Non-Muscle Invasive Carcinoma Bladder Management Protocol. CT (chest, pelvis)/MRI for muscle invasive disease only Before TURBT if MI suspected CT/MRI overstaged local tumor 80% accurate for local staging 80% accuracy for LN disease (>1cm) PET no additional value

1. Non-Muscle Invasive
Carcinoma Bladder
Management Protocol
Presenter- Dr Mukteshwar Gupta
Senior resident
Dept of urology and renal
transplant
Dr RMLIMS
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2. 2
Outline
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Incidence
Risk factor
Pathology / Genetics
Presentation
Hematuria & workup
Grading and staging of Ca bladder
Urinary marker for Ca bladder
Flexible cystoscopy and variants
Role of imaging: USG, IVU,CT, MRI, PET
NMIBC
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TURBT
Risk stratification after TURBT
Role of random biopsy
2ndlook TURBT
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Post TURBT adj intravesical therapy
Mx of T1HG disease
Mx of CIS

3. 3
Incidence
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7th Most common malignancy in Males & 10th – both
genders
3% of all cancer death
9.5 per 100 000 for men and 2.4 per 100 000 for
women
M: F = 4:1
Mortality: M: 3.3 per 100 000 and F: 0.86 per 100000
Presentation:
– 75% NMIBC
– 25% MIBC
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4. 4
Risk Factor
1. Male (4:1)
2. Age (60- 80)
3. Smoking ~3-fold risk in incidence (but also worse progression)
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alfa-naphthylamine, 4-aminobiphenyl
Reduction 40% within 1 to 4 years of quitting smoking and
reached 60% after 25 years of cessation
4. Occupation (10%): Industry at risk : printing, iron and aluminium
processing, industrial painting, and gas- and tar manufacturing–
aromatic amine like aniline
5. Pelvic RT
6. Chronic inflammation (SCC)
1. Bladder stone
2. Long term foley
3. Schistosoma haematobium (bilharziasis)
7. Drugs – phenacetin, cyclophosphamide

5. 5
Genetic Abnormality
• Main Karyotypic change:
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Chromosome 9 (>50% of tumor)
Chromosome 13 (retinoblastoma gene loci)
Chromosome 17 (p53 loci)
• Non-Muscle Invasive Bladder Cancer:
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Loss of retinoblastoma gene expression
Ha-ras activation
Overexpression of telomerase
• Invasive bladder cancer:
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p53 mutation (17)
FGF and VEGF over-expression
• 2 theories of Ca bladder development:
– Clonal theory: multifocal and recurrent tumor evolve from one single
transformed cell and all cell share same identical genetic mutation
– Field change / Oligoclonal theory: global change in the urothelium →
genetically pre-malignant cell transformed into clinical detectable tumor which are
genetically unrelated

6. 6
Pathology
• Benign: uncommon
– Inverted urothelial papilloma
– Nephrogenic adenoma
• Malignant: epithelial origin
– Transitional cell carcinoma (TCC): >90%
– Squamous cell carcinoma (SCC): 5%
– Adenocarcinoma : <1%
• Rare: Phaechromocytoma, melanoma,
lymphoma & sarcoma
• Secondary bladder Ca: GIT, prostate, kidney,
ovary

7. 7
Pathology
• Morphological subtypes
– TCC – >90%
– Squamous / glandular differentiation
• High grade, advanced stage, poor response to chemo, RT or surgery
– Small cell carcinomas
• Rapid growth, propensity for early metastasis. Early use of systemic chemo
– Urothelial carcinomas with squamous and glandular differentiation
• High grade, advanced stage, poor response to chemo, RT or surgery
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plasmocytoid, giant cell, signet ring, diffuse, undifferentiated
Urothelial carcinomas with trophoblastic differentiation
Micropapillary urothelial carcinoma
Nested carcinoma
Sarcomatoid carcinoma
• Often locally advance or metastatic disease

8. 8
Inverted Papilloma
• Submucosal proliferative lesion covered by normal
urothelium
• Trigone and vesical neck
• Benign lesion associated with chronic inflammation
and bladder outflow obstruction
• Associated with TCC elsewhere, need to resect
specimen completely to confirm benign
• Rare cases of malignant transformation

9. 9
Nephrogenic Adenoma
• More common in male
• Raised or papillary
• Histologically resemble collecting duct tubules
• Related to renal transplant, trauma, stone, catheter,
infection and RT(inflammation)
• Associated with irritative symptoms
• Malignant counterpart → mesonephric
adenocarcinoma

10. 10
Pathology
• Von Brunn's nests
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Islands of benign-appearing urothelium in the lamina propria
Cystitis cystica is von Brunn's nests in which urothelium in the
center of the nest has undergone eosinophilic liquefaction
Cystitis glandularis is similar to cystitis cystica except that the
transitional cells have undergone glandular metaplasia, may give
rise to adenocarioma
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• Postoperative spindle cell nodule
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Rare lesion resembling a sarcoma of the bladder.
Reactive proliferation of spindle cells
occurring several months after a lower urinary tract procedure or
infection

11. 11
Pathology : Pre-malignant
• Dysplasia : preneoplastic changes that are intermediate between normal
urothelium and carcinoma in situ (severe dysplasia)
• Kertatinising squamous metaplasia:
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Seen in extrophy, chronic bladder inflammation and schistosomiasis
Pre-malignant
• Leukoplakia:
– Squamous metaplasia with marked keratinization, downward growth of rete pegs
(acanthosis), cellular atypia, and dysplasia
– Response of the normal urothelium to noxious stimuli (chronic infection)
– a premalignant lesion that may progress to SCC (20%)
• Malakoplakia:
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Similar to if not the same as leukoplakia
Histologically Michaelis-Gutmann body and von Hansemann giant cells
FC: Yellow plaques on the urothelium
More common in transplant patients
Treatment is control of infection
Antibiotics, may need long term treatment

12. 1
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TCC
• 2% Ca bladder has synchronous upper tract TCC
– 8% if located at trigone and multifocal
• 70% papillary (Ta G1/2)
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> 7 TC layer covering fibro-vascular core
10% progress to MI or Met disease
• 20% T1
– 50% upstaging to muscle invasion
• 10% CIS
– Poorly differentiated Ca but confined to epithelium
– Intact basement membrane
– Flat velvety patch on bladder mucosa
– 50% isolated , 50% asso with muscle invasive
– ~100% +ve cytology (vs 20% in low grade)
– 50% untreated CIS will progress to muscle invasive
– 3 types:
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Primary: isolated CIS with NO previous CIS or concurrent papillary tumor
Secondary: CIS detect during FU of pt with previous tumor that was not CIS
Concurrent: CIS in the presence of any other urothelial tumors

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14. 14
Chance of CaB in hematuria
• Depends on age and hematuria
Age Gross Microscopic
>50 34% 7%
< 50 10% 5%
Overall 20% <5%
• Although low, there is still chance of 5-7% of patient
with microscopic hematuria will have Ca bladder, thus
workup is justified

15. 15
Symptoms and Diagnosis of Ca Bladder
• Common presenting symptoms:
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85 % present with painless gross haematuria
20% CIS presented with irritative symptoms
Lower limb swelling
Constitutional symptoms
• Sign:
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Pallor
Abd: suprapubic mass
Pelvic examination, PV in elderly female
DRE: pelvic mass or involvement of prostate
• At the time of diagnosis
– 85% are localized disease
– 15% are disseminated disease

16. 16
Urinary Markers for Ca bladder
• Aim to detect cancer in urinary tract
• 2 type of tests
– Protein based
• NMP22 (nuclear matrix protein 22)
• BTA (bladder tumor-associated antigen)
– Cell based
• Urovysion (FISH)
• Immunocyt

17. Protein Based
• NMP22
– “Bladder chek”
– Detect nuclear mitotic
apparatus protein
– Present in most cell as
part of mitotic spindle
– Cut of value:
• >10U/ml in incident
tumor
• >6U/ml in recurrent
tumor
– FDA approved
• BTA
– Detect complement
factor H related protein
(CFHrp)
– BTA-STAT
(qualitative-test kit)
– TRAK (quantitative-lab
test by ELISA)
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18. • Urovysion
– Detect aneuploidy of
chromosome or loss of
regions of chromosome
– By FISH (fluorescent in
situ hybridisation) via
different color probe
– Detect Chromosome
3,7,9,17 abnormality (loss
of 9p21, increase copies
in others)
– Expensive
• Immunocyt
– 3 monoclonal antibody
labeled with 2
fluorescent colour
– Detect antigen
expressed in tumor
cells
– (mucin glycoprotein,
glycoslyated CEA)
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19. 19
Other New Techniques
• Telomerase
– Telomerase express in many cancer
– Can be detect in urine with Telomerase repeat
amplification (TRAP) assay
– TRAP or RT-PCR in urine or bladder washing
– Sensitivity – 74%
– Specificity – 79%

20. Performance compared to cytology
• In general: Sensitivity: ~60-70 & Specificity: ~70
• More sensitive but less specific than cytology
Konety JU 2001
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21. 21
Current Use of Urinary Markers
• Replace cytology?
– Controversial
– Better sensitivity but lower specificity
• Replace cystoscopy?
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Currently no
But can be an adjunct to increase SP & SV
• For surveillance of bladder cancer?
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– When combined with cyto, NMP22 increase detection of cancer
– In atypical cytology > additional marker test (FISH/ immunocyt) > increase
predictive value of tests
Post BCG if FISH +ve > recurrence higher
But cannot safely replace cystoscopy
• For screening/ primary dx in high risk gp potentially?
– Still not sensitive, specific, cost effective enough currently
• Disadvantage:
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Some tests need specialized lab
Some tests more expensive

22. Ultrasound
• Ultrasound (US) may be performed as an adjunct to
physical examination as it has moderate sensitivity to
a wide range of abnormalities in the upper and lower
urinary tract.
• It permits
• characterisation of renal masses,
• detection of hydronephrosis, and
• visualisation of intraluminal masses in the bladder, but cannot
rule out all potential causes of haematuria (LE: 3).
• It cannot reliably exclude the presence of UTUC and cannot
replace CT urograph

23. 23
Cystoscopy
• For visualization of tumor + bx
– Flexible instrument
– Office base
– Site, size, number & appearance (papillary or solid)
– Mucosal abnormalities
• Bladder diagram is recommended
• Dx of CIS: Cystoscopy + urine cytology +
Random Biopsy

24. 24
Fluorescent Cystoscopy
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Photodynamic diagnosis (PDD) or blue light cystoscopy
MOA
– Depends on molecular handling of 5-ALA by tumor cell
– 5-aminolevulinate acid – precursor of porphyrins accumulate in
tumor cells (20x more than normal cell)
– Metabolized within 24hr and back to normal level
– Porphyrins emit red light when exposed to blue light
Procedure:
– Instill 50cc of agent into empty bladder and
– Perform white light and blue (380‐450nm) light cystoscopy within
1 hour
Used with Rigid Cystoscopy.
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25. • Indications
– Unexplained positive cytology
– Suspicion of and/or history of CIS
– High grade disease with sessile appearing
tumor
• Contraindications:
– Porphyria
– Allergic to ALA, HAL or related agents
– Gross hematuria
– Women of child bearing potential
• Advantage of HAL (Hexvix) over 5-ALA
– 5-ALA :highly charged, 3hr to pass lipid cell membrane
– Hexylester-ALA (HAL) – good in lipophilicity, urine solubility and high protoporphyrin
IX formation – 1 hour
– So lower concentration needed (20x less), faster and higher protoporphyrin IX level
• Disadvantage;
– Photosensitivity
– Local reaction incl. bladder spasm/ pain, dysuria (~3%)
– Avoid in pt with expected severe bladder inflammation (e.g. post IVBCG)
– Expensive and time consuming
– Use only with rigid cystoscopy (vs NBI)
• False +ve
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Inflammation
Post intravesical chemotherapy or BCG
Tangential view (BN, trigone, prostate urethra)
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Narrow band imaging (NBI)
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• Base on the phenomenon that depth of light penetration
increase with wavelength
White light is filters into two bands 415nm (blue) and
540nm (green)
Both absorbed by Hb more strongly than by other tissue
Blue light: enhance superficial capillary network
Green light: enhance visibility of deeper vessel
Thus vascular structures become dark brown
Enhances contrast between mucosal surface and
microvessels without the use of DYE
Can be use in flexible scope

27. • Optical Coherence Tomography-Use near infra red
light
• Confocal laser micro edoscpy-Fluorescien and 488nm
laser for endoscopic histological grading

28. 28
Summary of accuracy of differenct
diagnostic methods
Metaanalysis by
Cauberg, Mowatt
Sensitivity Specificity
White light cystoscopy 70% 70%
Cytology 50% 95%
PDD 90% 60%
NBI 95% 80%

29. 29
Role of CTU
• Accuracy ~85%
• Perform CT scan before TUR if muscle invasion
is suspected
• Adv:
– Distinguish , T2 from T3, T3 from T4 disease
– Single noninvasive exam of the kidneys, ureters and
bladder in one test
– Allows identification of stones, renal parenchymal
masses and urothelial abnormalities
– Has become the most useful imaging test of the
urinary tract
• Disadv: More expensive & higher radiation dose

30. 30
Role of MRI
• Used in selected patient populations in whom CTU was relatively
contraindicated, e.g. pregnant women, patients with contrast allergy
Accuracy of primary tumour staging ~ 85%, similar accuracy as
MDCT in detecting perivesical extension (T2 VS T3)
Superior to CT to determine depth of bladder wall involvement (T1
VS T2)
More sensitive than CT or bone scan in detecting bone metastasis
Fast dynamic contrast-enhanced MRI
– Differentiate bladder tumour from surrounding tissues because
enhancement of the tumour occurs earlier than the normal bladder wall
due to neovascularisation, acquired at one image per second helps to
distinguish tumour from postbiopsy reaction
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• However, due to limited resource , CT is still more commonly
performed

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Summary
• CT (chest, pelvis)/MRI for muscle invasive
disease only
• Before TURBT if MI suspected
• CT/MRI overstaged local tumor
– 80% accurate for local staging
– 80% accuracy for LN disease (>1cm)
• PET no additional value

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Grading and staging

33. 33
Grading System
• 2004/2016 WHO grading
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Urothelial papilloma
Papillary urothelial neoplasm of low malignant potential
(PUNLMP)
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Do not have cytological features of malignancy
but show normal urothelial cells in a papillary configuration,
can recur
Exaggeration of normal galndular creast in bladder
urothelium
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Low-grade papillary urothelial carcinoma (10% progression)
High-grade papillary urothelial carcinoma (23% progression)

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36. 36
T - Primary tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Ta Non-invasive papillary carcinoma
Tis Carcinoma in situ: ‘flat tumour’
T1 Tumour invades subepithelial connective tissue
T2 Tumour invades muscle
T2a Tumour invades superficial muscle (inner half)
T2b Tumour invades deep muscle (outer half)
T3 Tumour invades perivesical tissue
T3a Microscopically
T3b Macroscopically (extravesical mass)
T4 Tumour invades any of the following: prostate stroma, seminal vesicles, uterus, vagina, pelvic wall,
abdominal wall
T4a Tumour invades prostate stroma, seminal vesicles, uterus or vagina
T4b Tumour invades pelvic wall or abdominal wall
N – Regional lymph nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac, or
presacral)
N2 Metastasis in multiple regional lymph nodes in the true pelvis (hypogastric, obturator, external iliac,
or presacral)
N3 Metastasis in common iliac lymph node(s)
M - Distant metastasis
M0 No distant metastasis
M1a Non-regional lymph nodes
M1b Other distant metastases

38. 38
Role of Random Biopsies
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Bx of abnormal looking ureothelium is recommended
Random biopsy is not routine
The likelihood of detecting CIS, especially in low-risk
tumors, is extremely low (< 2%)
Indication
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1. Cytology is positive with normal looking mucosa
2. Exophytic tumour is of non-papillary appearance in TaT1 Ca
• R-biopsy:
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Trigone
Bladder dome
Left , Right, Anterior, Posterior bladder walls
Send in separate containers

39. 39
TURBT
• Before TURBT, EUA after emptying of the
bladder
• Further EUA after TURBT, residual mass
suggested residual invasive disease (T3)
• No standard for TURBT (33% upstaging)

40. 40
Second look TURBT
• Indications
1. Incomplete initial resection
2. High-grade and/or T1 tumor
3. When specimen contained no muscle
• AUA/EAU Guidelines: Without the presence of muscularis
propria the pathologist is unable to stage as Ta, T1 or T2
• Timing and strategy:
Most recommend 4-6 weeks after initial TUR
Should include resection of primary tumor site
Evidence: 2ndlook TURBT in T1 /HG tumor
1/2 will have residual disease on 2ndlook [EAU2020]
1/3 will have to change management [Herr JU1999]
1/4 will have upstage [Herr JU1999]
20% increase 5yr DFS [Germen observational study 2003]
Understage is more if muscle is absence (50% vs 15%) [Herr]
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41. Second look TURBT
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