Urinary bladder carcinoma

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95% of all bladder cancers are of urothelial origin, i.e. they originate from the inner mucous membrane of the bladder. Approximately 5% are adenocarcinomas and squamous cell carcinomas.

The distribution pattern of urothelial carcinomas correlates with the urothelial surface in the urinary tract. 92.5% of all urothelial carcinomas are therefore found in the urinary bladder, 3% in the ureter and 4.5% in the renal pelvic caliceal system.

Every year, around 30,000 people in Germany are diagnosed with bladder cancer. With 22,700 new cases every year, more than three times as many men are affected by bladder cancer than women (7,200). The average age of onset is 71.9 years for men and 73.4 years for women.

Many studies have shown an increased risk of bladder tumours for cigarette smokers. The relative risk compared to a non-smoker is between 2:1 and 6:1. The proportion of bladder tumours that are apparently caused by cigarette consumption is assumed to be between 30% and 40%. Aromatic hydrocarbons have a decisive influence on the development of carcinomas. In addition to tobacco consumption, drugs can also be associated with the development of bladder carcinomas (e.g. cyclophosphamide). Various working substances such as aromatic amines have also been identified as risk factors, although the most dangerous agents have long since been removed from work processes, at least in Europe. In addition, particularly vulnerable groups of people include employees in the paint industry, rubber processing industry, coal industry, laboratory workers, aluminium industry, textile dyeing and textile industry, printing industry, radiation industry and plastics industry.

The formation of nitrosamine, the carcinogenicity of which has been well documented experimentally, plays a significant role in many infections. An increased incidence of bladder carcinoma was found in patients with chronic urinary tract infections, especially if these were associated with bladder stones or permanent drainage. These tumours are usually squamous cell carcinomas. Chronic infection with schistosomiasis (Schistosoma haematobium widespread in many parts of Africa and Arab countries) also leads to infection-related nitrosamine formation and can favour the development of epithelial hyperplasia, dysplasia, squamous metaplasia and squamous cell carcinoma. Other risk factors discussed include the use of artificial sweeteners, coffee, tryptophan metabolites, previous radiotherapy of the pelvic organs and hereditary factors.

Urinary bladder carcinomas are often characterised by painless microhaematuria (blood in the streak test) or painless macrohaematuria (visible blood in the urine). Occasionally there are irritable symptoms with frequent urination and dysuria (difficult, unpleasant urination). In advanced stages, pain may occur in the bladder and bowel region.

Medical history and physical examination

During a detailed consultation, all symptoms and previous illnesses (including family hereditary diseases) are recorded. The symptom of painless macrohaematuria, microhaematuria or dysuria is often indicative here and gives rise to further diagnostics.

Urine laboratory

The urine status is analysed to determine whether there is blood in the urine. In urine cytology, urothelial cells are assessed microscopically and it is determined whether urothelial cells with dysplasia, low differentiation or dedifferentiation are present. Urine cytology is particularly sensitive in the diagnosis of aggressive carcinomas. However, when determining urine cytology, no conclusions can be drawn about the origin of the tumour cells (bladder or upper urinary tract). There are also bladder tumour marker systems (e.g. UroVysion FISH, Immunocyt/uCyt +, Bladder Tumour Antigens, NMP 22) that can indicate a bladder carcinoma in the urine.

Blood laboratory

The general blood laboratory provides information about the patient's general condition and certain organ functions. Changes in the blood such as anaemia can indicate chronic blood loss via the urinary bladder. There are no specific tumour markers for bladder carcinoma in the blood.

Urinary cystoscopy (urethrocystoscopy)

Urethrocystoscopy confirms the diagnosis and allows the location, size and number of tumours to be documented. Diagnostic urethrocystoscopy is usually possible without anaesthesia.

Histological confirmation is obtained by transurethral resection of the tumour (TURB) under anaesthetic. The exophytic parts and the base of the tumour, which in any case must also contain the muscles of the bladder wall, are sent in separately for histological assessment.

As part of the bimanual examination under anaesthetic, the presence of tumour growth extending beyond the organ can be assessed. Fixation of the bladder to neighbouring structures or the pelvic wall suggests organ-transcending growth.

Photodynamic diagnostics (PDD)

PDD is used to improve the detection of urothelial carcinoma. A fluorescent dye (hexyl-aminolevulinic acid; HAL; Hexvix ®) is instilled into the bladder via a bladder catheter approx. 60 minutes before the planned procedure. The accumulation of red-fluorescent porphyrins in the malignant cells leads to a visual improvement in the contrast between benign and tumorous tissue in the bladder. Under blue light, the areas with increased accumulation light up pink, while the normal urothelium appears blue-greenish. PDD shows an improved detection rate of tumours, particularly in the presence of carcinoma in situ (CIS). Despite the lack of long-term results regarding the survival rate and progression rate, a reduced recurrence and progression rate was confirmed for PDD using HAL. A possible disadvantage of the method is the high rate of so-called false positive findings.

Narrow band imaging (NBI)

Narrow band imaging (NBI) is another method for which some studies have shown a higher tumour detection rate compared to white light cystoscopy. Here, the white light is filtered into two wavelengths, 415 and 540nm. In these areas, the light is absorbed particularly well by haemoglobin. This results in an increased contrast between normal urothelium and hyperperfused areas, for example in more vascularised tumour tissue. NBI is currently only used in clinical studies.

Computed tomography (CT) of the abdomen, ultrasound examination (sonography) and excretory urogram (AUG)

A CT scan of the abdomen with imaging of the upper urinary tract using a urographic late phase is used to rule out tumours of the upper urinary tract. The CT examination appears to be superior to MRI diagnostics in this situation. Excretory urography (AUG) and in particular sonography play a subordinate role in the clarification of the upper urinary tract as, among other things, they only allow a limited diagnosis of the surrounding area. Urinary stasis kidneys can be caused by tumours in the upper urinary tract, by a superficial carcinoma in the area of the ureteral orifice or by a carcinoma growing into the muscles of the bladder.

Skeletal scintigraphy (bone scintigraphy)

By administering a small amount of radioactive substance into the bloodstream, tumour metastases in the bones can be visualised. This examination is only carried out on symptomatic patients.

Computed tomography of the thorax

Before any planned complete removal of the bladder, a diagnosis of the lungs should be carried out. The tomography of the lungs can be used to visualise or rule out metastases in the lungs.

In order to determine the most suitable therapy, the exact extent to which the tumour has spread, i.e. the tumour stage, must be determined using the diagnostics described above before starting therapy. The TNM classification is used for this purpose (see table below). T stands for the size and extent of the primary tumour, N stands for the number of affected regional lymph nodes and M stands for the occurrence and localisation of distant metastases (tumour metastases).

TNM for urinarybladder carcinomas

The treatment methods depend on the stage of the tumour. The earlier a bladder carcinoma is detected and the less it infiltrates from the superficial urothelial layer into the deeper layers of the bladder wall, the more favourable the prognosis for the patient. The patient's age and general state of health are also taken into account when selecting a therapy. Treatment options include transurethral resection of the bladder tumour, surgical removal of the bladder with reconstruction of the urinary tract, chemotherapy, radiotherapy or a combination of these therapies, as well as immunotherapy.

Non-muscle-invasive bladder carcinoma (Ta, T1, Tis)

Transurethral resection of the bladder (TURB)

In transurethral resection of the bladder, the exophytic tumour parts and then the tumour base including the bladder wall muscles are resected separately. In the following constellations of findings, a follow-up resection is recommended after 4-6 weeks following an initial TURB:

► incomplete initial TURB
► no musculature included in the resectate, except for TaG1 tumours or primary CIS
► for all T1 tumours
► for all G3 tumours except for primary CIS

Early instillation therapy

In superficial bladder cancer, a chemotherapeutic agent (e.g. mitomycin C) can be administered into the bladder immediately after TURB. The single intravesical instillation of a cytostatic drug immediately after TURB is intended to prevent the implantation of tumour cells and extend the time interval until a possible recurrence occurs.

Instillation therapy to prevent recurrence

Chemotherapeutic agents (e.g. mitomycin C) or immunotherapeutic agents (e.g. BCG) can be instilled into the bladder over a period of up to 36 months to prevent recurrence of superficial bladder carcinomas. The aim of further intravesical therapy is to prolong the recurrence interval and prevent progression (BCG only).

Radical cystectomy

Radical cystectomy is the treatment of choice for patients with a tumour recurrence of a high-grade urothelial carcinoma during or after BCG therapy (BCG failure). Patients with stage T1G3 urothelial carcinoma of the bladder (also in combination with CIS) can already be offered radical cystectomy as a therapeutic option.

Muscle-invasive bladder carcinoma (T2-4)

Curative (healing) surgery (cystectomy)

In men, the bladder, prostate and seminal vesicles are removed. In women, the cystectomy is combined with a hysterectomy and ovariectomy, including the anterior vaginal cuff. A bilateral pelvic lymphadenectomy is also performed as part of the radical cystectomy. After cystectomy, a continent or incontinent urinary diversion is created.

-- Continent urinary diversion

=> Orthotopic bladder replacement

The detubularised intestinal reservoir is anastomosed to the urethra while the external sphincter remains intact. The neobladder is possible in both sexes.

=> Urinary reservoir with continent stoma

This is a continent, supravesical urinary diversion. The bowel reservoir usually consists of ileocecal parts and is connected to the abdominal wall via a continent stoma. The bowel is emptied via a single catheterisation.

=> Ureterosigmoideostomy

The anal sphincter muscle is used as the continence apparatus during ureterosigmoid colon implantation. Ureterosigmoideostomy has been modified by implanting the ureter into an autoaugmented sigmoid colon. Due to possible deterioration of renal function, recurrent upper urinary tract infections, metabolic problems, continence problems in old age and the risk of secondary malignancies at the ureterointestinal anastomosis, this form of urinary diversion has clear limitations.

-- Incontinent urinary diversions

=> Conduit

The ureters are introduced into a segment of bowel that is switched off and drained to the skin without a continence mechanism.

=> Ureterocutaneostomy/Transureterocutaneostomy

One or both ureters are drained directly to the skin. With this form of incontinent urinary diversion, there is a high risk of scarring stenosis of the implantation site. For this reason, lifelong splinting of the ureters is recommended.

Palliative cystectomy (symptom-relieving surgery)

If there is locally extensive tumour growth (T4 tumour) or distant metastasis, a cure is unlikely. This is referred to as a palliative situation. In these cases, it may be necessary to remove the bladder to avoid local problems such as pain, urinary retention kidneys or heavy bleeding from the bladder. The aim of palliative cystectomy is to improve the general condition, control the tumour locally and eliminate or prevent tumour-related complications. The reconstruction of the lower urinary tract is adapted to the patient's needs and is usually performed as an artificial outlet.

Palliative TUR bladder

In patients in whom the removal of the bladder cannot be performed due to the stage of the tumour or secondary diseases, the bladder tumour is resected as extensively as possible with the aim of achieving local tumour control and haemostasis.

Chemotherapy

Cystostatic drugs are intended to kill tumour cells in the body. Several preparations are available as monotherapy or combination therapy for bladder cancer. Depending on the situation, chemotherapy is administered before bladder removal (neoadjuvant/inductive therapy), after bladder removal (adjuvant chemotherapy) or in the event of recurrence, or as the sole form of therapy (palliative chemotherapy).

Radiotherapy

Definitive radiotherapy is indicated for patients who are not suitable for a radical cystectomy, who refuse it or who wish to preserve their organs. A previous complete transurethral tumour resection is a favourable prerequisite for radiotherapy or radiochemotherapy.

Immunotherapy for bladder cancer

Immunotherapy or therapy with so-called checkpoint inhibitors has recently become available for patients with advanced and metastasised bladder cancer. Several substances have been approved for the treatment of these tumour stages.

If a local recurrence occurs, it must be investigated whether additional metastases have formed or whether the recurrent tumour has grown together with other organs. A decision must be made on a case-by-case basis as to which follow-up therapy is appropriate. If a tumour recurs in the former tumour area, radiotherapy may be advisable.

The following table shows a possible scheme.

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The risk of progression is highest in the first two years after bladder removal. 15-20% of recurrences occur in the pelvis, 10-15% of recurrences in pelvic and retroperitoneal lymph nodes. Distant metastasis is most common in the liver (approx. 43%), lungs (approx. 35%) and bones (28%). Recurrences in the male urethra occur in approx. 5-10% of cases.

Primary prognostic factors are the tumour stage and the degree of differentiation (see above). These largely determine the treatment strategy and long-term disease-free survival.

Due to the different behaviour with regard to the risk of recurrence and progression, further prognostic markers are sought that can be detected in the bladder tumour and / or urine.

There is currently no ideal marker that can predict the course of the disease and the success of the therapy as well as be used for follow-up.