Transcript Superficial Bladder Cancer

Non-Muscle Invasive Bladder
Urothelial Carcinoma
St. Louis University Hospital
Division of Urology
Michael Mastromichalis, MD
Outline
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Diagnosis & Epidemiology
Staging
Endoscopic Management
 Complications
 Repeat TURBT and Random Biopsies
Immunotherapy
Primary Intravesical Chemotherapy
Radiation
Surveillance Protocols
Secondary Prevention Strategies
Bladder Anatomy
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The urinary bladder has 3 distinct histologic layers
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Urothelium
Lamina Propria
Detrusor (Muscularis Propria)
Bladder Urothelial Carcinoma
 Bladder Cancer Presentation
 Typical Symptoms
 Risk Stratification
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Grade & Stage
CIS
Multicentricity
Lymphovascular Invasion
Cytology and Molecular Markers
 Asymptomatic Patients / Autopsy Rates
Urothelial Carcinoma
UC represents over 90% of all bladder cancers
diagnosed in the US
 68,000 new cases are diagnosed per year
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>90% diagnosed are older than 55
 13,000 deaths annually
 500,000 survivors currently in the US
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3:1 male to female, with incidence rising in all
groups
 Lifetime risk of 1/28
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Bladder Urothelial Carcinoma
Smoking is the #1 risk factor
Amines, 4-aminobiphenyl & analines are the culprits
Aromatic amines in dyes, solvents, paints, combustion
products, rubber, and textiles are also risk factors
Hairdressers, mechanics, truckers
Phenacetin derived analgesics
Not coffee and artificial sweeteners
Rarely familial syndrome with DNA mismatch repair
(Lynch II)
Slow acetylators (40% higher) vs fast acetylators
Bladder Urothelial Carcinoma
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The vast majority of bladder
UC are the result of
environmental exposuretobacco
 Endogenous molecular
factors play a role
 Cyclophosphamide &
ifosfamide chemo
 A. fangchi herbs & arsenic
 Radiation therapy
 Prostate, anal, cervix
Bladder Urothelial Carcinoma
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The entire urothelium is
susceptible to carcinogenic
insult and thus, to malignant
transformation
 A “field change disease”
 Tumorgenesis separated by
time and space
 Cells migrate and implant
vs. multifocal
carcinogenesis
Urothelial Carcinoma
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The urinary bladder is the reservoir of urine and
therefore has a prolonged “face-time” with
renally excreted carcinogens
UC has a long latency from exposure to cancer
development supporting the theory of a
carcinogenic cumulative effect on malignant
transformation of the urothelium
 48,000 Men over 10 years- UC incidence re: fluid
intake
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1.5L of water/day << less than 240mL
Non-Muscle Invasive UC
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Historically known as ‘superficial’ bladder cancer
 Wide range- Low-grade papillary to high grade
T1 with CIS
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70-75% are amenable to bladder sparing treatments
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Grade 1,2,3 vs. Low/High Grade- regardless of
invasion or CIS presence
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All tumors that have not invaded the detrusor
Tumor Grading
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Ta denotes a papillary (LG or HG) tumor confined to
the urothelium
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T1 is a papillary, sessile or nodular tumor invading the
lamina propria (LG or HG)
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Anything beyond the urothelial basement membrane until the
detrusor.
Examples of Cystoscopic Tumor
Examples of Cystoscopic Tumor
Cystoscopy
Cystoscopy
Tumor Grading
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CIS is a flat, high-grade, tumor confined to the
urothelium. No lamina propria invasion.
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Velvety, erythematous and easily missed on cystoscopy
Severe atypia and nuclear aplasia with disorderly architecture
Can be multicentric and often occur with high-grade tumors
Ominous
CIS undermining of adjacent healthy urothelium
Non-Muscle Invasive Bladder Cancer
Ta Urothelial Ca
Low Grade
Ta Urothelial Ca
High Grade
Carcinoma in Situ
Definition and Epidemiology
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75% of all urothelial bladder tumors are NMI
Ta (70%)
 T1 (20%
 CIS (10%)
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Gross Hematuria- 15-35% risk of bladder tumor
Microscopic Hematuria- 1-5% have bladder tumor
New Irritative Symptoms- double the risk + CIS risk
Non-Muscle Invasive Bladder Cancer
Who progresses% and dies% from NMIBC?
PUNLMP
 Papillary, LG
 Papillary, HG
 T1, HG
 CIS
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3
5-10
15-40
30-50
>50
0-1
1-5
10-25
30
HG precursor
Staging Non-Muscle Invasive Bladder Cancer
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Papillary Urothelial Neoplasm of Low
Malignant Potential- PUNLMP
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Orderly cellular arrangement
Minimal architectural abnormalities
Minimal cellular atypia
No cytologic features of malignancy, so unlikely to
progress, ergo, they are considered benign
Follow-up still recommended
Tumor Biology & Behavior
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Invasive vs Non-invasive
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Urothelium- devoid of vessels or lymphatics
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Lamina propria- rich in both providing a suitable
scaffold for metastasis and tumor dissemination
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Behavior (Progression) is primarily grade dependent
 HG
has high recurrence and progression regardless of Ta or
T1 status
Tumor Biology & Behavior
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Low Grade vs. High Grade Disease Pathways
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These are essentially different diseases with
different pathophysiology
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Bladder cancer, the early years...
Tumor Biology & Behavior
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First hit- it all starts with altered cellular metabolism after
exposure to detoxified or partially detoxified carcinogens
 Oxidative cellular DNA damage is the result
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Second hit- genetic or acquired cellular failure that promotes
tumor, fails to inhibit tumor, or fails to repair oxidized/damaged
DNA…
– Activate oncogenes (RAS gene family)
– Mutated tumor suppressor genes (Rb and P53)
– Damaged APEX-1
Tumor Biology & Behavior
Oxidative DNA damage causes chromosomal alterations
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Low Grade Pathway (Ta papillary tumors)
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More common
Much fewer chromosomal mutations & abnormalities
Usually indolent unless convert to high grade pathway
Loss of part or all of Chromosome 9 (q)
High Grade Pathway (CIS, T1, and muscle invasive)
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Numerous and variable chromosomal gains and losses
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Rb & P53 mutations, CH 7, 9, 17 (where p53 is located)
Aggressivity: high p53, Ki-67, loss of E-Cadherin
Low: No loss of E-Cadherin
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Tumor Biology & Behavior
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Most important risk factor in NMIUC progression is
GRADE…then presence of CIS
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Ergo, High Grade Ta = High Risk
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Should be surveyed as such
CIS=High Grade=High Risk and is a high grade,
invasive urothelial cancer precursor
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Should be treated as such because 45-80% will progress to
muscle invasive UC if untreated.
Tumor Biology & Behavior
NMIUC Prognosis correlates with:
 Tumor grade
 +/- CIS
 Tumor Size
 Multiplicity
 Papillary vs Sessile
 +/- Lymphovascular Invasion
Tumor Biology & Behavior
A Gentle Word re: HGT1 Lesions
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HGT1 tumors are usually papillary but are the most
understaged tumors in bladder cancer
 40% are understaged at time of cystectomy
 Only half of these are organ confined.
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Hydronephrosis usually indicates detrusor invasion
 85-90% association with MI urothelial carcinoma
Tumor Biology & Behavior
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Nodular or sessile appearance usually indicates deeper
muscle invasion
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Micropapillary cancer is a very aggressive variant
 BCG and chemo resistant
 Early cystectomy for non-muscle invasive disease
Tumor Biology & Behavior
A Gentle Word re: HGT1 Lesions
Some investigators have suggested a new grade if
 +deep lamina propria
 muscularis mucosae involvement
 LV invasion
“T1b”
Due to anecdotal risk of recurrence and progression.
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Endoscopic Management
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Office-based cystoscopy is the mainstay of diagnosis
and surveillance.
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Entire urethra, prostate, bladder neck, and bladder
Quality of efflux from each ureteral orifice
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Extent, location, number, and nature of tumors as well
as UO proximity, mucosal irregularities or urethral
involvement should be recorded and/or photographed.
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Urine cytology is encouraged for baseline and may
encourage future random biopsies if positive
Endoscopic Management
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TURBT is the initial treatment for visible lesions.
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Performed under regional or general anesthesia
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Need bimanual exam before prep and drape and after
case for staging.
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Cytology with cystoscopy can be helpful as a baseline
marker for future surveillance and treatment
monitoring
Endoscopic Management
Resectoscope
Examples Bladder Tumor Resection
Examples Bladder Tumor Resection
Endoscopic Management
 Retrograde pyelography if upper tract studies
are insufficient or a positive radiographic finding
 Ipsilateral ureteral cytology, saline lavage, brush
biopsy, or ureteroscopic resection for tissue
 Some advocate transurethral biopsy of the
prostatic urethra for complete staging in men
Endoscopic Management
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Essential to resect all of tumor ultimately to a depth of
the detrusor for accurate staging
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Separating superficial and muscle swipes may aid the
pathologist in identifying muscularis propria from
muscularis mucosa
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An increase in abdominal fullness or girth requires a
cystogram to r/o intraperitoneal perforation
 A cystogram is required prior to post-TURBT
intravesical instillation
Endoscopic Management
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Obturator Reflex
Minimized with paralytic and avoiding overdistention
 Bipolar in saline minimizes as well
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Cystoscopic planning via 70 degree lens
 Resection via 30 degree lens
 Use of continuous flow with minimal fill
 Minimal filling to minimize bladder movement
and detrusor thinning
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Endoscopic Management
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Conservative treatment of diverticular tumors
– Should be sampled rather than resected
– A minority advocate “purposeful perforation”
– Partial cystectomy
– Random biopsies would be warranted in preop
planning
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TURBT should proceed without worry of the UO
– Pure cut across UOs minimizes scarring
– Stenting to manage oedema and healing
Endoscopic Management
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Small, recurrent tumors- may be amenable to cold-cup
biopsy (older women) and Bugbee electrode to tumor
bed
– Laser fulguration of the tumor bed in high risk
patients is surgeon dependent
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Staged resections for bulky disease
Endoscopic Management
Complications
Obturator reflex perforation
 Bleeding
 TUR Syndrome
 UO Obstruction
 Unrecognized disease
 Perforation
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Extraperitoneal
 Intraperitoneal
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Why Do Patients Recur?
(and later, what can the urologist do about it)
Nature of the tumor…
 Poor Protoplasm
 Missed tumors at TURBT
 Incomplete TURBT resection
 Implantation of shed tumor cells at TURBT
 A de novo tumor due to a tumor-sensitized, “atrisk” urothelium
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Field change disease and the urothelium will
dedifferentiate at its leisure
Endoscopic Management
2nd Look (Restage) TURBT
When tumor volume, inaccessibility, and
intraoperative medical instability warrant a second
look for patient safety.
Recommended 2-6 weeks after all HGTa & T1
tumors OR if no muscle present
40% positivity of re-staging sites of HG tumors
and 20-50% likelihood of T-upgrade to MI
disease
Endoscopic Management
Random Biopsies
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Is controversial.
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Some advocate when office cytology is + or to f/u with
CIS treatment
But denuded bladder suitable for tumor implanation
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Cold-cup utilized, Bugbee for hemostasis
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Not indicated in low-risk patients and those with
negative cytology.
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Essential for preoperative planning in partial
cystectomy or neobladder (urethral sparing)
Frequently Asked…
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Concurrent TURP & TURBT with a hx of LG
appropriate
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Concurrent TURP + TURBT with hx of HG or
CIS should be staged
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In neobladder planning, prostate TUR biopsies
are necessary but must be weighed against risk
of high grade tumor seeding and possible
dissemination
MMC after TURBT
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Mitomycin C is the safest & most effective peri-TUR
intravesical chemotherapeutic agent
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Single dose within 6 hours
Intravesical “face-time” of 1 hour
Recommended in those with low and high risk features
Recurrence rate decreased by 30-50% and increased
recurrence-free interval
Destroys residual microscopic tumor at the TURBT site
Used to prevent tumor implantation
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Initial tumors on the floor and side walls while recurrences at
the dome
MMC after TURBT
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If “healthy” or “academic” swipes taken, a cystogram
can avert systemic complications from extravasated
absorption by holding MMC
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Local irritative symptoms are common and more
serious sequelae have occurred with perforation.
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Benefit seen from LGTa to HGT1, solitary papillary to
multiple tumors (across the board)
Staging
 CT urograms often accompany the patient after
hematuria discovered
 Chest Roentgenogram
 Chest CT if pulmonary metastasis suspected
clinically or an abnormal chest x-ray
 Comprehensive metabolic panel with hepatic
components and alkaline phosphatase, CBC, &
coagulation studies
 Elevated alk phos or bone pain = bone scan
Intravesical Therapy
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Urologists should discuss treatment options and
associated risks, side-effects, and benefits.
A wide variety of agents, combinations, durations, and
outcomes are reported.
There is a true lack of uniformity regarding optimal
doses, number of doses, and timing of instillations for
inductions and maintenance therapies
The optimal interval nor duration of cystoscopic follow
up has been defined.
“We’ve not done a great job with bladder cancer”
M.J. Chehval, MD
Intravesical Therapy
 Goal is to treat residual or unresected disease
 Prevent future recurrences and progression
 Delay the need for more aggressive surgical
intervention
 Prevent tumor implantation
Intravesical Therapy
 Takes advantage of the relatively low absorptivecapacity of bladder
 Noninvasive access to cancer site
 Relative avoidance of systemic exposure to
chemotherapy
Innovator and Pioneer of
Intravesical Immunotherapy
Immunotherapy
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Goal of immunotherapy is to
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Augment cancer cell recognition
Promote tumor cell-specific cytotoxicity
Recruit tumor cells that have evaded the immune system
“onto the radar”
If “revved” up, the BCG immune response can mimic tumor
stimulated, tumor specific cytotoxicity for years
Immunotherapy
BCG
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Bacillus Calmette-Guerin
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Live, attenuated Mycobacterium bovis
Developed by Albert Calmette and Camille Guerin at the
Pasteur Institute
• Used initially as a Tb vaccine
Massive local immune response all reflecting a Th1 process
driven by…
Direct binding of fibronectin within the bladder wall
Immunotherapy
BCG
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Use in CIS
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CIS is often diffuse preventing complete tumor resection
80% response rate
50% durable at 4 yrs and 30% at 10 yrs
Higher efficacy compared with intravesical chemo
Induction vs. induction + maintenance
Immunotherapy
BCG
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Use in residual tumor
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Effectively treats Ta papillary lesions, but not a surgical
substitute
TURP + delayed BCG to prostatic urethra is effective
treatment for prostatic CIS
Use as prophylaxis for 6 weeks after TURBT
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Induction* decreased recurrence by up to 40% for T1 lesions
compared to TUR alone
Induction* + Maintenance* can reduce progression by 2030% in HG tumors
Maintenance is thought to provide long-term
immunostimulation
BCG Scheduling
6 week induction alone is insufficient to achieve
optimal response
 Lamm and SWOG Maintenance
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(after 6 week induction)
@ 3 months- 3 weekly instillations
 @ 6 months- 3 weekly instillations
 then every 6 months for 3 years
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18 more instillations
BCG Scheduling
SWOG scheduling had a high dropout rate due
to side effects
 Most consider 1 year of maintenance to be
adequate
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Lengthening interval and decreasing the dose can
help with bothersome symptoms
 Multifocal, CIS & HG tumors are where benefit seen
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Contraindications
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Absolute
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Immunosuppressed and immunocompromised
Immediately after TURBT/TURP, gross hematuria or
traumatic foley (disrupted urothelium)
Hx of BCG Sepsis
Relative
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Active UTI
Total incontinence
Liver disease
Hx of TB
Poor performance status or advanced age
BCG Toxicity Treatments
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Moderate Irritative Symptoms, hematuria, afebrile
(<48hrs)
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Get urine culture
Anticholinergics, pyridium, analgesics & NSAIDS
Severe Irritative Symptoms, Fevers, or >48hrs
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Urine Culture, CXR, LFT’s
ID Consult
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Isoniazid and rifampin until symptoms resolve
Dose reduction when instillations resume
BCG Toxicity Treatments
Serious Complications
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Hemodynamic changes (BCG Sepsis), highgrade fevers, allergic reactions, solid organ
involvement with fevers & rigors
– Blood and Urine Cultures, CXR, LFT’s
– Steroids, antihistamines, broad-spectrum antibiotics
– ID Consult
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Isoniazid, rifampin, ethambutol, for 3-6 months
Immunotherapy
Interferon-2b/Interferon-α
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Mechanism is via lymphocyte activation, cytokine
release
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Less effective than BCG or intravesical chemo
Not effective at eradicating residual disease, preventing
recurrence, or treating CIS
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inherent antiproliferative and antiangiogenic properties
Has been studied as an adjunct to BCG in an effort to lower
BCG dose
Failed to demonstrate equivalence.
Garlic and Mistletoe extracts as immunogenics
University of Chicago
BCG Treatment and Surveillance Protocol for ≥HGTa
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Initial TURBT
After 4 weeks, Re-TURBT (bc HG Ta and all T1 disease)
*After 6 weeks, BCG x 6 weeks (induction)
Cystoscopy surveillance at 3 month mark*
3 Weeks of BCG
Cystoscopy surveillance at 6 month mark*
3 Weeks of BCG
Cystoscopy surveillance at 9 month mark*
3 Weeks of BCG
Cystoscopy surveillance at 12 month mark*
*from 1st dose of BCG induction
All in all, 1 year's worth of cancer treatment
induction + maintenance + 4 surveillance cystoscopies
Intravesical Chemotherapy
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Mitomycin C
An antibiotic derivative that inhibits DNA synthesis
via alkylation
 A “larger” molecule
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• systemic absorption rare unless perforation
Reduces recurrence and progression, although
inferior to BCG induction & maintenance
 Attractive due to much less toxic than BCG
 20-40mg/20-40mL of sterile water
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Palmar Desquamation
MMC Chemical Cystitis
Intravesical Chemotherapy
MMC
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Some advocate dehydration + oral sodium-bicarbinate days
prior to administration to reduce urinary degradation and
increase efficacy
Side effects- most common site
 Skin rash- palmar desquamation
 Irritative symptoms and chemical cystitis (10%)
 Rarely, contracted bladder
MMC I + M proved superior to MMC Induction alone
 In both recurrence and progression
MMC I + M proved inferior to BCG I + M in all comers
Intravesical Chemotherapy
Doxorubicin, Valrubicin & Epirubicin
Doxorubicin
Inhibits topoisomerase II and thus inhibits protein synthesis
Shown to prevent recurrence but not progression
Valrubicin
Approved for treatment of BCG refractory CIS who refuse or are
unfit for radical cystectomy
20% complete response
Epirubicin
Decreases recurrence when compared to TUR alone
Not FDA approved in US
Intravesical Chemotherapy
Thiotepa & Others…
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Only agent approved for treatment of papillary urothelial
bladder cancer
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Alkylating agent that is >50% absorbed
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The original and cheapest intravesical agent
Myelosuppression
Gemcitabine & docetaxel intravesically currently being
investigated
Radiation Therapy
• Has not been studied extensively in NMI
Urothelial Ca
• Initial very good response, short term
• Not effective long term for Ta or CIS
– 90% recur in 5 years
Clinical Follow-Up
Patient History and GU Physical
 U/A
 Cystoscopy
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esp 1st 3mo post-TURBT cystoscopy
Urine Cytology
 Urinary Markers?
 Upper tract imaging…
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Early Cystectomy
• Should be considered in patients who
Micropapillary Variant!
– Do not tolerate intravesical therapy
– Failed attempts at disease control with TURBT +IVT
– Lesions not amenable to endoscopic resection
– Failure of TURBT and intravesical therapy
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Recurrence at higher grade and multifocality
Progression on intravesical therapy (Grade Progression)
Invasion into detrusor (T progression)
Especially in HGTa or CIS
Extravesical Imaging Surveillance
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Most patients undergo upper tract imaging for initial
hematuria workup
High grade or multiple tumors warrant upper tract
annual imaging surveillance every 1-2 years
 Changes in cytology warrant investigation
If upper tract disease is discovered, mortality rate
jumps to ~50% for all-comers
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Must individualize based on patient’s risk of recurrence and
progression to extravesical sites.
Upper tract surveillance for low risk disease not required
Upper tract recurrence <0.9% in low grade Ta disease
Secondary Prevention Strategies
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Goal is to reduce the risk of recurrence and
progression
Minimize exposure to carcinogens and smoking
 Increased fluid intake
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 Reduces
concentration and dwell time of carcinogens
Low-fat, low cholesterol diet
 Vitamin A and B6 have been disappointing
 High Dose MTV- advantage seen at 5 years
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 Oncovite
championed by Don Lamm, MD
 Suppresses partially transformed cells
 Hepatotoxic >40K IU per day
Urine Cytology
Voided/Cystoscopically attained urine specimen
is examined for exfoliated cancer cells
 Less effective for LG tumors (30% sensitivity)
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Well differentiated and normal cells retain their
cohesive properties and are less commonly shed
Sensitivity and specificity are quite high for HG
and CIS, although subjective (pathologist)
 Positive test is not an indication for treatment
but does warrant upper and lower tract workup
+ TUR prostate strip
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Urine Cytology
Can be used to screen, evaluate, & follow-up
high risk patients
 Can be used to monitor recurrence, progression
and response to intravesical therapies
 Gravity vs. barbotage specimens
 Inform cytopathologist if specimen from bowel
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Urine Markers
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May aid in diagnosis and surveillance of patients
with NMIUC
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Many commercially available
NMP-22
 BTA TRAK
 ImmunoCyt
 Urovysion FISH
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Under Investigation
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Although radical cystectomy is beyond the scope of this
talk…. There is data re: early cystectomy in…
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high-risk, recurring and progressing patients
those recurring at 3month post-TURBT cystoscopy
Intravesical failures
HGT1 tumors are usually papillary but are the most
understaged tumors in bladder cancer
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40% are understaged at time of cystectomy
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Only half of these are organ confined at time of cystectomy
Long-Term Investigation
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Laser ablation therapy for known low-grade
papillary tumors
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Argon, KTP, Holmium, & Neodynium-YAG
In select lower and upper tract tumors with close surveillance
No obturator nerve stimulation
Not appropriate for new lesions or initial TURBT
Collateral damage
Office Fulguration
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In low risk and recurrent LGTa papillary tumors or
papillomas
Future
Fluorescent Cystoscopy
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5-aminolevulinic acid (5-ALA)
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A precursor to heme biosynthesis is instilled into the
bladder
Taken up by neoplasms
 Blue light excites the agent and can detect
otherwise unseen CIS on white light
 Many false + due to inflammatory lesions
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Fluorescent Cystoscopy
Fluorescent Cystoscopy
Future
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Photodynamic Therapy
Reactive oxygen species have an antitumor effect
 Activates a photosensitizing agent in the urothelium
delivered systemically or intravesically
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 Porfimer
sodium
 5-ALA
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In addition to irritative symptoms, tissue
sloughing, bladder contracture, and VUR are
well known side effects
Future
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Molecular markers are being studied to predict
recurrence, progression, and response to therapy
Flow cytometry
 p53 and Rb in serum & urine
 Proliferative indices
 Urinary growth factors
 Matrix metalloproteins (MMPs)
 Urinary Plasminogen Activator
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El Fin
References available upon request.
 Questions?
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