ARAB JOURNAL OF UROLOGY 2021, VOL. 19, NO. 1, 46–58 https://doi.org/10.1080/2090598X.2021.1883810 MANAGEMENT OF UTUC: REVIEW ARTICLE Diagnostic ureteroscopy for upper tract urothelial carcinoma: friend or foe? Angelo Territo, Andrea Gallioli, Iacopo Meneghetti, Matteo Fontana, Jordi Huguet, Joan Palou and Alberto Breda Urology Department, Fundació Puigvert, Autonomous University of Barcelona, Barcelona, Spain ABSTRACT ARTICLE HISTORY Introduction: The European Association of Urology guidelines recommend offering kidney- Received 25 September 2020 sparing surgery (KSS) as a primary treatment option to patients with low-risk tumours. Accepted 24 January 2021 Cystoscopy, urinary cytology, and computed tomography urography (CTU) do not always KEYWORDS allow correct disease staging and grading, and sometimes there is even a lack of certainty Diagnostic biopsy; diagnosis; regarding the diagnosis of UTUC. Diagnostic ureteroscopy (d-URS) may therefore be of crucial radical nephroureterectomy; importance within the diagnostic framework and fundamental in establishing the appropriate upper tract urothelial therapeutic approach. carcinoma; ureteroscopy Evidence acquisition and synthesis: A systematic review of the literature was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Risk of bias was assessed using Risk of Bias in Non-randomized Studies of interventions (ROBINS-I). Overall, from 3791 identified records, 186 full-text articles were assessed for eligibility. Finally, after a quantitative review of the selected literature, with the full agreement of all authors, 62 studies were considered relevant for this review. Results: CTU has a sensitivity and specificity for UTUC of 92% and 95% respectively, but is not able to detect small or flat lesions with adequate accuracy. The sensitivity of voided urinary cytology for UTUC is around 67–76% and ranges from 43% to 78% for selective ureteric urine collection. As no technique offers a diagnosis of certainty, d-URS can allow an increase in diagnostic accuracy. In the present review the pros and cons of d-URS were analysed. This technique may provide additional information in the selection of patients suitable for neoad­ juvant chemotherapy or KSS, distinguishing between normal tissue and low- and high-grade UTUC thanks to the emerging technologies. Conclusions: Information obtainable from d-URS and ureteroscopic-guided biopsy can prove extremely valuable when the diagnosis of UTUC is doubtful or KSS is being considered. Notwithstanding concerns remain regarding the potential risk of bladder recurrence, cancer dissemination, and/or delay in radical treatment. Abbreviations: CLE: confocal laser endomicroscopy; CSS: cancer-specific survival; CTU: CT urography; d-URS: diagnostic ureteroscopy; EAU: European Association of Urology; HR: hazard ratio; IMAGE1S: Storz professional imaging enhancement system; IVR: intravesical recurrence; KSS: kidney-sparing surgery; MFS: Metastasis-free survival; NAC: neoadjuvant chemotherapy; NBI: narrow-band imaging; OCT: optical coherence tomography; RFS: Recurrence-free survival; RNU: radical nephroureterectomy; ROBINS-I: Risk of Bias in Non-randomized Studies of inter­ ventions; URS(-GB): Ureteroscopy(-guided biopsy); UTUC: upper tract urothelial carcinoma; UUT: upper urinary tract Introduction such treatment. The EAU guidelines make a Grade-A recommendation for the performance of cystoscopy, Upper tract urothelial carcinoma (UTUC) accounts for urinary cytology, and CT urography (CTU) in the diag­ 5–10% of urothelial carcinomas [1]. To date, radical nostic evaluation of UTUC. They also advise that diag­ nephroureterectomy (RNU) with bladder cuff excision nostic ureteroscopy (d-URS) and biopsy should be still represents the ‘gold standard’ treatment for UTUC. performed in cases in which additional information Nevertheless, the European Association of Urology may have an impact on treatment decisions [1]. In (EAU) guidelines recommend offering kidney-sparing our opinion d-URS represents an extremely useful surgery (KSS) as a primary treatment option to patients tool that guarantees the possibility of carrying out with low-risk tumours [1,2]. The availability of preo­ a visual study of the conditions of the upper urinary perative predictive tools that yield reliable information tract (UUT). This means, for instance, identifying the on tumour location, size, stage, and grade and any actual number and size of the lesions. It also represents tumour-associated conditions is of fundamental an irreplaceable tool to seek for and possibly biopsy importance in guiding the selection of candidates for CONTACT Angelo Territo, territoangelo86@gmail.com Urology Department, Fundació Puigvert, Autonomous University of Barcelona, Barcelona, Spain. A.T. and A.G. worked equally in writing the manuscript. © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ARAB JOURNAL OF UROLOGY 47 flat lesions not identifiable on the CTU. The possibility problematic domains involved uncontrolled, single- of studying the UUT endoscopically is also of funda­ arm studies, small sample sizes, outcomes measure­ mental importance to design or evaluate the feasibility ment, and confounding. of a conservative approach, especially in those condi­ The reported studies had moderate, serious, or cri­ tions in which the lesion is difficult to reach or localise tical risk of bias. When using the ROBINS-I assessment, (i.e. lower calyx). Imaging and optical diagnostic tech­ it is recommended to exclude studies with a high-risk niques and new devices for performing biopsies repre­ of bias from analyses. Nevertheless, considering the sent an extraordinary tool for increasing diagnostic rarity of the disease and the various technical details accuracy. regarding diagnosis and therapy analysed, despite the However, the procedure is challenging so that not overall high risk of bias, all the studies have been always achieving optimal results. It is then necessary to retained for the purposes of the present review. carry out a risk stratification of patients to reduce costs, Moreover, we performed many subgroup analyses to complications, and potential risk of bladder recurrence, investigate so that it could be a source of further cancer dissemination, or delay in radical treatment. heterogeneity. A systematic review of the literature was performed Overall, from 3791 identified records, 186 full-text with the aim of taking stock of the current knowledge of original articles were assessed for eligibility. Finally, 62 the strengths and weaknesses of d-URS in UTUC. records were considered relevant for the present review. Evidence acquisition and synthesis Results A comprehensive literature search was performed in The findings reported in the present review relate to May 2020 using the PubMed/MEDLINE database using the pros of d-URS, such as histological characterisation the following terms: ‘upper tract urothelial carcinoma’ of UTUC in select patients eligible for endoscopic treat­ OR ‘UTUC’ OR ‘upper urinary tract’ AND ‘biopsy’ OR ment and/or neoadjuvant chemotherapy (NAC). The ‘bladder recurrence’ OR ‘complications’ OR ‘delay’ OR cons of d-URS, i.e. complications, inconclusive diagno­ ‘diagnosis’ OR ‘diagnostic ureteroscopy’ OR ‘confocal sis, risk of cancer dissemination and bladder recur­ laser endomicroscopy’ OR ‘grade’ OR ‘IMAGE1S’ OR ‘ima­ rence, and potential delay in treatment could also ging’ OR ‘narrow-band imaging’ OR ‘neoadjuvant che­ affect the prognosis. motherapy’ OR ‘optical coherence tomography’ OR ‘stage’. Pros Publications were filtered for English language and full-text availability and included original articles, clin­ Histopathological confirmation of disease ical trials, case reports, meta-analyses, professional CTU has the highest diagnostic accuracy among the society guidelines, and reviews. Letters to the editor, available imaging techniques, with a sensitivity and replies, textbooks, and contributions written in lan­ specificity of 92% and 95%, respectively [5]. However, guages other than English were excluded from our CTU may not be able to reliably estimate the actual research. No filters were applied for the publication three-dimensional extension of the disease or to detect date. small or flat lesions with adequate accuracy, especially Eligible articles were screened according to the in the case of ureteric localisation [6], thus potentially Preferred Reporting Items for Systematic Reviews and leading to misclassification and undertreatment [7]. The Meta-Analysis (PRISMA) criteria [3] (Figure 1). sensitivity of voided urinary cytology for UTUC is around Studies were not excluded a priori based on quality 67–76% and ranges from 43% to 78% for selective reporting assessment. Because only non-randomised ureteric urine collection, being higher for high-grade studies were retrieved, we adopted the Risk of Bias in UTUC [8,9]. Barbotage cytology detects up to 91% of Non-randomized Studies of interventions (ROBINS-I) cancers, being as effective as biopsy histology [10]. tool to assess the risk of bias in the included studies A d-URS allows exploration of the UUT and is crucial for the following domains: confounding bias, selection when diagnostic uncertainty exists and in patients who of participants bias, bias in classification of interven­ can benefit from KSS [1,11]. A d-URS has the advantage tions, bias due to deviation from intended interven­ to offer a direct view of the tumour for biopsy and to tions, bias due to missing data, the bias in the facilitate selective ureteric sampling for cytology in situ measurement of outcomes and bias in the selection [1,11]. Indeed, in situ collection of urine through the of the reported results [4]. We used the ROBINS-I tool barbotage technique has proven to be sensitive if to evaluate the risk of bias among the studies included correctly executed, with better diagnostic performance as one of the four levels (low, moderate, serious and than that of voided urine cytology [12]. It also enables critical). The results of our risk of bias assessment for all clarification of the nature of non-specific CTU findings, individual studies are shown in Table 1 [7,19–21,25–­ such as wall thickening, and to re-classify suspicious 27,30,32–36,38–40,42,43,46–48,55–58,62,63]. The most lesions as benign [13]. 48 A. TERRITO ET AL. Table 1. Risk of bias assessment using ROBINS-I. Bias in selection of Bias in classifi­ Bias due to devia­ Bias in mea­ Bias in selection Bias due to participants into cation of tions from intended Bias due to surement of of the reported Overall Reference cofounding the study interventions intervention missing data outcomes results bias Kleinmann Critical Serious Moderate Moderate Serious Moderate Moderate Serious et al., 2013 Critical Serious Moderate Moderate Moderate Moderate Moderate Serious [19] Critical Moderate Moderate Moderate Moderate Moderate Moderate Serious Lama et al., Critical Serious Moderate Moderate Critical Moderate Moderate Serious 2018 [21] Critical Serious Moderate Moderate No Moderate Moderate Serious Breda et al., Serious Moderate Moderate Moderate information Moderate Low Moderate 2019 [20] Critical Critical Serious Serious Low Serious Moderate Critical Golan et al., Critical Critical Serious Serious Moderate Serious Moderate Critical 2015 [25] Serious Serious Moderate Moderate Moderate Moderate Low Moderate Tsivian et al., Moderate Moderate Moderate Low Low Ciritcal Serious Serious 2014 [26] Moderate Low Low Low Low Serious Low Moderate Gallioli Moderate Low Low Low Low Serious Low Moderate et al.,2020 Moderate Low Low Low Low Serious Low Moderate [7] Moderate Moderate Low No information Low Moderate Moderate Moderate Lane et al., Moderate Low Low No information Moderate Moderate Critical Moderate 2010 [27] Moderate Low Low No information Moderate Moderate Critical Moderate Porten et al., Moderate Low Low No information Moderate Moderate Critical Moderate 2014 [30] Moderate Low Low No information Moderate Moderate Critical Moderate Traxer et al., Critical Serious Moderate Moderate Moderate Serious Critical Serious 2011 [32] Critical Serious Moderate Serious No Moderate Serious Serious Emiliani et al., Critical Serious Moderate Serious information Moderate Serious Serious 2017 [33] Critical Serious Moderate Serious Serious Moderate Serious Serious Bus et al., Critical Serious Moderate Serious Moderate Moderate Serious Serious 2016 [34] Critical Serious Moderate Serious Moderate Moderate Serious Serious Bui et al., Critical Serious Moderate Serious Moderate Moderate Serious Serious 2015 [35] Critical Critical Moderate Serious Moderate Moderate Serious Critical Breda et al., Critical Critical Moderate Serious Moderate Moderate Serious Critical 2018 [36] Serious No Traxer et al., information 2013 [42] Schoenthaler et al., 2014 [43] Whitehurst et al., 2017 [38] Somani et al., 2017 [39] Baş et al., 2017 [40] Hendin et al., 1994 [46] Ishikawa et al., 2010 [47] Gurbuz et al., 2011 [48] Lee et al., 2018 [54] Sung et al., 2015 [55] Lee et al., 2016 [56] Yoo et al., 2017 [57] Nison et al., 2013 [61] Boorjian et al., 2005 [62] Grahn et al. [14] compared the performance of CTU Grading, staging, and biopsy for histopathology and visual assessment during d-URS in 148 patients Ureteroscopic-guided biopsy (URS-GB) correctly deter­ with suspected UTUC. The d-URS showed a similar mines tumour grade in most cases, but stage assess­ sensitivity (89% vs 84%; P = 0.36), but greater specifi­ ment using URS-GB is notoriously difficult. city (51% vs 85%; P < 0.001) and accuracy (74% vs 84%; Subiela et al. [15] conducted a systematic review P = 0.04) than CTU. and meta-analysis including 23 studies on the diagnos­ Gallioli et al. [7] found that, among patients with tic accuracy of URS-GB in predicting stage and grade at positive CTU and d-URS, the lesions differed in dimen­ final pathology. The authors reported a grade concor­ sions, number or site in 45/107 (42.1%) cases. dance between URS-GB and final pathology of 66% ARAB JOURNAL OF UROLOGY 49 Table 2. Overview of biopsy devices during operative ureteroscopies used in UTUC in the included studies. Successful histol­ Unsuccessful his­ Patients ogy characterisa­ tology characteri­ Reference treated, n Devices tion, n/N (%) sation, n/N (%) Grade, n/N (%) Stage, n/N (%) Conclusion Kleinmann 127 3-F forceps 3-F forceps 150/ 3-F forceps 87/91 3-F forceps _ The flat wire basket was et al., 2013 (303 2.4-F flat 237 (63.3) (95.6) specified superior in achieving [19] biopsies) wire 2.4-F flat wire 2.4-F flat wire (80) pathological diagnosis and basket basket 62/66 basket 4/91 (4.4) 2.4-F flat wire in determining tumour (93.9) basket grade compared with the specified 3-F forceps. The forceps (93) were useful for small and sessile lesions. Lama et al., 145 3-F forceps 3-F forceps 31/39 3-F forceps 8/24 LG 71/137 _ The quality of specimens 2018 [21] (182 BIGopsy (79.5) (33.3) (51.8) from BIGopsy forceps was biopsies) forceps BIGopsy forceps BIGopsy forceps 7/ HG 66/137 rated similarly to nitinol 2.4-F nitinol 64/71 (90.1) 24 (29.2) (48.2) basket, and favoured over basket 2.4-F nitinol basket 2.4-F nitinol basket 3-F forceps specimens. No 63/72 (87.5) 9/24 (37.5) difference existed among the devices in the rate of acquiring a grade concordant biopsy. Breda et al., 85 3-F forceps 3-F forceps 164/ 3-F forceps 55/66 LG 75/140 Tx 129/140 BIGopsy forceps and the 2019 [20] (302 BIGopsy 219 (74.9) (83.3) (53.6) (92.1) 2.2-F nitinol basket were biopsies) forceps BIGopsy forceps BIGopsy forceps HG 50/140 Ta 11/140 (7.9) superior to 3-F forceps for 2.2-F nitinol 50/61 (81.9) 11/66 (16.7) (35.7) a successful histology basket 2.2-F nitinol basket CIS 15/140 characterisation. For 22/22 (100) (10.7) papillary lesions, the basket biopsy provided larger specimens. For flat or sessile lesions, the BIGopsy forceps provided larger, deeper, and less distorted specimens than 3-F forceps. CIS: carcinoma in situ; HG: high grade; LG: low grade. Identification Records identified through database searching Additional records identified through other sources (n = 3791) (n = 0) Screening Records after duplicates removed Non-matching records excluded (n = 2593) (n = 0) Records excluded based on title or abstract Records screened reading (n = 2593) (n = 2407) Inadequate patients population (n = 981) Not English records (n = 266) Lack of information on the outcomes of interest (n = 872) Not available data (n = 197) Eligibility Study design (n = 91) Full-text records excluded, with reasons Full-text records assessed for eligibility (n = 124) (n = 186) Comparators (n = 11) Lack of information on the outcomes of interest (n = 113) Records included in quantitative synthesis Included (n = 62) Figure 1. PRISMA diagram for study selection. 50 A. TERRITO ET AL. (95% CI 55–77%) for low-grade tumours and 97% (95% 63%, respectively; P < 0.001) and correct assessment of CI 94–98%) for high-grade tumours. They also found grade (93% vs 80%, respectively; P < 0.033). that identification of high-grade and subepithelial Breda et al. [20] found BIGopsy forceps and the invasion at URS-GB had a moderate (positive predictive 2.2-F nitinol basket to be superior to 3-F forceps in value [PPV] 60%, 95% CI 54–66%) and strong correla­ obtaining an adequate specimen for the pathology tion (PPV 94%, 95% CI 84–100%) with invasive UTUC at examination of UTUC. In addition, for papillary lesions, final pathology, respectively. Notwithstanding, under­ the basket biopsy provided larger specimens in compar­ grading and understaging rates at prior URS-GB com­ ison to the other biopsy devices, while for flat or sessile pared with final pathology were found in 32% (95% CI lesions, the BIGopsy forceps provided larger, deeper, 25–38%) and 46% (95% CI 38–54%) of cases, and less distorted specimens than the 3-F forceps. respectively. In a multi-institutional retrospective study on 145 It is evident that, to date, the accuracy of URS-GB patients, Lama et al. [21] evaluated URS-GB using back­ has been limited by several factors, including insuffi­ loaded cup forceps, a nitinol basket, or standard cup cient tissue quality and crush artefacts; even if there is forceps. The ability to distinguish low- and high-grade no unanimity over whether low biopsy volume in URS- UTUC prior to RNU was statistically higher using the GB affects tumour biopsy grading. Some authors try to backloaded cup forceps (P = 0.02). The authors also overcome these limitations by describing detailed reported that, compared with the standard cup for­ methods for URS inspection and URS-GB, while others ceps, the backloaded cup forceps showed have sought to find the best device to obtain an ade­ a significantly higher subjective score for biopsy qual­ quate biopsy sample. ity (P = 0.01), quality of basement membrane thickness In 1997, Tawfiek et al. [16] described in detail their (P = 0.02), and role of biopsy size in accurate diagnosis technique to inspect the UUT and perform URS-GB for (P = 0.04). However, no subjective differences were handling and processing the samples. In a series of 45 noticed between the backloaded cup forceps and niti­ patients, Guarnizo et al. [17] proposed a multi-biopsy nol basket biopsies. approach that was able to achieve a diagnostically accurate diagnosis of UTUC in 89% of cases. Case selection for conservative endoscopic Golan et al. [18] proposed a technique to achieve treatment maximal tissue preservation in which the specimen The main factors that correlate with the oncological was mounted on filter paper prior to embedding in outcomes of URS treatment are pathological grade, paraffin. tumour size, and tumour focality [2], although recent With the current diagnostic devices, an ideal studies suggest that tumour burden plays a secondary method to procure adequate tissue sampling is still role [22,23]. Therefore, risk stratification based on these missing. Basket and 3-F cup biopsy forceps represent factors is essential to limit the risk of under- and over­ the two most commonly used biopsy tools [19]. Basket treatment, with current guidelines recommending devices can be front loaded and allow the ensnare­ elective conservative treatment only in the case of ment of a piece or even the whole specimen from its small (<2 cm), unifocal, low-grade disease [24]. In this base. Thanks to their flexibility they are also more likely context, endoscopic exploration of the UUT plays a key to reach those lesions localised in calyces that require role in selecting those patients who are fit for KSS of considerable deflection of the instrument. Conversely, UTUC, together with urinary cytology and cross- flat lesions could not be sampled with this tool. Larger sectional imaging. Golan et al. [25], in their retrospec­ diameter forceps can capture large specimens and also tive study on 116 patients who underwent d-URS for flat lesions, but they need to be introduced in the suspected UTUC on CTU, found that RNU was spared in ureteroscope by backloading as the tip of the device 42% of cases, without reporting disease progression in is not compatible with the diameter of the working any of those cases. Tsivian et al. [26] found a lower rate channel. Unfortunately, they bestow stiffness to the of RNU (89% vs 69%; P = 0.01) and misdiagnosis (15.5% flexible ureteroscope, so that sampling of lesions vs 2.1%; P = 0.02) in patients evaluated with routine could be impossible if deflection is needed. d-URS. Gallioli et al. [7] reported a change in the indica­ Furthermore, they require the use of a double lumen tion of elective treatment after d-URS in 37/76 (48.1%) ureteroscope or the placement of ureteric access cases (Table 3 [7,25,26]). sheath to allow the insertion of the ureteroscope Given its ability to consistently evaluate tumour because of the consequent lack of irrigation fluid dimension, focality, and growth pattern through direct [20,21] (Table 2 [19–21]). visualisation, and to yield tumour grading via histo­ Kleinmann et al. [19] evaluated the pathological pathology and in situ cytology, URS represents an result obtained in 504 URS-GB performed for suspicion essential tool for risk stratification and case selection of UTUC. The 2.4-F basket device proved to be superior for conservative endoscopic treatment. to the 3-F cup forceps for disease confirmation (94% vs ARAB JOURNAL OF UROLOGY 51 Table 3. Summary of published studies focussed on case selection for conservative endoscopic treatment. Patients, Reference n Purpose of the study Results P Conclusion Golan et al., 116 Evaluation of diagnostic value of Positive urinary cytology PPV and _ RNU was spared in (16/38) 42% of 2015 [25] d-URS in cases suspected for UTUC NPV for UTUC: 47% and 58%. patients. In about half of those and assessment of the impact of Ultrasound PPV and NPV for UTUC: patients UTUC was ruled out and d-URS on the management of 89% and 65%. the others were managed UTUC. CTU (filling defect) PPV and NPV for endoscopically. UTUC: 76% and 80%. CTU (wall thickening) PPV and NPV for UTUC: 67% and 90%. UTUC confirmed at URS: 29/38 (76%) patients with characteristic filling defect on CTU -> d-URS ruled out UTUC in 9 patients. According to tumour characteristics based on URS-GB result, 7/29 patients underwent conservative approach. Tsivian et al., 118 Comparing the results and outcomes Group 1 pathology-confirmed UTUC: 0.347 Routine d-URS study for patients 2014 [26] in a group of patients who 49 (77.8%) 0.011 with suspected UTUC appeared to underwent routine d-URS (Group Group 2 pathology-confirmed UTUC: 0.021 decrease the rate of RNU. 2, n = 55) for suspected UTUC and 47 (85.5%) Moreover, d-URS increased the a group who did not (Group 1, Group 1 RNUs performed: 55 (89%) diagnostic accuracy and reduced n = 63). Group 2 RNUs performed: 38 (69%) the rates of misdiagnosis of UTUC. Group 1 misdiagnosis rate: 9/58 (15.5%) Group 2 misdiagnosis rate: 1/48 (2.1%) Gallioli et al., 208 Analysis of the correspondence URS was positive for UTUC in 107/ <0.001 A filling defect (P < 0.001) or 2020 [7] between imaging, d-URS and 115 (93%), 48/77 (62.3%), 15/27 0.04 hydronephrosis (P = 0.04) were histology for UTUC. (55.6%), 12/25 (48%) in positive, associated with d-URS outcome. suspicious, unlikely and negative The indication of elective CTU, respectively. treatment changed after d-URS in On cyto-histology, UTUC was 37/76 (48.1%) cases. confirmed in 164/182 (90.1%) cases. PPV on CTU was: 87.7% (121/138) for filling defect 65.6% (21/32) for stenosis 69.6% (64/92) for thickening 79.7% (59/74) for hydronephrosis NPV: negative predictive value; PPV: positive predictive value. Table 4. Results of NAC for UTUC in the included studies. Patients, Reference n Purpose of the study Results P Conclusion Lane et al., 336 Evaluate the eligibility to receive neoadjuvant Patients considered eligible to <0.001 Multimodal treatment 2010 [27] or adjuvant CBCC in patients with UTUC. receive CBCC before RNU: 48% strategies for UTUC should Patients considered eligible to consider NAC, as few receive CBCC after RNU: 22% patients were eligible for adjuvant CBCC after RNU. Porten et al., 112 Comparison of the survival rates of patients Group 1 patients: 31 (27.7%) <0.020 As NAC improved survival of 2014 [30] with UTUC who received NAC before Group 2 patients: 81 (72.3%) 0.002 patients with UTUC, surgery (Group 1) with the rates among Group 1, 5-year CSS rate: 90.1% patients with high-risk patients who did not (Group 2). Group 2, 5-year CSS rate: 57.6% UTUC should be Group 1, 5-year OS rate: 80.2% considered for NAC in view Group 2, 5-year OS rate: 57.6% of the limited opportunity to administer effective CBCC after RNU. Tse et al., _ Analysis of molecular predictors of complete The authors analysed molecular _ NAC offered advantages as 2019 [31] response after NAC in UTUC and bladder markers to try to predict the patients have better renal tumours. response to CBCC including function than after RNU. DNA repair genes (ATM, RB1, The use of biomarkers to FANCC, ERCC2, BRCA1, and stratify NAC administration ERCC1), regulators of apoptosis based on predicted (survivin, Bcl-xL, and emmprin), response could be a cost- receptor tyrosine kinases (EGFR effective option, although and erbB2), genes involved in prospective validation was cellular efflux (MDR1 and CTR1), necessary. in addition to molecular subtypes (basal, luminal, and p53-like). CBCC: cisplatin-based combined chemotherapy; OS: overall survival. 52 A. TERRITO ET AL. Table 5. Overview of optical/imaging techniques used during URS inspecting the UUT. Patients, Optical/imaging Patient’s histol­ Imaging modality Specificity Reference n technique ogy (n) technical details Sensitivity (%) (%) Conclusion Traxer et al., 2011 27 NBI UTUC (19) URF-V Olympus digital _ _ NBI for UTUC was [32] Benign (2) flexible a valuable method Invalid biopsy ureteroscope with because it (6) NBI system, 41 nm considerably improved blue light and tumour detection rate 540 nm green light. by 22.7% compared with White light. Emiliani et al., _ SpiesTM system _ White light, Spectra _ _ Clara and Clara + Chroma 2017 [33] A and B, Clara, were ranked as the Chroma, Clara + best SpiesTM Chroma. modalities with better image quality. Bus et al., 2016 26 OCT UTUC (24) C7-XR OCT system, Grading (86.7) Grading OCT, using backscattered [34] pTis-pTa (14) 1300 nm Staging (91.7) (78.6) light instead of back ≥pT1 (12) longitudinal 54 mm Staging reflected sound waves and 360° trajectory (78.6) to produce cross- taking 5.4 s. sectional images, had the potential to provide real-time information on grade and stage in UTUC. Bui et al., 2015 14 CLE UTUC (7) 0.85-mm diameter _ _ Optical biopsy using CLE [35] LG (4) probe, with a depth in the UUT was HG (3) of tissue penetration feasible and provided Benign (7) of 50 µm, field of real-time in vivo view of 320 µm, and microscopy with spatial resolution of sufficient resolution to 3.5 µm. distinguish between benign tissue and UC. Breda et al., 2018 14 CLE UTUC (12) Cellvizio system _ _ The authors found [36] LG (6) (Mauna Kea correspondence HG (5) Technologies). between the CLE CIS (1) images and the final Unknown (2) histopathological results in 7/7 cases of low-grade UTUC (100%), in 5/6 cases of high-grade UTUC (83%), and in 1/1 case of CIS (100%). CIS: carcinoma in situ; HG: high grade; LG: low grade. Case selection for neoadjuvant chemotherapy could in the future provide a molecular fingerprint of Several retrospective studies have shown the promising the disease. It could also provide information regarding role of NAC in the treatment of high-risk locally advanced DNA repair genes, expression of tyrosine kinase receptors, UTUC in comparison to RNU alone [24]. It must always be immune checkpoint inhibitors molecular targets and reg­ borne in mind that deterioration in renal function follow­ ulation of apoptosis; this would allow the medical oncol­ ing RNU may render a patient ineligible for further cispla­ ogist to select the best NAC or immunotherapy for tin-based combination chemotherapy in 49% of cases patients in a truly tailored approach [31]. Table 4 [27], strengthening the role of NAC as opposed to adju­ [27,30,31] summarises the results of NAC for UTUC vant chemotherapy. However, the criteria for candidate based on the included studies. selection remain unclear, although they commonly include high-grade pathology or locally advanced disease New diagnostic technologies to increase diagnostic (cT2–T4N0M0) [28]. accuracy In this setting, URS can provide histopathological diag­ Various new techniques have been developed to nosis, confirm the urothelial nature of the disease, and enhance diagnostic accuracy and risk stratification, yield information about its grade, which has been shown including narrow-band imaging (NBI), the Storz profes­ to correlate with a higher stage and worse outcomes [29]. sional imaging enhancement system (IMAGE1S), opti­ Furthermore, it helps candidate selection by detecting cal coherence tomography (OCT), and confocal laser the presence of high-risk features such as high-grade endomicroscopy (CLE) (Table 5 [32–36]). tumour sessile growth patterns or large tumour bur­ Traxer et al. [32] reported a 22.7% increase in the dens [30]. tumour detection rate in the UUT when using NBI In the challenge to select those patients who will compared with white light. Emiliani et al. [33] reported respond to NAC, the retrieval of a biopsy specimen CLARA and CLARA+CHROMA to offer better quality ARAB JOURNAL OF UROLOGY 53 Table 6. Intra- and postoperative complications rate reported in the studies included in our review during operative URS. Patients, Postoperative complications Reference n Intraoperative complications reported N (%) reported n/N (%) Traxer et al., 2013 [42] 359 Ureteric wall injuries resulting from insertion of 311 Pyelonephritis 6/311 a UAS (86.6) Pyelonephritis (1.93) Grade 0 (no lesion) and 1 (mucosal erosion 37 (10.3) 4/48 (8.33) without smooth muscle injury) 11 (3.1) Grade 2 (involvement of smooth muscle without 0 (0) adventitial) Grade 3 (adventitial perforation without ureteric avulsion) Grade 4 (total ureteric avulsion) Schoenthaler et al., 2014 100 Ureteral trauma (according to PULS) 43 (43) _ _ [43] Grade 0 (insignificant lesion) 44 (44) Grade 1 (superficial mucosal lesion) 13 (13) Grade 2 (submucosal lesion) and 3 (perforation with less than 50% partial transection) Whitehurst et al., 2017 [38] 8929 _ Perirenal haematoma 40 (0.45) Somani et al., 2017 [39] 11,885 Bleeding 167 Bleeding 54 (0.45) Perforation (1.41) Fever 204 (1.72) Failed access 124 UTI 113 (0.95) Conversion (1.05) Sepsis 36 (0.30) Other 198 Pain 39 (0.33) Mucosal injury (1.67) Urinary retention 13 (0.11) Infection 19 (0.16) Stent misplacement 12 (0.10) 177 Other 39 (0.33) (1.49) 15 (0.13) 8 (0.07) Baş et al., 2017 [40] 1395 Mucosal injury 37 (2.35) Fever 84 (5.35) Malfunctioning or breakage of instruments 2 (0.13) Bleeding 25 (1.59) Bleeding 40 (2.55) UTI 42 (2.67) 5 (0.32) Stent migration 11 (0.70) Perforation 9 (0.57) Ureteric stricture 2 (0.13) Other 12 (0.76) Severely bleeding PULS: post-ureteroscopic lesion scale; UAS: ureteric access sheath. Table 7. Summary of included studies analysing cancer dissemination. Patients, Survival analysis or difference between groups Reference n Treatments, (n) Surgical approach analysed P Hendin et al., 1994 [46] 96 RNU or DU (-URS) (48) RNU or DU with Metastases developed in RNU or DU (-URS) 0.58 URS + RNU or DU (48) bladder cuff group: 9 (18.8%) 1.00 Metastases developed in URS + RNU or DU 0.25 group: 6 (12.5%) 0.75 Death for metastases in RNU or DU (-URS) group: 5 (10.4%) Death for metastases in URS + RNU or DU group: 5 (10.4%) 5-year MFS in RNU or DU (-URS) group: 71% 5-year MFS in URS + RNU or DU group: 67% 5-year OS in RNU or DU (-URS) group: 76% 5-year OS in URS + RNU or DU group: 87% Ishikawa et al., 2010 [47] 208 RNU (-URS) (153) RNU (165 open, 43 2-year bladder RFS in RNU (-URS) group: 58.7% 0.972 URS + RNU (55) laparoscopic) 2-year bladder RFS in URS + RNU group: 60% 0.069 5-year CSS in RNU (-URS) group: 78.1% 5-year CSS in URS + RNU group: 88.3% Gurbuz et al., 2011 [48] 1268 ETA + RNU (175) RNU (970 open, 298 ETA + RNU 5-year RFS and CSS rates: 72% and 0.171 RNU without previous ETA laparoscopic) 77% 0.365 (1093) RNU without previous ETA 5-year RFS and CSS rates: 69% and 73% DU: distal ureterectomy; ETA: endoscopic tumour ablation; OS: overall survival. compared with white light and other IMAGE1S low-grade UTUC, respectively, and in one out of one modalities. case of carcinoma in situ. OCT might enhance the staging accuracy of d-URS. Bus et al. [34] reported concordance of lesion staging with OCT and final histopathology in 83% of cases. Cons CLE provides real-time in vivo microscopy of tis­ Risk of complications sue, allowing the distinction between benign tissue During URS, lesions of the UUT can occur, ranging from and UTUC [35]. Breda et al. [36] reported concor­ mucosal abrasion to false passage, perforation and fluid dance between CLE images and final histopatholo­ extravasation, intussusception, and ureteric avulsion gical results in 100% and 83% of cases of high- and [37]. Bleeding is usually self-limited; nevertheless, life- 54 A. TERRITO ET AL. Table 8. Overview of IVR after URS prior to RNU in the included studies. Patients, Median/mean follow- NAC/adjuvant Reference n Treatments (n) IVR rate (%) up, months Bladder cuffing therapy pT stage: % Grade (%) Conclusion Ishikawa et al., 2010 208 RNU (-URS) (153) RNU (-URS) group 44 Yes No Ta–CIS: 19.7 T1: 28.4 LG (68.3) The 2-year bladder RFS rate between the two [47] URS + RNU (55) (41.3) T2: 21.2 HG (31.7) groups was not significantly different URS + RNU group (40) T3: 26.9 (P = 0.972). T4: 3.8 Lee et al., 2018 [54] 502 RNU (-URS) (296) 138 patients (27.5) 76 Yes No Ta–CIS: 14.1 LG (22.1) URS-GB performed before RNU did not appear to URS + RNU (206) T1: 26.1 HG (77.9) be a prognostic factor of IVR (P = 0.609). T2: 25.3 T3: 28.7 T4: 5.8 Sung et al., 2015 [55] 630 RNU (-URS) (348) RNU (-URS) group 34.3 Yes 128 patients Ta: 17.3 I–II (55.1) URS was associated with increased IVR rate URS + RNU (282) (36.4) (20.3%) T1: 24.3 III (44.9) following RNU. Prior bladder tumour history, URS + RNU group T2: 16.3 multifocal UTUC, and extravesical cuff (57.4) T3–T4: 42.1 excision were also predictors of IVR. Lee et al., 2016 [56] 104 RNU (-URS) (30) RNU (-URS) group 37.0 _ No T ≤ 1: 38.8 T2: 45.6 LG (24) Delay of RNU after URS significantly increased URS + RNU (74) (16.7) 29.6 T3: 15.6 HG (76) IVR in patients with UTUC. Performing URS URS + RNU I session 36.4 and RNU in one session was preferable. group (24.2) URS + RNU II session group (51.2) Yoo et al., 2017 [57] 387 RNU (-URS) (318) RNU (-URS) group in 62 Yes No Ta–T1: 53.5 T2: 17.6 LG (50.6) URS-GB was a significant risk factor for IVR in URS + RNU (69) RPT (37.8) T3–T4: 28.9 HG (49.4) patients with RPT but not for UT. So that URS- RNU + URS group in GB should only be performed for suspected RPT (60.4) RPT. RNU (-URS) group in UT (54.2) RNU + URS group in UT (63.3) *CIS: carcinoma in situ; ETA: endoscopic tumour ablation; HG: high grade; LG: low grade; RPT: renal pelvic tumour; UT: ureteric tumour. ARAB JOURNAL OF UROLOGY 55 Table 9. Overview of delay in radical treatment and reported outcomes. Patients, Reference n Treatments (n) Survival analysis or difference between groups analysed P Conclusion Nison et al., 512 RNU (-URS) (342) Median treatment time in RNU (-URS) group: 44.5 days 0.04 Despite the increased time to 2013 [61] URS + RNU (170) Median treatment time in URS + RNU group: 79.5 days 0.23 radical surgery, URS could be 5-year CSS did not differ between RNU (-URS) and URS 0.89 systematically performed to + RNU group 0.35 refine the therapeutic strategy 5-year RFS did not differ between RNU (-URS) and URS + without significantly affecting RNU group oncological outcomes. 5-year MFS did not differ between RNU (-URS) and URS + RNU group Boorjian et al., 121 RNU (-URS) (34) Median FU in RNU (-URS) group: 38.7 months 0.73 URS and/or ETA were not 2005 [62] URS + RNU (75) Median FU in URS + RNU group: 40.1 months 0.99 associated with an increased URS + ETA + RNU Median FU in URS + ETA + RNU group: 37.2 months 0.16 frequency of adverse tumour (12) 23/34 patients of the RNU (-URS) group had Ta or T1 pathological features, and tumours neither the tumour grade nor 49/75 patients RNU + URS group had Ta or T1 tumours stage at RNU was significantly 8/12 patients of the group URS + ETA + RNU had Ta or different among the groups. T1 tumours URS and/or laser ETA before RNU 29/34 (85.3%) patients of the RNU (-URS) group had no did not significantly affect the evidence of disease at last FU postoperative outcomes. 61/75 (81.3%) patients of the RNU + URS group had no evidence of disease at last FU 10/12 (83.3%) patients of the URS + ETA + RNU had no evidence of disease at last FU Gurbuz et al., 1268 ETA + RNU (175) ETA + RNU 5-year RFS and CSS rates: 72% and 77% 0.171 In selected patients, ETA did not 2011 [48] RNU without RNU without previous ETA 5-year RFS and CSS rates: 0.365 adversely affect the recurrence previous ETA 69% and 73% and survival after subsequent (1093) RNU for UTUC. ETA: endoscopic tumour ablation; FU: follow-up. threatening haemorrhagic complications and perirenal a multi-institutional study of 208 patients, found the haematoma formation have been published as a result 5-year cancer-specific survival (CSS) to be comparable of forniceal or renal parenchyma rupture [38]. in the d-URS and control groups (88.3% vs 78.1%). Among the early postoperative complications, UTI Gurbuz et al. [48] explored the recurrence-free survival has been reported in 1–2.6% of cases, with severe (RFS) of patients with and without d-URS prior to RNU sepsis in 0.06–0.3% [39,40], the latter probably linked and found comparable results at 5-year follow-up (72% to the development of high intrarenal pressures during vs 69%; P = 0.17). the procedure [41]. Local oedema, ureteric spasm, or Guo et al. [49] published a meta-analysis that con­ blood clot can lead to acute obstruction of the UUT firmed the above findings. Despite the paucity of data and renal colic. VUR may occur after URS, but the use of and the retrospective design of all the eight studies small-calibre flexible and semi-rigid ureteroscopes has included, the authors concluded from that meta-analysis obviated ureteric dilatation in most cases and has likely that URS is not associated with overall survival, MFS, or reduced the incidence of reflux overall [37]. RFS. Table 7 [46–48] summarises the results of the studies Ureteric strictures can occur as a late postoperative concerning cancer dissemination included in the review. complication subsequent to ureteric lesions. Although the incidence of strictures has been reported to be Bladder recurrence <1% [39,40], the use of post-ureteroscopic lesion scores has revealed the incidence to be considerably In recent years, the risk of intravesical recurrence (IVR) higher [42,43] (Table 6 [38–40,42,43]). after URS prior to RNU has been addressed. The hypothesis is that the manipulation of the uretero­ Cancer dissemination scope and the irrigation back-flow may increase the The potential role of URS in cancer dissemination was risk of or seeding [45]. Audenet et al. [50] showed that initially explored by Kulp et al. [44] in 1994, who the majority of bladder tumours following RNU are reported on a series of 13 patients who underwent clonally related, supporting the hypothesis that IVR is URS prior to RNU. In the surgical specimens, no tumour caused by neoplastic cell implantation rather than cells were noted in vascular or lymphatic spaces. being a second primary tumour. Conversely, Lim et al. [45] described a case of suspi­ Two meta-analyses have summarised the current cious lymphatic invasion that the authors attributed to evidence. Marchioni et al. [51] found an IVR rate of high intrarenal pressures during URS. 39.2–60.7% and 16.7–46% in patients with and without Comparing patients with and without d-URS, URS prior to RNU, respectively. The pooled analysis Hendin et al. [46] found no significant differences in found a significant association between URS and IVR overall 5-year survival (87% vs 76%,) or metastasis-free (hazard ratio [HR] 1.56; P < 0.001). Guo et al. [49] survival (MFS) (67% vs 71%). Ishikawa et al. [47], in similarly found that IVR rates were lower in patients 56 A. TERRITO ET AL. without a history of bladder cancer who underwent Conclusions URS (HR 1.81). The main limitations of these two meta- A d-URS is an extremely valuable tool in cases of analyses are the retrospective design of all the suspected UTUC, especially when the diagnosis is equi­ included studies, the lack of data about the URS, and vocal or when KSS can be considered. Although nowa­ the bladder cuff management technique [52] with no days URS can be considered a safe procedure, it is not postoperative administration of mitomycin C [53]. without risks, some of which can endanger the Conversely, Ishikawa et al. [47] found that IVR at patient’s life. Risks can be related to the presence of 2-year follow-up was comparable (60% vs 58.7%) in neoplastic disease, which translates into the potential patients who underwent URS prior to RNU and con­ risk of bladder recurrence, cancer dissemination, and/ trols. Similar results were reported by Lee et al. [54]. or delays in radical treatment. Some technical devices Sung et al. [55] found that the interval between URS or precautions can aid in obtaining correct informa­ and RNU does not seem to affect the IVR rate, while Lee tion, above all concerning the grade of the disease. The et al. [56], reported that patients who underwent URS latest techniques such as NBI, IMAGE1S, CLE, and OCT and RNU in a single session had an IVR comparable to can also provide information of value in optimising that in a non-URS group. patient selection for KSS. NAC could represent an ‘ace Yoo et al. [57] found the IVR rate to be significantly up our sleeve’, but accurate staging and grading higher in patients with renal pelvic (but not ureteric) remain crucial for appropriate therapeutic decision tumours who underwent URS-GB prior to RNU (60.4%; making, and d-URS can be of decisive importance for HR 2.06; P = 0.01). A possible explanation is that the this purpose. endoscopic manipulation could have increased the shedding of cancer cells from the renal pelvis into the bladder. Table 8 [47,55–58] summarises the results of Disclosure statement bladder recurrence for UTUC based on the included studies. No potential conflict of interest was reported by the authors. 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