1. Non-Muscle Invasive Bladder Urothelial Carcinoma
St. Louis University Hospital
Division of Urology
Michael Mastromichalis, MD 1

2. Outline Diagnosis & Epidemiology Staging Endoscopic Management
Complications
Repeat TURBT and Random Biopsies
Immunotherapy
Primary Intravesical Chemotherapy
Radiation
Surveillance Protocols
Secondary Prevention Strategies 2

3. Bladder Anatomy The urinary bladder has 3 distinct histologic layers
Urothelium
Lamina Propria
Detrusor (Muscularis Propria)
Lamina propria begins deep to Urothelial basement membrane and contains the muscularis mucosa 3

4. Bladder Urothelial Carcinoma
Bladder Cancer Presentation
Typical Symptoms
Risk Stratification
Grade & Stage
CIS
Multicentricity
Lymphovascular Invasion
Cytology and Molecular Markers
Asymptomatic Patients / Autopsy Rates

5. Urothelial Carcinoma
UC represents over 90% of all bladder cancers diagnosed in the US
68,000 new cases are diagnosed per year
>90% diagnosed are older than 55
13,000 deaths annually
500,000 survivors currently in the US
3:1 male to female, with incidence rising in all groups
Lifetime risk of 1/28 5

6. 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 6

7. Bladder Urothelial Carcinoma
The vast majority of bladder UC are the result of environmental exposure- tobacco
Endogenous molecular factors play a role
Cyclophosphamide & ifosfamide chemo
A. fangchi herbs & arsenic
Radiation therapy
Prostate, anal, cervix 7

8. Bladder Urothelial Carcinoma
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

9. Urothelial Carcinoma
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
1.5L of water/day << less than 240mL 9

10. Non-Muscle Invasive UC
Historically known as ‘superficial’ bladder cancer
Wide range- Low-grade papillary to high grade T1 with CIS
70-75% are amenable to bladder sparing treatments
Grade 1,2,3 vs. Low/High Grade- regardless of invasion or CIS presence
All tumors that have not invaded the detrusor 10

11. Tumor Grading
Ta denotes a papillary (LG or HG) tumor confined to the urothelium
T1 is a papillary, sessile or nodular tumor invading the lamina propria (LG or HG)
Anything beyond the urothelial basement membrane until the detrusor. 11

12. Examples of Cystoscopic Tumor

13. Examples of Cystoscopic Tumor

14. Cystoscopy

15. Cystoscopy

16. Tumor Grading
CIS is a flat, high-grade, tumor confined to the urothelium. No lamina propria invasion.
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

17. Non-Muscle Invasive Bladder Cancer17

18. Ta Urothelial Ca Low Grade18

19. Ta Urothelial Ca High Grade19

20. Carcinoma in Situ 20

21. Definition and Epidemiology
75% of all urothelial bladder tumors are NMI
Ta (70%)
T1 (20%
CIS (10%)
Gross Hematuria % risk of bladder tumor
Microscopic Hematuria- 1-5% have bladder tumor
New Irritative Symptoms- double the risk + CIS risk 21

22. Non-Muscle Invasive Bladder Cancer
Who progresses% and dies% from NMIBC?
PUNLMP
Papillary, LG
Papillary, HG
T1, HG
CIS > HG precursor 22

23. Staging Non-Muscle Invasive Bladder Cancer
Papillary Urothelial Neoplasm of Low Malignant Potential- PUNLMP
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 23

24. Tumor Biology & Behavior
Invasive vs Non-invasive
Urothelium- devoid of vessels or lymphatics
Lamina propria- rich in both providing a suitable scaffold for metastasis and tumor dissemination
Behavior (Progression) is primarily grade dependent
HG has high recurrence and progression regardless of Ta or T1 status
LG rarely invades lamina propria or detrussor | Some consider any tumor past the mucosa to be HG/invasive 24

25. Tumor Biology & Behavior
Low Grade vs. High Grade Disease Pathways
These are essentially different diseases with different pathophysiology
Bladder cancer, the early years... 25

26. Tumor Biology & Behavior
First hit- it all starts with altered cellular metabolism after exposure to detoxified or partially detoxified carcinogens
Oxidative cellular DNA damage is the result
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
Oncogenes, tumor suppressor genes, DNA repair enzymes 26

27. Tumor Biology & Behavior
Oxidative DNA damage causes chromosomal alterations
Low Grade Pathway (Ta papillary tumors)
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)
Numerous and variable chromosomal gains and losses
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 27

28. Tumor Biology & Behavior
Most important risk factor in NMIUC progression is GRADE…then presence of CIS
Ergo, High Grade Ta = High Risk
Should be surveyed as such
CIS=High Grade=High Risk and is a high grade, invasive urothelial cancer precursor
Should be treated as such because 45-80% will progress to muscle invasive UC if untreated. 28

29. Tumor Biology & Behavior
NMIUC Prognosis correlates with:
Tumor grade
+/- CIS
Tumor Size
Multiplicity
Papillary vs Sessile
+/- Lymphovascular Invasion 29

30. Tumor Biology & Behavior A Gentle Word re: HGT1 Lesions
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.
Hydronephrosis usually indicates detrusor invasion
85-90% association with MI urothelial carcinoma 30

31. Tumor Biology & Behavior
Nodular or sessile appearance usually indicates deeper muscle invasion
Micropapillary cancer is a very aggressive variant
BCG and chemo resistant
Early cystectomy for non-muscle invasive disease

32. 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.

33. Endoscopic Management
Office-based cystoscopy is the mainstay of diagnosis and surveillance.
Entire urethra, prostate, bladder neck, and bladder
Quality of efflux from each ureteral orifice
Extent, location, number, and nature of tumors as well as UO proximity, mucosal irregularities or urethral involvement should be recorded and/or photographed.
Urine cytology is encouraged for baseline and may encourage future random biopsies if positive 33

34. Endoscopic Management
TURBT is the initial treatment for visible lesions.
Performed under regional or general anesthesia
Need bimanual exam before prep and drape and after case for staging.
Cytology with cystoscopy can be helpful as a baseline marker for future surveillance and treatment monitoring 34

35. Endoscopic Management
Resectoscope

36. Examples Bladder Tumor Resection

37. Examples Bladder Tumor Resection

38. 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

39. Endoscopic Management
Essential to resect all of tumor ultimately to a depth of the detrusor for accurate staging
Separating superficial and muscle swipes may aid the pathologist in identifying muscularis propria from muscularis mucosa
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 39

40. Endoscopic Management
Obturator Reflex
Minimized with paralytic and avoiding overdistention
Bipolar in saline minimizes as well
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 40

41. Endoscopic Management
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
TURBT should proceed without worry of the UO
Pure cut across UOs minimizes scarring
Stenting to manage oedema and healing 41

42. Endoscopic Management
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
Staged resections for bulky disease

43. Endoscopic Management Complications
Obturator reflex perforation
Bleeding
TUR Syndrome
UO Obstruction
Unrecognized disease
Perforation
Extraperitoneal
Intraperitoneal
TUR Syndrome: absorption of large volumes of irrigation fluid leading to a symptomatic dilutional hyponatremia and water intoxication.
Neurologic symptoms include restlessness, agitation, confusion, altered sensorium, seizure, and coma
Hyperammonaemia may occur in patients who have absorbed large quantities of glycine solution.
If serum sodium levels rapidly decrease to less than 120 mEq/L, negative inotropic effects are manifest as hypotension and ECG changes 43

44. 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, “at- risk” urothelium
Field change disease and the urothelium will dedifferentiate at its leisure 44

45. 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 45

46. Endoscopic Management Random Biopsies
Is controversial.
Some advocate when office cytology is + or to f/u with CIS treatment
But denuded bladder suitable for tumor implanation
Cold-cup utilized, Bugbee for hemostasis
Not indicated in low-risk patients and those with negative cytology.
Essential for preoperative planning in partial cystectomy or neobladder (urethral sparing) 46

47. Frequently Asked… Concurrent TURP & TURBT with a hx of LG appropriate
Concurrent TURP + TURBT with hx of HG or CIS should be staged
In neobladder planning, prostate TUR biopsies are necessary but must be weighed against risk of high grade tumor seeding and possible dissemination 47

48. MMC after TURBT
Mitomycin C is the safest & most effective peri-TUR intravesical chemotherapeutic agent
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
Initial tumors on the floor and side walls while recurrences at the dome 48

49. MMC after TURBT
If “healthy” or “academic” swipes taken, a cystogram can avert systemic complications from extravasated absorption by holding MMC
Local irritative symptoms are common and more serious sequelae have occurred with perforation.
Benefit seen from LGTa to HGT1, solitary papillary to multiple tumors (across the board) 49

50. 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

52. Intravesical Therapy
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 52

53. 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

54. Intravesical Therapy
Takes advantage of the relatively low absorptive- capacity of bladder
Noninvasive access to cancer site
Relative avoidance of systemic exposure to chemotherapy

55. Innovator and Pioneer of Intravesical Immunotherapy55

56. Immunotherapy Goal of immunotherapy is to
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 56

57. Immunotherapy BCG Bacillus Calmette-Guerin
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

58. Immunotherapy BCG Use in CIS
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

59. Immunotherapy BCG Use in residual tumor
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
Induction* decreased recurrence by up to 40% for T1 lesions compared to TUR alone
Induction* + Maintenance* can reduce progression by % in HG tumors
Maintenance is thought to provide long-term immunostimulation 59

60. BCG Scheduling
6 week induction alone is insufficient to achieve optimal response
Lamm and SWOG Maintenance
(after 6 week induction)
@ 3 months- 3 weekly instillations
@ 6 months- 3 weekly instillations
then every 6 months for 3 years
18 more instillations 60

61. BCG Scheduling
SWOG scheduling had a high dropout rate due to side effects
Most consider 1 year of maintenance to be adequate
Lengthening interval and decreasing the dose can help with bothersome symptoms
Multifocal, CIS & HG tumors are where benefit seen 61

62. Contraindications Absolute Relative
Immunosuppressed and immunocompromised
Immediately after TURBT/TURP, gross hematuria or traumatic foley (disrupted urothelium)
Hx of BCG Sepsis
Relative
Active UTI
Total incontinence
Liver disease
Hx of TB
Poor performance status or advanced age
Not prosthetics or VUR 62

63. BCG Toxicity Treatments
Moderate Irritative Symptoms, hematuria, afebrile (<48hrs)
Get urine culture
Anticholinergics, pyridium, analgesics & NSAIDS
Severe Irritative Symptoms, Fevers, or >48hrs
Urine Culture, CXR, LFT’s
ID Consult
Isoniazid and rifampin until symptoms resolve
Dose reduction when instillations resume 63

64. BCG Toxicity Treatments Serious Complications
Hemodynamic changes (BCG Sepsis), high- grade fevers, allergic reactions, solid organ involvement with fevers & rigors
Blood and Urine Cultures, CXR, LFT’s
Steroids, antihistamines, broad-spectrum antibiotics
ID Consult
Isoniazid, rifampin, ethambutol, for 3-6 months 64

65. Immunotherapy Interferon-2b/Interferon-α
Mechanism is via lymphocyte activation, cytokine release
inherent antiproliferative and antiangiogenic properties
Less effective than BCG or intravesical chemo
Not effective at eradicating residual disease, preventing recurrence, or treating CIS
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 65

66. University of Chicago BCG Treatment and Surveillance Protocol for ≥HGTa
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*
Cystoscopy surveillance at 9 month mark*
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 66

67. Intravesical Chemotherapy
Mitomycin C
An antibiotic derivative that inhibits DNA synthesis via alkylation
A “larger” molecule
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 67

68. Palmar Desquamation
MMC Chemical Cystitis

69. Intravesical Chemotherapy MMC
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

70. Intravesical Chemotherapy Doxorubicin, Valrubicin & Epirubicin
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 70

71. Intravesical Chemotherapy Thiotepa & Others…
Only agent approved for treatment of papillary urothelial bladder cancer
The original and cheapest intravesical agent
Alkylating agent that is >50% absorbed
Myelosuppression
Gemcitabine & docetaxel intravesically currently being investigated
Currently, (chemo combination) or (chemo + BCG) offer no clear advantage to (MMC alone) or( BCG induction) or (induction with maintenance) in HG disease or CIS 71

72. 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

73. Clinical Follow-Up Patient History and GU Physical U/A Cystoscopy
esp 1st 3mo post-TURBT cystoscopy
Urine Cytology
Urinary Markers?
Upper tract imaging… 73

74. 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
Recurrence at higher grade and multifocality
Progression on intravesical therapy (Grade Progression)
Invasion into detrusor (T progression)
Especially in HGTa or CIS

75. Extravesical Imaging Surveillance
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
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 75

76. Secondary Prevention Strategies
Goal is to reduce the risk of recurrence and progression
Minimize exposure to carcinogens and smoking
Increased fluid intake
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
Oncovite championed by Don Lamm, MD
Suppresses partially transformed cells
Hepatotoxic >40K IU per day 76

77. Urine Cytology
Voided/Cystoscopically attained urine specimen is examined for exfoliated cancer cells
Less effective for LG tumors (30% sensitivity)
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 77

78. 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

79. Urine Markers
May aid in diagnosis and surveillance of patients with NMIUC
Many commercially available
NMP-22
BTA TRAK
ImmunoCyt
Urovysion FISH 79

80. Under Investigation
Although radical cystectomy is beyond the scope of this talk…. There is data re: early cystectomy in…
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
40% are understaged at time of cystectomy
Only half of these are organ confined at time of cystectomy 80

81. Long-Term Investigation
Laser ablation therapy for known low-grade papillary tumors
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
In low risk and recurrent LGTa papillary tumors or papillomas 81

82. Future Fluorescent Cystoscopy
5-aminolevulinic acid (5-ALA)
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
False + after intravesical therapy or recent instrumentation 82

83. Fluorescent Cystoscopy83

84. Fluorescent Cystoscopy

85. Future Photodynamic Therapy
Reactive oxygen species have an antitumor effect
Activates a photosensitizing agent in the urothelium delivered systemically or intravesically
Porfimer sodium
5-ALA
In addition to irritative symptoms, tissue sloughing, bladder contracture, and VUR are well known side effects 85

86. Future
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 86

87. El Fin
References available upon request.
Questions? 87