• Introduction
• Risk factors
• Screening
• Symptoms
• Diagnostic procedures
• Therapy

Risk factors:
In addition to several causes not yet fully investigated, a number of carcinogens play an important role in the development of bladder cancer. Carcinogens are substances which have been proved to cause or promote development of malignant tumours in animal models. In the case of bladder tumours, these substances are primarily aromatic hydrocarbons and amines. These chemical bonds are, for instance, released during cigarette smoking. The risk increases with years of smoking and the number of cigarettes smoked. Smoking cigarettes is the number one risk factor for the development of bladder cancer.
On the other hand, aromatic amines are present in textiles and leather goods, in dietary products as residues of plant sprays, and as components of cosmetics and hair dyeing products.
Sources of aromatic hydrocarbons are, among others, coal and tobacco tar, soot and car emissions, asphalt, diesel oil and diesel emission, petroleum products, and substances for varnishing and impregnating. Professional vehicle drivers, workers in the oil industry, carpenters, floor layers, road construction workers, varnishers, those working in heavily cigarette-smoke-filled environments such as waiters in discos and smoke-filled pubs are exposed to the above-mentioned substances to a considerable extent, and are at possible high risk for developing bladder cancer. For this reason it makes sense for people in these occupations to undergo check-ups as a preventive measure.

As a rule it is recommended that over the age of 40, people should undergo a yearly urine and blood test as well as ultrasound investigation of the kidneys and bladder.

Screening

For early detection, timely and effective therapy and prevention of disease progression of bladder tumours, persons in these occupation groups are invited to undergo a series of urine tests (NMP22, cytology, FISH) which are simple and painless.

• FISH (Fluoreszenz-in-situ-Hybridisierung)

FISH is a molecular cytogenetic technique in which specific, fluorescent chemically labeled DNA probes are hybridised to chromosomal DNA specimens or cells in interphase and made visible by fluorescence signals. In principle, depending on the DNA probe used, FISH is a sensitive and useful adjunct to cytogenetic testing for the detection of abnormalities of chromosomal structure or numbers, eg deletions, translocations, duplications, aneuploidy.
A number of cytogenetic alterations have been identified in bladder tumour, of particular interest being changes (aneuploidy, polyploidy) in the chromosomes 3,7, 17 and deletion of the 9p21 locus.

Normal urothelial cells (interphase) after hybridisation with Vysis® UroVysion Bladder Cancer Recurrence Kit; Two signals each from the corresponding chromosomes (CEP 3 red), (CEP 7 green), (CEP 17 aqua) and LSI p16 (gold).

Malignant urothelial cells with 2 signals for chromosome 3 (red), 4 signals for chromosome 7 (green) and 5 signals for chromosome 17 (aqua), deletion of a p16 after hybridization normal urothelial cells (interphase) after hybridization with Vysis® UroVysion Bladder Cancer Recurrence Kit.

• NMP22 (Nuclear Matrix Protein 22):

Nuclear Matrix Proteins (NMP) provide the scaffold for the spatial structure of the cell nucleus and are involved in all important processes such as three-dimensional organisation of the chromosomes, DNS replication, RNS synthesis etc. The expression of these proteins varies according to cell type, stage of cellular differentiation, cell cycle and correspondingly also according to the tumour type.
The NMP-22 is associated with tumours of the urogenital tract. Previous studies have shown that a more than 10-fold concentration NMP 22 is present in tumour cells in comparison to healthy cells. At cell death, NMP disintegrates into soluble fragments which can be detected in urine with the help of monoclonal antibodies.

NMP22 has been approved by the Federal Drug Administration (American drug approval agency) for screening and monitoring of urinary bladder cancer.

At the University Clinic Innsbruck, NMP22 (NMP22-Bladder Chek®) has long been in use as a quick test for detection of NMP22 in urine.

NMP22-Bladder Chek®: 4 drops of urine are applied, after 30 minutes, the results (positive, negative, invalid) are read.

Symptoms of Disease

• presence of blood in urine (haematuria). passing of bloody urine is in most cases painless.
• traces of blood on laboratory investigation of the urine sample.
• strong urinary urge (inability to postpone voiding) and frequent voiding
• problems during voiding

These symptoms can also arise in other cases without malignant diseases such as urinary tract infection, stones in the urinaty tract, benign tumours etc. Only a doctor can interpret these symptoms and make the appropriate diagnosis: therefore, a medical check-up is indicated even if only one of these symptoms is noted.

Diagnostic procedures
In order to determine the cause of these symptoms, a series of investigations are carried out: Several Tests (NMP22, FISH) are currently being tried out at the University Clinic for Urology which might enable early detection of bladder cancer by investigating a urine sample.

Imaging Procedures such as ultrasound, X-ray of the urinary tract (voiding pyelography/cystourethrography), computer tomography or magnetic resonance tomography (MRI) may be necessary.
If bladder tumour cannot be excluded, direct inspection of the bladder is carried out with the help of an instrument called the cystoscope. The inspection procedure is called cystoscopy.

Treatment Method

If cystoscopy confirms suspicion of tumour, surgical removal is indicated. Treatment of superficial bladder cancer takes place in two main steps:

1. Endoscopic loop electroexcision of all detectable tumours in the bladder (TURB or ERB) under partial or complete anaesthesia. This is done through the urethra. Incision into the abdominal cavity is not required. In order to excise all possible tumour tissue, the so-called PDD is performed. Prior to TURB, the bladder is filled with a special fluid ( a so-called photosensitizer) with the help of a catheter. A photosensitizer has the characteristic of being absorbed particularly by tumour cells. When exposed to a special laser light, the photosensitizer is activated causing the tumour cells to become fluorescent. This enables thorough removal of the cancer cells. We use 5-aminolaevulinic acid (ALA) or chemically similar substances (e.g. Hexyl-ALA). ALA is a substance that is physiologically present in our bodies and is required for production of haemochrome. The depth and invasiveness of the tumour and thus the tumour stage can be determined by histological (microscopic) examination of the excised tissue.
   If the tumour has invaded the muscle layer of the bladder (invasive tumour), it is necessary to radically excise the entire bladder; an alternative way for urine outflow will then have to be devised.
2. After establishing the kind of tumour and assessing the probablity of tumour recurrence, usually additional treatment is given to prevent recurrence. For this purpose, the bladder is irrigated with several chemically or biologically active substances (bladder instillations).
   Washings with chemotherapeutic solutions should kill cancer cells which were not removed during surgery. The most widely used chemotherapeutic agent is mitomycin C.
3. The use of biologically active therapeutic agents such as BCG (weakened or dead tubercle bacillus) are intended to elicit an immune reaction in the mucous lining of the bladder and this should lead to killing of cancer cells.
4. Other therapeutic modalities for the treatment of superficial tumours: (within the framework of clinical studies):

•COMBINED THERMO-CHEMOTHERAPY FOR SUPERFICIAL (NON-INVASIVE) CARCINOMA OF THE BLADDER.

The effect of localized heat (hyperthermia) on malignant tissue has long been the subject of research. At temperatures between 42 and 45ºC, transformed (malignant) cells, in contrast to healthy cells, are destroyed. For local warming of tissue, microwaves, i.e. radio waves at a frequency of 300 MHz–300,000 MHz were found to be most effective with the best side-effect profile. Studies have shown that thermotherapy enhances the effectiveness of radiation- as well as chemo-therapy. In the combined thermo-chemotherapy of superficial bladder cancer, a special catheter containing a heat applicator is inserted into the bladder. During the period of time when uniform hyperthermia is induced on the superficial layers of the bladder wall, the chemotherapeutic agent mitomycin C is instilled into the bladder. Studies have shown that this combination clearly increases the cytotoxic effectiveness of mytomycin C. Whether this combined thermo-chemotherapy also reduces the frequency of recurrence in superficial bladder cancer is currently being investigated in clinical studies.

• PHOTODYNAMIC THERAPY
As in photodynamic diagnosis, in this procedure the bladder is filled with a photosensitizer. Exposing this substance to laser light results in the production of free oxygen, which has the capacity to kill cancer cells.

Treatment of muscle-infiltrating bladder tumour (invasive tumour)

In case of advanced bladder tumours, that is, tumours that have invaded the muscle layer (see above), the bladder must be radically excised (cystectomy). In males, as a rule the prostate and the the seminal vesicle are also be surgically removed (radical cystoprostatectomy); in females, the uterus, the ovaries and a part of the vagina are excised.
If the bladder is removed, it becomes necessary to provide other ways and means to store and void urine. There are several possibilities of urinary diversion. A neo-bladder constructed out of intestines is attached to the urethra above the sphinteric muscle. In this form of reconstructon, the patient can void in a normal fashion via the urethra and to a great extent urinary continence is maintained.
In males, sexual potency can be maintained by a surgical technique in which the neuro-vascular bundle responsible for erection is preserved. This surgical option is available in Innsbruck (nerve-sparing, potency- and continence-maintaining radical cystoprostatectomy).
If it is impossible to construct an ersatz bladder, urinary diversion can be accomplished in other ways also (e.g. directly out of the abdominal wall ; Ileal conduit or ileouretostomy). There are several variants to this procedure.

The decision is made after patients are given extensive information and advice.

Therapy of Metastatic Bladder Tumour:

If at the time of diagnosis there is clinical evidence of distant metastases or highly advanced tumour growth, an immediate surgical intervention is often not meaningful. In our clinic, patients are offered treatment options in accordance with modern chemotherapeutic schmemata and/or radiation therapy.