SUPERFICIAL BLADDER CANCER

Done By

Ehab Ahmed

KAAU

Outlines Epidemiology Risk factors Molecular pathway Pathology Presentation Diagnosis Chemoprevention Management Non-urothelial Bladder Cancer

Epidemiology

The most common malignancy affecting the Urinary System

80% in patients over 60 years of age M:F is 3.4:1 In some high incident regions, Bladder

Cancer is associated with specific disease status or toxins exposures as in Balkan countries, Urinary Transitional Cell Carcinoma is associated with Balkan nephropathy

Risk Factors

Chemical carcinogenesis:o Aromatic Amines or its derivatives as 2-

Naphthylamine, Benzidine, Azodyes, and 4-Aminobiphenyl

Occupational :o Aluminum, Dye, Paint, Petroleum, Rubbero 20% Of cases

Environmental :o Smoking :

Increase by 6-10 folds Related to the extent of exposure, with long

termo Analgesic abuse :

Chemical structure similar to Analine dye Phenactin has been linked to CRD, Cancer of

the Bladder, Renal Pelvis, and Ureters

o Artificial sweeteners : Saccharin, and Cyclamates

o Coffee consumption : Week association Reflect the confounding influence of Smoking

o Upper tract cancer (TCC)o Pelvic radiation :

Cervical, Ovarian, and Prostate cancers

o Chronic infections : Cystitis, Schistosomiasis Mechanisms :

1. Repeated chronic irritations can lead to metaplastic changes, then dysplasia, and finally carcinoma

2. It predispose to obstructive uropathy, bacterial super infection, and production of Nitrosamines in the acidic urine environment

3. Inflammatory cells are rich sources of reactive oxygen species

4. Genetic variations in the genes involved in the inflammatory response alter their expression and function, potentially affecting the risk of developing cancer

o Chemotherapy : Cyclophosphamide have up to 9 fold increase

risk of Bladder Cancero Others :

Black foot disease Renal transplant recipient (prolong

immunosuppressant)

Molecular Pathways

Metabolic activation of carcinogens :o arylamines require in vivo activation to

acquire carcinogenic potential o Through P45 enzymes

Detoxification of carcinogens :o Acetylation phenotypeo Glutathione S transferase

Pathology

Pathologic tumor staging :o Lamina Propria

Invasiono Muscularis

Propria

Invasiono Vascular

Invasion

Non-invasive Urothelial Neoplasm

Flat lesions

CIS Dysplasia

Papillary lesions

Urothelial Papilloma

Inverted Papilloma

PUNLMP LGPUC HGPUC

Malignant Epithelial Tumors :o Transitional Cell Carcinoma :

90% of Bladder Cancer 75% Papillary and solid

o Squamous Cell Carcinoma o Adenocarcinomao Small Cell Carcinomao Metastatic :

15% of cases Usually from Colon, Rectum, Prostate, and Cervix Less commonly from Melanoma, Stomach, Breast,

and Lung

Presentation Hematuria :

o Intermittent, gross, painless, and total Pain :

o Usually due to locally advanced or metastatic diseaseo Flank, Suprapubic, Bone, and Perineal pain

Voiding symptoms :o Functional decrease in the bladder capacity, detrusor

overactivity, invasion of the trigone, and obstructiono Irritative (more common), and Obstructive

Constitutional symptoms :o Signs of advanced or metastatic diseases

Staging

Histological grade :o Based upon the degree of resemblance to

the normal tissue architecture, and degree of nuclear anaplasia

o Bladder tumors are now classified as either low or high grade. This replaces the previous system of classification in which tumors were designated as low (G1), intermediate (G2), or high (G3) grade

Clinical staging (TNM) :o Tx – Primary tumor cannot be assessedo T0 – No evidence of primary tumoro Ta – Non-invasive papillary carcinomao Tis – Carcinoma in situo T1 – Invade subepetheilial connective tissueo T2 – Invade the muscles

o T2a – Superficial muscle (inner half)o T2b – Deep muscle (outer half)

o T3 – Invade perivesical tissue o T3a – Microscopicallyo T3b – Macroscopically (extravesical mass)

o T4 – Invade other organso T4a – Invade Prostate, Uterus, and Vaginao T4b – Invade Pelvic and Abdominal wall

o Nx - Regional lymph node cannot be assessed

o N0 - No lymph node metastasiso N1 - Single lymph node, 2 cm or less o N2 - Single lymph node 2-5 cm, or multiple

lymph nodes less than 5 cmo N3 - Lymph nodes more than 5 cm o Mx - Distant metastasis cannot be assessed o M0 - No distant metastasiso M1 - Distant metastasis

Stage groupingM N

T Stage

M0 N0 Ta Stage 0a

M0 N0 Tis Stage 0is

M0 N0 T1 Stage 1

M0M0

N0N0

Ta Tb

Stage 2

M0M0M0

N0N0NO

T3aT3bT4a

Stage 3

M0M0M0M0M1

N0N1N2N3

Any N

T4bAny TAny TAnt TAny T

Stage 4

Diagnosis1. Urinalysis :

o Microscopic, gross examinations, and dipstick chemical test

2. Urine cytology :o 90% is sensitive for Ciso Limited sensitivity for upper tract TCCo Overall false negative rate is 65%o Specificity is 81-100%o Positive cytology considered poor prognostic factor

3. Urine flow cytometry :o Evaluation of abnormal DNA ploidy may be more

accurate than cytology for detecting the presence of exfoliated malignant cells

4. Urine immunocytochemistry and proteomocis assaays :o Immunocytochemistry :

More sensitive in detecting Low Grade Tumor than cytology

o NMP22 Proteomics assays : Analysis of protein expression in tissues,

serum in order to identify tumors on the basis of unique protein expression pattern

5. Radiographic evaluation : IVP :

o Cystogram phase detect 60-85% of large bladder cancer

Ultrasound :o Can confirm Bladder mass

but cannot determine

depth of invasion, nodal

involvement, and

extravesical extensiono Useful in evaluating upper

tract

CT Scan :o 80% accurate in differentiating locally

advanced tumor form less invasive tumor

o Advantages : Demonstrate extravesical extension, nodal

involvement, visceral, pulmonary, or osseous metastasis

o Disadvantages : Cannot differentiate depth of Bladder wall

invasion, although thickened wall suggest muscle invasive disease

Sensitivity for identification of nodal involvement is relatively low (false negative is 86%, and false positive is 16%)

6. Cystoscopy :o Gold standardo It begins with bimanual examination under

anesthesiao Abnormal areas should be sampledo RGP should be done if upper tract cannot be

visualized by IVPo Cytology specimen should be taken if not previously

doneo Should document the following :

Tumor size, number, position, and growth pattern Mucosa Lower tract as urethra and prostate

7. Fluorescence cystoscopy :o Intravesical installation of a porphryin such as 5-aminolevulinic

acid o More effective than white light endoscope for the detection of

multifocal tumors, thereby improving outcomes of TURBT o Sensitivity is 87-97%

Purpose

Comparison between hexaminolevulinate fluorescence cystoscopy with white light

cystoscopy for detecting Ta and T1 papillary lesions in patients with bladder cancer

Methods

A total of 311 patients with known or suspected bladder cancer underwent bladder instillation with 50 ml 8 mM HAL

for 1 hour. The bladder was inspected using white light cystoscopy, followed by blue light (fluorescence)

cystoscopy. Papillary lesions were mapped and resected for histological examination

Conclusion

HAL fluorescence cystoscopy detected at least 1 more Ta and T1 papillary tumor than white light cystoscopy in

approximately a third of the patients with such tumors. Whether this would translate to improved patient

outcomes has yet to be determined.

University of Texas M.Grossman HB et al, July 2007

8. Metastatic work up :o Chest x-ray :

Non calcified densitieso MRI

Sensitive to detect Lymph Node metastasiso Bone Scan

In patients with invasive or locally advanced tumors, and other skeletal symptoms or unexplained elevation in serum Alkaline Phosphatase (ALP)

Chemoprevention

Use of various systemic agents to prevent or reverse changes in the urothelium

Two types :

1. Primary chemoprevention :o Block the formation of de novo Bladder

Cancer in healthy individuals

2. Secondary chemoprevention :o Avoiding formation of additional tumors in

patients who have been treated for bladder cancer

Agents :1. Retinoids (Vitamin A component)

2. Pyridoxine (Vitamin B6)

3. Vitamin C

4. Alpha tocopherol (Vitamin E)

5. Multivitamins

6. Difluoromethylomithine Although some of the data supporting these

agents is suggestive, NO role has been established for any of these agents in either primary or secondary chemoprevention

Management

Prognostic factors :o Stage

Stage Ta, Tis, T1o Gradeo Multicentricity and frequency of recurrence :o Molecular markers

Treatment options :o Endoscopic surgical managemento Immunotherapyo Intravesical chemotherapyo Radical cystoectomyo Radiotherapy

Risk stratification :

High Risk Patients Low Risk Patients

Multiple superficial recurrence within sort time period

Initial presentation with superficial tumor

>3 cm lesions, sessile, and on a thick stalk Long interval between tumor recurrence

Invasion of the lamina propria, poorly differentiated histology

3-4 Lesions, all of which are small (<3 cm) with a papillary appearance and on fine stalk

Incomplete resection due to diffuse bladder involvement or unfavorable location

No lamina propria invasion, well differentiated histology

Presence of diffuse Tis, or Tis in association with papillary tumors

Initial Treatment

Transurethral Resection (TURBT) :

o Despite complete TURBT, up to 80% of patients with high risk tumors will recur within 12 month. So, adjuvant therapy is widely used

Restaging TURBT :o Patients with high risk bladder cancer who

are candidate for Intravesical therapy should undergo a repeat cystoscopy with biopsies of previous areas of involvement prior to therapy. This approach is important to detect previously under diagnosed disease and to reduce the tumor burden prior to therapy

Random biopsies post-TURBT :

o Any suspicious areas should be sampledo Not indicated in low-risk pto 12.4% positive in high risk with normal cystoscopyo Prostatic urethral biopsy may be performed if neobladder

creation is anticipatedo ?tumor implantation

Purpose

evaluation of whether restaging transurethral resection (TUR) of

superficial bladder cancer improves the early response to bacillus Calmette-

Guerin (BCG) therapy

Methods

A total of 347 patients with high risk superficial bladder cancer (high grade Ta and T1 tumors

associated with carcinoma in situ) underwent a single transurethral resection (TUR, 132 patients) or

restaging TUR (215 patients) before receiving 6 weekly intravesical BCG treatments The patients

were evaluated for response (presence or absence of tumor) at first follow up cystoscopy, at 6 and 12 months after treatment, and evaluated for disease

stage progression within 3 years of follow up

Result

• Of the 132 patients who underwent a single TUR before BCG therapy, 75 (57%) had residual or recurrent tumor at the first cystoscopy and 45 (34%) later had progression

• compared with 62 of 215 patients (29%) who had residual or recurrent tumors and 16 (7%) who had progression after undergoing restaging TUR (p = 0.001)

Conclusion

Restaging TUR of high risk superficial bladder cancer improves the initial response rate to BCG therapy, reduces the frequency

of subsequent tumor recurrence and appears to delay early tumor progression

Herr HW, Memorial Sloan-Kettering Cancer Center, Dec

2005

Intravesical therapy :o Permits high local concentrations of a therapeutic

agent within the bladder, potentially destroying viable tumor cells that remain following TURBT and preventing tumor implantation

o Indications :1. Multiple, or large (>3cm) at presentation

2. Recurrence within 1 year

3. High grade Ta

4. Any T1

5. Cis

6. Positive cytology after resection of a visible tumor

o Intravesical chemotherapy :

○ Metaanalysis of seven randomized trial has demonstrated that one immediate installation of chemotherapy after TUR decrease the relative risk of recurrence by 40 %

○ Up to 24 hours

1. Intravesical BCG :o Most commono Live attenuated form of Mycobacterium

Boviso The exact mechanism of action is

UNKNOWN

Antitumor mechanism

Mononuclear cell infiltrate (CD4 T, Macrophages)

Presence of Interferon gamma in the bladder

Cytokines level are increased in the urine

following treatment

o Dose : Induction dose as Weekly injection for sex weeks Each dose consist of a vial of reconstituted theracys

(81mg) or one 2 ml ampule of TICE BCG (50mg), plus 50 ml of sterile saline injected into the bladder through a catheter and retained for 2 hours

o Maintenance therapy : Maintenance therapy consisted of intravesical BCG

each week for 3 weeks given 3, 6, 12, 18, 24, 30 and 36 months from initiation of induction therapy

Purpose

The role of maintenance therapy, and its long-term effect on recurrence and progression

Methods

• All patients in the study had transitional cell carcinoma of the bladder with carcinoma in situ or an increased risk of recurrence.

• The criteria for increased risk were 2 or more episodes of tumor within the most recent year, or 3 or more tumors within 6 months. At least 1 week following biopsy of carcinoma in situ and resection of any stage Ta or T1 transitional cell tumors 660 patients were started on a 6-week induction course of intravesical BCG

• Three months following initiation of BCG induction therapy 550 consenting patients were stratified by purified protein derivative skin test and the presence of carcinoma in situ, and then randomized by central computer to receive BCG maintenance therapy (maintenance arm) or no BCG maintenance therapy (no maintenance arm).

Result

No toxicities above grade 3 were noted in the 243 maintenance arm patients. The policy of withholding maintenance BCG from patients with increased side effects may have diminished the

opportunity to observe severe toxicity. Estimated median recurrence-free survival was 35.7 months in the no

maintenance and 76.8 months in the maintenance arm (p<0.0001). Overall 5-year survival was 78% in the no

maintenance compared to 83% in the maintenance arm

Conclusion

Compared to standard induction therapy maintenance BCG immunotherapy was beneficial in patients with

carcinoma in situ and select patients with Ta, T1 bladder cancer. Median recurrence-free survival time was twice as long in the 3-week maintenance arm compared to the

no maintenance arm, and patients had significantly longer worsening-free survival

Lamm Dlet al, West Virginia University Medical Center,April 2000

o Efficacy : Delay tumor progression, decrease the need

for subsequent cystectomy, and improve overall survival rate

o Long term outcome : Studies showed that the survival rate at 4-5

years (70-86%) following BCG is similar to that achieved after Cystectomy

o Complications : Cleavland Clinic approach for toxicity

management

Moderate symptoms less than 48 hours Grade 1

Mild to moderate irritative symptoms, mild hematuria, and fever <38.5

Presentation

Urine culture to rule out UTI Assessment

Anticholinergic, Antispasmodic, NSAID, Analgesia Management

Severe symptoms and\or more than 48 hours Grade 2

Severe irritative symptoms, hematuria, or symptoms lasting more than 48 hours

Presentation

Urine culture, chest radiograph, and liver function Assessment

Infectious consultation, treat culture result as appropriateAntimicrobial agents: INH 300 mg\day PO and Rifampin 600 mg\day PO

Management

Serious complications (hemodynamic instability, persistent high grade fever

Grade 3

Allergic reaction (joint pain, rash) Presentation

Urine culture, chest radiograph, and liver function Assessment

INH 300 mg\day PO and Rifampin 600 mg\day PO for 3-6 month depend on the responseConsider Prednisone 40 mg\day, when response is inadequate for septic shock (NEVER given without effective antibacterial therapy)

Management

o Contraindications :

Relative Contraindications Absolute Contraindications

UTI Immunosuppressed patients

Liver disease Personal history of BCG sepsis

TB Gross hematuria

Poor overall performance status Traumatic catheterization

Advanced age Total incontinence

Immediately after TURBT, risk of intravasation

o BCG Failure : Predictors of BCG Response

skin testing and granuloma formation some studies have suggested that p53 status might

provide a useful predictor for BCG response Llopis et fli showed that p53 expression analyzed at a

cutoff of 20% positivity is a significant predictor of progression

Sub classified to BCG Refractory BCG-Resistant BCG-Relapsing

o Recommendations for the use of BCG : BCG is superior to chemotherapy for preventing

recurrence Patients with intermediate risk and high risk tumors

are suitable for BCG therapy BCG delay, prevent progression to muscle invasive

disease Maintenance therapy is necessary for optimal

therapy, but the optimal schedule and does have not yet been defined

At least 1 year maintenance therapy is advised

EUA 2007

2. Mitomycin C :o Alkylating agent that is minimally absorbed from the

bladder circulation into the systemic circulationo 20-60 mgo Weekly for 6-8 weekso Side effects include chemical cystitis and skin reactions

3. Anthracyclines :o Epirubicin, Doxorubicin, and Valrubicino Approved for use in patients who have failed BCG, and

in whom immediate cystectomy is either refused or contraindicated

4. Interferon :o 10-100 million unitso Weekly for sex weekso Side effects include Flu-like symptomso Still under trial

5. Thiopeta :o Seldom usedo High incidence of irritative voiding

symptoms, myelosupression, and secondary leukemia

Cystectomy :o Indications :

1. Muscle invasive disease

2. Failure to control symptoms (hemorrhage) with other parameters

3. Multiple tumors with unfavorable locations

4. Recurrent within short period of time despite use of Intravesical therapy

5. Superficial tumor of the prostatic urethra particularly if complete resection cannot be accomplished

Adjuvent Treatment

Papillary or solid Any Cis

Papillary or Solid

Ta,low grade

chemotherapy

into the bladder within

24 h of surgery

Cystoscopy Q 3 m

Ta, high grade or T1, low

grade

BCG

• Cystoscopy, cytology Q3 month for 2 years, then

Q6 month for 2 years, the each year

• UT Q1-2 year

T1, high grade

T1, high grade : o Cystectomy and intravesical BCG therapy are both

acceptable primary therapies For high-grade Tl disease and both options should be discussed

o The ideal candidate for conservative treatment of Tl bladder cancer is ○ a patient with a solitary or at least completely

resectable tumor, ○ a negative upper tract evaluation, and ○ no evidence of invasive disease in the prostatic urethra

o Primary intravesical therapy should comprise induction BCG immunotherapy with 6 weekly instillations beginning no sooner than 2 weeks after tumor resection .

o Cystoscopy with urinary cytology and possible biopsy should be done at 3 months to confirm the absence of recurrence or progression .

o Maintenance therapy should be given . although comparison studies have not been done, the SWOG regimen of 3 weekly instillations at 3, 6, and every 6 months for 3 years is recommended

o For patients with initial induction BCG therapy failure Who are unfit, refuse cystectomy, or have low- or .intermediate-grade disease >>> an additional course of a BCG-containing intravesical therapy is the preferred option

o Cystectomy is indicated if salvage therapy fails, and it should be performed in a timely

o Early cystectomy is recommended in diffuse high grade tumor who fail to response to Intravesical therapy

Patients undergoing delayed cystectomy ( > 2 years) have a poorer prognosis than those undergoing more immediate cystectomy.

Any Cis

BCG Installation

• Cystoscopy Q 3month for 2 years, then Q6

monthe for 2 years, the each year

• Upper tract imaging Q1-2 year

• Urinary biomarkers is optional

Post Treatment Follow Up Recurrent disease can develop any

where in the genitourinary epithelium including Renal pelvis, Ureters, Urethra, and the Bladder

1. Cystoscopy

2. Urinary biomarkers

3. Urethra (prostatic)

4. Upper urinary tract :o 3-20%, median time to discover of such

tumors are 3-7 yearso IVP, CT Urography, RGP, and MRI

Urogramo Factors that may increase the risk of

developing upper tract tumors are:1. Urethral involvement

2. VUR

3. Occupational exposure

4. Multiple tumor, Tis

o Patients with negative cytology after TURBT, imaging of the upper tract every 1-2 years is recommended and should continued for 5 years in patients with low risk disease and for life in patients with high risk disease

o Patients with positive cytology and NO obvious intravesical tumor, carful periodic evaluation of the upper tract is important by CT Urography

Treatment of Recurrent, Persistent Disease Cancer present on follow up cystoscopy:

o TURBTo Adjuvant treatment according to the type

and grade of the tumoro Follow up Q3 month for 2 years then Q6

month for 2 years then each year

Positive cytology with Negative cystoscopy :

Random biopsies of the bladder and prostate (in men)

NO Cancer found

Follow up, or BCG into the bladder

Cancer found

Cancer found

BCG

Complete response

Maintenance BCG, Follow

uo

Incomplete response

Different drug trial

Persist

Cystectomy

Recurrent post 2 cycle of BCG, Mitomycin C

treatment

Complete response

Maintenance BCG

Recurrent as Tis, Ta

Cystectomy or different drug into

the bladder

Recurrent as T1, high

grade

Cystectomy

Non-urothelial Bladder Cancer

The development of METAPLASIA and the presence of CHRONIC INFECTIONS are believed to be important factors in tumorgenesis

Non-Schistosomal SCC Adenocarcinoma Schistosomal Bladder Cancer Non-epethilial Bladder Cancer

Non-Schistosomal SCC :o 3-5% in North America and Europe, 75% in areas where

Schistosoma Haematobium is endemic

o Risk factors include chronic UTI, bladder stones, pelvic radiation, cyclophosphamide exposure, and smoking

o Hematuria and irritative symptoms are presento Tumors are commonly bulky and locally invasive at diagnosis,

but distant metastases are present in only 8 to 10 percent of cases at diagnosis

o Treatment : Surgery Chemoresistant

Adenocarcinoma :o 0.5-2%, 10% Urachal Adenocarcinomao Non-urachal Adenocarcinoma :

Low grade Treatment :

Radical Cystectomy and lymph node dissection Chemotherapy for unrespectable tumor RT have been utilized by some centers with mixed

resultso Urachal Adenocarcinoma :

Treated with surgical resection and resection of the Urachal ligament and Umbilicus

No role for Chemotherapy or Radiotherapy

Schistosomal Bladder Cancer :o 70% SCC, 20% TCC, and 5% Adenocarcinomao Tumors are usually low- to moderate-grade. At diagnosis, lymph

node metastases are present in about 20%, and distant metastases in 3%, possibly due to mural fibrosis causing

delayed spread of the tumor o Treatment :

Non-metastatic tumor treated with Radical Cystectomy and Lymph Node dissection

Adjuvant Radiotherapy improve survival rate Neoadjuvent Chemotherapy improve survival rate ( 74% vs.

38% with cytectomy alone)

Non-epithelial Bladder Cancer :o Sarcomao Paragangliomao Melanomao Lymphomao Lymphepithelioma-like carcinomao Metastatic tumor

Thank You