Nephron-Sparing Surgery for Upper Urinary Tract Urothelial Carcinoma

Sung Han Kim; Ilma S. Savul; Seth P. Lerner

doi:10.22465/juo.244600180009

J Urol Oncol > Volume 22(1); 2024 > Article

Kim, Savul, and Lerner: Nephron-Sparing Surgery for Upper Urinary Tract Urothelial Carcinoma

Invited Review

Bladder Cancer

Journal of Urologic Oncology 2024; 22(1): 68-77.

Published online: March 31, 2024

DOI: https://doi.org/10.22465/juo.244600180009

Nephron-Sparing Surgery for Upper Urinary Tract Urothelial Carcinoma

Sung Han Kim

, Ilma S. Savul

, Seth P. Lerner

Scott Department of Urology, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

Corresponding author: Seth P. Lerner Scott Department of Urology, Beth and Dave Swalm Chair in Urologic Oncology, Vice-Chair for Faculty Affairs, Baylor College of Medicine Medical Center, 7200 Cambridge, MC BCM380, Houston, TX 77030, USA Email: slerner@bcm.edu

Received February 16, 2024 Revised March 19, 2024 Accepted March 20, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Radical nephroureterectomy (RNU) remains the gold standard for the surgical management of upper tract urothelial carcinoma (UTUC) from the ureterovesical junction to the renal pelvis. However, the removal of the ipsilateral intact kidney causes morbidity due to renal functional deterioration after RNU. Recently, the indications for nephron-sparing surgery (NSS) in UTUC have been expanded to preserve the intact kidney. Minimally invasive surgical approaches, including endourological, laparoscopic, and robotic-assisted techniques for segmental resection of the distal ureter with ureteral reimplantation have shown favorable oncological and clinical outcomes (for both noninvasive and invasive ureteral tumors). The established guidelines for UTUC have limited indications for NSS. Because of low tumor burden, stage Ta/T1 UTUC is considered the best indication for NSS. NSS requires close follow-up and managing the risk of recurrence in the preserved ipsilateral ureter and/or renal pelvis. To overcome these limitations, adjuvant administration of various immuno-chemotherapeutic agents is being explored to overcome the resistance to therapeutic cell death and evasion of immune destruction from current therapies with better prognostic outcomes. The aim is to reduce urothelial cancer recurrence improving the effectiveness of NSS and to achieve comparable outcomes to RNU in UTUC. In this review article, we have comprehensively discussed the different types of NSS in UTUC, the indications for NSS in the international guidelines, and oncological outcomes of each of the NSS techniques.

Key Words: Urologic neoplasms, Transitional cell, Endoscopy, Ureteral neoplasm, Ureteroscopy

INTRODUCTION

Upper tract urothelial carcinoma (UTUC) is relatively uncommon, and accounts for only 5%-10% of all urothelial tract tumors. The annual incidence of UTUC in Western countries is estimated to be approximately 2 cases per 100,000 individuals [1]. At present, due to improved detection techniques and better survival outcomes of patients with bladder cancer, the rate of detection of UTUC has increased. However, despite these advancements, approximately twothirds of patients with UTUC have progressed to invasive disease at the time of initial diagnosis [2].

To improve survival outcomes of patients with UTUC, the current guidelines emphasize prevention and early diagnosis of UTUC at both the individual and population levels [3]. The standard treatment of high-risk UTUC is open radical nephroureterectomy (RNU) with simultaneous complete bladder cuff excision [1]. However, with the emergence of improved endoscopic technology, it has become feasible to manage UTUC by removal of the intraureteral tumor itself endoscopically or percutaneously by partial ureterectomy, while preserving the kidney [4]. The advancements in endoscopic management and adjuvant intraureteral instillation regimens have provided an incentive over RNU as endoscopic management protects against loss of kidney function, which is associated with the aggressive surgical approach.

Nephron-sparing surgery (NSS) is the surgical concept of preserving the kidney and removing only the tumor or the affected ureteral segment. It has become an alternative to RNU in UTUC, which avoids renal functional deterioration that occurs after RNU in patients with solitary kidneys, bilateral disease, or renal insufficiency. Clinicians are now encouraged to use NSS with achievable success by applying the endoscopic approach [4]. NSS provides the advantage of reducing postoperative complications as it shortens the operation time and length of hospital stay without affecting survival, especially in older patients [5]. The wide array of NSS includes endoscopic ablation and surgical techniques using robot-assisted segmental ureterectomy (SU) [6]. Despite heterogeneous patient and tumor characteristics, several retrospective series and systemic reviews have consistently demonstrated comparable and acceptable oncologic outcomes after SU and standard RNU in terms of overall survival (OS), 3- and 5-year cancer-specific survival (CSS), and intravesical tumor recurrences, emphasizing SU as the first-line treatment for low-risk UTUC [7-10]. In this review, we have discussed the diverse surgical techniques of NSS and their recommended indications and surgical outcomes.

INDICATIONS IN THE RECOMMENDED GUIDELINES

There are concerns regarding tumor recurrence within the remnant UTUC with NSS. However, recent evidence on the outcomes of NSS in individuals suitable for these techniques is less controversial, leading to the establishment of several guidelines for using NSS for UTUC management [7,11]. These guidelines highlight risk stratification based on several clinicopathologic characteristics to assist in clinical decision-making. However, these guidelines are derived from evidence-based suggestions for selecting patients suitable for NSS based on (1) stratifying tumors into low- and highrisk of progression to identify patients who are more likely to benefit from NSS versus RNU. (2) In real practice, as tumor staging is difficult to perform clinically in patients with complex UTUC, about half of the urologists still perform endoscopic NSS without adhering to the guidelines of tumorgrade recommendations. NSS using endoscopic surgery was recommended even in patients with high-risk multifocality, with multiple studies providing evidence that low-grade multifocal UTUC was not related to progression-free survival [12,13].

Globally, NSS is indicated for patients with low-risk UTUC, especially those with a single-functioning kidney, chronic renal failure, or bilateral disease, irrespective of the status of the contralateral kidney, although RNU is considered the best surgical modality for UTUC [7,11]. The National Comprehensive Cancer Network (NCCN) guidelines 2024 v1.0 stratify UTUC based on favorable or unfavorable clinical and low and high-grade pathological criteria, including tumor size, grade, focality, and invasiveness for nephron preservation [11,14,15]. Favorable cases include low-grade tumors based on cytology and biopsy, papillary architecture, tumor size <1.5 cm, unifocal tumor, and crosssectional imaging showing no concerns of invasive disease. Less favorable cases include multifocal tumors, flat or sessile tumor architecture, tumor size ≥1.5 cm, high-grade tumors, cT2-T4 tumors, midureteral and proximal ureteral tumors (due to technical challenges), and tumors crossing the infundibulum or ureteropelvic junction.

The European Association of Urology (EAU) guidelines stratify UTUC patients into “low risk” and “high risk” according to tumor focality, size, grade, variant histology, clinical stage on computed tomography (CT), and hydronephrosis based on clinical, endoscopic, radiographic, and histopathologic factors [16]. Low-risk cases include unifocal disease, tumor size <2 cm, low-grade cytology and/or ureteroscopic (URS) biopsy, and noninvasive disease on imaging. High-risk cases include hydronephrosis, multifocal disease, tumor size ≥2 cm, high-grade cytology and/or URS biopsy, invasive disease on imaging, and prior radical cystectomy. Although it may be feasible to treat high-grade tumors with NSS endoscopically, it is not in line with either the NCCN or EAU guidelines, or the common practice of most urologists [17].

The main concerns about NSS are related to more procedures requiring stringent endoscopic surveillance, residual tumors, recurrence, disease progression, and the burden of repeat treatments. Urologists are getting more inclined towards endoscopic management, especially for patients with low-grade UTUC as research has proven that it reduces morbidity, such as the loss of kidney function associated with RNU without compromising the oncological outcomes, including CSS and OS, which were equivalent to those with RNU [7]. NSS is valuable for high-grade UTUC, predominantly in patients with imperative indications for NSS, who possess unfavorable factors for an invasive surgical approach, and those requiring palliative treatment [18]. Thus, patients with UTUC who will benefit from NSS have to be identified along with formulating an efficient follow-up strategy for surveillance.

IMPORTANCE OF THE DIAGNOSTIC MODALITY

The diagnostic precision of UTUC within the ureter segment is crucial for choosing the optimal NSS option of either open surgery or endoscopic surgery. An accurate determination of the tumor grade and stage enables successful NSS. Nevertheless, tumor staging is difficult in UTUC because of the difficulty in assessing the tumor depth and stage, especially with ureteroscopy [19]. Consequently, tumor grade is routinely used to approximate staging given the association between high-grade pathology and invasive disease [20].

Diverse diagnostic methods for UTUC include endoscopic modalities, biopsy, and cytologic techniques. Flexible ureteroscopy is essential and enables direct visualization of the tumor and specimen retrieval [21]. Optical coherence tomography and confocal light endomicroscopy offer visual means for tissue diagnosis with high sensitivity and specificity for tumor invasion, and staging concordance with the final histopathology [22]. Barbotage cytology is another important tool to rule out high-grade UTUC and has been shown to be an equally efficient tool in detecting cancer compared to histological biopsy if the lower urinary tract has been completely evaluated and determined to be cancer negative [23].

In UTUC, there is difficulty in determining the pathological stage based on the biopsy grade for selecting the appropriate surgical option [24]. The smaller tissue size and individualized morphology of UTUC necessitates different biopsy approach strategies, and various new biopsy techniques and equipment have been introduced and improved, such as sheath, forceps, light, and magnifying scope for better acquisition of tissues, higher yielding rate, and greater accuracy [18,19]. For example, basket devices can be used to debulk large amounts of tissue and provide an accurate diagnosis for large papillary lesions; the flat-wire basket was shown to be the most accurate device, with a diagnosis rate of 94% and grade determination rate of 93% [8], whereas forceps devices may be preferable for smaller, sessile, or nonpapillary lesions [9].

PROGNOSTIC OUTCOMES OF NSS AND RNU

No randomized studies have compared NSS and RNU, and most of the relevant studies encompassed fewer than 100 patients, with mostly small-sized, low-grade tumors. A meta-analysis of 8 published retrospective studies reported that endoscopic NSS had similar OS and CSS to RNU using pooled data of 1,002 patients with organ-localized UTUC [25]. Systemic reviews of retrospective studies have also reported consistent conclusions based on heterogeneous evidence that NSS has comparable survival outcomes to RNU in low-risk patients or patients with favorable disease criteria [7,9,16,17,26,27]. Recurrence of UTUC is common and occurs in most patients, which mandates regular surveillance [28]. Thus, the risks of poor oncologic control and tumor progression with endoscopic management must be weighed against the perioperative risks, such as poor life expectancy associated with end-stage renal failure and consequent hemodialysis, which are associated with RNU [28]. Thus, the endoscopy-based approach is indicated for compliant patients who will adhere to a strict follow-up regimen [9].

SURGICAL MODALITIES

1. Segmental Ureterectomy

NSS comprises several surgical techniques: endoscopic resection and SU with ureteroureterostomy or ileal ureter substitution or distal ureterectomy. The fundamental principles for SU have not been standardized yet; however, they include atraumatic, “no-touch” ureteral dissection, identification of the limits of the ureteral tumor (with or without the use of concomitant ureteroscopy), isolation of the affected ureteral segment to prevent tumor spillage [29], and tumor resection with adequate (1-2 cm) safety margins considering the patient’s underlying comorbidity and tumor grade, size, and stage, along with negative frozen biopsy of the remaining tumor within the ipsilateral ureter [30]. If a wide margin with SU has been achieved, it gives favorable perioperative, functional, and oncologic outcomes, provides accurate pathologic staging and grading, and completely preserves ipsilateral renal function [6,31-33].

SU was shown to have acceptable oncological results regarding local, metastatic, and bladder recurrence, similar to those of RNU [34]. A study of 3,061 patients with UTUC from The National Cancer Database showed SU as a valid surgical method that did not meaningfully sacrifice oncologic control in appropriately selected patients with UTUC [35]. Tumor recurrence rate in the urinary tract, including the ipsilateral ureter, after SU was between 4.1% and 7%, with a mean time to procedure of 33.3-54 months [36,37]. A recent propensity-matched study reported a recurrence rate of 6.8% for distal ureterectomy and bladder cuffing [38].

The NCCN and EAU guidelines have highlighted SU with distal ureterectomy with concomitant ureteroneocystostomy or segmental ureteral resection with ureteroureterostomy as the most radical approach for distal ureteral tumors [7,11]. The most “radical” and extirpative way of performing SU would be a complete ureterectomy with ileal ureter replacement with/without lymphadenectomy of which the degree and implementation of bladder cuffing have not been clearly described [17,39].

For proximal and midureteral tumors, ureteroureterostomy is the simplest alternative to SU, but no guidelines recommend SU as the primary treatment option [8,9,29]. Especially, SU for tumor in the proximal two-thirds of the ureter is associated with high failure rates than for distal ureter tumor [10,40]. Therefore, distal ureterectomy with ureteroneocystostomy is indicated for low-risk tumors in the distal ureter that cannot be removed completely endoscopically [10].

For high-risk cancer with an imperative indication, distal ureterectomy with/without lymph node dissection could be an alternative option, provided it is low grade [8,9,29]. The EAU guidelines recommend complete distal ureterectomy with neocystostomy with/without lymph node dissection for high-risk distal tumors [16], whereas the NCCN guidelines selectively recommend distal ureterectomy with ureteral reimplantation and regional lymphadenectomy for highgrade tumors only in the distal ureter [8,9,14].

Indeed, the standard surgical management for the highgrade UTUC is RNU and the role of lymph node dissection during RNU has not accumulated sufficient evidence to support its adherence to the guideline recommendation recommended in real-world practice [11,14,41]. However, the role of lymph nodal dissection (LND) during RNU for high-grade UTUC improves lymph node staging and prognostication in order to identify patients who may benefit from adjuvant treatment. Patients who underwent LND have better disease-free survival, CSS and OS compared with those who did not. In addition, the pathological node positivity (pN+) is associated with poor survival outcome compared with pN0 and higher number of lymph nodes removed is associated with improved CSS and OS, even in pT0 patients [42-46].

2. Endoscopic Surgery

The ureteroscopic resection of intraureteral tumors is performed to preserve the upper urinary tract (UUT) above the tumor. The existing approaches of endoscopic surgery for intraluminal UTUC are either retrogradely through the distal urethra or by a percutaneous anterograde approach via the renal parenchyma. The principal advantage of the percutaneous approach is the ability to use larger-diameter endoscopic resectoscopes for more efficient resection and debulking of the tumor [11,20]. For tumors located in the lower caliceal system that are inaccessible or difficult to manage even with flexible ureteroscopy, percutaneous (anterograde) access can be utilized. The disadvantages of the percutaneous approach include a higher complication rate of up to 30% including transfusion, renal failure, and emergency nephrectomy or angioembolization [28]. It is also associated with greater invasiveness of renal parenchyma with a higher risk of tumor seeding along the nephrostomy tube, compared to the retrograde approach [11,47,48].

Endoscopic surgery comprises an initial debulking with a cold cup or basket, followed by ablated cauterization via electricity or laser [8,9,14,29,49,50]. Laser is more recommended because of complete achievable tumor resection or destruction [16], and lesser risk of ureteral stricture [19,21,51]. A frequently used energy source, named holmium yttrium aluminum garnet (Ho:YAG), provides an achievable safety depth of penetration (<0.4 mm) for surgical ablation of UTUC. However, for high-grade disease secondary to imperative indications (i.e., solitary renal unit, baseline renal insufficiency, inability to tolerate surgery) for endoscopic surgery, a median OS of 29.2 months with a 2-year OS rate of 54% were not superior compared to those with other surgical modalities [52].

Endoscopic management for UTUC differs from RNU in several aspects, such as the approach, either antegrade or retrograde. Larger tumors, low-grade UTUC in the renal pelvis (>1.5-2.0 cm), and tumors in the lower caliceal system should be preferably managed with an anterograde approach by obtaining a percutaneous tract through the kidney parenchyma because of the difficult access and management via flexible URS [7,11]. Regarding percutaneous access with endoscopic management, stringent surveillance is necessary because of the risk of disease progression [53,54] and tumor seeding [55], despite various studies showing comparable and equivalent efficacy of endoscopic resection and RNU in terms of disease-specific and OS in patients with low-grade UTUC [52,56-58].

The classic retrograde approach by using a ureteroscope is good for small-sized tumors in the distal ureter [21]. Middle and distal ureter tumors are generally accessed using semirigid URS. The recent popularity of flexible devices has enabled access to middle and distal ureter tumors via retrograde endoscopic ablation to obtain maximal debulking of the tumor within the ureter [16,39]. The percutaneous approach with a resectoscope through the renal parenchyma and electrocautery with adequate energy generators such as Ho:YAG laser and Nd:YAG (neodymium-doped yttrium aluminum garnet) laser was performed successfully for large tumors >2 cm due to the high rate of ipsilateral recurrence and risk of tumor seeding [49,55,59]. Scotland et al. [23] showed a 90.5% ipsilateral recurrence rate for retrograde endoscopic treatment of tumors larger than 2 cm, with an OS of 75% and CSS of 84% in a 5-year follow-up. However, other studies have shown that retrograde endoscopic treatment is feasible with good oncologic outcomes even for tumors larger than 2 cm and multifocality when the tumor is low-grade with a progression-free rate of 93.2% in a median follow-up of almost 2 years [50].

3. Robot-Assisted Laparoscopic Segmental Ureterectomy

Endoscopic minimal invasive surgery has been applied to UTUC using robot-assisted laparoscopic SU (RALSU) [60-62]. Patients with a low-grade distal ureteral tumor, impaired renal function, and high-grade distal UTUC are ideal candidates for SU with ureteral reimplantation, as well as RALSU [28,47,63,64]. The required reduction in the length of the ureter for optimal oncological results is challenging during SU for UTUC. Still, robotic surgery with 3-dimensional magnified instrumental view helps to overcome these limitations of conventional laparoscopic and open approaches by the application of tension-free ureteral reimplantation procedures for reconstruction after SU. Several reports have proven the feasibility of RALSU with acceptable oncological outcomes, including surgical morbidity [39,60,61,65,66]. Furthermore, the safety and feasibility of the reimplantation and anastomosis techniques has also been demonstrated [61]. Robot-assisted ureteric reimplantation with Boari flap (RABFUR) and psoas hitch (RAPHUR) have shown favorable 1-year outcomes. However, it is worth noting that robotic surgical procedures require a high level of experience similar to laparoscopy, and the learning process is vital for patient safety as well as the oncological outcome of RALSU [67].

4. Laparoscopic Segmental Ureterectomy

Similarly to RALSU, laparoscopic segmental ureterectomy (LSU) is an alternative surgical option for distal ureteral tumors in a setting where robot laparoscopy is not available [62,68,69]. Not many groups have performed LSU because laparoscopic nephroureterectomy has been the preferred surgical option for UTUC. No consensus has been achieved yet on the preferred surgical technique for LSU; however, several research groups have established the safety profile and feasibility of LSU with psoas hitch ureteral reimplantation for distal UTUC, including optimal perioperative, renal functional, and oncologic outcomes [68].

5. Intravesical Instillation Therapy

Endoscopic treatments offer acceptable outcomes for patients with low-grade/low-volume disease despite a higher rate of ipsilateral remnant ureteral recurrence compared to RNU (15%-90% vs. 3%-33%) [9]. Therefore, intraluminal instillation of adjuvant agents into the UUT has been attempted to reduce the likelihood of tumor recurrence in the ipsilateral renal pelvis and ureter while preserving renal function [67,70].

A systematic review and meta-analysis assessing the oncological outcomes of patients with papillary UTUC or carcinoma in situ (CIS) of the UUT treated with NSS and adjuvant intraluminal treatment found no difference between the drug administration methods (antegrade vs. retrograde vs. combined approach) in terms of recurrence, progression, CSS, and OS. The recurrence rates following adjuvant instillations were comparable to those reported in the literature for untreated patients, calling their efficacy into question [71].

Bacillus Calmette-Guerin (BCG) has been the best-studied adjuvant therapy despite the uncertainty regarding its dosage and mechanism of action as intraluminal therapy for UTUC because of variable institutional results [27,71]. It has been recommended for papillary tumors and CIS by the non- muscle-invasive bladder cancer guidelines [9]. Carmignani et al. revealed that an induction course of BCG in CIS could convert positive cytology to negative with a mean recurrence rate of 32% at 19 to 57 months follow-up [72].

Mitomycin C (MMC) is another reported adjuvant intraluminal agent [12,73]. A study of 28 patients with UTUC stage Ta,/T1 tumors receiving postoperative intraluminal MMC showed 3-year recurrence-free, progression-free, nephrouretectomy-free, and OS rates of 60%, 80%, 76%, and 92.9%, respectively [73]. Another series of 20 patients with low-grade UTUC receiving MMC therapy showed a recurrence-free survival of 65% at a mean follow-up of 24 months without any postoperative renal impairment [74].

Jelmyto (UGN-101, formerly MitoGel, UroGen Pharma, Israel) is an enhancing gelatinous form of the MMC matrix that achieves more sustained contact with the UUT. A single-arm phase 3 trial using UGN-101 instillation in a chemoablation setting via a retrograde catheter in the renal pelvis and calyces showed significantly promising results, with complete response in 42 patients (59%) with lowgrade UTUC (<15 mm), among which 52% of the patients sustained complete remission for 12 months, with an estimated durability rate of 82% [70,75].

FOLLOW-UP

The aims of follow-up after either SU or endoscopic surgery for UTUC are to detect locally recurrent or new primary tumors within the remnant urothelium, including the bladder, and to detect regional and distant metastases based on the individual patient’s NSS type and tumor characteristics. Importantly, endoscopic management has a risk of understating and undergrading UTUC with a higher risk of recurrences [16]. Therefore, thorough ureteroscopy and UUT imaging at 3- to 12-month intervals should be considered [14,16].

A more frequent and stricter follow-up regimen than that for RNU should be planned with prolonged surveillance of the ipsilateral ureter via cystoscopy, ureteroscopy, and urine cytology. The EAU guidelines recommend these follow-up modalities every 3 and 6 months, then every 6 months for 2 years, and annual investigations thereafter for the remnant ureter, including annual CT or ureteroscopy [16]. The NCCN guidelines recommend imaging of the upper tract collecting system or ureteroscopy at 3- to 12-month intervals and radiologic evaluation including abdominal/pelvic CT or magnetic resonance imaging with or without contrast, and chest imaging after NSS. Long-term surveillance 5 years after NSS includes urine cytology, radiologic evaluation of the UUT, and endoscopic inspection due to the high risk of disease recurrence [14].

For low-risk tumors without any upstaging and upgrading, an early second-look ureteroscopy should be scheduled after 6-8 weeks of NSS [53], with cystoscopy and CT urography at 3 and 6 months, and then yearly for 5 years [76]. For highrisk tumors, the surveillance regimen might be influenced by the consequences of recurrent disease. The ipsilateral UUT still requires careful and long-term follow-up owing to the high risk of disease recurrence [77] and progression, even beyond 5 years [78]. Stage pT0 or pT1 tumors should be followed up with serial cystoscopies at 3-month intervals for the first year and longer intervals in case of a negative test.

CONCLUSION

NSS has some advantages over standardized RNU in UTUC, as nephron sparing prevents major postoperative morbidity, such as renal functional deterioration. The advanced technologies of NSS have expanded the surgical indications for UTUC despite the existing limitations of intraureteral detection and identification of tumor staging with a risk of under-staging and grading of UTUC. However, NSS has demonstrated comparable efficacy to RNU in terms of oncological outcomes of low-volume/low-grade UTUC. Furthermore, the improved efficacy of endoscopic surgery and SU have expanded the indications of UTUC, although the current guidelines still suggest a narrow range of indications for SU and endoscopic surgery in patients with UTUC. However, improvements in the technology of endoscopic equipment and introduction of diverse adjuvant instillation regimens suggests positive future perspectives for NSS in UTUC. Further clinical trials with improved diagnostics and treatment regimens may shift this paradigm and are eagerly anticipated in UTUC.

NOTES

Funding/Support

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflicts of Interest

Seth P. Lerner: Clinical trial support from Aura Bioscience, Endo, FKD, JBL (SWOG), Genentech (SWOG), Merck (Alliance) QED Therapeutics, Vaxiion, Viventia; Consultant/advisory board for Astra Zeneca, Aura Bioscience, BMS, C2iGenomics, Ferring, Incyte, Pfizer/EMD Serono, Protara, Stimit, Vaxiion, Verity; Patent for TCGA classifier; Honoraria from Grand Rounds Urology, UroToday. The other authors have nothing to disclose.

Author Contribution

Conceptualization: SHK; Writing - original draft: SHK; Writing - review & editing: SHK, ISS, SPL.

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