Transcript 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, Rubber
o 20% Of cases

Environmental :
o Smoking :
 Increase by 6-10 folds
 Related to the extent of exposure, with long
term
o 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.
2.
3.
4.
Repeated chronic irritations can lead to
metaplastic changes, then dysplasia, and finally
carcinoma
It predispose to obstructive uropathy, bacterial
super infection, and production of Nitrosamines in
the acidic urine environment
Inflammatory cells are rich sources of reactive
oxygen species
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 Cancer
o 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 phenotype
o Glutathione S transferase
Pathology

Pathologic tumor staging :
o Lamina Propria
Invasion
o Muscularis
Propria
Invasion
o Vascular
Invasion
Non-invasive Urothelial
Neoplasm
Flat lesions
CIS
Papillary lesions
Dysplasia
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 Adenocarcinoma
o Small Cell Carcinoma
o 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
disease
o Flank, Suprapubic, Bone, and Perineal pain

Voiding symptoms :
o Functional decrease in the bladder capacity, detrusor
overactivity, invasion of the trigone, and obstruction
o 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

o
o
o
o
o
o
Clinical staging (TNM) :
Tx – Primary tumor cannot be assessed
T0 – No evidence of primary tumor
Ta – Non-invasive papillary carcinoma
Tis – Carcinoma in situ
T1 – Invade subepetheilial connective tissue
T2 – Invade the muscles
o T2a – Superficial muscle (inner half)
o T2b – Deep muscle (outer half)
o
T3 – Invade perivesical tissue
o T3a – Microscopically
o T3b – Macroscopically (extravesical mass)
o
T4 – Invade other organs
o T4a – Invade Prostate, Uterus, and Vagina
o T4b – Invade Pelvic and Abdominal wall
o
o
o
o
o
o
o
o
Nx - Regional lymph node cannot be
assessed
N0 - No lymph node metastasis
N1 - Single lymph node, 2 cm or less
N2 - Single lymph node 2-5 cm, or multiple
lymph nodes less than 5 cm
N3 - Lymph nodes more than 5 cm
Mx - Distant metastasis cannot be
assessed
M0 - No distant metastasis
M1 - Distant metastasis
Stage
T
Stage grouping
N
M
Stage 0a
Ta
N0
M0
Stage 0is
Tis
N0
M0
Stage 1
T1
N0
M0
Stage 2
Ta
Tb
N0
N0
M0
M0
T3a
T3b
T4a
N0
N0
NO
M0
M0
M0
T4b
Any T
Any T
Ant T
N0
N1
N2
N3
M0
M0
M0
M0
Stage 3
Stage 4
Diagnosis
1.
2.
3.
Urinalysis :
o
Microscopic, gross examinations, and dipstick chemical
test
Urine cytology :
o
90% is sensitive for Cis
o
Limited sensitivity for upper tract TCC
o
Overall false negative rate is 65%
o
Specificity is 81-100%
o
Positive cytology considered poor prognostic factor
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 :

o
More sensitive in detecting Low Grade
Tumor than cytology
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 extension
o 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
o
Gold standard
It begins with bimanual examination under
anesthesia
Abnormal areas should be sampled
RGP should be done if upper tract cannot be
visualized by IVP
Cytology specimen should be taken if not
previously done
Should document the following :
o
o
o
o



Tumor size, number, position, and growth pattern
Mucosa
Lower tract as urethra and prostate
7.
Fluorescence cystoscopy :
o
o
o
Intravesical installation of a porphryin such as 5-aminolevulinic
acid
More effective than white light endoscope for the detection of
multifocal tumors, thereby improving outcomes of TURBT
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 :

o
MRI

o
Non calcified densities
Sensitive to detect Lymph Node metastasis
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
2.
Block the formation of de novo Bladder Cancer
in healthy individuals
Secondary chemoprevention :
o
Avoiding formation of additional tumors in
patients who have been treated for bladder
cancer

1.
2.
3.
4.
5.
6.

Agents :
Retinoids (Vitamin A component)
Pyridoxine (Vitamin B6)
Vitamin C
Alpha tocopherol (Vitamin E)
Multivitamins
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, T1
o Grade
o Multicentricity and frequency of recurrence :
o Molecular markers

Treatment options :
o Endoscopic surgical management
o Immunotherapy
o Intravesical chemotherapy
o Radical cystoectomy
o Radiotherapy

Risk stratification :
Low Risk Patients
High Risk Patients
Initial presentation with superficial tumor
Multiple superficial recurrence within sort
time period
Long interval between tumor recurrence
>3 cm lesions, sessile, and on a thick stalk
3-4 Lesions, all of which are small (<3 cm)
with a papillary appearance and on fine
stalk
Invasion of the lamina propria, poorly
differentiated histology
No lamina propria invasion, well
differentiated histology
Incomplete resection due to diffuse bladder
involvement or unfavorable location
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 sampled
o Not indicated in low-risk pt
o 12.4% positive in high risk with normal cystoscopy
o Prostatic urethral biopsy may be performed if neobladder
creation is anticipated
o ?tumor implantation
Purpose
evaluation of whether restaging
transurethral resection (TUR) of
superficial bladder cancer improves the
early response to bacillus CalmetteGuerin (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
•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)
Result
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 SloanKettering 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.
2.
3.
4.
5.
6.
Multiple, or large (>3cm) at presentation
Recurrence within 1 year
High grade Ta
Any T1
Cis
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.
o
o
o
Intravesical BCG :
Most common
Live attenuated form of Mycobacterium
Bovis
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
Grade 1
Moderate symptoms less than 48 hours
Presentation
Mild to moderate irritative symptoms, mild hematuria, and
fever <38.5
Assessment
Urine culture to rule out UTI
Management
Anticholinergic, Antispasmodic, NSAID, Analgesia
Grade 2
Severe symptoms and\or more than 48 hours
Presentation
Severe irritative symptoms, hematuria, or symptoms lasting
more than 48 hours
Assessment
Urine culture, chest radiograph, and liver function
Management
Infectious consultation, treat culture result as appropriate
Antimicrobial agents: INH 300 mg\day PO and Rifampin 600
mg\day PO
Grade 3
Serious complications (hemodynamic instability, persistent
high grade fever
Presentation
Allergic reaction (joint pain, rash)
Assessment
Urine culture, chest radiograph, and liver function
Management
INH 300 mg\day PO and Rifampin 600 mg\day PO for 3-6
month depend on the response
Consider Prednisone 40 mg\day, when response is
inadequate for septic shock (NEVER given without effective
antibacterial therapy)
o
Contraindications :
Absolute Contraindications
Relative Contraindications
Immunosuppressed patients
UTI
Personal history of BCG sepsis
Liver disease
Gross hematuria
TB
Traumatic catheterization
Poor overall performance status
Total incontinence
Advanced age
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
o
o
o
3.
Alkylating agent that is minimally absorbed from the
bladder circulation into the systemic circulation
20-60 mg
Weekly for 6-8 weeks
Side effects include chemical cystitis and skin reactions
Anthracyclines :
o
o
Epirubicin, Doxorubicin, and Valrubicin
Approved for use in patients who have failed BCG, and
in whom immediate cystectomy is either refused or
contraindicated
4.
Interferon :
o
o
o
o
5.
10-100 million units
Weekly for sex weeks
Side effects include Flu-like symptoms
Still under trial
Thiopeta :
o
o
Seldom used
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 .intermediategrade disease >>> an additional course of a BCGcontaining 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 Q12 year
•Urinary biomarkers is
optional
Post Treatment Follow Up

1.
2.
3.
Recurrent disease can develop any
where in the genitourinary epithelium
including Renal pelvis, Ureters, Urethra,
and the Bladder
Cystoscopy
Urinary biomarkers
Urethra (prostatic)
4.
Upper urinary tract :
o
o
o
3-20%, median time to discover of such
tumors are 3-7 years
IVP, CT Urography, RGP, and MRI
Urogram
Factors that may increase the risk of
developing upper tract tumors are:
Urethral involvement
2. VUR
3. Occupational exposure
4. Multiple tumor, Tis
1.
o
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
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 TURBT
o Adjuvant treatment according to the type
and grade of the tumor
o 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
Incomplete response
Different drug trial
Maintenance
BCG, Follow
uo
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 present
o 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 Adenocarcinoma
o 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
results
o 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% Adenocarcinoma
o 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 Sarcoma
o Paraganglioma
o Melanoma
o Lymphoma
o Lymphepithelioma-like carcinoma
o Metastatic tumor
Thank You