Upper Urinary Tract Transitional Cell Carcinoma: Recurrence Rate after Percutaneous Endoscopic Resection

european urology 51 (2007) 709 714 available at www.sciencedirect.com journal homepage: www.europeanurology.com Urothelial Cancer Upper Urinary Tract Transitional Cell Carcinoma: Recurrence Rate after Percutaneous Endoscopic Resection Morgan Rouprêt a,b, *, Olivier Traxer a, Mohamed Tligui a, Pierre Conort a, Emmanuel Chartier-Kastler a, François Richard a, Olivier Cussenot a,b a Department of Urology, Groupe Hospitalo-Universitaire EST, Pitié-Tenon, Assistance Publique-Hôpitaux de Paris (AP-HP), University Paris VI, Paris, France b CeRepp Group, Unité EA3104, University Paris VII, Paris, France Article info Article history: Accepted July 14, 2006 Published online ahead of print on July 28, 2006 Keywords: Urinary tract Carcinoma Transitional cell Percutaneous Endoscopy Prognosis Kidney Pelvis Abstract Objectives: To assess oncologic outcomes in patients undergoing percutaneous management for upper urinary tract transitional cell carcinoma (UUT-TCC) of the renal cavities. Methods: We performed a retrospective review of data for patients who underwent percutaneous conservative surgery for a UUT-TCC between 1989 and 2005: sex; age at diagnosis; mode of diagnosis; smoking; history of bladder cancer; type of surgery; complications; tumour site, size, stage and grade, and recurrence and progression. We evaluated recurrence and survival rates. Results: Data were analyzed for 24 patients. Median age was 70 yr. The tumour was located in the renal pelvis in 11 patients and in the caliceal system in 13 patients. Mean tumour size was 1.8 cm (range: 0.8 2.9). Four patients had a history of bladder carcinoma. Three patients experienced perioperative blood loss requiring transfusion, and one experienced colon wound. Median follow-up was 62 mo. Eight (33.3%) patients experienced local recurrence (three in the treated urinary tract, one in the contralateral tract, four in the bladder). Five patients underwent nephroureterectomy (NUT) during follow-up. Five (20.8%) patients have died, four from disease progression and one from cardiovascular causes. The 5-year disease-specific and tumour-free survival rates were 79.5% and 68%, respectively. Conclusions: Percutaneous management can be recommended as an alternative to NUT or ureteroscopy for low-grade or superficial UUT- TCCs localised in the renal cavities. These patients require long-term postsurgical surveillance. For patients with high-grade or invasive tumours, open NUT remains the gold standard. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. 23 quai d Anjou, 75 004 Paris, France. Tel. +33 6 60 54 41 66; Fax: +33 1 60 84 79 76. E-mail address: mroupret@club-internet.fr (M. Rouprêt). 0302-2838/$ see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2006.07.019

710 european urology 51 (2007) 709 714 1. Introduction Upper urinary tract transitional cell carcinomas (UUT-TCCs) are rare and account for only 5% of all urothelial carcinomas [1,2]. The gold standard treatment is still open nephroureterectomy (NUT) with bladder cuff excision despite morbidity and the systematic loss of a renal unit [2]. Whether it should remain a gold standard under all circumstances is a moot point [3 6]. Currently, laparoscopy reduces the length of the incision, surgical morbidity, postoperative pain, and length of hospital stay and convalescence. Preliminary oncologic outcomes are similar to those for open NUT. However, laparoscopy is still radical surgery that does not spare the renal parenchyma [7]. Advances in endourologic techniques and materials have led to first-line conservative endoscopic management, with encouraging results [3,4,8 10]. Endoscopic management (ureteroscopic or percutaneous) is indicated in patients who would otherwise be on dialysis after NUT (i.e., patients with a solitary kidney, bilateral disease, or renal insufficiency), but it is also becoming the preferred option in some patients with a normal contralateral kidney [11 13]. The percutaneous approach to the renal pelvis, although more invasive than ureteroscopy, provides a better working environment in patients with bulky tumours or lower calyx tumours in whom easy access and resection are not feasible by ureteroscopy [6,14,15]. Ureteroscopic access to the lower pole is limited by visibility and by the loss of deflection caused by instrument passage through the working channel. Direct access via the antegrade percutaneous approach avoids these problems [13,16]. There are relatively few published studies on the percutaneous approach since, in many instances, it is being superseded by ureteroscopy [6,8,10,14,15]. The aim of this study was to assess oncologic outcomes in 24 patients who underwent antegrade percutaneous tumour ablation for a UUT-TCC of the renal cavities. 2. Methods Between 1989 and 2005, 141 patients were treated surgically for a UUT-TCC in our two university hospitals. Of these, 24 underwent a percutaneous endoscopic procedure. We reviewed data for the following variables retrospectively: sex, age at diagnosis, mode of diagnosis, smoking, history of bladder cancer, treatment, complications, tumour characteristics (TNM stage 2002, World Health Organization grade 2004 [17], site, size), and disease recurrence and progression. All patients had undergone cystoscopy, urine cytology, intravenous urography, and/or a renal computed tomography (CT) scan. Tumour size was determined on CT scan and/or intravenous urography. Patients with a performance status >2 and metastatic disease at diagnosis were excluded from the study. The reasons for resorting to a percutaneous endoscopic approach were imperative (n = 9), the surgeon s discretion (n = 10), and failed ureteroscopy (n = 5). By imperative we mean patients with a solitary kidney (n = 4), prohibitive operative risk (n = 4) (American Society of Anesthesiologists score 3), or a chronic renal insufficiency (n = 1). At the surgeon s discretion means that the antegrade percutaneous approach was used in a patient with a healthy contralateral kidney. The tumour was located in the renal cavities and appeared noninvasive, complete resection was feasible (i.e., multifocal localization), and it was large (1 2.5 cm in diameter) and/or apparently not accessible by ureteroscopy (i.e., a lower calyx tumour). The patient had no history of urinary tract surgery and gave their informed consent to the percutaneous procedure. Prior to surgery, 14 patients underwent diagnostic ureteroscopy and biopsies. The percutaneous procedure has been described in detail [10,13,18]. Briefly, a ureteral catheter was passed up into the renal pelvis with a cystoscope, the patient was moved into the prone position, contrast agent was injected to opacify the cavities, the calyx was punctured, and the tract was dilated, making sure to avoid extravasation, to accommodate an Amplatz sheath used to reduce intrarenal pelvic pressure. Direct access was preferred for single tumours. An upper calyx was chosen to access multiple tumours or a tumour in the renal pelvis. A nephroscope was inserted, the upper tract was carefully inspected, and all small suspicious areas were removed by biopsy. For tumour resection and haemostasis, we used either a 24F resectoscope (n = 6) with a standard loop electrode, a neodynium:yttrium-aluminum-garnet (YAG) laser (n = 12) (power setting 20 45 W with a pulse setting of 2 s) or a holmium:yag laser (n = 6). A nephrostomy tube was left in place for 2 5 d postoperatively. Three patients received adjuvant topical treatment with mitomycin C as described previously [19]. Patients were seen every 6 mo for at least 3 yr, then yearly. They underwent a CT scan, cystoscopy, ureteroscopy, and urine cytology at each visit. Recurrence time was evaluated from the date of the endoscopic procedure. The Kaplan-Meier method was used to calculate survival. Disease-free survival was defined as the time from the procedure to either the first local recurrence (urothelial tumour of the urinary tract), the detection of distant metastases, or the close of the study. Prognostic factors were established by univariate analysis with the use of the log-rank test. A p value <0.05 was considered significant. All tests were carried out with the Statistical Package for the Social Scientists, version 2 (SPSS Inc, Chicago, IL). 3. Results The characteristics of the 24 patients included in our study are given in Table 1. Median age was 70 yr. The male:female ratio was 1.7. Eleven of the UUT-TCCs were in the renal pelvis and 13 in the caliceal system.

european urology 51 (2007) 709 714 711 Table 1 Patient characteristics (N = 24) Variable N * (%) Sex Male 15 (62.5) Female 9 (37.5) Mean age at diagnosis (yr) Male 71.3 8.6 Female 69.6 9.2 Presentation Haematuria 17 (70.8) Flank pain 3 (12.5) Urinary tract infection 1 (4.2) Fever 1 (4.2) Other 2 (8.3) History of bladder tumour Yes 4 (16.7) No 20 (83.3) Primary tumour location Renal pelvis 11 (45.8) Lower calyx 10 (41.7) Middle calyx 2 (8.3) Upper calyx 1 (4.2) Multiple location in renal cavities 2 (8.3) Concomitant bladder tumour 2 (8.3) * Results are given as number of patients with percentage in parentheses except for age (mean SD). Table 2 Pathology results and outcomes No. of patients (%) * Mean tumour diameter (cm) 1.8 (0.8 2.9) Grade Low 17 (70.8) High 7 (29.2) Tumour stage Superficial 20 (83.3) pta 10 (41.7) ptis 2 (8.3) pt1 8 (33.3) Invasive 4 (16.7) pt2 3 (12.5) pt3 1 (4.2) Recurrence site Bladder 4 (16.7) Urinary tract 4 (16.7) Controlateral 1 (4.2) Treated side (local) 3 (12.5) Metastases 2 (8.3) Subsequent NUT 5 (20.8) Follow-up Alive 18 (75) Dead 5 (20.8) Lost to follow-up 1 (4.2) Median follow-up 62 NUT: nephroureterectomy. * Tumour diameter is given as mean with range. Two patients presented with tumours at more than one site in the renal cavities. Four patients had a previous history of bladder TCC. Sixteen (66.7%) patients were smokers. Preoperative cytology was positive in 12 cases: 7 low-grade tumours and 5 highgrade tumours. Fourteen (58.3%) patients had a diagnostic ureteroscopy. Results of diagnostic ureteroscopic biopsy are as follows: 10 low-grade tumours and 4 nonevaluable. On final analysis, 9 of 10 tumours were indeed of low grade. Perioperative complications occurred in four patients. Three (12.5%) patients experienced blood loss requiring transfusion of more than 4 blood packs; the fourth patient had an accidental colonic puncture during percutaneous access. A localised collection was diagnosed on CT scan and treated successfully with conservative management (i.e., antibiotics). Pathologic findings, recurrence rate, and disease progression are given in Table 2. Median follow-up was 62 mo (range: 18 188). Local recurrence occurred in 8 (33.3%) patients. There were four cases of recurrence in the upper urinary tract (three in the treated urinary tract [two in renal cavities and one in the distal ureter], one in the contralateral ureter) and four in the bladder (Table 3). Median time to urothelial recurrence was 17 mo. Two patients underwent a repeat percutaneous procedure for incomplete ablation. Five patients with high-grade and/or invasive tumour subsequently underwent an open NUT, one immediately (pt3) and the others during follow-up. Three patients with initial imperative indications have had terminal renal failure and went on dialysis. Two patients with invasive tumours (1 pt3, 1 pt2) had distant metastases within 26 mo after the procedure and died within 3 yr. Two other patients (both pt2) developed highgrade recurrence and aggressive disease that led to death within 5 yr. Of the 24 patients, 5 (20.8%) have died, 4 from disease progression and 1 from cardiovascular causes. Prognostic factors studied by univariate Table 3 Relationship of grade between original tumour of the upper tract and subsequent local recurrences No. Renal pelvis tumour Recurrence (location) 1. High grade High grade (bladder) 2. High grade High grade (bladder) 3. High grade High grade (bladder) 4. High grade Low grade (bladder) 5. High grade Low grade (contralateral ureter) 6. Low grade Low grade (renal pelvis) 7. Low grade Low grade (renal pelvis) 8. Low grade High grade (ureter)

712 european urology 51 (2007) 709 714 Table 4 Prognostic factors for survival in patients undergoing percutaneous endoscopic surgery analysis are given in Table 4. Only clinical stage and tumour grade, and neither patient age nor tumour size, were prognostic factors for recurrence and survival. There was a strong significant association ( p = 0.003) between low-grade tumours and superficial tumours. The 5-year disease-specific and tumour-free survival rates were 79.5% and 68%, respectively. 4. Discussion p value (univariate log-rank test) Tumour-free survival Disease-specific survival Tumour stage 0.001 0.001 Grade 0.002 0.001 Age <70 yr 0.09 0.05 Tumour diameter >2 cm 0.06 0.6 Multifocality 0.7 0.2 Modern endoscopy techniques are bringing about profound changes in the management of UUT-TCCs. Whenever possible, open NUT is being supplanted by endoscopic techniques, and the percutaneous approach is being superseded by less-invasive ureteroscopy, causing less injury to the urinary tract [11,13,16]. Most of our percutaneous procedures were carried out at the beginning of this retrospective study, and it is likely that, with further technical advances in instrumentation (e.g., yet smaller flexible ureteroscopes, new lasers), we may need to resort even less often to this approach [9,16,20,21]. However, currently, it is still the best endoscopic procedure for large (>1 cm), noninvasive tumours of the renal cavities or for tumours of the lower calyces. It provides better visibility than ureteroscopy and allows the passage of more and larger tools through the nephroscope [14,18,22]. Tumour grade and stage are considered by many to be more important prognostic factors than extensive surgical resection of the tumour (i.e., systematic radical NUT) [4,16,18]. Furthermore, ureteral tumours seem to have a worse prognosis than tumours from the renal pelvis [23]. Our disease recurrence and 5-year survival rates (68% and 79.5%, respectively) after percutaneous management of renal cavity tumours confirm the good outcomes that have already been reported [6,10,14]. Although concerns have been voiced about nephrostomy track seeding, only one case has been reported so far [24]. To our knowledge, seeding did not occur in our study. Other concerns are incomplete tumour removal and pyelolymphatic or pyelovenous backflow leading to metastasis [10,14]. Three of our 24 patients received adjuvant topical mitomycin C. However, the effect of local chemotherapy (i.e., bacillus Calmette-Guérin or mitomycin) after percutaneous access on tumour recurrence remains unclear, and no protocol of treatment has been accepted yet [19,25]. Only two of our patients developed metastases during followup. We observed three recurrences in the treated upper urinary tract. Two of these patients benefited from a repeat percutaneous procedure, as advocated in the literature for noninvasive recurrence [14,15]. We also observed recurrence in the contralateral urinary tract (one case) and bladder (four cases) [26,27]. Five of our 24 patients proceeded to NUT (i.e., 20.8% vs. 14% in the literature) [8,10]. The only significant perioperative complication in our study was bleeding (12.5% transfusion rate). The incidence of blood loss varies among investigators and depends greatly on the size and extent of the treated lesion [6,10,14]. It is recommended that all patients with a UUT filling defect undergo diagnosis by ureteroscopic biopsy because (1) staging errors are common with contrast imaging as it does not evaluate wall infiltration by a UUT-TCC and (2) at presentation, 30 55% of UUT-TCCs are already invasive or highgrade tumours that are likely to recur after conservative management [2,28,29]. Only 14 of our 24 patients had ureteroscopic biopsies before percutaneous treatment because in the early 1990s this examination was not yet routine in our departments and obviously, in some cases, the tumour also was not accessible. If biopsy had been routine, patients with tumours understaged by imagery could have benefited from earlier radical NUT, and additional candidates may have been identified for percutaneous management [30]. Patient selection has to be rigorous [10,15]. In cases of doubt and in the absence of histologic data, open NUT remains the treatment of choice. 5. Conclusions The percutaneous approach is still an alternative to open radical NUT for the treatment of superficial and/or low-grade UUT-TCCs of the renal cavities in selected patients. It needs to be considered before ureteroscopic management for bulky tumours of the lower renal pole. The technique provides good outcomes, but all patients require close long-term endoscopic surveillance.

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714 european urology 51 (2007) 709 714 Editorial Comment François Rozet francois.rozet@imm.fr The standard treatment of upper urinary tract transitional cell carcinomas (UUT-TCCs) is open radical nephroureterectomy (NUT). A laparoscopic NUT procedure has been developed and gives encouraging results. However, the risk of tumour dissemination due to manipulation in a high-pressure environment has not been definitively discounted. With advances in fibre optic technology and ever smaller calibre instruments, first-line conservative endoscopic treatment has also been introduced for the management of UUT-TCCs. Ureteroscopic or percutaneous endoscopic management is indicated in patients who would be on dialysis after NUT, that is, those with a solitary kidney, bilateral disease, or renal insufficiency. However, it is also being increasingly performed in patients with a normal contralateral kidney. No randomised controlled study has yet compared NUT with conservative endoscopic procedures. Despite this, 21% of US surgeons in a recent survey are already offering ureteroscopy as first-line treatment for high-grade, large distal ureteral UUT- TCCs [1]. Currently, ureteroscopy is supplanting percutaneous management. This study from Rouprêt et al., however, pinpoints the fact that the percutaneous approach is still indicated currently for large tumours or tumours in the lower calices. Oncologic outcomes are encouraging from this series and this technique should be considered as an available therapeutic option when urologists have to deal with such cases. Appropriate staging should be performed in a patient with a UUT filling defect to decide on the most fitting surgical procedure. The work-up should therefore include diagnosis by ureteroscopic biopsy. Some bulky tumours that appear invasive are, in fact, of low grade and could be treated percutaneously. Readers should keep in my mind that, with adequate experience, the direct access with the percutaneous approach offers both good vision and enough space to make a complete resection. Reference [1] Razdan S, Johannes J, Cox M, et al. Current practice patterns in urologic management of upper-tract transitional-cell carcinoma. J Endourol 2005;19:366 71.