Carcinoma of the bladder

Carcinoma arising within the bladder may be of three cell types: transitional, squamous and adenocarcinoma [or mixed owing to metaplasia in a transitional cell carcinoma (TCC)]. Over 90 per cent are transitional cells in origin. Pure squamous carcinoma is uncommon (approximately 5 per cent), apart from areas where bilharzia is endemic. Primary adenocarcinoma, which arises either from the urachal remnant or from areas of glandular metaplasia, accounts for 1—2 per cent of cases.

Transitional cell carcinoma

Aetiology. The first suspicion of a chemical cause for bladder cancer was raised by Rehn in 1894 when he recorded a series of tumours in workers in aniline dye factories. Hueper was able to show that 2-naphthylamine was carcinogenic in dogs. Subsequent investigation demonstrated that the following compounds may be carcinogenic:

      2-naphthylamine;

      4-aminobiphenyl;

       benzidine;

       chlornaphazine;

      4-chloro-o-toluidine;

      o-toluidine;

      4,4’-methylene bis(2-choloraniline);

       methylene dianiline;

       benzidine-derived azo dyes.

Occupations which have been reported to have a significantly excess risk of bladder cancer are shown below

Occupations with an excess risk of bladder cancer

Textile workers

Dye workers

Tyre rubber and cable workers

Petrol workers

Leather workers

Shoe manufacturers and cleaners

Painters

Hairdressers

Lorry drivers

Drill press operators

Chemical workers

Rodent exterminators and sewage workers

Bladder cancer became a prescribed industrial disease (No. 39) in 1953 and ex-workers may be entitled to compensation. Cigarette smoking is associated with a two to three­fold excess risk, and certain genetic polymorphisms for N-acetyl tranferase, glutathione transferase and one of the cytochrome P45Os (CYP2D6) may increase the risk of occupationally acquired bladder cancer. In areas where S. haematobium is endemic bladder cancer is more common, and this tends to be squamous in type. Balkan nephropathy has been associated with an increased incidence of upper tract urothelial tumours (see Chapter 63).

A series of genetic events has been clearly implicated in cancer formation that is outside the remit of this chapter. Activation of dominantly acting oncogenes such as ras and c­erbB-2 has been reported in bladder cancer, as has the inac­tivation of tumour suppressor genes such as p53, p16 and retinoblastoma. Activation of other genes is responsible for the phenotypic changes seen in the cancer cell. These include the activation of enzymes which may dissolve the basement membrane such as the metalloproteinases (stromelysin, colla­genases and elastase), lysosomal enzymes such as the cathepsins and others including urinary plasminogen activators; angiogenic factors [vascular endothelial growth factor (VEGF)] and other peptide growth factors such as the epidermal growth factor and its receptor also have a role to play. These changes are common to several tumour types including prostate cancer.

Tumour staging and grading (Fig. 65.50)

Study of the biological behaviour of transitional cell cancer of the bladder shows that they fall into the three following groups.

       Non muscle invasive tumours (pTa) and pT1 account for 70 per cent of all new cases. These tumours may be single or multiple. Histological examination may reveal invasion of the lamina propria (pTl) but not of the muscle or no invasion of lamina propria (pTa) —single papillary pTa tumours account for a significant proportion of bladder cancers and carry an excellent prognosis.

Muscle invasive disease (accounts for 25 per cent of new cases). Such tumours carry a much worse prognosis as they are subject to local invasion and distant metastasis.

Flat, noninvasive carcinoma in situ (primary cis — accounts for 5 per cent of new cases). Unless diagnosed and treated promptly, this carries a poor prognosis.

Superficial bladder cancer (pTa and pT1)

These are usually papillary tumours which grow in an exophytic fashion into the bladder lumen. They may be single or multiple and may appear pedunculated arising on a stalk with a narrow base, but if the’ tumours are less well differentiated they are more solid with a wider base. The mucosa around the tumour is often rather oedematous with angry-looking, dilated blood vessels. These areas may contain in situ changes (concomitant cis).

Some patients with bladder cancer have urinary infection, although this is more common with muscle invasive disease. Occasionally, calcium salts are deposited on these tumours, giving them a crusted exterior. The urothelium elsewhere in the bladder may also appear rather oedematous and velvety; this suggests a generalised ‘field change’ with the presence of widespread carcinoma in situ. The most common sites for superficial tumours are the trigone and lateral walls of the bladder.

After initial complete treatment by endoscopic transurethral resection (TURT) patients with pTa or pTl disease may develop two problems:

  50—70 per cent develop recurrent tumours which may be single or multiple, and the recurrences may occur on one or on many occasions. Usually the recurrent tumours are of the same stage or grade as the primary tumour. Highgrade, multiple tumours with concomitant cis are most likely to develop recurrent disease;

  about 15 per cent will develop a recurrent tumour which is invading the bladder muscle. The risk of such progression increases with high grade, with pTl disease, with multiple primary disease and with concomitant cis. Many urologists now regard the presence of pTl G3 tumours as an indication for more radical treatment.

This behaviour provides the rationale for performing check cystoscopies. The factors which result in an increased recurrence and progression rates are:

high grade;

  pTl disease;

•concomitant cis;

multiple primary tumours;

recurrent disease at the first check cystoscopy.

Patients presenting with a solitary grade 1 or grade 2 pTa tumour, without concomitant cis and which do not recur within the first 6 months have an excellent outcome.

Muscle invasive transitional cell carcinoma

The tumour with muscle invasion is nearly always solid (Fig. 65.51), although there may be a low tufted surface. These tumours are often large and broad based, having an irregular, ugly, sometimes ulcerated, appearance within the bladder. The incidence of metastases, whether from lymphatic invasion in the pelvis or blood-borne to the lung, liver or bones, is much more common and will cause the death of 3 0—50 per cent of patients.

In situ carcinoma

The histological appearance of irregularly arranged cells with large nuclei and a high mitotic index replacing the normally well ordered urothelium is known as carcinoma in situ. This may occur alone (primary cis) or in association with a new tumour (concomitant cis) or occur later in a patient who has previously had a tumour (secondary cis). This change may be appreciated macroscopically at the time of cystoscopy, although often is only diagnosed when a biopsy is examined under the microscope. The association of in situ carcinoma with papillary tumours increases the chance of recurrent disease and progression. It may cause severe symptoms of dysuria, suprapubic pain and frequency (hence its old name of malignant cystitis).

World-wide experience of this condition seems to indicate that symptomatic cis carries a high malignant potential. Fifty per cent of patients will die of bladder cancer.

Pure squamous cell carcinoma of the bladder

Squamous cell tumours tend to be solid and are nearly always associated with muscle invasion. This is the most prevalent form of bladder cancer in areas where bilharzia is endemic. Squamous cell tumours may be associated with chronic irritation caused by stone disease in the bladder as a result of metaplasia.

Pure adenocarcinoma

This accounts for approximately 1—2 per cent of bladder cancer. It usually arises in the fundus of the bladder at the site of the urachal remnant. Occasionally, primary adenocarcinomas arise at other sites and probably originate from areas of glandular metaplasia. Such tumours need to be distinguished from secondary cancer.

Clinical features

Painless haematuria is by far the most common symptom and should be regarded as indicative of a bladder carcinoma until proven otherwise. The haematuria may occur on only one or two occasions, and because the urine once again becomes clear patients only too often fail to declare the symptom to their general practitioner. Many months may elapse before it recurs and causes concern. The bleeding if more severe may give rise to clot formation and subsequent clot retention. It is fairly uncommon for the bleeding to be so profuse that emer­gency admission to hospital and blood transfusion is necessary. Occasionally, a pedunculated tumour or clot may occlude the bladder neck, causing retention of urine. The development of recurrent urinary tract infections, particularly in women in the later decades of life, should also arouse one’s suspicions.

Constant pain in the pelvis usually heralds extravesical spread. There is often frequency and discomfort associated with urination. Pain in the loin or pyelonephritis may indicate ureteric obstruction and hydronephrosis. A late manifestation is nerve involvement causing pain referred to the suprapubic region, groins, perineum, anus and into the thighs.

It is also important to assess the patient as a whole. Many are elderly men who have been life-long smokers and suffer from chronic obstructive airways disease or cardiovascular disease. Their suitability for anaesthesia must be borne in mind.

Investigation

Urine. Urine should be cultured and examined cytologically for malignant cells. This is not a good screening test for patients with haematuria as, particularly with low-grade tumours, malignant cells may not be identified unless a specimen obtained from a bladder washout is examined. False-positive results occur infrequently and are usually associated with stone disease. New tests are being developed based on the presence of antigens, such as nuclear matrix proteins, which may be good at detecting new or recurrent tumours.

Blood. Estimation of the haemoglobin and the serum electrolytes and urea should be carried out.

IVU. This should be performed on patients with haematuria. Occasionally, the preliminary film shows a faint shadow of an encrusted neoplasm of the bladder. The most common radiological sign is a filling defect. Occasionally, irregularity of the bladder wall may herald the presence of an invasive tumour (Fig. 65.52). Hydronephrosis may occur if a superficial tumour grows up the intramural ureter or if direct invasion of the ureteric wall occurs. Ultrasound scanning should be carried out if the kidney is nonfunctioning.

Cystourethroscopy. 

Cystourethroscopy is the mainstay of diagnosis and should always be performed on patients with haematunia. It can be done with a rigid instrument under general anaesthesia or with a flexible instrument under local anaesthesia. The urethra is inspected at the initial insertion of the instrument (urethroscopy) and the bladder is then examined in a systematic fashion (cystoscopy).

Bimanual examination. A bimanual examination with the patient fully relaxed under general anaesthesia should be performed both before and after endoscopic surgical treatment of these tumours. The bladder should be empty and the bimanual examination is executed with the right index finger in the rectum of a male and placed per vaginam in a female. The four fingers of the left hand push down on the anterior abdominal wall in the suprapubic region. Occasionally, a very large superficial fronded tumour may be felt as a soft but mobile thickening prior to resection. Superficial tumours are not usually palpable bimanually at the beginning and by definition are not palpable after resection. Once there is muscle invasion the differentiation between T2 and T3 disease depends on whether a mass is palpable bimanually at the end of the procedure (T3). Where invasion has spread into the prostate in a male or the vagina in a woman it is classified as T4a. If the tumour is fixed to the lateral pelvic side wall it is staged as T4b.