Full blood count should be arranged to exclude anaemia.
• Urea and electrolytes should be arranged to check renal function.
• Urine cytology may be helpful but negative results do not exclude disease.
• Newer, voided urine assays of tumour markers are being developed. They include bladder tumour antigen (BTA-Stat) and nuclear matrix protein (NMP-22). Fibrinogen degradation products are being used for the detection and surveillance of transitional tumours. False positive and false negative rates are high. In the future, assays based on telomerase and microsatellite analysis may prove to be better at detection than urinary cytology.
• 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.

This is important to decide prognosis and most appropriate treatment. The TNM classification is as follows:

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 carcinoma in situ.

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 in predicting disease-specific survival than TNM classification.¹⁹

• BCG vaccine is used for intravesical immunotherapy.¹¹ It must not be used if there is gross haematuria. It may reduce recurrence or progression and can be used for carcinoma in situ or unresectable tumours. It is usually instilled into the bladder weekly for 6 weeks. It may cause mild systemic symptoms. It may be necessary to prolong treatment. If carcinoma in situ (CIS) persists despite BCG then cystectomy should be considered, as the risk of progression is high.
• Intravesical chemotherapy with valrubicin is used in CIS if there is no response to BCG. Mitomycin C, doxorubicin and epirubicin are used for superficial tumours.²⁰
• One dose of intravesical chemotherapeutic agent (usually mitomycin) after a transurethral resection is effective for the reduction of disease recurrence within the first 1-5 years.¹⁰
• Alfa-interferon is also sometimes used for intravesical therapy.¹⁰
• General complications of intravesical therapy include irritative voiding symptoms, such as frequency, urgency and dysuria and the long-term potential for bladder fibrosis and contracture.¹⁰
• Methotrexate, vinblastine, adriamycin and cisplatin are used in combination for metastatic disease. New agents that may be promising are ifosfamide, paclitaxel, docetaxel, gemcitabine and carboplatin.
• External beam radiotherapy for invasive tumours tends to have poorer results than cystectomy.
• Bladder-sparing treatment using a combination of chemotherapy and radiotherapy is currently being explored.¹⁰
• Targeted therapy using molecular biology techniques to arrest tumour growth is also being evaluated.¹⁰
• Stopping smoking reduces the risk of recurrence.²¹

• For superficial cancer at CIS, Ta or T1, endoscopic resection and fulguration (electrical destruction) of the tumour is required but follow-up is essential, as tumours can recur at other sites. New imaging techniques and inclusion of developments, such as laser surgery, are being explored as means to reduce the risk of recurrence.²²
• For stage 2 and 3 in men the operation is radical cystoprostatectomy. This involves taking bladder, prostate and pelvic lymph nodes.
• An anterior pelvic exenteration is performed on women with disease involving the muscle layer. It involves removal of the bladder, urethra, uterus, ovaries and anterior vaginal wall. If the bladder neck is not involved, the urethra and anterior vaginal wall may be spared with the construction of an orthotopic neobladder.
• There is some evidence that lymph node dissection may be beneficial for staging and survival in lymph node-negative as well as lymph node-positive patients.²³
• After removal of the bladder, urinary diversions are created from various segments of bowel. An ileal conduit is the most commonly used.

Even superficial tumours have a very high rate of recurrence and progression. The whole epithelium should be seen as unstable and there is a recurrence rate of 70% within 5 years. Surveillance for superficial transitional cell carcinoma includes cystoscopy and bladder wash cytology every 3 months for 2 years, then every 6 months for a further 2 years and then at least annually. Upper urinary tract imaging should be done every 1-2 years as 5% of patients with bladder cancer have a lifetime risk of developing transitional cell carcinoma.²⁴ The perioperative mortality rate of total cystectomy is 1 or 2%. In early disease the recurrence rate is 5 to 19% but for T3 and T4 this increases to 15 to 25%. Complications of surgery include bowel obstruction, obstruction of the ureter, pyelonephritis and infection of the wound.

Radical cystectomy has a complication rate around 25%. Many patients are in their 70s or 80s with co-existent disease. Radical cystectomy will damage the S2,3,4 outlet and cause complete erectile dysfunction, although a nerve-sparing approach can reduce this to about half. Orthotopic bladders have a risk of daytime incontinence of 10%, rising to 15% at night.

As always, 5 years' survival is related to stage:

• CIS, Ta, T1 have 5 years' survival of between 82 and 100%
• T2 is 63 to 83%
• T3a with microscopic invasion has figures of 67 to 71%

If invasion is visible giving T3b, it falls to a very wide range of 15 to 67%. Macroscopic involvement of nodes carries a much worse prognosis.²⁵ T4 gives an abysmal 0 to 22% survival at 5 years. Metastatic disease leaves only 5% alive at 2 years. Tumours are graded according to differentiation and this has prognostic significance with regard to progression. Progression means either an increase in grade or an increase in stage. The risk for grade I is 10 to 15%. For grade II it is 14 to 37% and for grade III it is 33 to 64%. Unlike most tumours, where catching it at CIS level is very favourable, CIS of transitional cell tumours of the bladder carries a rather poor prognosis. CIS alone or with a Ta or T1 tumour has a recurrence rate of 63 to 92%. Other risks for recurrence and progression include the tumour size, multifocal tumours, number of tumours, high grade, advanced stage, the presence of CIS and the time interval to recurrence. If recurrence occurs within 2 years, and especially if it happens within 3 months, the tumour is very aggressive and prognosis is poor.

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.²⁶

The cost-effectiveness of national bladder cancer screening programmes is currently being evaluated.²⁷