Urology course Bladder tumors

10. Urinary bladder tumors

EPIDEMIOLOGY The cancer of the bladder represents 2% of all malignant tumors. It is the 4th place in men cases after pulmonary, prostate and colon tumors, while at women it is on the 10th place. It is the most common tumor of the urinary tract. The age of choice of cancer of the bladder occurrence is 65-70 years. Similarly to the pyelocaliceal and ureteral tumors a noticeable downward trend in age of bladder tumor occurrence can be observed, which can be found in recent years even in the second decade of life. Men are affected at a 3-4 times higher rate than women. The difference increases with age. About 75% of all patients with bladder tumors at the time of first diagnosis present a superficial bladder tumor, 20% an invasive cancer, while 5% have a metastatic bladder cancer. The incidence of bladder cancer is higher in industrialized countries than in rural areas. ETIOPATHOGENESIS Involvement of toxins in the bladder tumor carcinogenesis has been studied and clarified the most complete, compared with other tumors. In 1895, Rehn observed the more frequent occurrence of cancer of the bladder in workers in aniline dye industry. In 1938 it has been experimentally proved at animals that aromatic amines produce cancer of the bladder. The best known carcinogenic substances acting in the bladder are: 2--naphthylamine, 1-naphthylamine, benzidine, magenta, phenacetin,

cyclophosphamide, diclorbenzidina and aniline. Latency time between the exposure to pollutants and development of cancer of the bladder is 10-40 years. Aromatic amines: become cancerigenic after hepatic metabolism by hydroxylation and glucuronation and it is then excreted by urine. They can be activated with N-acetyltransferase. Individuals who due to genetic have a rapid acetylation, have a lower cancer risk, compared to so-called more slow acetylated persons. Smoking: smokers have a 2-6 times higher risk of developing cancer of the bladder. After 40 years of smoking the risk is 2 times higher than after 20 years of smoking. And in 1

Urology course Bladder tumors

this case 2 - -naphthylamine has the decisive role in occurrence of cancer of the bladder. Saccharin and cyclamate according to studies have a carcinogen action in humans. Drugs: 3 drugs may be involved, certainly, in the increased frequency of cancer of the bladder: - Clornafazine, a therapeutic agent of polycythemia, which, from the point of view of its chemical structure, is related to the of 2 - -naphthylamine, but no longer used since 1963; - Phenacetin produces, in addition to an increased incidence of cancer of the bladder an interstitial nephritis (nephropathy of analgesic); - Cyclophosphamide - alkylating anticancer agent. Chronic urinary infections chronic carriers of bladder catheter by the bladder mucosal epithelium metaplasia, especially develop epidermoid cancer cell (pavement or squamous) or epidermoid cancer. Most at risk are patients with neurogenic disorders of bladder evacuation, bearing for decades this catheter. Urinary infection, blader catheter, bladder stones produce chronic irritation of the lining of the vesical mucosa. Bilharzia is an endemic parasitosis in various countries in Africa and Arab countries, in the acute phase of infection with hematobium Schisostoma granulomatous polyps form in the bladder. It is assumed that the increased incidence of cancer of the bladder in patients with chronic urinary infections is due to the growth of nitrosamines in the urine during urinary infections. Balkan nephropathy. Etiologic factor seems to be a fungus. It grows as a saprophyte on stored grain and produces nefrotoxine and mycotoxins with a cancerigenic action. PATHOLOGY Macroscopic - about 75% of all bladder tumors are localized in the trigone - during development they catch ureteral orifices, 10% are localized in the bladder dome and have other embryological origin and the remaining 15% are distributed in the lateral and posterior bladder wall mucosa. On inspection they have the following aspects: Pediculated tumors - single or multiple, implanted in the bladder mucosa by a thin

pedicle.

Urology course Bladder tumors

Sessile tumor with large implantation basis, with short fringes, less mobile, they Infiltrative tumors they are vegetative tumors, with large implantation in the

seem to be fixed to the mucosa, less exophytic than the previously described category.

bladder wall, with an irregular surface. Generally, the larger a tumor is, and has a larger implantation basis, the more malignant it is. Microscopic they are divided into epithelial tumors and non-epithelial ones (Table IV). PRIMITIVE TU. I. EPITHELIAL TU. (95%) A. Benign - papilloma B. Malignant: Transitional carcinoma Epidermoid carcinoma Adenocarcinoma SECONDARY TU. 1. Gastric metastasis, ileal or colic, pheochromocytoma, from the lung, mammary gland, pelvic organs. 2. Endometriosis, dermoid cysts. Table IV - Histological appearance of bladder tumors 2. TU. MEZENCHIMALE (4%) A. Benign (3,5%): fibroma, myoma, etc. B. Malignant (0,5%) Sarcoma Reticulum cell sarcoma Lymphosarcom

In the epithelial tumors, urothelial carcinomas are most common. In 7% of cases, epidermoid carcinomas are found and in 1% of cases bladder adenocarcinomas are found, in the anterior wall of the bladder, opening place of the urachus. Normal bladder urothelium is composed of 6-7 cell layers. The number of cell layers reduces upward to the pelvis of the kidney, where only 2-3 layers can be found. Typical for urothelium are the so-called umbrella cells located on the lumen. These cells are covered with a layer of mucopolysaccharides containing sialic acid, forming mucous layer, in the area from muscle, the epithelium is delimited by the basal mucosa. Papillomas are considered benign tumors. This rare form of tumor is composed of microscopic view of a normal epithelium, which increases similarly to a cauliflower to bladder 3

Urology course Bladder tumors

lumen (exophytic) with a greater number of cell layers (T0G0). G1 carcinomas have multiple epithelial layers with partial loss of appearance of stratification. The nucleus is uniform and resembles to the cells of the basal membrane. Cellular polymorphism has not yet outlined. G3 tumors - this group of tumors is malignant aspects with anaplasia are evidenced, with increased nuclear polymorphism. Epithelial stratification can no longer be recognized. G2 tumors are located between those with G1 and G3. Currently, there are two types of grading for bladder tumors: OMS 1973 Urothelial papilloma Grade 1: well differentiated Grade 2: moderately differentiated Grade 3: poorly differentiated OMS 2004 Urothelial papilloma Urothelial papillary neoplasm with low malignancy Urothelial papillary carcinoma of lower malignancy grade Urothelial papillary carcinoma with high degree of malignancy Carcinoma in situ - is an intraepithelial neoplasm with a high degree of malignancy. Pathological studies performed on total cystectomy pieces showed urothelial bladder tumors are tumors with multicenter growth. Because they have a high potential of malignancy, all epithelial bladder tumors should be considered transitional carcinomas. Extension at distance - bladder carcinoma invade locally penetrating the bladder wall layers. Perivesical ganglions, pelvic, of obturator fossa, presacrum and iliac are infiltrated through lymphogene way. Hematogenous metastases occur in lung, bone and liver. T1G3 tumors present, in over 10% of cases, invaded lymph nodes or hematogenous metastases. In T2 stage 29-30% of cases there are invaded lymph nodes, and in T3a and T3b stages in 40-60% of cases metastases can be observed. STAGING Bladder tumors are classified as other urogenital cancers by TNM system.

Urology course Bladder tumors

Tx - Primary tumor cannot be explored T0 - no primary tumor highlights Ta - Noninvasive papillary carcinoma in the lamina propria Tis - carcinoma in situ T1 - carcinoma that invaded the lamina propria T2 - carcinoma which permeates the muscle layer of the bladder T2a - tumor invades superficial of the muscle layer of the bladder T2b - tumor invades deep of the muscle layer of the bladder T3 - Tumor invades perivesical tissue T3a - microscopically T3b macroscopic T4 - Tumor invades prostate, uterus, vagina, pelvic or abdominal wall T4a - Tumor invades prostate, uterus, vagina T4b - Tumor invades pelvic or abdominal wall N- ganglions Nx - Regional ganglions cannot be evaluated N0 - no lymph metastasis reveals N1 - one lymph node invasion with more than a 2 cm in diameter N2 - invasion of one lymph node with a diameter between 2-5 cm, or more than 5 cm diameter lymph N3 - lymph nodes over 5 cm diameter M - Metastases Mx - possible metastases cannot be explored M0 - no metastasis M1 - distant present metastasis If P element is added, this means the correct staging of the tumor (T) by histological exam-PT. EVOLUTION Non-infiltrative papillary tumors - can be radically cured by total exeresis, but a proportion of up to 50% relapses in the next 5 years and 80% in the first 10 years. Relapses are of the same type T and G, or progress to invasion (T) and (G) anaplasia. 5

Urology course Bladder tumors

Invasive tumors - evolve locally by direct extension, invade lymphatics and lately it metastasizates hematogenous, SYMPTOMATOLOGY In about 20% of cases, in early stages, cancers of the bladder have no symptoms, they are accidentally discovered during the occurrence of hematuria or when conducting an endoscopic examination for other conditions (BPH, prostatic cancer, urethral strictures after urethrotomy or when installing ureteral catheter for PCNL). The most common symptom in bladder cancer is macroscopic haematuria, painless, but macro-and microscopic hematuria can be caused by other urinary tract tumors. In general, papillary tumors are massive bleeding, blood clean that clots either in the bladder. In contrast, infiltrated tumors hematuria may be of lesser intensity, but may accompanied by signs of suppurations of pathological mucosa of the bladder capacity reduction. Pollakiuria - is especially observed in infiltrated forms, which reduces bladder capacity and flexibility. It is generally a sign of late stage in the evolution of bladder tumors. Dysuria it appears as a consequence of infiltration after bladder neck, in case of cervico-trigonal location of the tumor. Sometimes, dysuria may result from the presence of clots in the bladder, or appearance of tumor (pediculated) in cervix. Pyuria is a rare sign, is present mainly in infiltrative tumors.

Pelvic pain - is due to perineurial neoplastic infiltration. It manifests as a painful sensation with hypogastric, pelvic or perineal center. DIAGNOSIS Cystoscopy. In patients with macro and microscopic isolated hematuria, carrying out a cystoscopy is mandatory. This method of investigation will be preceded by non-invasive methods such as ultrasonography which is useful also for exclusion of renal origin of hematuria. Cystoscopy is performed either with rigid cytoscopes or lately, with flexible ones. The bladder will be examined using an optical angulated - 70 . If no changes appear in the bladder, ureteral orifice from which the bloody urine is coming should be
Fig. 10.1. Cystoscopic aspect of bladder tumors

Urology course Bladder tumors

pursued, hematuria is sometimes bilateral. With a 0 optical the distal urethra can be explored, bulbar or prostatic (Fig. 10.1). Cytology - transitional epithelial cells (normal) and the carcinoma can be identified in samples of urine, testing is performed by repeated instillations of 50 ml physiological saline into the bladder. The first morning urine should not be collected because cells that have stalled for some time in the bladder may be damaged. Urine samples are kept for sedimentation or passed through micro-filters. The supernatant is mounted and studied under a microscope as the native preparation, either using different staining techniques: Papanicolau technique or Giemsa. It is studied the microscopic appearance of cells, studying the following malignancy criteria: the changing of nuclear plasma protrusions and irregular of nuclear membrane increasing the amount of chromatin, with decrease of the nucleus transparency; multiplication and change of shape of nuclear particles; various aspect of the form of nucleus. After carrying out the Papanicolau test, there are five gradations of cytology appearance: grade 1 and 2 shall be considered as benign, grade 3 is atypical, grades 4 and 5 shall be assessed as malignant. The sensitivity of urinary cytology is 30% in G1 tumors, of 40-60% in G2 tumors and 80-90% in G3 tumors, including carcinomas in situ. False positive results are frequently found in chronic inflammation, especially in urinary stones. Biological markers - have a decreased role in bladder tumors and therefore they are no longer used for diagnosis. IMAGING Ultrasound in many cases it can identify a bladder tumor, if the examination is carried out in a state of bladder fullness (Fig. 10.2). Tumor located on the anterior wall is more difficult to identify in a transabdominal ultrasonography, or small ones with any location. IVU is mandatory for a macro or microscopic investigation of hematuria. Bladder tumors are
Fig.10.2. US aspect of the bladder tumors

Urology course Bladder tumors

satisfactory noticeable on the cystography of the urography, which allows the exclusion of a likely cause of bleeding with a pyelo-calyx, basin or ureteral center. It also gives information about renal echo, when the bladder tumor has produced the infiltration of the terminal ureters, with secondary ureterohydronephrosis. CT in most cases identifies the bladder tumor. Also can provide information on local expansion, especially the neighboring organs. Lymph nodes cannot be identified very well with CT, because only lymph nodes over 1 cm in diameter, can be identified, ganglions with micrometastasis cannot be identified. MRI gives less good results compared with CT. Although imaging methods progress, neither ultrasound, nor CT or MRI cannot accurately fit a bladder tumor in one of the stages of the known TNM staging, cannot allow a full diagnosis of primary tumor. CYTOSCOPY AND TUR B The final confirmation of bladder tumor diagnosis is made by cystoscopy in anesthesia. In TUR-B tumor is usually removed entirely. Samples are taken from the basis of tumor which is sent to histopathology examination, separate from the rest of tumor, allowing a sure classification of depth of tumor invasion secure employment. Biopsy samples are taken from the apparently normal urothelium, to identify the precancerous state such as dysplasia or carcinoma in situ. At the end of the operation the bladder examination is performed by bimanual examination. Relaxation of the abdominal wall after anesthesia, allows appreciation of bladder tumor infiltration in the bladder wall and into neighboring organs, or pelvic wall. Thus it is possible to differentiate a tumor in T3a stage from one in a T4 stage. If bladder wall has an increased consistency, or even hard, but mobile, we can talk about a tu. that penetrates muscles, excluding stages Ta and T1. After the diagnosis of bladder tumor is established, one will proceed to tumor staging, especially to exclude the presence of metastasis. The following investigations are used: CT of the pelvis, which allows the identification of lymph nodes in the iliac area, obturator fossa and lymph paraaortic ganglions; The upper abdominal US allows to identify the status of the liver; Lung x-ray in two planes permits to exclude any lung metastasis;

Urology course Bladder tumors

Bone scintigraphy, excludes bone metastasis. Bone metastasis are characterized by increased accumulation of the isotope. This sign may be due to different processes of bone regeneration, caused by chronic inflammation, healing after fractures, etc..

New diagnostic methods o Cystoscopy in polarized light after the hematoporphyrin. o A DNA analysis of mucosal epithelial cells using flow cytometry can be performed. You can use cell surface markers (ABO antigens) for determining prognosis of the bladder tumor. The prognostic significance is the loss of surface antigens, which are always present on epithelial cells. Using monoclonal antibodies one may identify tumor antigens on the surface of tumor cells, using immunohystologic or immunocytologic processes.

DIFFERENTIAL DIAGNOSIS Due to these complex investigative methods that allow not only to objectify the tumor, but also to know its histological nature, the possibility of confusion with another urology entity seems impossible. Before having these very complex possibilities of diagnosis, the differential diagnosis is made with: Bladder tuberculosis - as proliferative form, bladder stones. prostate adenoma, hypertrophic cystitis ureterocele, bladder clots, etc. The diagnosis of bladder tumor is determined by several methods of investigation that converge. PROGNOSIS Assuming that all bladder tumors are malignant (except papilloma), we must admit that there are very different degrees of malignancy, ranging from favorable prognosis, to the perception of very short survival. The most important prognostic factors are: the stage of tumor invasion (the invasion is more advanced, the prognosis is worse); histological grade - lethality index of bladder tumor directly increases with tumor gradation; according to histological type, epidermoid tumors and adenocarcinomas have a worse prognosis; 9

Urology course Bladder tumors

tumors that develop on the lesions of carcinoma in situ are infiltrative from the beginning and aggressive. TREATMENT At this stage with multiple technical resources, the only way to improve the prognosis of

bladder tumors is early detection of tumor, correct treatment and complex of this first urothelial neoplasic manifestation and permanent monitoring of the patient. Urologist is faced with two major groups of tumors: superficial, localized in the mucosa and infiltrative, penetrating the detrusor urinae, with the possibility of invasion at distance. 1. Treatment of bladder tumors non-invasive muscle (Ta, T1, N0, M0)

1.1. Surgical methods 1.1.1 Transurethral resection of the bladder tumors (TUR B) (Fig. 10.3) - is open to all superficial bladder tumors Ta, T1. After resection of the exophyt portion and basis of the tumor 5 biopsies will be taken (in the center of the basis of the tumor and 4 points of the resection surface, at 3, 6, 9, 12 hours) to be sent separately from resected fragments of tumor itself biopsies Bressel. Histopathological outcome of these biopsies is an objective information of the radical endoscopic tumor resection. 1.1.2. Total cystectomy - the man is made a total cystoprostateveziclectomy, which means removal of the
Fig. 10.3. Transurethral resection of the bladder tumors (TUR B)

bladder and seminal vesicles with prostate block with all perivesical fat. At women, total cystectomy combines with total colpohysterectomy, making so-called previous peivectomy. Muscle non-invasive bladder tumors cystectomy indication is reduced and relates to tumor malignancy highly recurrence, with T1 or CIS bladder tu with high degree of malignancy.

1.2. Adjuvant therapy 1.2.1. Intravesical chemotherapy. A single dose of mitomycin C, epirubicin or doxorubicin. This 10

Urology course Bladder tumors

instillation is carried out within 24 hours after TUR V and is designed to kill circulating cells after resection. This therapy reduces the risk of relapse by 12%. 1.2.2. Intravesical immunotherapy with BCG. Intravesical BCG therapy after TUR has superior results comparetive with TUR alone or TUR and intravesical chemotherapy. After an induction period of 6 weeks with weekly BCG instillation the treatment is continued at 3, 6 months, then every 6 months for 3 years. This led to a reduction in tumor recurrence and progression of bladder tumors by about 37%. BCG treatment imply some risks on its advese effects: fever, arthralgia, cystitis, hematuria, even deaths by sepsis. These were due to systemic absorption of BCG. To prevent this administration will not be faster than 2 weeks after TUR B or if the patient has hematuria. FOLLOW-UP patients with nonivasive bladder muscle tumor will be based on tumor grading:

for low-malignancy tumors cystoscopy should be performed at 3 months and then every 9 months (if it is negative); for highly malignant tumors with cystoscopy and urinary cytology will be performed every 3 months.

2. Locally advanced bladder tumors (T2-T4a, N0-Nx, M0) 2.1. Surgical methods 2.1.1.Radical cystectomy - is the main indication of surgery in patients with locally advanced bladder tumors. The following derivatives can be made vacant by ureters urinary total cystectomy: implantation in sigma (Fig. 10.4)

Fig. 10.4. Uretero-sigma anastomosis

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Urology course Bladder tumors

in Bricker ileal bladder (Fig. 10.5)

Fig. 10.5. Bricker ileal bladder

at the skin level (ureterostomy) neobladder urinary bypass pouch of ileum or colon: Mainz II, Koch, Indiana, Padua, etc. Indication for this operation were the following situations: bladder tumors are not resectable endoscopically papillary bladder tumors, even superficial, associated with multiple anaplastic carcinoma in situ sites; bladder tumors in stage T2-T4a without lymphnode invasion. 2.1.2. Partial cystectomy - is extremely limited indication that just about tumors because

of size, location or intraoperative complications occur in TUR B (bleeding, peritoneal perforation). Resection must include 3 cm of healthy tissue to limit apparent parietal insertion of parietal tumor. All the bladder wall thickness resection. 2.1.3. Transurethral resection of the bladder tumors (TUR B) is not a curative therapy in the majority of these patients. Is a viable alternative in patients who re-TUR showed a pTa or pT1bladder tumor. For other patients TUR V is performed only palliative purposes (haemostatic, for heavy bleeding, bladder capacity reduction, to increase) 2.2. Radiation - the tumor is well differentiated, is more resistant to irradiation. Undifferentiated tumors are radiosensitive. Today, using either external radiotherapy with high energy radiation such as electron linear accelerator, or interstitial radiation therapy consisting of intratumoral implantation, of radium, radioactive gold or tantalum in bladder wall after excision 12

Urology course Bladder tumors

of the tumor. Radiation therapy is used only in patients who are not candidates for radical cystectomy or hemostatic effect when this can be done by TUR B. Preoperative radiation therapy is used to prevent the local relapses after radical cystectomy. 2.3. Chemotherapy as a unique therapeutic method, gave poor results. For systemic combination therapy methotrexate, vinblastine, adriamycin plus cisplatin appears to have encouraging results. 3. Metastatic bladder tumors treatment In this population chemotherapy with methotrexate, vinblastine, cisplatin plus adriamycin can bring survival up to 14 months. A second line chemotherapy consists of paclitaxel, docetaxel, etc. It seems that the last generation of chemotherapy - vinflunina - has the best results and therefore the only chemotherapy approved for a second line chemotherapy. In patients with bone metastases bisphosphonates in combination with calcium and vitamin D improves quality of life by decreasing pain and reducing the number of pathological fractures.

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