Bladder cancer

BLADDER CANCER
Dr. YEE WEI HOONG
08/03/2021
Ref: Jameel Mushtaq, Ramesh Thurairaja and Rajesh Nair. Bladder cancer. Surgery, 2019-09-01, Volume 37, Issue 9, Pages 529-537, Copyright © 2019

Epidemiology
• Malignancy affecting urothelium of bladder
• Most common malignancy of urinary tract
• 3.2% of all cancer worldwide
• 7th most commonly diagnosed malignancy in
men worldwide1
• Incidence in men 3x more than women
1 Moch H, Humphrey P, Ulbright T, Reuter V, eds. World Health Organization classification of tumours. Pathology and genetics of tumours of the urinary system and male Genital
Organs. Lyon: IARC Press, 2016

Aetiology
Bladder cancer
Inherited
Genomic variantions in N-
acetyl transferase
enzymes (NAT1, NAT 2)
Inherited mutation in
Retinoblastoma tumour
suppressor gene
Acquired
Tobacco smoking (50%) Occupational exposure
Aromatic amines
Polycyclic aromatic
hydrocarbon
Chlorinated hydrocarbons
Environmental exposure
to arsenic
Medical therapy
ERBT for pelvic
malignancies
Cyclophosphamide for
hematological
malignancies (SCC
bladder)
Chronic inflammation
Chronic schistosomiasis
hematobium
Chronic cystitis
Bladder calculi
Indwelling urinary
catheter

Tobacco smoking
• Contributes to ~50% of bladder tumours
• Smokers have 2.5x higher risk to get bladder cancer
• It contains carcinogens β-naphthylamine & polycyclic aromatic
hydrocarbon ->Excreted through kidneys--> carcinogenic to
whole urinary system (urinary stasis increases exposure)
• Latency period of ~20-30 years from start smoking to
developing bladder cancer
• Smoking cessation: Risk reduction of ~40% within 1-4 years,
reaching baseline equivocal with non-smokers in 20 years.

Occupational hazards
-Exposure to aromatic amines, polycyclic aromatic hydrocarbons, chlorinated hydrocarbon
• Dye industries
• Rubber industries
• Paint industries
• Metal products industries
• Petroleum industries

• Enzymes involved in detoxification of extrinsic carcinogens
• Slow NAT2 genotype (less effective) increase risk of bladder cancer if
exposed to environmental factors
N-acetyl transferase (NAT1, NAT2) Enzymes

Pathophysiology
• Urothelial/ Transitional cell carcinoma - 90%
• Squamous cell carcinoma - 5%
• Adenocarcinoma - 2%
• Rare tumours (sarcoma, small cell carcinoma, metastatic deposits)
Countries with prevalent schistosomiasis infection- SCC is more
common

• Bladder cancers originate from urothelial
layer --stage migration--> direct invasion
into submucosa, lamina propria,
muscularis mucosa, serosa.
• Can spread directly to adjacent pelvic
structures. Eg prostate, urethra, vagina,
uterus, bowel.
• Lymphatic spread is through obturator,
presacral, iliac, paraaortic lymph nodes
• Hematogenous spread typically results
in metastatic deposits to liver, lungs,
bones, adrenal glands

Classification
• TNM (tumour, node, metastasis)
Staging
• WHO Grading

Prognostic Stage Groups Learning Pearls
Note: NMIBC: Stage 0-I; MIBC Stage
II-IV
Any non-nodal metastasis
(M1b)= Stage IVb
Any T4b without non-nodal
mets =Stage IVa
Any distant nodal mets beyond
common iliac nodes (M1a)=
Stage IVa
Any T except T4b with nodal
mets >1 (N2-3)
T3, T4a without nodal mets
(N0) = Stage IIIa
Any T except T4b with single
nodal mets (N1) = Stage IIIa
Pure T2=stage I
Pure Ta=stage 0a; Pure
Tis=stage 0is; Pure T1=Stage I

Non-
muscle-
invasive
bladder
cancer
(NMIBC)
75% of
bladder
cancer
Disease confined till lamina
propria
Confined to
mucosa
pTa
Tis
Up till lamina
propria
pT1
Muscle
invasive
bladder
cancer
(MIBC)
25% of
bladder
cancer
Tumours invade the
muscularis propria
pT2 and above

Diagnosis
• Clinical presentation
• Hematuria (painless in 70% pt)
• non-specific lower urinary tract
symptoms (LUTS)
-recurrent infections
-frequency
-urgency
-nocturia
• Lab Investigations
• Urine cytology
-Good sensitivity & specificity for high
grade tumours & CIS (median
sensitivity 64%; but only 12% for low
grade tumours )
• Nuclear matrix protein-22 (NMP-
22)
• Bladder tumour antigen (BTA)
• ImmunoCyst
• microsatellite analysis
• Fluorescence in situ hybridisation
(FISH)

Urine Tumour Markers in Bladder Cancer
• Fluorescence in situ hybridization (FISH) probe set (UroVysion)
• Nuclear matrix protein (NMP-22)
• BTA stat
• BTA TRAK
• Fluorescent monoclonal antibodies against M344, LDQ10, and 19A211
(ImmunoCyt/uCyt+)
• Multiplex immunoassays (CertNDx)
• Reverse transcription quantitative polymerase chain reaction (CxBladder)
Ref: Urine Tumor Markers in Bladder Cancer Diagnosis Overview of Urine Tumor Markers. Website:https://emedicine.medscape.com/article/1953022-overview#a4. Paul T Gellhaus, MD; Chief Editor: Bradley Fields
Schwartz, DO, FACS. Updated: Aug 25, 2020

Urinary markers have better sensitivity
than urine cytology, but score lower in
specificity and cost.

Urinary Tract Imaging
1. Transabdominal USG
• Useful screening tool for visible
& non-visible hematuria
• Identifies renal & large
intraluminal bladder lesions,
hydronephrosis secondary to
obstructing bladder tumour
• User dependent & reliant on
whether bladder is filled
• Negative USG doesn't exclude
bladder tumour.
Transverse plane:Multiple papillary tumours in bladder
Ref: Kim, Seung Hyup & Cho, Jeong & Lee, Hak Jong & Sung, Chang &
Kim, Sun. (2007). Ultrasound of the Urinary Bladder, Revisited. Journal
of Medical Ultrasound. 15. 77-90.

2. CT Urography
• Mandatory test in visible hematuria
• Sensitivity 95%, Specificity 83% for
detection of dupper tract urothelial
lesions
• Well-filled bladder needed to detect
smaller lesions
• Papillary lesions in urinary tract seen
as filling defect
• Able to give status of LN & distant
metastasis
• Further staging done via CT TAP Coronal CT urogram (delayed phase) demonstrating a right ureteric
filling defect suggestive of an urothelial tumour (circled), and left renal
cysts (arrows).
Ref:Hayne, Dickon & Mccombie, Steve. (2014). How to treat: Visible
haematuria. Australian Doctor.

3. MRI Pelvis
• Provides better soft tissue
differentiation
• Helps differentiate NMIBC from
MIBC
Pic Ref: Role of MRI in Staging Urinary Bladder Tumors. Mehraj A, et al. Role of MRI in Staging Urinary Bladder Tumours. Ann Med Health Sci Res. 2017; 7: 116-121

Cystoscopy
• White light cystoscopy (WLC) is
the gold standard in bladder
cancer diagnosis.
• Can be down in outpatient
under local anesthetic
• Flexible cystoscopy:Sensitivity
98%, Specificity 94%
• If tumour is seen by flexible
cystoscopy, next stage is to
perform TURBT Cystoscopic view of bladder cancer
Image obtained from:
https://www.tanurology.com.sg/urinary/bladder-cancer/

Risk Stratification Criteria Management
Low-risk tumours Primary, <3cm, solitary, Ta, G1/G2 (low grade), no
CIS
• Single postoperative intravesical
chemotherapy
• Cystoscopic follow up at 3 months following
initial resection
• If disease free, subsequent follow up at 12
months and annually for 5 years thereafter
Intermediate-risk tumours Not part of adjacent groups
*High probability of recurrence (62%) and
progression (17%) at 5 years
• Single postoperative intravesical
chemotherapy, followed by induction and 1
year maintenance intravesical therapy
• Cystoscopy and cytology at 3 months
• If clear, cystoscopy at 3-6 monthly for 5 years,
then annually thereafter
High-risk tumours pT1, high grade G3, CIS or multiple, recurrent and
large (>3cm) low grade
*High probability of recurrence (78%) and
progression (45%) at 5 years
• Multidisciplinary team discussion
• Restaging TURBT in 4-6 weeks
• If indications present, for radical cystectomy.
• If no indication, single postoperative
intravesical chemotherapy, followed by
induction and 3 year maintenance intravesical
therapy
• Cystoscopy & cytology at 3 months. If
negative, cystoscopy cytology every 3
months for 3 years, 6 monthly for 5 years,
then yearly thereafter.
• CT or IVU done yearly.

Indications of Cystectomy in High-Risk NMIBC
1. Extensive bladder involvement with inability to attain complete resection of all visible
disease despite multiple attempts at TURBT
2. Men with CIS involving the prostatic ducts/acini
3. Pure squamous cell or adenocarcinoma histology
4. T1 tumor with lymphovascular invasion or variant histology, such as micropapillary,
neuroendocrine/small cell, or sarcomatoid features
5. T1 grade 3 tumors that are large/diffuse/multifocal or persistent lesions identified on
re-resection
6. T1b tumors (ie, deep or extensive involvement of the lamina propria).
For T1 high-grade tumors with CIS, the use of radical cystectomy is controversial.

TURBT
• first line treatment for NMIBC
• Complete resection is essential
for good prognosis
• Drawbacks of TURBT:
• Scattering and seeding of tumour
tissue (due to “Piecemeal
resection”)
• Thermal damage
• high rate of incomplete resections
• Alternatives to improve quality
of resection:
1. En-bloc resection technique
(ERBT)-lower complication
& decreased recurrence
rate
2. Improve visualisation of tumour
deposits via several ways
• Photodynamic diagnosis (PDD)
• Narrow band imaging (NBI)
• Image enhancement system: SPIES

En-bloc resection technique (ERBT)
1. Lower complication &
decreased recurrence rate
2. Types:
 e-ERBT (electrocautery;
monoplar or bipolar)
 l-ERBT (lasers; with tm:YAG
or Ho: YAG)
3. Has higher rate of complete
resections , but show similar
perioperative morbidity vs
conventional TURBT
ERBT
Conventional
TURBT
Pic source: https://www.tanurology.com.sg/urinary/bladder-cancer/

Photodynamic diagnosis (PDD)
• Better visualisation of tumour
deposits (sensitivity 81% vs 65%
from WLC)
• Requires intravesical instillation
of 5-aminolevulinic acid (5-ALA)
or hexaminolevulinate (HAL)
• 5-ALA is absorbed by malignant
cells & metabolised to
protoporphyrin IX, which emits
red fluorescence when exposed
to blue light

Intravesical Treatment
1. Instillation of Cytotoxic Agent, ie Mitomycin-
C (MMC)
• Antibiotic chemotherapeutic agent
• Inhibits DNA synthesis resulting in cell death
• Single instillation of intravesical MMC within
24H post resection reduces absolute risk of
recurrence by 39%
 Recommended for all superficial bladder cancers
(low- & intermediate risk) post TURBT
• Improved method of delivery:
chemohyperthermia therapy (C-HT; reduces
recurrence by 59%), Electromotive
administration (EMDA)
2. Immunotherapy with BCG
• Preferred treatment for high-risk NMIBC
• BCG stimulates antigen-mediated type IV
immune response against malignant cells.
• Several side effects of BCG:
• cystitis
• hematuria
• prostatitis
• systemic effects. Eg fever, arthralgia, malaise
• Radical cystectomy (RC) is recommended in
failed BCG therapy
• If RC contraindicated, options include C-HT,
intravesical gemcitabine or combinations
therapy (eg EMDA-MMC)

MANAGEMENT OF MIBC
• ~30% pt present with MIBC at
diagnosis
• Prognosis depends on stage and
pelvic lymph node involvement
• MIBC confined to bladder muscle
(T2) without LN metastasis: ~90%
disease free survival (DFS) at 5
years
• pT3-T4: 40-50% 5-year DFS
• LN mets: 15-35% 5- year DFS
• >22% pt succumb to systemic
disease (7% recurrence despite
surgical mx), probably due to
micrometastatic disease at
diagnosis

All patients with established MIBC should get (with or
without MRI pelvis) for staging.
-Ideally performed 6 weeks prior to considering radical treatment-
due to rapid disease progression.

Neoadjuvant chemotherapy
For pt with good performance status & baseline renal function (eGFR > 60ml/min)
• Aim to downstage a proportion
of malignancies which would
otherwise be inoperable
• There is significant under
utilization of neoadjuvant
chemotherapy -only 15% of
patients receive these prior to
surgery
• Neoadjuvant [cisplatin,
methotrexate & vinblastine
(CMV)] regime improved 10-year
survival from 30%->36%
• Methotrexate, vinblastin,
doxorubicin and cisplatin
(MVAC) improved survival of 77
months vs 46 months with
surgery alone.
• Not suitable for :
• Impaired renal function
• Bilateral upper urinary tract
obstruction
• intractable hematuria
• severe lower urinary tract
symptoms
• poor performance status

Radical cystectomy with urinary diversion
• mainstay of surgical treatment
for MIBC
• unfit/unwilling pts are treated
with external beam radiotherapy
• RC can be done via open/MIS
(laparoscopic/robotic)
• MIS associated with less blood
loss, reduced need for blood tx, &
less analgesic requirement
• Pelvic lymphadenectomy, being
part of RC, is both prognostic
and therapeutic
• No. of lymph nodes removed
directly impacts oncological
outcome of urothelial ca
• However, there is no consensus on
the level of lymph node dissection
needed to significantly impact
cancer-specific survival

Urinary diversion techniques
Urinary diversion
Continent
Orthotopic bladder
substitution
Continent
catheterizable
pouches
Mainz-II
Incontinent
Cutaneous
ureterostomy
ileal/colonic
conduit

Cutaneous ureterostomy
• direct drainage of urine from
ureters to an appliances over
abdominal wall
• Most suitable for:
• elderly, frail pt requiring
cystectomy
• high-risk pts with symptomatic
bladder cancer with palliative
cystectomy
• pt with urinary fistula
• salvage surgery
• Not suitable for:
• obese pt
• pt who had pelvic radiotherapy
• short ureteric stumps
• denuded or poorly vascularised
ureters
• Main risk of this technique:
Ureteric stricturing, which needs
periodic dilatation/stenting

Cutaneous ureterostomy
“Smiley” cutaneous ureterostomy
Pic source: Sanjoy Sureka*, Rahul Jena, Rakesh Kapoor, Anil Mani. “SMILEY” CUTANEOUS
URETEROSTOMY : A SATISFACTORY OPTION FOR URINARY DIVERSION IN SELECTED CASES
OF RADICAL CYSTECTOMY. Journal of Urology.

Ileal Conduit/Colonic conduit
• Most commonly performed diversion
• Passive conduit for urine to drain into
appliance
• Ileal segment commonly used; but colonic
segment may be used in case of previous
pelvic radiation
• Complications:
 Early:
1. Ischemia/infarction
2. ileus/bowel obstruction
3. bowel/urinary leak
 Delayed:
1. Upper tract deterioration
2. urinary tract infection
3. stomal retraction

Catheterizable Pouch
• First described by Mitrofanoff in
1980, using appendix on vascular
pedicle
• The catheterizable channel can be
integrated into ileal or colonic pouch
to allow drainage of bladder
substitution
• Alternatives to appendix:
• small bowel
• Fallopian tube
• colon
• vas deferens
• stomach
Pic Source: European Urology Supplements 2010 9754-762DOI: (10.1016/j.eursup.2010.09.003). Copyright © 2010 European Association of Urology

The Lundiana pouch is built from the ileocaecal segment with an
intussuscepted ileal nipple, including the ileocaecal valve as efferent
segment
Ref: European Urology Supplements 2010 9754-762DOI: (10.1016/j.eursup.2010.09.003). Copyright © 2010 European Association of Urology

The original Mainz pouch I: (a) Intraoperative view showing the intussuscepted
terminal ileum serving as continence mechanism, and (b) ureters are implanted using
submucosal tunnels as antireflux mechanism.

(a) The appendix vermiformis is used as a stoma in the modified Mainz pouch I. (b)
The appendix is submucosally embedded into the cecal pole

The Mainz pouch III is built from 30–40cm of nonirradiated transverse colon and
either ascending or descending colon. (a) A tailored bowel segment serves as
continence mechanism in the U-shaped reservoir. (b) A refluxing anastomosis is used
for ureterointestinal implantation

The Mansoura pouch. A continent cutaneous ileal reservoir is constructed from a
detubularized ileal segment. Two tapered bowel segments are embedded and fixed
within serous-lined troughs and the appendix vermiformis can serve as efferent limb.

Orthotopic bladder substitution
• “Orthotopic”-> Tissue or an
organ that is transplanted
into its normal place in the
body
• The urinary diversion option
closet to the native bladder
• Pros:
• Patient may void
spontaneously
• Continent
• Maintains body image
• Cons:
• Produces mucus, which needs drainage
• Requires regular emptying (3-hourly)
• Night incontinence is common (50-80%)--
>Needs long term self catheterisation
• Most widely used technique: Studer
technique
Simple to construct
Avoids the use of staples
Gives great flexibility to urologists with
the uretero-ileal and urethral
anastomoses
Accommodates short ureters
Has a low rate of anastomotic stricture
Provides for excellent continence rates
Ref: Studer UE, Burckard FC, Schumacher M, Kessler TM, Thoeny H, Fleischmann A, Thalmann GN. Twenty years experience with an ileal orthotopic low pressure bladder substitute—lessons to be learned. J Urol.
2006;176:161–6.

Studer technique of neobladder
Ref:
[1] Studer UE, Casanova GA, Luisier J, Zingg EJ. Vessie de substitution réalisée au moyen de l'iléon replié [Bladder substitute realized by means of an ileal segment]. J Urol (Paris). 1988;94(5-6):273-7. French.
PMID: 3058812.
[2] Cheney S.M., Castle E.P. (2015) Orthotopic Bladder Substitution. In: Patel H., Mould T., Joseph J., Delaney C. (eds) Pelvic Cancer Surgery. Springer, London. https://doi.org/10.1007/978-1-4471-4258-
4_17
The Studer neobladder is formed with a tubularized
“chimney” to prevent retrograde reflux of urine. The
distal bowel segment is folded into a U configuration
and folded on itself to resemble a sphere.
a) Isolate and harvest 50–60 cm terminal ileum;
b) ureters anastomosed to the 10 to 15 cm chimmney;
c) U-shape created from detubularized ileum;
d) the pouch is folded on itself to create a sphere; and
e) final closure of the Studer pouch with stents
externalized

Orthotopic bladder substitution

Enhanced Recovery After Surgery (ERAS) in Major
Urological Surgery
• is a multimodal multidisciplinary
approach to reduce postoperative
complications & expedite recovery
from surgery
• originally designed for colorectal
surgery in 1990s
• significantly reduce morbidity,
length of stay (LOS), and total costs
• Radical cystectomy (RC) patients
may be ideal candidates for an ERAS
pathway, considering its significant
postop complications & significant
morbidities.
• 4 major principles:
1. preoperative planning &
preparation
2. reducing stress of surgery
3. postoperative care
4. early mobilization

Early Recovery After Surgery- Pathway
Ref:
Crettenand F., Martel P., Lucca I., Daneshmand S., Cerantola Y. (2020) ERAS for Major Urological Procedures: Evidence Synthesis and Recommendations. In: Ljungqvist O., Francis N., Urman R. (eds)
Enhanced Recovery After Surgery. Springer, Cham. https://doi.org/10.1007/978-3-030-33443-7_44
General ERAS principles for urology.
PONV: postoperative nausea and vomiting,
PPOI: prolonged postoperative ileus

Bladder Preservation Strategies in Patients Unfit
for RADICAL Surgeries
1. Trimodal therapy: TURBT +
concomitant radiation +
chemotherapy
• median 10 year survival rate:
30.9% (vs 35.1% in RC)
• Recommended for:
T2N0M0 with no CIS
pt unfit for radical surgeries
RADIOTHERAPY:
• Given as split-dose regimen or single
continuous regimen
• May be offered alone as palliation
(hematuria)
• CHEMOTHERAPY:
• Regimens vary
• No evidence of superiority of
either neoadjuvant or adjuvant
regimes
• Most commonly used agents:
cisplatin
MMC
5 fluorouracil

Disease recurrence
• 48.6% post RC over 20-year follow up; most cases seen within first 2
years
• Recurrence can occur:
Locally in: Pelvis, Upper urinary tract, Urethra
Metastasise to: Lung, Liver, Bone
CROSS-SECTIONAL IMAGING is needed during follow up, with intervals
depending on:
• Postoperative stage of disease
• Nodal involvement

Metastatic Disease
• Approx. 10-15% present with metastatic disease at diagnosis
• Systemic chemotherapy can prolong survival up to 12-14 months
• Cisplatin-containing combination chemotherapy is the first-line treatment
• Metastatic bone disease is common(30-40% of advanced bladder Ca)
• Zoledronic acid and densumab -> Inhibits bone resorption-> Help alleviate
bone pain
• Palliative cystectomy is only offered when it's the only option.
• Alternatives:
• repeated TURBT
• palliative radiotherapy
• palliative chemotherapy
• best supportive care with or without nephrostomy insertion

MVAC Regime
Ref:
[1] Loehrer PJ, et al. J Clin Oncol 1992; 10:1066.

GC Regime
-Similar efficacy, less toxic than MVAC regime
Ref:
[1] van der Maase H, et al. J Clin Oncol 2000; 17:3068.
* An alternative regimen uses a three-week cycle consisting of
gemcitabine (1200 mg/m2) on days 1 and 8 and cisplatin (75 mg/m2)
on day 2 for a median of six cycles.
¶ Alternatively, may dilute in 2 L 5% dextrose in half or one-third
normal saline containing 37.5 g of mannitol and infuse over a six to
eight hour period.[2] Do not administer with aluminum needles or sets.

Novel Immunotherapeutic Agents
• Works to stimulate body's own immune defense to target tumour cells (by
inhibiting PD-L1)
• Main focus: Programmed death ligand-1 (PD-L1) on /
Programmed cell death protein-1 (PD-1) on
• Tumour cells avoid detection by host immune system by:
Downregulation of tumour antigens
Expression of immunosuppressive cell surface protein
• PD-L1 (of binds to PD-1 (of --> Immunosuppresive
effect-->Allows tumour cells to avoid detection by host immune system
• Increased PD-L1 expression is associated with:
• Increased postoperative recurrences
• BCG resistance
• Reduced survival in bladder cancer

Conclusion
Bladder urothelial carcinoma is
divided into NMIBC & MIBC, due to
their distinct molecular features &
clinical outcomes.
 NMIBC recurs frequently. It can, but
rarely progress to MIBC.
 MIBC is usually diagnosed de novo
and frequently metastasise.
Better visualisation of tumours can be
achieved with PDD, NBI, SPIES
ERBT overcomes drawbacks of TURBT
Efficacy of intravesical therapies for
NMIBC can be improved via C-HT, BCG
combined with EMDA-MMC,
intravesical gemcitabine.
Minimally invasive RC is gaining
popularity in past 10 years.
Trimodal therapy (TURBT+ chemo+
radio) show equivalent outcomes to
radical surgery in selected patients.
Management of metastatic bladder
cancer is revolutionalised with use of
novel systemic immunotherapy

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