Oncology 7Upper Tract TCC

James DyerRichard Robinson

Dan Burke

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Introduction

• Epidemiology• Risk Factors• Pathology• Diagnosis• Relevant outcome studies• Treatment

– Update on bladder cuff resection strategy– Role of lymphadenectomy

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Epidemiology• Urothelial carcinoma 4th and

14th commonest cancer diagnosis in UK amongst men and women respectively (ONS)

• Incidence 1-2 per 100,000/year

• Peak incidence 10 per 100,000/year in 8th decade

• Mean age at presentation is 65

• Increasing incidence– Munoz et al. J Urol. 2000

Bladder Cancer 90%

Ureteric Cancer 5-10%

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Epidemiology (2)

• 1-4% risk of synchronous contralateral tumour at presentation

• 3-6% risk of metachronous contralateral tumour

• 30% multifocal• Median time to diagnosis is 48 days (27days

for bladder)

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Incidence renal pelvis:ureter = 2:1

8-13% synchronous bladder TCC

33-60% muscle-invasive at diagnosis

Munoz JJ. J Urol. 2000

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Histology

• 95% TCC• 2004 TNM• WHO criteria 2004

– PUNLMP– Low– High

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Staging

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Risk factors

• As for bladder TCC– Smoking– Occupation aromatic amine exposure

• HNPCC– Index of suspicion in those <60 with other HNPCC

tumours• Colon• Endometrium• Stomach

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Presentation

• US single centre series of 252 pts over 32 years• Presenting features

– Haematuria 78%– Flank pain 18%– Dysuria 6% – UTI 5%– Prior TCC

• Bladder 12%• Upper tract 2%

• Hall M.C. et al. Urology 1998 52(4):594-601

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Diagnosis

• MDCTU – 96% sensitive lesions 5-10mm– Pre-contrast– Nephrogenic– Excretory phase

• Gadolinium MRI when CTU contraindicated• Cystoscopy +/- retrograde• Cytology – in situ, independent predictor of

high stage >pT3 & N+– Retrospective single centre analysis n=469

• Brien JC. J Urol. 2010 Jul

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Diagnostic ureteroscopy

• Useful in diagnostic uncertainty– Sensitivity of MDCTU falls with smaller lesions

• 96% lesions 5-10mm• 89% lesions < 5 mm• 40% lesions < 3 mm

• Not mandated in EAU guidelines• Concerns over effect on subsequent bladder recurrence

and DFS unfounded– Retrospective multicentre study

• n=208, 55 preoperative ureteroscopy with no significant difference in survival/recurrence

• Ishikawa et al. J Urol. 2010

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Endoscopy and biopsy

• Accuracy of simple inspection – Low grade 71% high grade 80%– El-Hakim Urology 2004; 63, 647-650

• Grade on biopsy predicts surgical stage– 75-90% accuracy – 87% low grade on biopsy staged Ta,T1– 67% high grade on biopsy staged T2-3– Keeley J Urol 1997; 157, 33-7

• T1 on biopsy – rarely upgraded• Ta on biopsy – 45% upgraded

– Guarnizo J Urol 2000; 163, 52-5

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Instruments

What are these?

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Treatment - Localised Disease

• RNU gold standard• Emerging evidence regarding lap vs. open• Oncological principles of;

– Avoid opening urinary tract to avoid seeding– Essential to excise ureteric orifice with bladder cuff

• Role of neo-adjuvant chemotherapy unclear• POUT trial analysing adjuvant chemotherapy post surgery

(GC)

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Bladder cuff

• Multicentre retrospective case notes analysis of both lap and open RNU– Xylinas et al Eur Urol. 2014

• 2681 patients across 24 centres comparing distal cuff strategy– Transvesical– Extravesical– Endoscopic

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Intravesical recurrence

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Lymph nodes

• Lymphadenectomy allows accurate staging• Roscigno et al 2009 J Urol

– Retrospective analysis 1130 pts with pN0,pNx and pN+ disease– pT1 pNx vs. pN0 – 5-year survival no difference– pT2-4 pNx vs. pN0 – 5-year survival (58% vs. 70%)

• Rosignco et al Eur Urol 2009– Number of nodes associated with lower recurrence but not CSM– Number of nodes in N0 disease

• >8 nodes HR 0.49 and 0.42 for recurrence and survival respectively

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Treatment - Localised disease• Conservative surgery

– Ureteroscopy and LASER– PCN– Segmental resection– +/- adjuvant MMC/BCG

• MMC 40mg in 40 mls given at 13mls/hr for 3 hours via ureteric catheter

• Reserved for;– Small <1cm, low stage, low grade TCC when contralateral kidney is normal– Renal insufficiency– Solitary functioning kidney

• Supported by a number of small single centre retrospective analyses– Traxer group, Paris - Ureteroscopy– n=35, all for solitary kidney/comorbidity. – Follow up 30 months– Median time to recurrence 10 months

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Results - URSSeries N Recurrence n (%) DSS, % F/U mo

Elliot Urology 96 44 17 (38) 86.5 3-132

Martinez-Pineiro J Urol 96 28 8 (29) 93 2-119

Tawfiek Urology 97 205 65 (31.7) ND 2-132

Keeley J Urol 97 38 8 (28) 100 3-116

Chen J Urol 00 23 15 (65) 100 8-103

Daneshmand Cancer 03 26 23 (88) 100 4-106

Suh J Urol 03 18 3 (37.5) 100 3-48

Johnson BJUint 05 35 24 (68) 100 3-84

Sowter J Endourol 07 35 26 (74) 100 5-115

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Results – Ureteroscopic management

• Recurrence– 30-40%

• G1 – 30%• G2 – 57%• G3 – 60%

Keeley J Urol 97

• 5y survival

• G1 – 100%• G2 – 80%• G3 – 60%

Elliot Urology 96

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Segmental ureterectomy

• Segmental resection with re-implantation or interposition

• Results show feasibility for distal ureterJeldres et al J Urol 2010;183:1324–9

• Segmental resections of more proximal ureter associated with high recurrence rate

Mazeman Eur Urol 1976; 2, 120-8

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Percutaneous approach

• large tumours (renal, upper ureteric)• Percutaneous access as per PCNL• Resectoscope down access sheath• Loop resection• Retrograde balloon occlusion of ureter• Nephrostomy tube

– Adjuvant treatment– Second examination (easier if tract present)

• Risk of tumour implantation– Large sheath to reduce pressures and protect tissue– Tract irradiation (Iridium wire)

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Results – Percutaneous Series N (Renal units) Recurrence % DSS % F/U mo

Jarrett J Urol 95 34 (36) 33 87 9-111

Patel J Urol 96 26 (26) 23 92.3 1-100

Clark J Urol 99 17 (18) 33 83 1.7-75

Jabour 2000 54 (54) 38 84 11-168

Goel J Urol 03 22 (22) 55 69.2 24-132

Suh J Urol 03 19 (19) 88 89.5 3-58

Palou J Urol 04 34 (34) 44.2 94.1 3-131

Roupret E Urol 06 24 (24) 33 79.5 18-188

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Outcome and Recurrence Studies

• Raman et al Eur Urol 2010• No difference in recurrence between pelvic and ureteric

TCC (HR 1.0)– Multicentre retrospective analysis of >1200 pts following RNU– 5-year cancer specific survival 78%– Only nodal status, stage, grade predicted recurrence and poor

survival– However, 38% pelvic had pT2 disease and 22% of ureteric had

pT2 disease• Contradicts previous theory that thin adventitia and rich blood supply

contributed to greater muscle invasion and poor outcome in ureteric TCC

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Outcome and Recurrence Studies

• Cha et al Eur Urol 2012• Multicentre (23 unit) study of 2244 patients with lap or

open RNU over 20 year period with 44 median month FU

• Used AJCC staging system• No prior MIBC or chemotherapy • 22.3% recurrence• 18.6 Cancer mortality• Data used to develop nomograms for DFR and CSS• Bladder recurrence not coded

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Therefore;• LVI• Sessile architecture• CISIncluded on pathology report but tumour stage is the most important independent variable

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Bladder recurrence

• Hall et al Urology 1998• Single centre series (n=252)

– RNU and conservative tx– Heterogenous group of procedures/techniques

• 27% recurrence over median FU of 64 months– 50% bladder equating to 13.5%

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Bladder recurrence

• Retrospective review of 301 patients with RNU.• Comparison of distal ureteric excision

• Intravesical• Extravesical• Transurethral

• Median FU 33 months– bladder recurrence – 21.9%– No difference in recurrence rates with technique

• Oddities!– More ureteric tumours than renal pelvic tumour– More women than men

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Follow up – RNUEAU guidelines 2012

• Metacronous tumour– Cystoscopy and cytology 3 months then yearly

• Local recurrence– CTU annually (6 monthly for 2 years if invasive

disease)• Distant metastasis

– CTU

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Follow up – conservative treatment

• MDCT and cytology – 3 months, 6 months then yearly

• Cystoscopy, ureteroscopy and cytology – 3 months, 6 monthly for 2 years then annually

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Cases 1

• 70 year old smoker• Isolated episode of painless visible haematuria• How to proceed?

– 2 week wait referral – dedicated haematuria clinic• Flexible cystoscopy• MSU• Renal function tests• CT urogram

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Case 3

• 75 Yr male.• pT1 TCC upper ureter.• Smoker• CKD stage 2• Diabetic• Monday morning.• Patient admitted for lap nephroureterectomy.• Discuss procedure and consent.

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Consent Lap. NephroureterectomyDiscuss:

– operative procedure (including discussion of management of distal ureter).– peri-operative management.– complications – follow up (including cystoscopy surveillance)– alternatives to treatment.

ComplicationsCommon (greater than 1 in 10)

Shoulder tip pain. Abdominal bloating. Recurrence of disease elsewhere in the urinary tract.

Occasional (between 1 in 10 and 1 in 50)

Bleeding, infection, pain or hernia of the incision needing further surgery. Need for additional treatment for cancer after surgery.

Rare (less than 1 in 50) Recognised (or unrecognised) entry into the pleural cavity and possible chest drain insertion. Recognised (or unrecognised) injury to organs/blood vessels needing conversion to open surgery (or deferred open surgery). Anaesthetic or cardiovascular problems possibly requiring intensive care admission (including chest infection, pulmonary embolus,

stroke, deep vein thrombosis, heart attack and death). Renal failure (temporary or permanent) requiring dialysis. The pathology in the kidney may subsequently be shown not to be cancer. Persistent urine leakage from the bladder needing prolonged catheterisation or further surgery.

Hospital-acquired infection Colonisation with MRSA (0.9% - 1 in 110). MRSA bloodstream infection (0.02% - 1 in 5000). Clostridium difficile bowel infection (0.01% - 1 in 10,000).

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• 67 Yr female.• Smoker.• CKD stage 3a.• Previous recurrent multifocal G2pTa TCC bladder. • Course of mitomycin 3 years ago (no recurrence

since).• Visible haematuria 6 weeks ago.

What would you do?

Case 4 - introduction

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Case 4 – initial evaluation

• History - 2 episodes of visible haematuria 6 weeks ago (none since).

• Examination - normal• MSU – no evidence of infection.• Flexible cystoscopy – normal.• CTU – poor contrast filling of distal ureters, but no

obvious abnormality.

What next?

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Case 4 – first URS

• Bilateral ureteroscopy.• Small papillary tumour distal 1/3 left ureter.• Removed with basket and LASER to base of tumour.• No other abnormalities.

Low grade TCCPath report – G2pTa

What next?

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Case 4 – follow up

• Follow up URS in 3 months.• Normal bladder.• No evidence of upper tract tumour.

• Lost to follow up, living in Costa Brava for 3 years.• Represents again with visible haematuria.

• What do you do?

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Case 4 – re-evaluation

• History – intermittent haematuria for 12 months.

• Examination normal.• Flexi cystoscopy:

– 5 small papillary tumours in bladder.– ? tumour protruding from left U.O.

What next?

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CT 2 days prior to ureteroscopy. What does it show?

Bilateral URS – large tumour in right renal pelvis – biopsy taken. Multiple small papillary tumours left distal 4 cm ureter – biopsy and LASER.

High grade TCC Path report - right renal pelvis G3pT1

- left lower ureter G2pTa

- bladder G2 pTa

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Case 4 – definitive managment

• Patient returns to clinic to discuss results and treatment options:

• Summary of case– 67 Yrs, female, CKD stage 3a and smoker. – CT thorax requested at time of URS reported as clear. – CTU – renal pelvis TCC right – no other disease visible.– Recurrent G2 pTa bladder– Recurrent G2 pTa left distal ureter– New large G3 pT1 right renal pelvis