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154 Challenging Concepts in Urological Surgery
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24. Martignoni G, Pea M, Rigaud G, et al. Renal angiomyolipoma with epithelioid sarcomatous transformation and metastases: demonstration of the same genetic defects in the primary and metastatic lesions. Am J Surg Pathol. 2000;24(6):889– 894.
25. Espinosa M, Roldan- Romero JM, Duran I, et al. Advanced sporadic renal epithelioid angiomyolipoma: case report of an extraordinary response to sirolimus linked to TSC2 mu­tation. BMC Cancer. 2018;18(1):561.
26. Wagner AJ, Malinowska- Kolodziej I, Morgan JA, et al. Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors. J Clin Oncol. 2010;28(5):835– 840.
27. Kenerson H, Folpe AL, Takayama TK, Yeung RS. Activation of the mTOR pathway in spor­adic angiomyolipomas and other perivascular epithelioid cell neoplasms. Hum Pathol. 2007;38(9):1361– 1371.
28. Kawaguchi K, Oda Y, Nakanishi K, et al. Malignant transformation of renal angiomyolipoma: a case report. Am J Surg Pathol. 2002;26(4):523– 529.
29. Li W, Guo L, Bi X, Ma J, Zheng S. Immunohistochemistry of p53 and Ki- 67 and p53 mutation analysis in renal epithelioid angiomyolipoma. Int J Clin Exp Pathol. 2015;8(8):9446– 9451.
30. Bukowski RM. Natural history and therapy of metastatic renal cell carcinoma: the role of interleukin- 2. Cancer. 1997;80(7):1198– 1220.
31. Rock EP, Goodman V, Jiang JX, et al. Food and Drug Administration drug approval sum­mary: sunitinib malate for the treatment of gastrointestinal stromal tumor and advanced renal cell carcinoma. Oncologist. 2007;12(1):107– 113.
32. Voss MH, Molina AM, Motzer RJ. mTOR inhibitors in advanced renal cell carcinoma. Hematol Oncol Clin North Am. 2011;25(4):835– 852.
33. Ljungberg B, Albiges L, Abu- Ghanem Y, et al. European Association of Urology guidelines on renal cell carcinoma: the 2019 update. Eur Urol. 2019;75(5):799– 810.
34. Giles RH, Choueiri TK, Heng DY, et al. Recommendations for the management of rare kidney cancers. Eur Urol. 2017;72(6):974– 983.
35. Sanfilippo R, Jones RL, Blay JY, et al. Role of chemotherapy, VEGFR inhibitors, and mTOR inhibitors in advanced perivascular epithelioid cell tumors (PEComas). Clin Cancer Res. 2019;25(17):5295– 5300.
36. Kohno J, Matsui Y, Yamasaki T, et al. Role of mammalian target of rapamycin inhibitor in the treatment of metastatic epithelioid angiomyolipoma: a case report. Int J Urol. 2013;20(9):938– 941.
37. Shitara K, Yatabe Y, Mizota A, Sano T, Nimura Y, Muro K. Dramatic tumor response to everolimus for malignant epithelioid angiomyolipoma. Jpn J Clin Oncol. 2011;41(6):814– 816.
38. Margulis V, McDonald M, Tamboli P, Swanson DA, Wood CG. Predictors of onco­logical outcome after resection of locally recurrent renal cell carcinoma. J Urol. 2009;181(5):2044– 2051.
39. Dabestani S, Marconi L, Hofmann F, et al. Local treatments for metastases of renal cell car­cinoma: a systematic review. Lancet Oncol. 2014;15(12):e549– e561.
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CASE
Upper urinary tract urothelial carcinoma
Richard Nobrega
Expert commentary Mark Sullivan
Case history
A 74- year- old gentleman presents to his district general hospital as a 2- week wait with visible haematuria. His flexible cystoscopy was normal, and his renal func­tion revealed an estimated glomerular filtration rate of 49 mL/ min with a serum creatinine of 126 μmol/ L. A computed tomography urogram (CTU) revealed bi­lateral ureteric filling defects: a right ureteric lesion at L4/ L5 and left ureteric lesion at L3/ L4 with a long stricture distally. His right kidney was hydronephrotic (Figure 16.1).
Subsequent cystoscopy was undertaken under general anaesthesia demonstrating a normal bladder. Retrograde study on the right showed dense ureteric filling defects and an impassable right ureter with both rigid and flexible ureteroscopy. A left retrograde study confirmed the computed tomography (CT) findings of a distal ur­eteric stricture with more proximal filling defects. Cytology was aspirated and the left ureter was subsequently perforated on attempting rigid ureteroscopy; biopsy was unsuccessful and a JJ stent left in situ. Cytology showed atypical cells only. The patient was then referred to our tertiary centre upper tract MDT for further management given the high index of suspicion for bilateral upper tract urothelial carcinomas (UTUC). The right side was thought likely to be a high- grade invasive tumour while on the left, possibly superficial disease proximal to a long benign distal ureteric stricture.
Figure 16.1 (a) CTU of case study patient with bilateral UTUC showing dilated right kidney. (b) Blue
arrow shows irregular, thickened distal right ureter radiologically suspicious for high- grade disease. (c) A dilated distal left ureter just above the stricture indicated by the green arrow and filling defects within the left proximal and mid ureter shown by the blue arrow also suspicious for TCC.
156 Challenging Concepts in Urological Surgery
CTU = c *All these f **Any of these factors need to be present.
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Learning point Incidence, clinical presentation, and diagnosis of UTUC
UTUCs are malignant lesions that arise from the lining of the proximal urinary tract from the renal pelvis to the distal ureter. Non- urothelial cancers are rare at <5%. The incidence of UTUC is slowly
Learning point
Pre- intervention risk stratification and management of UTUC
The EAU guidelines on UTUC stratify UTUC into low risk and high risk based on a variety of pre- intervention features including tumour size, cytology, ureteric biopsy, CTU, and previous radical cystectomy for bladder cancer (Figure 16.2). The subsequent management of UTUC is based on this risk stratification, with high- risk disease being managed with radical nephroureterectomy (RNU) with or without template lymphadenectomy (Figure 16.3).
rising but it remains a rare tumour when compared with bladder cancers, which are ten times more common.
The European Association of Urology (EAU) guidelines suggest that 60% of upper tract tumours are invasive at diagnosis compared with 15– 25% of bladder tumours. cancer where approximately 30% are invasive at diagnosis.5 UTUC is twice as common in men compared with women and peak incidence in patients aged 70– 90 years.
The most common presentation of UTUC is painless visible or non- visible haematuria. In 17% of cases it is associated with a synchronous bladder tumour.7 Recurrence in the bladder occurs in 24– 47% of UTUC patients gold- standard investigation for UTUC, and as per Figures 16.2 and 16.3 shown from current EAU guidance, it forms part of the pre- intervention risk stratification and management algorithm.14 The European Society of Urogenital Radiology (ESUR) also advocates CTU.15 Positive urine cytology is highly suggestive of UTUC in the presence of a normal cystoscopy although it has a high specificity and low sensitivity with a high false- negative rate in low- grade tumours.
1,2
8– 10
compared with 2– 6% recurrence in the contralateral upper tract.
Low-risk UTUC*
Unifocal disease
Tumour size <2 cm
Low-grade cytology
Low-grade URS biopsy
No invasive aspect on CTU-urography
omputed tomography urography; URS = ureteroscopy; UTUC = upper urinary tract urothelial carcinoma.
actors need to be present.
UTUC
3,4
This compares with bladder
6
11– 13
CTU is the
16
High-risk UTUC**
Hydronephrosis
Tumour size >2 cm
High-grade cytology
High-grade URS biopsy
Multifocal disease
Previous radical cystectomy for high-
grade bladder cancer Variant histology
Expert comment The need
for rigid/ flexible ureteroscopy?
If you have convincing CTU findings for invasive transitional cell carcinoma (TCC) as in this case and your retrograde study confirms this, obtaining positive cytology is more valuable than pursuing with a difficult ureteroscopy and causing a perforation and having to leave a stent without taking any biopsies. Stents tend to cause periureteric inflammation and can make nephroureterectomy more difficult. There is also a theoretical risk of tumour seeding on perforation.
Figure 16.2 Pre- intervention risk stratification of UTUC.
Adapted from EAU 2020 UTUC guidelines with permission (www.uroweb.org/ guideline).
157Case 16 Upper urinary tract urothelial carcinoma
*In patients with solitary kidne
y, consider a more conservative approach.
CTU = c
omputed tomography urography; RNU = radical nephroureterectomy;
UTUC = upper urinary tract urothelial carcinoma.
UTUC
Low-risk UTUC
Diagnostic evaluation:
CTU, urinary cytology, cystoscopy
± Flexible ureteroscopy with biopsies
Kidney-sparing surgery: flexible ureteroscopy or
segmental resection
or percutaneous approach
High-risk UTUC*
RNU ± template lymphadenectomy
± perioperative platinum-based
combination chemotherapy
Open
(prefer open in cT3, cN+)
Laparoscopic
Recurrence
Close and stringent follow-up
Single postoperative dose of intravesical
chemotherapy
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Evidence base Ureteroscopy
before RNU and dissemination
Does ureteroscopy before RNU cause dissemination? A meta- analysis of eight studies (N = 3975) showed a cancer­specific survival hazard ratio of
0.76 (95% confidence interval
0.59– 0.99; p = 0.04) (in favour of ureteroscopy). Overall survival, recurrence- free survival, and metastasis- free survival were all equivalent.
17
Figure 16.3 Proposed flowchart for the management of UTUC.
Adapted from EAU 2020 UTUC guidelines with permission (www.uroweb.org/ guideline).
The patient is otherwise fit with a history of hypertension and benign prostate en­largement. His regular medications are codeine, finasteride, lactulose, and amlodipine. Unfortunately, preoperatively the patient developed shortness of breath and a CT pul­monary angiogram showed a pulmonary embolus necessitating anticoagulation with treatment dose low- molecular- weight heparin (dalteparin). After further preopera­tive assessment and echocardiography he was deemed fit for surgery and bridged perioperatively as per local haematology advice.
This patient with suspected bilateral UTUC was discussed at our tertiary multidis­ciplinary team meeting and a decision made for Open bilateral nephroureterectomies via midline laparotomy and ex vivo bench surgery under cold ischaemia for both kid­neys with the intent of autotransplantation of the more favourable kidney with renal pelvis free of TCC and viable ureter for bladder reimplantation.
Expert comment Management of bilateral high- grade UTUC
UTUC is rare in itself, with bilateral high- grade disease even more so. Given the paucity of published management on these cases with most evidence being low level, there is no established treatment protocol. Midline laparotomy and bilateral nephroureterectomies is a viable option in a patient with high- grade, invasive bilateral disease involving the renal pelvis and proximal ureters. Other options would be to consider nephroureterectomy on the side of high- grade/ invasive disease and either renal autotransplantation, ileal interposition or if feasible a Boari flap if on the contralateral side, the renal pelvis with or without the upper ureter is free of invasive tumour. With a distal invasive ureteric tumour, a distal ureterectomy and reimplantation can be considered.
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Expert comment Nephron- sparing surgery in bilateral UTUC
The challenge in this situation is for patients to recognise that with nephron- sparing surgery, there may be an increased risk of recurrence in the remaining renal unit(s), but they may accept this, if it is the only options of maintaining adequate renal function and stay off dialysis. One also should consider at this point the ease of endoscopic access to the remaining renal unit for surveillance and/ or endoscopic ablation of recurrences. If there was high- grade disease on one side, and the contralateral ureter had low- grade disease only, an endoscopic approach could be taken with the low- grade disease initially and RNU on the contralateral side. Close 3- monthly endoscopic surveillance with or without laser ablation would be the mainstay of treatment to the remaining kidney and ureter containing low- grade disease.
Via midline laparotomy, the right RNU was undertaken first. After the bladder cuff was taken, the renal pedicle was dealt with in a surgical manner consistent with live related donor nephrectomy in order to preserve vessel length and minimize warm is­chaemic time. Ex vivo bench surgery under cold ischaemia demonstrated a strictured and thickened right ureter macroscopically suspicious for high- grade TCC up to the renal pelvis. This was set aside as the least likely favourable kidney for autotrans­plantation. The left RNU was then performed in a similar fashion and the specimen inspected macroscopically ex vivo under cold ischaemia. The distal ureter seemed involved by only a benign stricture only, with superficial- looking TCC in the middle ureter; the very most proximal ureter and renal pelvis were free of disease on flexible renoscopy and were thus separated from the ureteric TCC under cold ischaemia. The vessels were prepared as for renal transplantation. Renal autotransplantation was per­formed in the right iliac fossa in an ordinary extraperitoneal fashion with single renal artery and vein anastomosed to the external iliac vessels and direct ureterovesical reimplantation performed.
Clinical tip Technical elements of autotransplantation
The kidney should only be devascularized once it and the entire ureter have been dissected free, irrespective of the method of excision at the bladder end, in so doing keeping warm ischaemia to a minimal. Once out, the kidney is perfused with transplant medium (e.g. Soltran) and put on ice. Bench surgery starts with sharp dissection of the fat off the kidney to expose the pedicle and collecting system. The ureter is inspected macroscopically and a flexible ureterorenoscope used to identify tumour burden. In the case of bilateral disease, this can help identify the kidney best preserved for autotransplantation. The ureter is excised as far proximally as is required and a final flexible ureterorenoscopy performed to check all macroscopic disease has been removed. The bench surgery can usually be performed in 30– 45 minutes, not that dissimilar to standard bench surgery times for preparing a donor nephrectomy.
Evidence base Autotransplantation
Renal autotransplantation is a rare, safe, and effective surgical procedure for the treatment of complex urological conditions. It was first reported by J.D. Hardy in 1963 when he repaired a high ureteric injury following aortic surgery by reimplanting the repaired kidney into the ipsilateral iliac fossa.
The longest follow- up on patients with renal autotransplants was reported by Holmäng and Johansson in 2005.19 Their study was conducted on 23 patients with urothelial carcinoma in the upper urinary tract, operated with resection and autotransplantation then followed for 7– 20 years. Nine of these patients had either bilateral UTUC or disease in a single kidney. Of these nine, two survived without needing dialysis or having recurrences for 127 and 238 months, respectively. Three patients required haemodialysis 0– 3 times weekly for 27, 85, and 108 months, respectively. Three
18
patients with low- grade disease developed invasive recurrences in the autotransplanted kidney
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after 16, 27, and 90 months, respectively, and later died from the disease. One patient died in an accident after 14 months.
Expert comment Autotransplantation
Renal pelvic resection, ureterectomy, and renal autotransplantation with direct pyelo- or ureterocystostomy implies increased radicality and safety in the conservative treatment of patients with urothelial tumours of the upper urinary tract. The technique also simplifies follow- up. If a recurrence is diagnosed, it can often be treated by the transurethral route. The procedure should be considered as an alternative in the treatment of patients with bilateral tumours of the ureter and/ or renal pelvis and in patients with a ureteric and/ or pelvic tumour within a solitary kidney.20 It should be noted that both Pettersson’s and Holmäng’s groups only advocate autotransplantation in the context of UTUC in a solitary kidney or bilateral disease.21 This is due to the significant surgical morbidity and mortality of an autotransplant and the risk of recurrence in the preserved renal unit when compared to a RNU in a patient who has a normal contralateral kidney.
The patient in this case study had their catheter removed after a cystogram at 14 days (Figure 16.4). Rigid cystoscopy at 8 weeks allowed removal of JJ stent from the renovesical anastomosis. Inspection of the bladder at this time and biopsy of the trans­plant ureteric orifice and flexible renoscopy of the autotransplant was normal. Final histology showed:
● Right: G3T1 TCC + carcinoma in situ, clear margins
● Left: low- grade TCC mid ureter, no carcinoma in situ, clear margins.
159Case 16 Upper urinary tract urothelial carcinoma
Clinical tip Post- RNU
mitomycin C
All patients should receive a single course of intravesical 40 mg mitomycin C post RNU. Logistically, the best way to give this is for the patient to come back to a specialist nurse clinic or urology triage the day of their postoperative cystogram (day 10– 14), at which point mitomycin C can be given if there is no leak. The evidence for this is laid out in the ODMIT- C
22
trial.
Figure 16.4 Cystogram post bilateral RNU and renal autotransplantation. Check cystogram 2 weeks post
bilateral RNU and autotransplant demonstrating no leak and non- dilated well- opacified pelvicalyceal system of autotransplanted kidney. Metal clips are at the site of the vascular anastomosis with the external iliac vessels.
Evidence base Benign
disease following RNU
In a Korean series in 2014 in which 244 patients underwent RNU without biopsy over 6 years, seven patients had (2.9%) benign disease (five in the ureter, two in the renal
23
pelvis).
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Learning point Five- year disease- specific survival rates by tumour stage in UTUC
The UTUC 5- year disease- specific survival rates stratified by tumour stage range from 100% in pTa/ carcinoma in situ to <5% in pT4 disease (Table 16.1).
There are subtle differences in managing UTUC between the EAU guidelines and what is practised in the UK. Moon et al.25 summarized what we practice in the UK and made a comparison with the EAU guidelines (Table 16.2).
Table 16.1 Disease- specific 5- year survival rates
by tumour stage in UTUC
Stage Disease- specific 5- year survival
rates by tumour stage (%)
pTa/ CIS 100 pT1 91.7 pT2 72.6 pT3 40.5 pT4 <5.0
CIS, carcinoma in situ. Adapted from Craig et al. Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30- year experience in 252 patients. Urology, Volume 52, Issue 4, 594– 601.
Table 16.2 A comparison of the major differences between the EAU guidance and UK
practice
24
EAU UK practice
Low risk UUT- TCC should be offered
kidney- sparing surgery
Invasive or large tumours are a
contraindication to laparoscopic NU
Lymphadenectomy is recommended for
invasive UUT- UC Neoadjuvant chemotherapy is optional Neoadjuvant chemotherapy is not offered Annual CT- IVU for all stages of disease Annual CT for high- risk tumours only (pT1 and
Routine use of urine cytology in follow- up Urine cytology is not offered as routine follow- up
CT, computed tomography; CT- IVU, computed tomography intravenous urography; NU, nephroureterectomy; UUT- TCC, upper urinary tract transitional cell carcinoma. Adapted from Moon et al. Urothelial carcinomas of the upper urinary tract – how does UK practice compare with European guidelines: is there a difference? Journal of Clinical Urology 2018;11(2):139– 143.
In the presence of a normal contralateral kidney
NU remains the current standard of care for the majority cases of UUT- UC
Laparoscopic NU is the most common surgical
option for UUT- UC and significant numbers of patients will have invasive disease
Lymph node dissection is not performed routinely
above)
A final word from the expert
Bilateral simultaneous nephroureterectomy and nephroureterectomy of a single kidney as radical treatment for high- grade urothelial carcinoma of the upper tract is relatively rare. However, surgical techniques to deal with the oncological burden while avoiding the rendering of a patient anephric should be considered. With an ageing population and patients rightly valuing quality of life, bearing in mind the potential burden of dialysis on our patients is
important. It should be noted that to be listed for a renal transplant in the UK, patients have to
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be cancer- free for 5 years. Given that 50% of patients with UTUC will have a bladder recurrence, once patients are anephric it is likely they may never receive a transplant as they will at some point have a de novo bladder cancer while on surveillance and thus be removed from, or never reach, the transplant waiting list. This case demonstrates that careful multidisciplinary team planning and joint working with our nephrology and transplant colleagues can allow us to offer and perform nephron- sparing surgery under cold ischaemia in selected cases of UTUC bilaterally or in a solitary kidney in patients who would otherwise become anephric and require renal replacement therapy. Autotransplantation for upper tract TCC from our institution has followed five patients from 2004 to 2019, with a mean 3- year follow- up and shows a cancer­specific survival of 100%: 100% of patients are recurrence- free and 100% of patients are dialysis free. These patients are highly selected, require a very careful informed discussion of recurrence risk, and need meticulous intensive follow- up utilizing cytology, CTU, and ureteroscopy.
161Case 16 Upper urinary tract urothelial carcinoma
References
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3. Babjuk M, Oosterlinck W, Sylvester R, et al. EAU guide- lines on non- muscle- invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol. 2011;59(6):997– 1008.
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5. Stewart GD, Bariol SV, Grigor KM, et al. A comparison of the pathology of transitional cell carcinoma of the bladder and upper urinary tract. BJU Int. 2005;95(6):791– 793.
6. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;66(1):7– 33.
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8. Xylinas E, Rink M, Margulis V, et al. Multifocal carcinoma in situ of the upper tract is asso­ciated with high risk of bladder cancer recurrence. Eur Urol 2012;61(5):1069– 1070.
9. Zigeuner RE, Hutterer G, Chromecki T, et al. Bladder tumour development after urothelial carcinoma of the upper urinary tract is related to primary tumour location. BJU Int. 2006;98(6):1181– 1186.
10. Novara G, De Marco V, Dalpiaz O, et al. Independent predictors of metachronous bladder transitional cell carcinoma (UC) after nephroureterectomy for UC of the upper urinary tract. BJU Int. 2008;101(11):1368– 1374.
11. Li WM, Shen JT, Li CC, et al. Oncologic outcomes following three different approaches to the distal ureter and bladder cuff in nephroureterectomy for primary upper urinary tract urothelial carcinoma. Eur Urol. 2010;57(6):963– 969.
12. Mazeman E. Tumours of the upper urinary tract calyces, renal pelvis and ureter. Eur Urol. 1976;2(3):120– 126.
13. Novara G, De Marco V, Dalpiaz O, et al. Independent predictors of contra­lateral metachronous upper urinary tract transitional cell carcinoma after nephroureterectomy: multi- institutional dataset from three European centers. Int J Urol. 2009;16(2):187– 191.
14. Roupret M, Babjuk M, Bohle A, et al. Urothelial Carcinomas of the Upper Urinary Tract. Arnham: European Association of Urology; 2015.
15. Van Der Molen AJ, Cowan NC, Mueller- Lisse UG, Nolte- Ernsting CC, Takahashi S, Cohan RH. CT urography: definition, indications and techniques: a guideline for clinical practice. Eur Radiol. 2008;18(1):4– 17.
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16. Messer J, Shariat SF, Brien JC, et al. Urinary cytology has a poor performance for predicting invasive or high- grade upper- tract urothelial carcinoma. BJU Int. 2011;108(5):701– 705.
17. Guo RQ, Hong P, Xiong GY, et al. Impact of ureteroscopy before radical nephroureterectomy for upper tract urothelial carcinomas on oncological outcomes: a meta- analysis. BJUI. 2018;121(2):184– 193.
18. Dean RH, Meacham PW, Weaver FA. Ex vivo renal artery reconstructions: indications and techniques. J Vasc Surg. 1986;4(6):546– 552.
19. Holmäng S, Johansson SL. Tumours of the ureter and renal pelvis treated with resec­tion and renal autotransplantation: a study with up to 20 years of follow- up. BJU Int. 2005;95(9):1201– 1205.
20. Pettersson S, Brynger H, Henriksson C, Johansson SL, Nilson AE, Ranch T. Treatment of urothelial tumors of the upper urinary tract by nephroureterectomy, renal autotransplant­ation, and pyelocystostomy. Cancer. 1984;54(3):379– 386.
21. Pettersson S, Brynger H, Johansson S, Nilson AE. Extracorporeal surgery and autotrans­plantation for carcinoma of the pelvis and ureter. Scand J Urol Nephrol. 1979;13(1):89– 93.
22. O’Brien T, Ray E, Singh R, et al. Prevention of bladder tumours after nephroureterectomy for primary upper urinary tract urothelial carcinoma: a prospective, multicentre, random­ised clinical trial of a single postoperative intravesical dose of mitomycin C (the ODMIT- C trial). Eur Urol. 2011;60(4):703– 710.
23. Hong K, Kwon T, You D, et al. Incidence of benign results after laparoscopic radical nephroureterectomy. J Soc Laparoendosc Surg. 2014;18(4):e2014.00335.
24. Hall MC, Womack S, Sagalowsky AI, Carmody T, Erickstad MD, Roehrborn CG. Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30- year experience in 252 patients. Urology. 1998;52(4):594– 601.
25. Moon A, Frew J, Johnson MI. Urothelial carcinomas of the upper urinary tract – how does UK practice compare with European guidelines: is there a difference? J Clin Urol. 2018;11(2):139– 143.
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SECTION 7
Penile cancer
Case 17 Localized penile cancer
Case 18 Advanced and metastatic penile cancer