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7/31/2019 Tumori vezicale engleza

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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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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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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



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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)



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Continent Cutaneous ReservoirINDIANA POUCH

Appendix removed

Right colon is opened

lengthwise andfolded down tocreate a sphere



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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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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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15-20 cm

44 cm

Uretersattached

Connect to urethra

Ileum

detubularized Reservoir

STUDER ILEAL NEOBLADDER


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22 cm

22 cm

15-20 cm

Isolation of ileal segment

h bl dd


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Afferent Limb

Detubularization of ileum

h bl dd


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Afferent Limb Reservoir

Opening to urethra



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O h i N bl dd


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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

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