BLADDERBLADDER

CANCERCANCER

BACKGROUNDBACKGROUND

The incidence of bladder carcinoma is rising in Western The incidence of bladder carcinoma is rising in Western countries. countries.

In 1996, approximately 53,000 patients were diagnosed In 1996, approximately 53,000 patients were diagnosed with bladder cancer in the USA, 9,000 in France, 2,000 with bladder cancer in the USA, 9,000 in France, 2,000 in Sweden 8,000 in Spain and 1,120 in Belgium.in Sweden 8,000 in Spain and 1,120 in Belgium.

Approximately 75-85% of patients present with disease Approximately 75-85% of patients present with disease confined to the mucosa (stage Ta-Tis) or submucosa confined to the mucosa (stage Ta-Tis) or submucosa (stage T1). The other 15-25% have muscle invasion or (stage T1). The other 15-25% have muscle invasion or nodal disease (stages T2-T4, N+) at presentation. nodal disease (stages T2-T4, N+) at presentation.

EpidemiologyEpidemiology

Carcinoma of the bladder is Carcinoma of the bladder is three times more common three times more common among men then women.among men then women.

Neoplasm of bladder can Neoplasm of bladder can occur at any age of patients occur at any age of patients but it is most common in but it is most common in elderly persons (55 years and elderly persons (55 years and older) and incidence of bladder older) and incidence of bladder cancer increases directly with cancer increases directly with age.age.

The median age at the time of The median age at the time of diagnosis is, depending on the diagnosis is, depending on the country, 60-70 years.country, 60-70 years.

EpidemiologyEpidemiology

The rise in incidence of bladder The rise in incidence of bladder cancers is observed in the last 20 cancers is observed in the last 20 years.years.

Bladder cancer is diagnosed 1,5 to Bladder cancer is diagnosed 1,5 to 2 times more common among 2 times more common among whites then among blacks, whites then among blacks, depending on gender. depending on gender.

The bladder cancer was the cause The bladder cancer was the cause of death of 11 200 patient and this of death of 11 200 patient and this accounts for 2,6% all cancers accounts for 2,6% all cancers death in man and 1,4% in women.death in man and 1,4% in women.

BLADDER CANCERBLADDER CANCER

During last 50 years incidence rate of During last 50 years incidence rate of bladder cancer has increased of bladder cancer has increased of approximately 50% but mortality has approximately 50% but mortality has decreased of approximately 33%.decreased of approximately 33%.

It is hard to state, to which factors It is hard to state, to which factors

changing in the biology of cancer, changing in the biology of cancer, earlier diagnosis, better treatment or earlier diagnosis, better treatment or alteration in risk factors this alteration in risk factors this phenomenon can be attributed.phenomenon can be attributed.

Histological grading of World Health Organisation and Histological grading of World Health Organisation and International Pathology Concensus Committee 1988International Pathology Concensus Committee 1988

PTNM pathological classificationPTNM pathological classification The pT, pN, and pM categories correspond to the T, N, The pT, pN, and pM categories correspond to the T, N,

and M categories.and M categories. GG - - Histopathological gradingHistopathological grading GXGX - - Grade of differentiation cannot be assessedGrade of differentiation cannot be assessed G1G1 - - Well differentiatedWell differentiated G2G2 - - Moderately differentiatedModerately differentiated G3G3-4 - -4 - Poorly differentiated/undifferentiatedPoorly differentiated/undifferentiated

2002 TNM classification of urinary bladder cancer2002 TNM classification of urinary bladder cancer

T - Primary tumourT - Primary tumour TTXX Primary tumour cannot be assessedPrimary tumour cannot be assessed T0T0 No evidence of primary tumourNo evidence of primary tumour Ta Non-invasive papillary carcinomaTa Non-invasive papillary carcinoma Tis  Carcinoma Tis  Carcinoma in situin situ: 'flat tumour‘: 'flat tumour‘ T1Tumour invades subepithelial T1Tumour invades subepithelial

connective tissueconnective tissue T2Tumour invades muscle T2Tumour invades muscle  T2aTumour invades superficial muscle T2aTumour invades superficial muscle

(inner half) (inner half)  T2bTumour invades deep muscle (outer T2bTumour invades deep muscle (outer

half)half) T3Tumour invades perivesical tissue: T3Tumour invades perivesical tissue:  T3aMicroscopically T3bMacroscopically T3aMicroscopically T3bMacroscopically

(extravesical mass)(extravesical mass) T4Tumour invades any of the following: T4Tumour invades any of the following:

prostate, uterus, vagina, pelvic wall, prostate, uterus, vagina, pelvic wall, abdominal wall abdominal wall 

T4aTumour invades prostate, uterus or T4aTumour invades prostate, uterus or vagina vagina 

T4bTumour invades pelvic wall or T4bTumour invades pelvic wall or abdominal wallabdominal wall

2002 TNM classification of urinary bladder cancer2002 TNM classification of urinary bladder cancer

N - Lymph nodesN - Lymph nodes NXNX Regional lymph nodes cannot be assessedRegional lymph nodes cannot be assessed N0N0 No regional lymph node metastasisNo regional lymph node metastasis N1N1 Metastasis in a single lymph node 2cm or less in greatest Metastasis in a single lymph node 2cm or less in greatest

dimensiondimension N2N2 Metastasis in a single lymph node more than 2 cm but not more Metastasis in a single lymph node more than 2 cm but not more

than 5 cm in greatest dimension, or multiple lymph nodes, none than 5 cm in greatest dimension, or multiple lymph nodes, none more than 5 cm in greatest dimensionmore than 5 cm in greatest dimension

N3 Metastasis in a lymph node more than 5 cm in greatest N3 Metastasis in a lymph node more than 5 cm in greatest dimension dimension 

M - Distant metastasisM - Distant metastasis MXMX Distant metastasis cannot be assessedDistant metastasis cannot be assessed M0M0 No distant metastasisNo distant metastasis M1M1 Distant metastasisDistant metastasis

CLASSIFICATIONCLASSIFICATION

More than 90% of bladder More than 90% of bladder cancers are transitional cancers are transitional cell carcinoma (TCC); the cell carcinoma (TCC); the remainder are squamous remainder are squamous cell or adenocarcinoma. cell or adenocarcinoma.

Bladder tumours are Bladder tumours are considered superficial (Tis-considered superficial (Tis-Ta-T1) or infiltrative (T2-T3-Ta-T1) or infiltrative (T2-T3-T4) based on cystoscopy, T4) based on cystoscopy, transurethral resection transurethral resection (TUR), imaging studies and (TUR), imaging studies and histopathological findings. histopathological findings.

RISK FACTORSRISK FACTORS

Aromatic amines were the first to be recognized. AtAromatic amines were the first to be recognized. At risk groups risk groups include workers in the following industries: printing, iron foundry, include workers in the following industries: printing, iron foundry, aluminium smelting, industrial painting, gas and tar aluminium smelting, industrial painting, gas and tar manufacturing. manufacturing.

Another prominent risk factor is cigarette smoking. Smoking Another prominent risk factor is cigarette smoking. Smoking leads to higher mortality from bladder cancer during long-term leads to higher mortality from bladder cancer during long-term follow-up, even though in a multivariate analysis, the prognostic follow-up, even though in a multivariate analysis, the prognostic effect of smoking was weaker than that of other factors, such as effect of smoking was weaker than that of other factors, such as stage, grade, size and multifocality of the tumour . Patients with stage, grade, size and multifocality of the tumour . Patients with initial grade III tumours were significantly more likely to be heavy initial grade III tumours were significantly more likely to be heavy smokers than those with less aggressive disease .smokers than those with less aggressive disease .

SymtomatologySymtomatology

Haematuria is the most Haematuria is the most common finding in bladder common finding in bladder cancer. The degree of haematuria cancer. The degree of haematuria does not correlate with the extent does not correlate with the extent of the disease. It may be grossly of the disease. It may be grossly visible to the patient or simply visible to the patient or simply found on routine urinalysis. found on routine urinalysis.

Bladder cancer may also Bladder cancer may also present symptoms of voiding present symptoms of voiding irritability. Patients may complain irritability. Patients may complain of urgency, dysuria and of urgency, dysuria and increased urinary frequency. increased urinary frequency.

Urinary tract infection is Urinary tract infection is observed in 30% of patients.observed in 30% of patients.

SymtomatologySymtomatology

Pain appears in advanced Pain appears in advanced stages of the tumour. When it is stages of the tumour. When it is located in the suprapubic region located in the suprapubic region it signals that the tumour it signals that the tumour infiltrates the perivesical infiltrates the perivesical tissues.tissues.

Flanc pain, often accompanied Flanc pain, often accompanied by fever, is due to the ureteral by fever, is due to the ureteral obstructions.obstructions.

DIAGNOSIS DIAGNOSIS Physical examinationPhysical examination Physical examination, including Physical examination, including

digital rectal examinationdigital rectal examination and and bimanual pelvic palpation, is bimanual pelvic palpation, is recommended when haematuria recommended when haematuria is found. is found.

However, 85% of patients with However, 85% of patients with bladder cancer initially present bladder cancer initially present with superficial disease. with superficial disease.

Therefore, physical examination Therefore, physical examination plays a limited role in the plays a limited role in the diagnosis, except to exclude co-diagnosis, except to exclude co-existing pathologyexisting pathology..

DIAGNOSISDIAGNOSIS (Laboratory Findings) (Laboratory Findings)

The most commonly assessed The most commonly assessed laboratory parameters are:laboratory parameters are:

Haemoglobin and erythrocyte Haemoglobin and erythrocyte sedimentation rate: prognosis sedimentation rate: prognosis

Creatinine: overall kidney Creatinine: overall kidney function function

Alkaline phosphatase: liver Alkaline phosphatase: liver metastasis, bone metastasis. metastasis, bone metastasis.

Serum calcium is frequently Serum calcium is frequently included in the preoperative included in the preoperative assessment because of its assessment because of its association with paraneoplastic association with paraneoplastic manifestation, which may have manifestation, which may have clinical implicationsclinical implications..

The The erytrocit-erytrocit-, , protein-protein- and and leukocyturialeukocyturia are exposed in are exposed in urine.urine.

DIAGNOSIS ImagingDIAGNOSIS Imaging

Urography with cystography are Urography with cystography are performed in all patients performed in all patients suspected of bludder tumours.suspected of bludder tumours.

Filling defects in the central part Filling defects in the central part of the cystogram can indicate the of the cystogram can indicate the papillary growth of the tumour.papillary growth of the tumour.

Marginal filling defects are typical Marginal filling defects are typical of flat tumours, which are always of flat tumours, which are always invasive.invasive.

DIAGNOSIS ImagingDIAGNOSIS Imaging Intravenous pyelography IVPIntravenous pyelography IVP Large tumours may be seen as filling Large tumours may be seen as filling

defects in the bladder or may restrict defects in the bladder or may restrict symmetrical bladder wall expansion symmetrical bladder wall expansion during filling in invasive tumours.during filling in invasive tumours.

Intravenous pyelography (IVP) is also Intravenous pyelography (IVP) is also used to detect filling defects in the used to detect filling defects in the calices, renal pelvis and ureters, and calices, renal pelvis and ureters, and hydronephrosis, which may indicate hydronephrosis, which may indicate the presence of a ureteral cancer or a the presence of a ureteral cancer or a muscle-invasive bladder cancer at the muscle-invasive bladder cancer at the ureteral orifice. ureteral orifice.

The necessity to perform routine IVP at The necessity to perform routine IVP at initial diagnosis is now questioned initial diagnosis is now questioned because of the low incidence of because of the low incidence of important findings obtained with this important findings obtained with this

methodsmethods. .

DIAGNOSIS ImagingDIAGNOSIS Imaging

DIAGNOSIS ImagingDIAGNOSIS Imaging (metastasis) (metastasis)

In order to specify staging of the bladder tumour, besides clinical In order to specify staging of the bladder tumour, besides clinical examination, USG and bimanual investigation of patients, following examination, USG and bimanual investigation of patients, following additional procedures are performed:additional procedures are performed:

1. transurethral diagnostic (primary) resection1. transurethral diagnostic (primary) resection 2. transurethral ultrasonography2. transurethral ultrasonography 3. computed tomography of pelvis minor, retroperitoneum and liver3. computed tomography of pelvis minor, retroperitoneum and liver 4. magnetic resonance of pelvis minor and bones - sites suspected 4. magnetic resonance of pelvis minor and bones - sites suspected

of the metastases,of the metastases, 5. chest radiograph.5. chest radiograph.

DIAGNOSIS ImagingDIAGNOSIS Imaging

UltrasonographyUltrasonography Transabdominal sonography makes it Transabdominal sonography makes it

possible to identify exclusively possible to identify exclusively exophytic tumours whose diameter exophytic tumours whose diameter exceeds 10 mm.exceeds 10 mm.

USG is more discriminationg method. USG is more discriminationg method. It helps to determine the depth of the It helps to determine the depth of the tumour invasion into the bladder wall.tumour invasion into the bladder wall.

Transabdominal ultrasound permits Transabdominal ultrasound permits characterization of renal masses, characterization of renal masses, detection of hydronephrosis and detection of hydronephrosis and visualization of intraluminal filling visualization of intraluminal filling

defects in the bladderdefects in the bladder. .

DIAGNOSIS ImagingDIAGNOSIS Imaging

Computed tomography is of little use in the diagnosis of Computed tomography is of little use in the diagnosis of bladder cancers.bladder cancers.

Computed tomography (CT) scanning may be part of the Computed tomography (CT) scanning may be part of the evaluation of invasive bladder tumours and the evaluation evaluation of invasive bladder tumours and the evaluation of pelvic and abdominal lymph node metastasis. of pelvic and abdominal lymph node metastasis.

DIAGNOSIS CystoscopyDIAGNOSIS Cystoscopy

TheThe diagnosis of bladder diagnosis of bladder cancer ultimately depends on cancer ultimately depends on cystoscopic cystoscopic eexamination of the xamination of the bladder and pathological bladder and pathological evaluation of the resected lesion. evaluation of the resected lesion.

Cystoscopy shows the size of Cystoscopy shows the size of the tumour, its appearance and the tumour, its appearance and

surroundingsurrounding..

DIAGNOSISDIAGNOSIS BiopsyBiopsy

Biopsy is also applied the histology of the tumour as well Biopsy is also applied the histology of the tumour as well as its grade can be determined.as its grade can be determined.

The biopsy of non-affected parts of the bladder should The biopsy of non-affected parts of the bladder should be obtained in search of carcinoma in situ.be obtained in search of carcinoma in situ.

DIAGNOSISDIAGNOSIS Biopsy Biopsy and TURand TUR

Biopsy specimens of the tumour and Biopsy specimens of the tumour and suspected area should be taken to suspected area should be taken to map the extent of the disease. map the extent of the disease.

Both cold cup biopsies to preserve Both cold cup biopsies to preserve the histological architecture and TUR the histological architecture and TUR biopsies to determine the extent of biopsies to determine the extent of the disease should be performed. the disease should be performed. Random biopsies of normal mucosa Random biopsies of normal mucosa are indicated in the presence of are indicated in the presence of positive cytology, even in the absence positive cytology, even in the absence of a tumour, or in any non-papillary of a tumour, or in any non-papillary tumour. tumour.

Prostatic urethra biopsies by TUR are Prostatic urethra biopsies by TUR are indicated if there is suspicion of Tis of indicated if there is suspicion of Tis of the bladder in view of the high the bladder in view of the high frequency of involvement of the frequency of involvement of the prostatic urethraprostatic urethra..

DIAGNOSISDIAGNOSIS Cytological examination Cytological examination

Cytological examination is Cytological examination is particularly useful for patients who particularly useful for patients who underwent treatment due to bladder underwent treatment due to bladder cancer. It may also be used as a cancer. It may also be used as a screening procedure for people who screening procedure for people who are especially vulnerable to bladder are especially vulnerable to bladder cancers because of their cancers because of their professions.professions.

The sensitivity of the method The sensitivity of the method increases with the tumour grade. In increases with the tumour grade. In grade 3 tumours it varies from 60 to grade 3 tumours it varies from 60 to 87%. The drawback of cytological 87%. The drawback of cytological examination is its low specificity.examination is its low specificity.

Surgical treatmentSurgical treatment Three methods of Three methods of

surgical treatment are surgical treatment are commonly used in commonly used in bladder cancer. bladder cancer.

These are: transurethral These are: transurethral resection, partial resection, partial cystectomy and radical cystectomy and radical cystoprostatectomy. cystoprostatectomy.

The choice of the The choice of the appropriate procedure is appropriate procedure is determined by the determined by the following factors: tumour following factors: tumour stage, grade and stage, grade and multifocal growth. multifocal growth.

Transurethral resectionTransurethral resection

Transurethral resection as primary therapy should be Transurethral resection as primary therapy should be reserved for patients who have small, solitary, low grade reserved for patients who have small, solitary, low grade superficial carcinomas and bladder papillomas. The superficial carcinomas and bladder papillomas. The procedure makes it possible to remove deep layers of procedure makes it possible to remove deep layers of the bladder muscle, which renders the treatment more the bladder muscle, which renders the treatment more radical.radical.

Partial resection of the bladderPartial resection of the bladder

Partial resection of the bladder is Partial resection of the bladder is performed rarely.performed rarely.

The treatment is reserved for The treatment is reserved for patients with solitary muscle-patients with solitary muscle-infililtrative tumours localised on infililtrative tumours localised on top of the bladder, far from the top of the bladder, far from the trigone or vesicle neck. A tumour-trigone or vesicle neck. A tumour-free margin of 1,5 to 2,0 cm must free margin of 1,5 to 2,0 cm must be obtained. The results for be obtained. The results for patients selected carefully for the patients selected carefully for the procedure were not inferior to procedure were not inferior to those of cystectomy.those of cystectomy.

In order to improve the In order to improve the therapeutic results partial therapeutic results partial resection was combined with resection was combined with chemotherapy. chemotherapy.

Radical cystectomyRadical cystectomy

indications for the operation. indications for the operation. These are:These are:

1 invasive bladder cancer 1 invasive bladder cancer irrespective of the tumour grade,irrespective of the tumour grade,

2 recurrences of the tumour after 2 recurrences of the tumour after transurethral resection, transurethral resection, particularly when the grade particularly when the grade increases,increases,

3 high grade tumours coexisting 3 high grade tumours coexisting with carcinoma in situ,with carcinoma in situ,

4 multifocally growing superficial 4 multifocally growing superficial bladder cancers resistant to bladder cancers resistant to intravesical chemo- or intravesical chemo- or immunotherapy administered immunotherapy administered after transurethral resection,after transurethral resection,

5 recurrences of carcinoma in 5 recurrences of carcinoma in situ following chemo- or situ following chemo- or immunotherapy.immunotherapy.

Radical cystectomyRadical cystectomy

At present radical cystectomy appears to be the most effective At present radical cystectomy appears to be the most effective therapeutic option for patients with invasive bladder cancer.therapeutic option for patients with invasive bladder cancer.

Five-year survival is assessed by different authors as 30-54% of Five-year survival is assessed by different authors as 30-54% of cases. However, the operation is dangerous, technically difficult, for cases. However, the operation is dangerous, technically difficult, for which the risk of perioperative morbidity is high. which the risk of perioperative morbidity is high.

RadiotherapyRadiotherapy Poorly differentiated or multiple T1-T2 Poorly differentiated or multiple T1-T2

tumours may be treated by local tumours may be treated by local radiotherapy to the bladder and radiotherapy to the bladder and perivesical tissues with five- year survival perivesical tissues with five- year survival rates of 40-60%. Lymphatic involvement rates of 40-60%. Lymphatic involvement occurs in about 60% of patients with T3 occurs in about 60% of patients with T3 tumours and radiation is usually given to tumours and radiation is usually given to the whole pelvis. Five-years survival rates the whole pelvis. Five-years survival rates after radiotherapy, however are less than after radiotherapy, however are less than 35%.35%.

Brachytherapy should only be applied in Brachytherapy should only be applied in selected patients with solitary tumours of selected patients with solitary tumours of less than 5 cm in diameter. less than 5 cm in diameter.

External -beam radiotherapy is often first External -beam radiotherapy is often first line therapy in Great Britain and Europe, line therapy in Great Britain and Europe, with salvage cystectomy reserved for with salvage cystectomy reserved for

treatment failures.treatment failures.

Complication of radiation therapyComplication of radiation therapy

Radiotherapy is generally well Radiotherapy is generally well tolerated, most patients tolerated, most patients experience dysuria, urgency, experience dysuria, urgency, urinary frequency, and urinary frequency, and diarrhea as acute self limiting diarrhea as acute self limiting symptoms.symptoms.

Late complication included Late complication included hematuria, bladder and rectal hematuria, bladder and rectal ulceration, rectal stricture, and ulceration, rectal stricture, and small bowel obstruction.small bowel obstruction.

Severe complication requiring Severe complication requiring surgery occurred in 12%. surgery occurred in 12%.

Intravesical chemotherapyIntravesical chemotherapyTable : Advantages and disadvantages of therapeutic compounds used in treatment of bladder cancer

Name

Molecular weigh

tAdvantages Disadvantages

Therapeutic use

Thiotepa Small InexpensiveSystemic absorption leading to

myelosuppression and renal failure

+/-

Epodyl Small InexpensiveSystemic side-effects;

myelosuppression+/-

Adriamycyn Large Minimal absorption Chemical cystitis; expensive + +

Epirubicin Large Minimal absorption Chemical cystitis; expensive + +

Mitomycin C Large Minimal absorptionChemical cystitis, bladder ulceration;

expensive+ +

Mitoxantron C Large Minimal absorption Chemical cystitis, expensive + +

BCG LargeRelatively inexpensive

Local toxicity, BCG-itis (absorption) + + +

Cytokines Interferon Relatively small

Effective Systemic toxicity; extremely expensive

+

Intravesical Bacille Calmette-Guerin (BCG) Intravesical Bacille Calmette-Guerin (BCG) therapytherapy

In 1976 Morales et al. presented the first results of In 1976 Morales et al. presented the first results of intravesical BCG instillation in the treatment of superficial intravesical BCG instillation in the treatment of superficial bladder tumours.bladder tumours.

BCG is commonly given in three clinical settings: BCG is commonly given in three clinical settings: (1)prophylaxis in tumour-free patients, (2) treatment of (1)prophylaxis in tumour-free patients, (2) treatment of residual tumour in patients with papillary TCC and residual tumour in patients with papillary TCC and (3)treatment of patients with carcinoma in situ.(3)treatment of patients with carcinoma in situ.

RECOMMENDATIONSRECOMMENDATIONS

Mandatory evalutionsMandatory evalutions: : Physical examination (including digital rectal and pelvic examination) Physical examination (including digital rectal and pelvic examination) Renal and bladder ultrasonography and/or IVP Renal and bladder ultrasonography and/or IVP Cystoscopy with description of the tumour: size, site, appearance (a diaCystoscopy with description of the tumour: size, site, appearance (a dia

gram of the bladder should be included) gram of the bladder should be included) Urinalysis Urinalysis Urinary cytology Urinary cytology TUR with: TUR with:

biopsy of the underlying tissue biopsy of the underlying tissue random biopsies in the presence of positive cytology, large or non-papillary trandom biopsies in the presence of positive cytology, large or non-papillary t

umour umour biopsy of the prostatic urethra in cases of Tis or suspicion of it biopsy of the prostatic urethra in cases of Tis or suspicion of it

When the bladder tumour is muscle infiltrative and radical treatment When the bladder tumour is muscle infiltrative and radical treatment is indicated, the following tests are mandatory is indicated, the following tests are mandatory Chest X-ray Chest X-ray IVP and/or abdominal/pelvic CT scan IVP and/or abdominal/pelvic CT scan Liver ultrasonography Liver ultrasonography Bone scan if symptoms are present or alkaline phosphatase level is elevBone scan if symptoms are present or alkaline phosphatase level is elev

atedated

THANK YOU FOR ATTENTIONTHANK YOU FOR ATTENTION