Cancer of the Urinary Bladder

Copyright 2006 Radoslaw Pilarski

Etiology

Above all, occupational exposure to chemical compounds (among others from the group of aromatic amines) is considered to be the factor leading to falling ill with cancer of the urinary bladder. Smoking tobacco is also mentioned (cancerogenic substances found in tobacco smoke such as nitrosamines, as well as tryptophane metabolites excreted in the urine). An additional risk factor, which may contribute to the development of more aggressive forms of cancer of the urinary bladder is a long exposure to foreign bodies and infections (mainly Schistosoma haematobium, it concerns African and Small Asia countries, as well as medicines – cyclofosphamide) and small pelvis irradiation due to another tumors in that area.

Genetic disturbances observed in the case of cancers of the urinary bladder are mainly the mutations within suppressor gene p53, oncogene erbB-2, p21, c-myc.

Symptoms

One of the most frequent symptoms of cancer of the urinary bladder, which forces the patient to visit a doctor is haematuria, sometimes with clots. With the advance of the tumor process disuric symptoms may take place, namely pain, bladder tenesmus, burning sensation during miction, sometimes temporary retention of urine. Pain in the lumbar area as well as features of urinary tracts infection may appear during a stasis of urine in the upper urinary tracts. The pain in pelvis and around groin as well as swelling of the lower extremities usually accompany further symptoms of the disease. The first ‘signaling’ symptoms are the pains caused by metastatic changes in bones.

Diagnosis

Even one haematuria or earlier mentioned pain symptoms are an absolute indication for a patient to be examined in order to exclude the possibility of cancer of the bladder. Ultrasonography should be the first examination in the diagnosis of cancer of the urinary bladder, when the tumor change may be depicted, provided that it is big enough, the bladder is full and the place on the wall accessible during examination.

In contrast examination unevenness of bladder contour, filling defects and rigidity of infiltrated wall may be observed depending on the value and the degree of infiltration.

When a suspicious change is detected in bladder, the character of the change should be explained as soon as possible by the means of histopathologic examination. Having done bimanual examination (in order to find any out of bladder changes) cystoscopy is done. During the examination, segments are taken for histopathologic examination.

The urine cytology examination seems proper, nonetheless the negative result does not exclude the presence of a tumor process.

Apart from the above-mentioned examination, morphology, general urine examination, urography (the evaluation of urethers and kidneys) as well as small pelvis computer tomography (the evaluation of local infiltration and the invading stage of lymph nodes) are done. In the case of pain disorders, radiological examination and bone system scinigraphy seem advisable. Similarly to other tumors, chest RTG, gynecological examination in women and an evaluation of prostate’s state in men are recommended. From the prognosis perspective, determining the degree of histological tumor malignancy (basic prognostic factor apart from the state of primeval tumor determined according to TNM classification) seems vital. The following degrees of differentiation are distinguished: well-differentiated cancer (G1) – about 45% of detected cancers, moderately differentiated (G2), poorly differentiated (G3) and undifferentiated cancer (G4). The diagnostic value of BTA and NMP-22 markers is being checked and their determination does not constitute a norm as far as diagnostic methods are concerned.

Histological Classification

Epithelial tumors:

- transitional cell papilloma - transitional cell papilloma infiltrating the bladder wall - planoepithelial papilloma - transitional cell carcinoma - kinds of transitional cell carcinoma: " with planoepithelial transformation " with adenous transformation " with planoepithelial and adenous transformation - basal cell carcinoma - adenocarcinoma - anaplastic tumor

Non-epithelial tumors:

- adenoma - fibroma - myxoma - myoma - angioma - lipoma - pheochromocytoma - sarcoma

Classification

In order to estimate the level of progression the TNM classification or modified system by Jewett and Marshall are applied.

TNM Classification

Pathological classification pT, pN corresponds to T, N clinical classification.

T - primary tumor

Tx - Primary tumour cannot be assessed T0 - No evidence of primary tumour Tis - Carcinoma in situ, preinvasive tumor with focusal anaplasy (G1, G2, G3) within epithelium Ta - Noninvasive papillary carcinoma T1 - Tumor invades subepithelial connective tissue T2 - Tumor invades muscle T3 – Tumor deeply infiltrates a part of muscular coat not exceeding it (T3a) Tumor infiltrates the muscular coat (T3b) Tumor invades perivesical tissue T3a - extracapsular extensions (unilateral) T3b - extracapsular extensions (bilateral) T3c – Seminal vesicles infiltration T4 – Tumor invades other organs T4a - Tumor invades the prostate, uterus, vagina T4b - Tumor invades the pelvic wall, abdominal wall

N – regional lymph nodes

Nx - Regional lymph nodes cannot be assessed N0 - No regional lymph node metastasis N1- Regional lymph node metastasis N2 - Metastasis in a single lymph node, >2 cm but ≤5 cm in greatest dimension; or multiple lymph nodes, ≤5 cm in greatest dimension N3 - Metastasis in a lymph node, >5 cm in greatest dimension

M – distant metastases

MX - Distant metastases cannot be assessed M0 - No distant metastases M1- Distant metastases M1a – lymph nodes other than regional M1b – bone(s) M1c – other organs

In Whitmor-Catalon’s classification A, B, C, D degrees correspond to T1, T2, T3 and T4 respectively in TNM classification.

Classification by Jewett and Marshall

Stage 0: No tumor found in the specimen superficial tumour not invading the submucosa carcinoma in situ Stage A: superficial tumour invading the submucosa Stage B: muscle invasive tumour Stage B1: superficial invasion (less than halfway) Stage B2: deep invasion (more than halfway) Stage C: invasion into the perivesical fat Stage D: Extra vesical disease, further specified in Stage D1: invasion of contiguous organ or regional lymph nodes metastases Stage D2: Extra metastases to distant organs

Treatment

The choice of treatment for patients suffering from urinary bladder cancer depends on the degree of progression according to TNM classification, the level of tumor’s histological malignancy and the general state of the patient.

Surgical treatment

Transurethral resection of tumor (TURT)

This method is used in the case of surface changes (Ta, T1, T2, as well as the multiple ones and when treating preinvasive tumor Tis, if the number of focuses is low and the atypy insignificant). TURT may be done also in the case of T3a tumors if the diameter of the base does not exceed 2 cm. In the case of advanced stages (T3, T4 ) it is sometimes used as paliative treatment.

Partial resection of urinary bladder

It is applied when a 3 cm microscope margin of healthy tissue is possible in big, individual focuses of T2 tumor and in the early period of T3.

Complete resection of urinary bladder (cystectomy)

A two-stage surgery which consists in cutting out a bladder together with lymph nodes and recreating the possibility to drain the urine from the upper urinary tracts.

The operation concerns patients suffering from:

- poorly differentiated cancer (G3) - early recurrence after treatment using other methods - tumors invading the neck of urinary bladder, prostate urethra, bladder triangle when urine flow from kidneys is impeded - extended and multifocal pre-invasive tumors - bleeding from the bladder impossible to control

Cystectomy is also done among patients who underwent unsuccessful partial resection and after recurrences after radiotherapy.

Three ways of urine flow are applicable. One of them, known as the Bricker’s is about creating ileal conduit for the urine to flow to a bag stuck to the skin. The second option is the creation of an intestinal cistern, which when full is emptied by the patient by self catheterization through a skin fistula. The most comfortable way is the creation of a surrogate urinary bladder linked to the urethra (a patient urinates moving his/her stomach muscles).

Radiotherapy

It is applied among patients who do not give their consent to the treatment or when a radical cystectomy is often impossible in their cases. Radiotherapy among patients in T2 to T4 progression stage creates a possibility of attaining a 5-year survival without disease recurrence among 35 to 45% of patients and a 5-year complete survival among 23-40%.

A 45 Gy dose is given for the pelvis and then a boost for bladder tumor is done up to 65 Gy dose. The introduction of conformal radiotherapy which consists in 3-dimensional planning system (3D CRT) into clinical practice in the recent years enables more effective application of radiotherapy in the radical treatment of urinary bladder cancer. Chemotherapy

In the case of urinary bladder cancer it is applied mainly as palliative treatment or together with surgical methods or radiotherapy.

Inductive chemotherapy aims at reducing the size of tumor most often before the radiation.

Most often applied treatment schemes are:

M-VAC

Metotreksat 30 mg/m2 im Doksorubicine 30 mg/m2 iv Cisplatine 70mg/m2 iv Vinblastine 3mg/m2 iv The pause between the cycles 28 days

M-VC

Metotreksat 30 mg/m2 im Cisplatine 70mg/m2 iv Vinblastine 3mg/m2 iv The pause between the cycles 28 days

CISCA

Cyklofosfamide 650 mg/m2 iv Doksorubicine 50 mg/m2 iv Cisplatine 100mg/m2 iv The pause between the cycles 21 - 28 days

Paclitaxel (monotherapy)

Paclitaxel 250 mg/m2 iv 1 day, the cycles repeated every 21 days

Direct bladder treatment

Such a method is recommended in the cases of:

- tumors of T1 degree (multiple) - multifocal changes of Ta type - lesions of Tis character

Most often used drugs are: thipotepa, BCG vaccine, mitomycine, doksorubicine.

BCG therapy of the surface tumor has been more effective so far than direct bladder chemotherapy, as it decreases the risk of regional recurrence and, what is more, decreases probability of undergoing the disease process at invasive cancer stage.

Prognosis

In the case of urinary bladder cancer the prognosis depends on the level of progression as well as the choice of optimal treatment and the internal state of patients. A percentage of 5-year cure most often oscillates around 50-70% as for the I and the II degree, and 20-30% as for the III degree. Longer survival periods are rarely reported in the IV degree.