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BLADDER CANCER
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Urothelial Carcinoma
UC represents over 90% of all bladder cancersdiagnosed in the US68,000 new cases are diagnosed per year
>90% diagnosed are older than 5513,000 deaths annually 500,000 survivors currently in the US
3:1 male to female, with incidence rising in allgroupsLifetime risk of 1/28
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Bladder cancer: Epidemiology Incidence: 20/100000/year (Europe) Mortality: 8-9/100000/year
Fourth most common cancer in men Incidence: 31.1 mortality: 12.1
Seventh most common cancer in women
Incidence: 9.5 mortality: 4.5
At diagnosis >70%: > 65 y of age
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Bladder Anatomy The urinary blad
der has 3 distinct histologic layersUrotheliumLamina PropriaDetrusor (Muscularis Propria)
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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, combustionproducts, rubber, and textiles are also risk factors
Hairdressers, mechanics, truckersPhenacetin derived analgesicsNot coffee and artificial sweeteners
Rarely familial syndrome with DNA mismatch repair(Lynch II)
Slow acetylators (40% higher) vs fast acetylators
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Bladder Urothelial Carcinoma
The vast majority of bladderUC are the result of environmental exposure-tobacco
Endogenous molecularfactors play a roleCyclophosphamide &ifosfamide chemo
A. fangchi herbs & arsenicRadiation therapy
Prostate, anal, cervix
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Bladder Urothelial Carcinoma
The entire urothelium issusceptible to carcinogenicinsult and thus, to malignanttransformation
A field change disease Tumorgenesis separated by time and spaceCells migrate and implant
vs. multifocalcarcinogenesis
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Urothelial Carcinoma
The urinary bladder is the reservoir of urine andtherefore has a prolonged face -time withrenally excreted carcinogens
UC has a long latency from exposure to cancerdevelopment supporting the theory of acarcinogenic cumulative effect on malignant
transformation of the urothelium48,000 Men over 10 years- UC incidence re: fluidintake
1.5L of water/day
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Bladder cancer: Histology
90-95% transitional-cell carcinoma
3% squamos-cell carcinoma 2% adenocarcinoma
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Pathology
MACROSCOPIC ASPECT: the balder tumors are mainly situated around theorifices of the bladder: urethral and ureteral
The repartition of the tumor implantation on the bladder walls-lateral and posterior walls 70 %,
-trigone and bladder nec 20 %,-anterior wal andcalota 10 %.
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G I - over 75 % differentiated cellsWell-differentiated
G II - between 50 75 % differentiated cells
Moderately differentiated G III - between 25 50 % differentiated cellsPoorly differentiated
G IV - under 25 % differentiated cellsHigh-grade urothelial carcinoma
Tumor grading BrodersFor urothelial cancers or transitional cell carcinomas
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pTx - it is not possible to determine the infiltration tumoral degreepT0 - free of malignant histological pattern
pTa - non invasive papilary carcinoma
pTis - flat, in situ carcinoma
pT1 - carcinoma with invasion of lamina propria
pT2a - carcinoma with invasion in first superficial layers of smooth musclepT2b - carcinoma with invasion of the whole muscular thickness
pT3a - carcinoma with microscopic invasion of perivesical fatpT3b - carcinoma with macroscopic invasion of perivesical fat
pT4a invading the pelvic viscera: prostatic stroma, rectum, uterus, vaginapT4b extending to the pelvic sidewalls or abdominal wall
The T element
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Bladder cancer: Entities 75-85% superficial bladder cancer
pTa, pTis, pT1 10-15% muscle-invasive bladder cancer
pT2, pT3, pT4
5% metastatic bladder cancerN+, M+
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Bladder cancer: Stage and PrognosisStage TNM 5-y. Survival
0 Ta/Tis NoMo >85%
I T1 NoMo 65-75%II T2a-b NoMo 57%III T3a-4a NoMo 31%
IV T4b NoMo 24%each T N+Mo 14%each T M+ med. 6-9 Mo
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-N1 single positive node less than or equal to 2 cm in diameter
-N2 one or more positive nodes less or equal to 5 cm in diameter-N3 positive nodes greater than 5 cm in diameter
The N element
-M0 no metastases-M1 distant metastases
The M element
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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
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Tumor Grading
Ta denotes a papillary (LG or HG) tumor confined tothe urothelium
T1 is a papillary, sessile or nodular tumor invading thelamina propria (LG or HG)
Anything beyond the urothelial basement membrane until thedetrusor.
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Examples of Cystoscopic Tumor
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Examples of Cystoscopic Tumor
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Cystoscopy
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Tumor Grading
CIS is a flat, high-grade, tumor confined to theurothelium. No lamina propria invasion.
Velvety, erythematous and easily missed on cystoscopy
Severe atypia and nuclear aplasia with disorderly architectureCan be multicentric and often occur with high-grade tumorsOminousCIS undermining of adjacent healthy urothelium
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Tumor Grading
CIS is a flat, high-grade, tumor confined to theurothelium. No lamina propria invasion.
Velvety, erythematous and easily missed on cystoscopy
Severe atypia and nuclear aplasia with disorderly architectureCan be multicentric and often occur with high-grade tumorsOminousCIS undermining of adjacent healthy urothelium
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Carcinoma in Situ
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Pulmonary and skeletal radiography ;for eventual metastasis, should beperformed before proceeding to pelvic lymphadenectomy
Computed Tomography Scan in addition to assessing the extent of theprimary tumor, CT scanning also provides information about the presenceof pelvic and para-aortic lymphadenopathy and visceral metastases
To accurately assess the depth of penetration, CT scanning should be donebefore transurethral resection
Magnetic Resonance Imaging Good and accurate results for can beobtained with MRI
Lymphadenectomy Pelvic lymphadenectomy is the most accurate way of determining regionallymph node involvement. Some patients have only limited nodal metastasesbelow the bifurcation of the common iliac arteries, and without invasion of adjacent organs they may be cured by pelvic lymphadenectomy.
The primary regions of lymphatic drainage of the bladder are the perivesical,hypogastric, obturator, external iliac, and presacral lymph nodes
DIAGNOSIS & Staging
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The evolution of the bladder tumors
The urothelial tumors have a natural evolution to extension, infiltration anddissemination to the lymphatic nodes, first of all in the pelvic lymph nodesand then, very quickly in the other nodes, including the mediastinal andsupraclaviculary ones.
The dissemination in the other organs is most of all hematogenous. The
common sites of vascular metastases are bones (pelvic bones, lumbarvertebra, ribs) liver, lung, adrenal glands, the kidneys, testicles. Any otherorgan may be involved
The evolution depends on the superficial or invasive aspect of the tumor,the degree of differentiation and the genetic aspect of the tumor
Almost 25% of patients with newly diagnosed bladder cancer have muscle-invasive disease, the vast majority being tumors of high histologic grade.
Most patients (85% to 92%) with muscle-invasive bladder cancer alreadyhave this level of invasion at the time of initial diagnosis.
Almost 50% of patients with muscle-invasive bladder cancer already haveoccult distant metastases.
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Endoscopic ManagementOffice-based cystoscopy is the mainstay of diagnosisand surveillance.
Entire urethra, prostate, bladder neck, and bladderQuality of efflux from each ureteral orifice
Extent, location, number, and nature of tumors as wellas UO proximity, mucosal irregularities or urethralinvolvement should be recorded and/or photographed.
Urine cytology is encouraged for baseline and may encourage future random biopsies if positive
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Endoscopic Management
TURBT is the initial treatment for visible lesions.
Performed under regional or general anesthesia
Need bimanual exam before prep and drape and aftercase for staging.
Cytology with cystoscopy can be helpful as a baselinemarker for future surveillance and treatmentmonitoring
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Examples Bladder Tumor Resection
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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 thepathologist in identifying muscularis propria frommuscularis mucosa
An increase in abdominal fullness or girth requires acystogram to r/o intraperitoneal perforation
A cystogram is required prior to post-TURBTintravesical instillation
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Endoscopic ManagementConservative 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
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Endoscopic ManagementComplications
Obturator reflex perforationBleeding
TUR SyndromeUO ObstructionUnrecognized disease
PerforationExtraperitonealIntraperitoneal
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Why Do Patients Recur?(and later, what can the urologist do about it)
Nature of the tumor Poor ProtoplasmMissed tumors at TURBT
Incomplete TURBT resectionImplantation of shed tumor cells at TURBT
A de novo tumor due to a tumor- sensitized, at -risk urothelium
Field change disease and the urothelium willdedifferentiate at its leisure
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Endoscopic Management2nd Look (Restage) TURBT
When tumor volume, inaccessibility, andintraoperative medical instability warrant a secondlook for patient safety.
Recommended 2-6 weeks after all HGTa & T1tumors OR if no muscle present
40% positivity of re-staging sites of HG tumorsand 20-50% likelihood of T-upgrade to MIdisease
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Intravesical Therapy
Goal is to treat residual or unresected disease
Prevent future recurrences and progression
Delay the need for more aggressive surgicalintervention
Prevent tumor implantation
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ImmunotherapyBCG
Bacillus Calmette-GuerinLive, attenuated Mycobacterium bovisDeveloped by Albert Calmette and Camille Guerin at the
Pasteur Institute Used initially as a Tb vaccineMassive local immune response all reflecting a Th1 processdriven by
Direct binding of fibronectin within the bladder wall
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ImmunotherapyBCG
Use in CISCIS is often diffuse preventing complete tumor resection80% response rate
50% durable at 4 yrs and 30% at 10 yrsHigher efficacy compared with intravesical chemoInduction vs. induction + maintenance
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BCG Scheduling
6 week induction alone is insufficient to achieveoptimal responseLamm and SWOG Maintenance
(after 6 week induction)
@ 3 months- 3 weekly instillations
@ 6 months- 3 weekly instillationsthen every 6 months for 3 years18 more instillations
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Contraindications
AbsoluteImmunosuppressed and immunocompromisedImmediately after TURBT/TURP, gross hematuria ortraumatic foley (disrupted urothelium)
Hx of BCG Sepsis
Relative Active UTI
Total incontinenceLiver diseaseHx of TBPoor performance status or advanced age
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BCG Toxicity Treatments
Moderate Irritative Symptoms, hematuria, afebrile(48hrsUrine Culture, CXR, LFTs ID Consult
Isoniazid and rifampin until symptoms resolve
Dose reduction when instillations resume
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BCG Toxicity TreatmentsSerious Complications
Hemodynamic changes (BCG Sepsis), high-grade fevers, allergic reactions, solid organinvolvement with fevers & rigors Blood and Urine Cultures, CXR, LFTs Steroids, antihistamines, broad-spectrum antibiotics ID Consult
Isoniazid, rifampin, ethambutol, for 3-6 months
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University of ChicagoBCG 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 BCGCystoscopy surveillance at 6 month mark*3 Weeks of BCGCystoscopy surveillance at 9 month mark*3 Weeks of BCGCystoscopy 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
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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 BCG20-40mg/20-40mL of sterile water
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Palmar Desquamation
MMC Chemical Cystitis
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Intravesical ChemotherapyDoxorubicin, Valrubicin & Epirubicin
DoxorubicinInhibits 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 areunfit for radical cystectomy
20% complete response
EpirubicinDecreases recurrence when compared to TUR alone
Not FDA approved in US
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Intravesical Chemotherapy Thiotepa & Others
Only agent approved for treatment of papillary urothelialbladder cancer
The original and cheapest intravesical agent
Alkylating agent that is >50% absorbedMyelosuppression
Gemcitabine & docetaxel intravesically currently being investigated
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Early Cystectomy
Should be considered in patients whoMicropapillary 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
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FutureFluorescent Cystoscopy
5-aminolevulinic acid (5-ALA) A precursor to heme biosynthesis is instilled into thebladder
Taken up by neoplasmsBlue light excites the agent and can detectotherwise unseen CIS on white lightMany false + due to inflammatory lesions
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Fluorescent Cystoscopy
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Fluorescent Cystoscopy
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Long-Term InvestigationLaser ablation therapy for known low-gradepapillary tumors
Argon, KTP, Holmium, & Neodynium-YAGIn select lower and upper tract tumors with close surveillance
No obturator nerve stimulationNot appropriate for new lesions or initial TURBTCollateral damage
Office FulgurationIn low risk and recurrent LGTa papillary tumors orpapillomas
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Surgical Management of InvasiveBladder Cancer
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Radical Cystectomy
Radical Cystectomy Removal of bladder with surrounding fat
Prostate/seminal vesicles (males)
Uterus/fallopian tubes/ovaries/cervix (females)+ Urethrectomy
Pelvic Lymphadenectomy More is better
Urinary DiversionIleal conduit
Continent cutaneous reservoir
Orthotopic neobladder
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Radical Cystectomy
- Midline incision- Thorough intraabdominal exploration (rule outmetastatic disease)- Assess resectability of bladder
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Step 1: mobilize the urachus from the umbilicus
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Step 2: mobilize the bladder from the bowel
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Step 3: isolate and transect ureters
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Step 4: complete lymph node dissection
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Step 5: separate bladder from sigmoid colon
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Step 6: complete posterior dissection and cut off bladder
blood supply
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Step 7: complete anterior dissection and isolate urethra
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Step 8: transect urethra and remove specimen
Impact of Surgical Technique on
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Impact of Surgical Technique onOutcomes
More extended lymph nodes dissection = betteroutcomes
More lymph nodes removed = better outcomesLower positive margin rate = better outcomesMore experienced surgeons = better outcomes
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Pelvic Lymphadenectomy
~25% have LN involvement at cystectomy
Accurate stagingAssessment of prognosis
Adjuvant therapies (chemotherapy, clinical trials)
Therapeutic benefitRemoval of micrometastatic disease
Pelvic Lymphadenectomy
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Pelvic Lymphadenectomy
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Modifications in technique
Nerve sparing for potency Prostate sparing Gynecologic organ sparing
Anterior vaginal wall sparing Urethral sparing in women
Urethral sparing in men
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Urinary Diversion
Use of intestinal segment to bypass/ reconstruct/ replace the normal urinary tract
Goals:Storage of urine without absorption
Maintain low pressure even at high volumes to allowunobstructed flow of urine from kidneys
Prevent reflux of urine back to the kidneysSocially-acceptable continence
Empties completely
Ideal diversion has yet to be discovered
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Types of Urinary Diversion
ILEAL CONDUIT(incontinent diversion to
skin)
CONTINENT CUTANEOUSRESERVOIR
(continent diversion toskin )
ORTHOTOPIC NEOBLADDER
(continent diversion tourethra)
Figures from www.clevelandclinic.org/health/health-info/docs
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Ileal Conduit
15-20 cm of smallintestine (ileum) isseparated from the
intestinal tract
Intestines are sewnback together (re-establish intestinalcontinuity)
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Ileal Conduit
Ureters are attached toone end of the segmentof ileum
Natural peristalsis of intestine propels urinethrough the segment
Other end is brought outthrough an opening onthe abdomen
Ileal Conduit
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Ileal Conduit
Ileal Conduit
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Ileal Conduit
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Ileal Conduit
ADVANTAGESSimplest to perform
Least potential forcomplications
No need forintermittentcatheterization
Less absorption of urine
DISADVANTAGES
Need to wear an external
collection bagStoma complications
Parastomal herniaStomal stenosis
Long-term sequelaePyelonephritisRenal deterioration
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Continent Cutaneous Reservoir
Many variations (same theme)Indiana Pouch, Penn Pouch, Kock Pouch
All use various parts of the intestine
ileum, right colon most commonlyReservoir
Detubularized intestine - low pressure storage
Continence mechanismIleocecal valve (Indiana)Flap valve (Penn, Lahey)Intussuscepted nipple valve (Kock)
Continent Cutaneous Reservoir
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Continent Cutaneous ReservoirINDIANA POUCH
Appendix removed
Right colon is opened
lengthwise andfolded down tocreate a sphere
Continent Cutaneous Reservoir
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Continent Cutaneous ReservoirINDIANA POUCH
Ureters attached to back of reservoir (not shown)
RESERVOIREFFERENT LIMB
(to skin)
Continence maintained by ileocecal valve
ont nent utaneous eservo r
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INDIANA POUCH
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Continent Cutaneous Reservoir
ADVANTAGESNo external bag
Stoma can be coveredwith bandaid
DISADVANTAGESMost complexNeed for regular
intermittentcatheterizationPotential complications:
Stoma stenosisStonesUrine infections
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Orthotopic Neobladder
Currently the diversion of choiceStuder, T-Pouch, Hautmann, Ghoniem, etc.
COMPONENTS: Internal reservoir detubularized ileum
Connect to urethra (efferent limb)
Urethral sphincter provides continenceAfferent Limb ureteral connection
Antirefluxing (T-Pouch, Kock)
Low pressure isoperistaltic limb (Studer)
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Orthotopic Neobladder
15-20 cm
44 cm
Uretersattached
Connect to urethra
Ileum
detubularized Reservoir
STUDER ILEAL NEOBLADDER
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Orthotopic Neobladder
22 cm
22 cm
15-20 cm
Isolation of ileal segment
h bl dd
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Orthotopic Neobladder
Afferent Limb
Detubularization of ileum
h bl dd
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Orthotopic Neobladder
Afferent Limb Reservoir
Opening to urethra
Orthotopic Neobladder
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Orthotopic Neobladder
O h i N bl dd
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Orthotopic Neobladder
ADVANTAGESNo external bag
Urinate throughurethra
May not needcatheterization
DISADVANTAGESIncontinence (10-30%)Retention (5-20%)
Risk of stones, UTIs Need to trainneobladder
Ch i f U i Di i
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Choice of Urinary Diversion
Disease FactorsUrethral margin
Patient Factors
Kidney function / liver functionManual dexterityPreoperative urinary continence/ urethral
stricturesMotivation
Surgeon FactorsFamiliarity with various types of diversions
U i Di i
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Urinary Diversions
Enterostomal therapist is CRITICAL forsuccess
Urinary diversions require lifelong follow-upImaging (kidneys/ureters/diversion)
Labs (electrolytes, acid-base, B12 levels)
Cancer follow-up (surveillance imaging, cytology)
C l i
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Conclusions
Surgery is the cornerstone of treatment forinvasive bladder cancer
Accurate staging (after surgery) is the mostimportant determinant of prognosis
A properly performed lymph node dissectionmakes a difference
Choice of urinary diversion must beindividualized for optimal outcomes
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New Frontiers
Laparoscopic cystectomy Robotic cystectomy with intracoporeal diversion