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.