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