Bladder cancer - Genitourinary oncology

Bladder cancer

Definition

Bladder cancer is the most common urological malignancy, âˆ¼90% of cases are transitional cell carcinoma, with the rest being squamous cell carcinoma, adenocarcinoma or mixed/undifferentiated tumour.

Incidence/prevalence

Common malignancy; 1 in 5000 in United Kinddom.

Age

Peak age 50–70 years.

Sex

M > F

Geography

Increased in the Middle East and industrialised areas.

Aetiology

There are several risk factors for the development of bladder cancer.

Environmental:

·        Exposure to certain carcinogens and industries cause as many as 20% of cases. Aromatic amines, or derivatives, which are strongly carcinogenic are commonly found in the printing, rubber, textile and petrochemical industries. Diesel exhaust fumes also modestly increase the risk (e.g. for taxi and bus drivers).

·        Smokers are two to three times more likely to have bladder cancer than non-smokers.

·        Chronic cystitis, bladder stones and schistosomiasis through chronic inflammation and squamous metaplasia predispose to squamous cell carcinoma.

Genetic:

·        Through polymorphisms of various cytochrome P450 enzymes, some individuals appear to oxidise arylamines more rapidly, which makes them more prone to malignancy, as this is the first step towards activation of these carcinogens.

·        Acetylator status also affects predisposition. Slow acetylators deactivate carcinogens more slowly, increasing the risk of cancer.

·        Half of Caucasians inherit the complete lack of the Glutathione S transferase M1 allele. This enzyme detoxifies carcinogens and these individuals have almost twice the risk of bladder cancer compared to those with one or two copies of the GSTM1 allele.

Radiotherapy, for example for pelvic tumours, predisposes to later development of bladder cancer. Cyclophosphamide is an important cause of bladder cancer. It generally appears within a decade of treatment and is dose-related, but the risk is reduced by the concomitant use of Mesna.

Pathophysiology

It is thought that in most cases, the bladder and ureters become exposed to carcinogenic agents which are excreted in high concentrations in the urine. This may explain why, in many cases, there is a ‘field change’ to the whole of the urothelium from renal pelvis to urethra, so that multiple and recurrent tumours occur. However, an individual’s tumours have also been shown in many cases to be monoclonal, so that local spread may also be partly the cause. Adenocarcinoma arises from the urachal remnants in the dome of the bladder.

Clinical features

The most common presenting feature is painless frank haematuria. Other symptoms include pain and symptoms such as increased urinary frequency, dysuria and/or urgency. Whilst all these symptoms are most commonly caused by other conditions such as urinary tract infection, if they persist, bladder carcinoma should be suspected. Pain may be felt in the loin when there is obstruction, or suprapubically if there is invasion through the bladder wall. Haematuria over the age of 40 should be considered to be due to bladder cancer, until proven otherwise.

Macroscopy

Low-grade tumours have a papillary structure and look like seaweed. T2 is coral-like. Higher grade tumours appear more solid, ulcerating lesions. TNM staging is used which requires cystoscopy and examination under anaesthesia (EUA):

Ta Papillae projecting into the bladder lumen.

Tis     Transitional cell carcinoma in situ: intraepithelial tumour with a flat, red appearance.

T1 Started invading bladder wall: in mucosa or submucosa (not palpable at EUA).

T2 Superficial muscle involved (rubbery thickening on EUA).

T3 Deep muscle involved, through bladder wall (mobile mass).

T4 Invading adjacent structures (fixed mass).

Microscopy

Transitional cell carcinomas are graded from I to IV or G1 to G3, according to the cellular and nuclear pleomorphism and mitoses.

G1     Well-differentiated.

G2     Moderately well differentiated.

G3     Poorly differentiated/anaplastic.

Complications

Tumours of stage >T3 metastasise, but this is uncommon. There is spread to lymph nodes and vascular spread to liver and bone.

Investigations

Cystoscopy is the main investigation, although all patients should also have a renal US or CT to exclude renal tumour or obstruction. IVU is useful at showing any filling defects in the ureters, as well as the bladder. If IVU is not possible (e.g. due to renal impairment), then ureteroscopy and/or retrograde contrast studies should be performed from the bladder upwards.

Management

Depends on stage:

i Tis or Ta, and T1 are initially treated by cystoscopic transurethral resection of the bladder tumour

(TURBT). Follow-up 3 months later has a 50% recurrence rate and regular follow-up is needed, usually for 5–10 years. Those at higher risk of recurrence, e.g. rapid recurrences, multiple, large and in particular flat lesions, and stage Tis or T1, require further treatment with adjuvant intravesical therapy. Bacillus Calmette-Guerin (BCG), i.e. the live attenuated form of Mycobacterium bovis, instilled into the bladder at intervals is very effective, although other agents are also used.

ii. Localised, muscle-invasive disease (T2, but also high-grade T1) is optimally treated by a radical cystectomy – males are treated by cystectomy with proximal urethral and prostate removal, females require cystectomy with the whole urethra removed and an ileal conduit with urinary diversion (ureters to ileum). In males it is possible to use a piece of ileum to form a bladder substitute ‘substitution urethroplasty’ be cause the sphincter is below the prostate. However this is a major operation and patients may be medically unfit.

iii. Locally advanced disease (T3 and T4) is life threatening and requires radical cystectomy in combination

with radiotherapy or chemotherapy.

Radical radiotherapy may be used where surgery is contraindicated, or post-surgery. Morbidity results from radiation cystitis and proctitis leading to a small fibrosed rectum. In females radiation vaginitis and/or an asensate vagina, and in males impotence occurs due to nerve damage.

Chemotherapy is increasingly used with surgery, or may be used alone as a palliative measure. Neoad-juvant chemotherapy (i.e. chemotherapy before surgery) may be advised in those thought to be non-resectable (as they may render the tumour resectable), or more conventional post-surgery chemotherapy or radiotherapy. Most regimens are cisplatin based.

Prognosis

Depends on stage and grade at presentation and the age of the patient. Recurrence is common and may be of a higher grade (25%). Some patients appear to have a few, minor recurrences, whereas others have widespread, invasive recurrences. T1 has an 80% 5-year survival and T4 has 10% 5-year survival (but very age dependent).