Minimally Invasive Therapy for Upper Tract Urothelial Cell Cancer

Abstract

Minimally invasive therapy for upper tract urothelial cell cancer has assumed an important role in the management of this relatively uncommon genitourinary malignancy. In this review, current standards for patient selection, surgical approach, as well as overall outcomes will be discussed. Moreover, the use of intraluminal agents in upper tract disease is examined along with its efficacy and associated complications.

Introduction

Nephroureterectomy with bladder cuff excision is the gold standard of management in upper tract urothelial cell cancer (UTUC).¹ In recent years, however, the advancements in surgical techniques, miniaturization of endoscopic instruments, and better risk stratification have significantly changed the approach of surgical intervention. Kidney-sparing surgeries include segmental ureterectomy, total ureterectomy with reconstruction, as well minimally invasive endoscopic approaches.^2
–4 Endoscopy has a firm foothold in the visual confirmation and tissue acquisition needed to diagnosis UTUC. Furthermore, ureteroscopy and percutaneous surgery are gaining acceptance as viable treatment options, with comparable disease-specific survival (DSS) in appropriately selected individuals. In this review, we discuss minimally invasive nephron sparing therapies for UTUC, including ureteroscopic and percutaneous techniques, the role for intraluminal therapy, and follow-up surveillance.

Patient Selection/Indication

Indications for endoscopic management of UTUC fall into two broad categories: imperative vs elective. The European Association of Urology (EAU) published a risk-adapted protocol for renal sparing management of UTUC (Table 1).⁵ Principal among the imperative indications for minimally invasive approach include: (1) anatomic or functional solitary kidney, (2) significant renal impairment, (3) bilateral tumors, and lastly (4) poor surgical candidacy. Endoscopic treatment of UTUC balances cancer control and preservation of residual nephrons. Data suggest that in the imperative setting, such a treatment protocol not only produced a comparable 5 year overall survival (OS),⁶ but also the delay of renal replacement therapy yielded an overall reduction in healthcare expenditures.⁷ The ability to postpone or avoid dialysis altogether confers obvious survival benefits, as the average expected life span post initiation of hemodialysis is a meager 4.5 years.⁸

Table 1.

Indications for Kidney-Sparing Surgery

Imperative indications

Anatomic or functional solitary kidney

Substantial renal insufficiency

Bilateral tumors

Lack of fitness for radical nephreoureterectomy

Elective indications

Low-risk UTUC

Highly selected high-risk UTUC: multifocal, large tumors, with low-grade and superficial features

Adapted from Seisen et al.⁵

UTUC = upper tract urothelial cell cancer.

Elective indications for endoscopic management rely heavily on preoperative risk stratification and patient selection. As pathologic staging of UTUC is often times limited by the paucity and depth of tissue procured, other diagnostic modalities such as cross-sectional imaging, cytologic assays, and even the novel optical coherence tomography may play a role in preoperative risk assessment.⁹ Tumor grading has been used as a surrogate for stage, with negative predictive value of low-grade (LG) tumor found to be non-muscle invasive in 72% of final specimens.¹⁰ According to the EAU guidelines for risk stratification (Table 2), low-risk UTUC has the following characteristics: LG on biopsy/cytology, non-invasive features on cross-sectional imaging, unifocal disease, and lastly tumor size <1 cm.¹¹ In multivariate analysis, when there are absent hydronephrosis, LG biopsy, and negative cytology, the predictive value for non-muscle invasive disease reaches 100%.¹² In the current era of advance endoscopic instruments, tumor size >1 cm may no longer pose as an absolute contraindication to endoscopic management.

Table 2.

Risk Stratification of Upper Tract Urothelial Cell Cancer in Elective Cases

High-risk UTUC

Clinical factors

Hydronephrosis

High grade

Tumor >1 cm

Invasive features on imaging

Multifocal disease

Failed endoscopic treatment

Clinical factors

Smoking

Previous bladder UCC and/or cystectomy

Low-risk UTUC

Clinical factors

Low-grade biopsy

Low-grade cytology

Tumor <1 cm

No invasive features on imaging

Unifocal disease

Close follow-up possible and acceptable to patient

Adapted from Roupret et al.¹¹

UCC = urothelial cell carcinoma.

Lastly, patient compliance is an important factor to consider when offering endoscopic management for UTUC as both short- and long-term local recurrences have been reported.⁵ Large-scale review studies have pooled data demonstrating recurrences upward around 70%, with additional dependence on grade.^13,14 In describing their institutional 30-year experience with endoscopic UTUC management, Motamedinia and colleagues had a primary recurrence 116 months after initial diagnosis. Although a complete resection and durable response is possible, recurrence later in life cannot be fully excluded.¹⁵ Patients treated using this conservative approach will need frequent surveillance of their upper tracts, in the form of repeat ureteroscopy and radiographic studies.

Ureteroscopic Techniques

Retrograde access to the upper urinary tract allows for initial tissue diagnosis, concurrent treatment, as well as subsequent surveillance. Although it is not an absolute requirement, if there is unequivocal selective cytology and image findings,¹⁶ most urologists perform an ureteroscopic evaluation and a biopsy to: diagnose, grade, and possibly stage the UTUC. Miniaturization of endoscopic equipment has drastically enhanced retrograde access in recent years. Ureteroscopes have diameters ranging from 5 to 9F and come in semi-rigid or flexible varieties. Semi-rigid ureteroscopes afford additional control in the distal ureter, good visualization, and large channels with adequate irrigation during basket or forceps manipulation, and they are relatively durable. Newer-generation ureteroscopes offer narrow caliber bodies with tapered tips that allow for easy access to a non-dilated ureter. Depending on the degree of ureteral tortuosity, this comes at the cost of decreased maneuverability and limited access to the upper tract. Patients generally require deeper sedation and, on rare occasion, muscle relaxation. The advent of specialized wires and balloon dilators has obviated the need for ureteral stenting and passive dilatation, thereby consolidating the number of trips to the operating theater. In terms of anatomic location, tumors of the ureter and upper pole calyces are amenable to ureteroscopic access. Conversely, lower pole and most interpolar lesions require significant flexion and secondary deflection afforded only by a flexible ureteroscope. Some may even require percutaneous access, which will be discussed later.

Before endoscopy, all patients should have a documented, recent, and negative urine culture or be on the appropriate treatment for a positive urine culture as per American Urologic Association (AUA) guidelines.¹⁷ The procedure should begin with a thorough cystourethroscopy to identify the location and caliber of both ureteral orifices (UOs), and it should rule out any suspicious bladder or urethral lesions. Edematous mucosal lesions may be false positive findings if a ureteral stent has been left indwelling from a prior endoscopic event. Any suspicious lower tract lesions should be mapped, biopsied, and fulgurated with meticulous hemostasis. If upper tract urine cytology has not been previously collected, this may be an opportune juncture. In line with a “no touch” technique, a cytologic aspiration may alternatively be performed through the working channel of the flexible ureteroscope after complete direct visual surveillance to defer potential urothelial trauma and false positive findings. Should bilateral collections be indicated, utilize designated left and right ureteral catheters to avoid cross-contamination of results. The side with suspected pathology should be sampled second. Next, a standard retrograde pyelogram should be performed. In addition to noting filling defects throughout the upper tract, the surgeon should also take note of the ureteral course, especially the uretero-vesicle junction, the ureteropelvic junction, and any points of curvature, kinking, or narrowing. One should also note the relative caliber of the ureter and the distribution of the caliceal collecting system. Positive radiographic findings as well as the caliceal “map” should be saved for later reference.

Depending on the caliber of the UO, its position relative to the bladder neck, and the surgeons' experience with flexible ureteroscopy, one may decide to place a guidewire to aid with ureteroscope introduction into the ureter or attempt the “free-hand” technique. One benefit of the free-hand technique is that it avoids the false positive findings of wire-induced trauma; however, it is technically more challenging and may not be possible in patients with a narrow ureter. For a patient with a particularly tight UO, an extra-stiff wire or dilatation with a graduated coaxial dilator may be necessary. Bear in mind that this maneuver will result in mucosal trauma, which hampers visual diagnostic sensitivity. As such, dilatation should be limited to the shortest possible segment. Once the ureteroscope is introduced into the distal segment of the ureter, it should be driven retrograde under direct vision, ideally avoiding traumatic distortion to the mucosa. If the ureter is exceedingly tight, or the lesion of interest is confined to the renal collecting system, a flexible ureteroscope may be passed over the wire to just beyond the ureteropelvic junction. Another viable technique would be to cannulate the UO initially with a semi-rigid ureteroscope and examine the ureter as far proximally as possible. When the ureteral tortuosity or caliber precludes further advancement, deposit wire, and continue the retrograde inspection with a flexible ureteroscope. However, a semirigid ureteroscope may not allow for circumferential visualization of the ureter as easily as a flexible ureteroscopy, especially at the tortuous mid-ureter or while crossing the great vessels. All in all, good practice dictates visual surveillance of the entire ureter at some point during the procedure. In the event that all of the maneuvers fail, a ureteral stent maybe left to passively dilate the system and ureteroscopy may be reattempted after 2–4 weeks. Simple diagnostic ureteroscopy does not necessitate leaving an indwelling ureteral stent. Use of a temporary stent should be considered in the setting of active dilatation, significant ureteral trauma, biopsy with fulguration, or if a second look is planned.

A comprehensive endoscopic exam is the most important first step because even minimal urothelial manipulation can result in bleeding and decreased visibility. Suspicious findings and tumors should be mapped with a fluoroscopic snap-shot to help with the subsequent localization, biopsy, and fulguration once diagnostic endoscopy is complete. A biopsy may be taken by using a basket or forceps. Current ureteroscopes have working channels as much as 3.6F, but insertion of instruments significantly reduces irrigation inflow resulting in reduced visibility. Depending on the size and shape of the tumor (papillary vs sessile), debulking can be performed most efficiently using a basket, followed by forceps to sample the base, and concluding with vaporization and cauterization. Kleinman et al. have shown that the 2.4F steel flat wire basket outperformed the 3F biopsy forceps in establishing tissue diagnosis for papillary lesions.¹⁸ Sessile lesions, conversely, may require multiple “bites” by using a conventional ureteroscopic forceps. The biopsy forceps may be passed through a ureteroscope to obtain a small sample of tissue. If the forceps is pulled through the ureteroscope, the sample may be sheared off; removal of the entire ureteroscope with the biopsy cup just beyond its tip would be preferred to maintain tissue integrity. Multiple biopsies of the same lesion have been shown to improve diagnostic accuracy through increased aggregate tissue yield.¹⁹ The back-loaded BIGopsy forceps provides a large volume biopsy and has been shown to outperform the 3F forceps with regards to definitive diagnosis and more accurate staging and grading.²⁰ The downside of the BIGopsy is that it requires back-loading, which mandates a ureteral sheath. Its size can also limit visualization and intra-renal maneuverability. It is the authors' practice to utilize a Zero-tip basket for large, papillary tumors and to reserve biopsy forceps for the base of papillary tumors, after debulking, or for more sessile lesions. The BIGopsy is preferred when a sheath is already in place and if the location is favorable; however, in most cases, we utilize the 3F biopsy forceps. One must also consider that the passage of instruments through the working channel will limit the range of ureteroscope deflexion, hampering the ease of access to the lower pole. Also, the passage of instruments may not be possible through a deflected ureteroscope (or may damage the channel) and will require passage in a neutral position. We find this as a common challenge as you briefly lose sight of your target lesion to pass the instrument and then have to re-identify it with limited flow once the instrument is passed.

There are no set recommendations regarding ureteral sheath utilization in the management of UTUC. Benefits are similar to those in stone management, in that a sheath allows for repeated passage with a flexible ureteroscope, a decreased pressure transmission to the upper tract.²¹ Utilization of a sheath also allows for less traumatic remove of the specimen (less shearing), and the use of a BIGopsy forceps.^20,22 A theoretical benefit may be the bypass of the distal ureter and bladder to limit seeding, but a full upper tract evaluation should always precede the introduction of the access sheath. A large caliber sheath may not impart any additional benefit, such as in the case of extraction of larger stone fragments. Narrower sheaths may be surgically adequate; they are more easily deployed, better tolerated by the patient without sacrificing visualization. Post-operative ureteral stenting, however, will likely be necessary after sheath usage.

Lasers have more or less supplanted mono-polar electrocautery in the ureteroscopic management of urothelial cancers given the latter's propensity for delayed stricture formation. Two classes of lasers are commonly employed in the urologic practice: the neodymium yttrium aluminum garnet (Nd:YAG) and the holmium ytrium aluminum garnet (Ho:YAG) lasers. The two lasers may be available in a combined unit with a dual foot switch. Nd:YAG is a continuous beam laser with a wavelength of 1064 nm, delivering a depth of penetration of 5–10 mm, and is well suited for tissue coagulation. Given its significant depth of penetration, use is limited to larger tumors within the renal pelvis and ureteral use is discouraged for fear of ureteral stricturing. Ho:YAG is a pulsatile laser with a wavelength of 2100 nm and a penetration depth <0.4 mm. By altering settings, the surgeon can coagulate with a longer pulse, low energy (0.5–0.6 J), and low frequency (5 Hz), or by defocusing the laser beam (more fiber distance from tissue). Ablation/vaporization can be achieved with shorter pulse, higher energy (0.6–1 J) and frequency (10 Hz), and by focusing the beam (less fiber to tissue distance). Ablation is preferred in the ureter to decrease stricture length. Both lasers can be used through 200–365 μm fibers, the smaller of which maintains adequate ureteroscopy deflexion and flow. Use of thulium lasers in the upper tract has been limited to date but may be promising for future application. Current small-caliber lasers are end-fire and may present situations in which aiming the beam is imperfect and a tumor cannot be ablated. In such situations, one may employ a monopolar 2F Bugbee, which allows for side contact and possibly more versatility in constricted quarters.²³ Lastly, it is worthy of noting that monopolar cautery and Nd:YAG laser may interfere with digital ureteroscopes, resulting in image distortion.

A second look ureteroscopy in 6–8 weeks post-endoscopic ablation is generally recommended⁵ and is our current practice. If there is no evidence of recurrence, we employ a risk-graduated surveillance protocol of ureteroscopic surveillance every 3 months for the first 2 years, every 6 months for years 3 and 4, and annually thereafter. Cross-sectional imaging should be obtained every 1–2 years to rule out extra-renal progression.²⁴

Complications of ureteroscopy are uncommon, but they include perforation of the ureter or the upper tract. In most cases, when a clinically significant perforation occurs as evident by active contrast extravasation or noting retroperitoneal fat, the procedure should be aborted and a ureteral stent should be placed. Ureteral stricture formation is also a concern. Although strictures occur in about 1% of patients with stone disease,²⁵ the nature of UTUC intervention mandates tissue destruction with invasive surveillance, and possible repeat interventions. As such, the stricture rates are considerably higher than stone disease but still low at about 8.6%.²⁶

Retrograde, ureteroscopic management of UTUC, in appropriately selected candidates, allows for a minimally invasive, nephron-sparing approach for low-risk patients, or those with limited renal function or who cannot tolerate a major operation.

Percutaneous Techniques

First described in 1982 by Tomera et al.,²⁷ the percutaneous access to the renal collecting system boasts the advantages of larger working channels, enhanced visualization, and ease of access to the bulk of the upper genitourinary tract.¹⁶ Difficulty in accessing lower pole tumors ureteroscopically has allowed for the growth of percutaneous management of UTUC. Although ureteroscope maneuverability has improved in the modern era of endourology, flexible ureteroscopes continue to be restricted by their working channels, narrow scope of view, and subpar visualization with even minor hematuria. Despite the EAU recommendation that endoscopic management be limited to tumors <1 cm, we argue that larger tumors can be managed through a percutaneous approach. Ultimately, grade, not size, should be the final determinant when endoscopic management should be abandoned in favor of nephroureterectomy.^15,28,29 The percutaneous approach also has an important role in patients with prior urinary diversions precluding ureteroscopic access.

Pre-surgical planning for percutaneous access is paramount. A pre-operative computed tomography urogram (delayed contrast) details the calyceal anatomy, relative location of the tumor, facilitating the selection of a point of entry. The calyx allowing for the shortest tract will also allow for maximal intra-renal maneuverability with a rigid nephroscope. This is especially important in obese patients, or in the setting of large and multifocal tumors. We favor a prone percutaneous approach under fluoroscopic guidance, as this is also our preferred approach for percutaneous nephrolithotomy (PCNL); those who are more facile with supine PCNL or ultrasound guidance should proceed accordingly. A posterior calyx containing a tumor should be directly accessed. If a tumor is located in an anterior calyx, direct access may be more challenging and, thus, an upper or lower pole puncture may allow for better trajectory into the calyx of interest. Tumors in the renal pelvis and proximal ureter should be treated with access into the upper or middle pole calyx, which offers a more direct angle of approach to the ureteropelvic junction.

The percutaneous tract should be established just short of the tumor to avoid direct contact. Puncture into the renal pelvis should also be avoided due to the proximity of hilar vessels and the propensity for significant hemorrhage. Furthermore, the lack of robust renal parenchymal around the pelvis increases the risk of soft tissue tearing with nephroscope manipulation.³⁰ Should the puncture and subsequent dilatation cause significant bleeding, the surgeon may consider placing a nephrostomy tube to: (1) tamponade the bleeding and (2) allow for tract maturation and a repeat procedure at a later date.

Similar endoscopic techniques of tumor debulking have been described in this setting, although with instruments of a larger caliber compared with the ureteroscopic counterpart. Papillary lesions are amenable to cold forceps removal, resection, ensnaring using baskets, or even laser excision at the stalk. Our preference is to use cold-cup biopsy forceps to debulk the tumor. An added benefit of the percutaneous approach is that a standard resectoscope with a cutting loop or roller-ball can be used through the percutaneous tract. Bipolar energy with saline irrigation eliminates the risk of electrolyte abnormalities that are associated with excessive hypotonic fluid absorption that is possible with monopolar resection. To aid in accurate tumor staging, we take care to biopsy or resect the base of the tumor and submit the tissue as a separate specimen. One must take caution not to resect too deeply, as the infundibular and pelvis urothelium lacks significant muscular backing and will perforate easily. In addition, second- and third-order renal vasculature branches run parallel to the infundibula.

Use of lasers is also an option. Once the bulk of the tumor has been removed, Nd:YAG or Ho:YAG lasers can be utilized to ablate the bases. Nd:YAG laser with its greater depth of penetration may be useful after a substantial resection, as it can induce non-contact coagulation. Ho:YAG laser with a depth of penetration of 0.5 mm will be inadequate in achieving hemostasis for larger bleeding vessels and has a tendency to accumulate tissue on the fiber tip.³⁰

When bleeding is encountered after a deeper resection or ablation, continued tissue coagulation may be futile and only serve to exacerbate bleeding. A preferred maneuver would be to place a nephrostomy catheter with a balloon to tamponade the site.

After percutaneous intervention, especially for bulky tumors, “second look” nephroscopy may be performed in 4–14 days to eradicate any residual tumor burden.¹⁶ Repeat procedures usually afford better visualization and improved hemostasis, because the tract is now mature. After confirmation of complete resection, an endoscopic surveillance should be planned in 3 months. A retrograde ureteroscopic approach is preferred, as it is noninvasive. It allows for concomitant evaluation of the bladder, ureter, and access to most, if not all, of the calices. If pathologic analysis of the tissue returns as high grade (HG) or there is muscle invasion, nephroureterectomy should be considered based on patient candidacy.

The risks of percutaneous UTUC resection are similar to PCNL, including: infection, bleeding, collecting system perforation, hemothorax/hydrothorax (supracostal access), and rarely injury to the liver, spleen, or bowel. Risk of bleeding may be higher than conventional PCNL given the vascularity of tumors and need to resect and ablate urothelium as a goal of the procedure. Older studies have quoted transfusion requirement upward to 20%–50% and vascular complications that correlate to tumor grade.^31,32 Unique to the percutaneous approach of UTUC management, tumor seeding along the tract of access has always been a concern. Likely an exception rather than the rule, only sporadic case reports have been published on this rare complication.^27,33,34 To this end, percutaneous resection of urothelial carcinoma remains a safe and effective treatment of properly selected patients.

Intraluminal Therapy

AUA guidelines have been established for the use of intraluminal therapy for bladder cancer.³⁵ Bacillus Calmette-guéron (BCG) has well-established indications for the management of carcinoma in situ (CIS), recurrent LG bladder cancer, multifocal or large-volume LG bladder cancer, and HG non-muscle invasive bladder cancer (NMIBC). BCG has been advocated for some patients with recurrent HG NMIBC with an initial response and subsequent recurrence. Intravesicle mitomycin C (MMC) is commonly used immediately after transurethral resection of bladder tumor (TURBT) in low- to intermediate-risk patients to prevent recurrence, and in broader applications as induction/maintenance therapies similar to BCG in high-risk patients.³⁶ The common utilization of intraluminal therapy for NMIBC is based on large volume, randomized trials and has rightfully become the standard of care.

Evidence for intraluminal therapy in UTUC is not well established, and its usage is often extrapolated from lower urinary tract management. The incidence of UTUC is low, and given the high rate of invasive disease at presentation, advocacy for conservative management in the face of potential progression is small. As such, the development of strong comparative studies between conservative and extirpative therapies is difficult. There has been no randomized control trial to date, and the majority of evidence is based on retrospective series. Although there is likely some role for intraluminal therapy in the management algorithm of UTUC, we must be careful in limiting its usage until data are sufficiently robust to allow for better patient selection.

Various delivery methods of upper tract intraluminal therapy have been proposed. Antegrade instillation via the percutaneous nephrostomy tube is the most direct yet requires maintenance of the nephrostomy tube through the duration of therapy. A retrograde approach through cystoscopic placement of a ureteral catheter has been described and performed with success in some selected candidates. Accommodation of UO may allow for attempts in the office under local anesthetic, and it may be as effective as nephrostomy tube placement, obviating the need for a persistent indwelling catheter.³⁷ One should note the trigonal anatomy relative to the UO, and determine the appropriate catheter length to situate the proximal tip in the renal pelvis without mucosal injury. This will facilitate subsequent office-based cystoscopic placement without the need for fluoroscopy. The retrograde refluxing methods involving ureteral meatotomy or indwelling ureteral stent have also been described. However, one must confirm the presence of and volume necessary to induce reflux before induction therapy. Reflux-based methods likely perform inconsistently, requiring more than the normal established treatment volumes, and they deliver a relatively low concentration of the desired agent to the upper collecting system.³⁸

Upper tract CIS (UT-CIS) is a difficult diagnosis to make. In many cases, patients are noted to have positive urine cytology with negative upper tract imaging and lower tract random biopsies. Selective upper tract cytology can help localize laterality; however, UT-CIS is inferred rather than biopsy proven. Carmignani and colleagues reviewed outcomes of 12 studies including 185 patients (218 renal units), 165 with UT-CIS.³⁹ In all involved studies, a selective positive urine cytology localized presumed UT-CIS, with some including negative bladder and prostatic urethral biopsies. Intraluminal (upper tract) BCG was administered over 6 weeks, and response was gauged with cytology conversion to negative. Over a median follow-up of 19–57 months, mean recurrence rate was only 32% (0%–53%). Shapiro and colleagues³⁷ described their experience of using BCG-interferon in patients with biopsy-confirmed UT-CIS. They included 11 patients, of whom 8 (73%) had a complete response (negative biopsy and cytology), and only 1 patient experienced biopsy-proven recurrence.³⁷

The experience with adjuvant BCG after resection or ablation of UTUC has been less promising. Rastinehad found no difference in recurrence rates with adjuvant therapy, regardless of grade (LG 26% vs 33%, HG 38% vs 39%).²⁹ In a follow-up study, BCG showed no improvement in time to recurrence (p = 0.85) or OS (p = 0.91).¹⁵ Giannarini et al. noted that after BCG, papillary UTUC recurred in 59% of patients compared with only 40% of those with UT-CIS. In addition, UT-CIS was less likely to progress by stage or to nephroureterectomy.⁴⁰ It is unclear, though, whether the favorable response to BCG in UT-CIS vs papillary tumors is the susceptibility of CIS to BCG or the more indolent nature of UT-CIS overall.

Similar to post-TURBT single instillation of MMC, groups have discussed the use of MMC after UTUC ablation.^41

–44 Recurrence rates after a post-ablation MMC instillation range from 28.5% to 54%, and progression to nephroureterectomy ranges from 5% to 21%. We cannot assess the actual benefit incurred from utilizing MMC given that there was no comparison to ablation alone. In addition, the benefit in the possible reduction of bladder seeding after upper tract instrumentation for UTUC was not discussed either. Complications, however, are rare with one study citing a single patient with a ureteral stricture. The use of MMC or other intraluminal chemotherapeutics in a maintenance regimen has not been widely discussed and is likely far from widespread utilization.

Adjuvant intraluminal therapies for UTUC have been disappointing relative to outcomes seen in bladder cancer. Studies so far suggest that there may be a limited role for patients with UT-CIS who do not have a discrete tumor to ablate. For patients with papillary tumors, surgical removal and ablation will likely remain the mainstay of treatment. In the future, better risk characterization may identify a subset of patients who would benefit from immediate adjuvant and possibly maintenance instillation.

Outcomes

Several meta-analyses have been published on the topic of endoscopic management of UTUC. Despite the limitations of data heterogeneity and selection bias, these studies have generally demonstrated comparable disease-specific and OS between UTUC treated with radical nephroureterectomy (RNU) and those treated with endoscopic resection.^45,46 Recurrence-free survival (RFS) after ureteroscopic/percutaneous intervention, however, is clearly inferior to radical resection, but the vast majority of the recurrences are successfully managed by utilizing the same endoscopic approach.¹⁴ Interestingly, upper tract recurrence is seemingly more infrequent after percutaneous resection compared with ureteroscopic interventions (pooled data of 37% and 52% respectively).⁴⁵ These data must be interpreted with reservation given the tendency to select for low-risk patients, those with imperative indications and competing mortalities, and the difficulty of standardized reporting of disease recurrence. Trials with randomization between conservative management and RNU do not exist to date.

Large-scale single institution series have been published in the recent years, with evidence in support of endoscopic management of UTUC. Grasso and colleagues¹³ reported on their 15-year experience with 160 consecutive patients. They found a 2-, 5-, and 10-year cancer-specific survival rate of 98%, 87%, and 81% for low-grade disease, which was not significantly different from those treated with RNU.⁴⁷ Echoing prior studies, patients with high-grade disease had a much poorer outcome: Median survival for imperative indication was 29.2 months with a 2-year OS of only 54%.¹³

In 2012, Cutress et al. published their 20-year experience, which included 73 patients who had endoscopic management of UTUC.¹⁴ This group of patients notably had low-grade disease, with only 8.2% of patients with confirmed World Health Organization Grade 3 pathology. Similarly, only 8 (10.9%) of patients underwent nephron sparing management due to imperative indication. This study conveyed an estimated 5 year OS and DSS of 69.7% and 88.9% respectively. Stratifying for tumor grade again revealed reduced DSS for patients with G2 or G3 disease. Overall renal unit preservation rate was 84.6% at 5 years, favoring those with low-grade disease.

Almas and colleagues published a report on the Scandinavian experience early in 2016, summarizing a single center experience of 43 patients.⁴⁸ Within this cohort, 28 were patients who pursued endoscopic management for elective indications, in comparison to 15 who were relegated for imperative indications. The study had a mean follow-up duration of 58 months and the patients between the two subgroups differed in age, glomerular filtration rate, and Charlson Comorbidity index, but not in tumor grade. This study, interestingly, looked at the survival estimates based on preoperative indication. Five-year OS and DSS for patients treated electively were 71% and 94%, in stark contrast to patients treated with imperative indications: 25% and 41%. Overall, the low-risk patient group had a 5-year renal preservation rate of 51%. Multivariate analysis suggests that tumor grading is an independent predictor of DSS but age predicts overall survival.

Lastly, Motamedinia et al. published the longest series to date of UTUC managed with percutaneous resection, the result of their 30 year experience.¹⁵ In this study, a total of 141 patients were included, with 68 for imperative indications. The average follow-up duration was 76.9 months. Low-risk disease managed endoscopically had an RFS of 71.4 months, whereas HG disease had an RFS of 36.4. Moreover, kidney preservation rate was 87% for elective indications and 90% for imperative indications. The Kaplan–Meier survival analysis still demonstrated the poor overall survival of patients with high-grade disease. This study advocated for expanding the criteria for endoscopic management, as 17% had multifocal lesions and 45% had HG. Surprisingly, multifocality did not seem to translate to shortened RFS, progression, or death. Perhaps the most prominent finding from this study was that after controlling for age, imperative indication, and a history of bladder cancer, tumor grade seems to lose significance as a predictor for OS. While it is known that low-grade UTUC can be managed endoscopically with similar outcomes (when compared with RNU), this finding may help clarify the proper treatment algorithm for patients with high-risk disease but overall limited life expectancy. Prolonging cancer-specific survival through radical surgery may not translate into overall survival, as renal function is compromised.

Conclusion

Minimally invasive, endoscopic management of UTUC has evolved to become a viable treatment option for low-risk patients. Conversely, it can be an alternative to nephroureterectomy for patients with imperative indications for renal preservation or significant comorbidities precluding major surgery. Studies have confirmed the excellent outcomes for low-risk disease, and the newer data suggest that expanded inclusion criteria may not jeopardize overall survival. Certainly, additional well-designed studies are necessary to clearly define the nuances of patient selection, improve surgical techniques, and investigate the various benchmarks of clinical outcomes.

Footnotes

Author Disclosure Statement

No competing financial interest exist.

Abbreviations Used

References

Roupret

, Babjuk

, Comperat

, et al. European guidelines on upper tract urothelial carcinomas: 2013 update. Eur Urol, 2013; 63:1059–1071.

Fang

, Seisen

, Yang

, et al. A systematic review and meta-analysis of oncological and renal function outcomes obtained after segmental ureterectomy versus radical nephroureterectomy for upper tract urothelial carcinoma. Eur J Surg Oncol, 2016; 42:1625–1635.

Raheem

, Alatawi

, Kim

, et al. Feasibility of robot-assisted segmental ureterectomy and ureteroureterostomy in patient with high medical comorbidity. Int Braz J Urol, 2016; [Epub ahead of print]; DOI: 10.1590/S1677-5538.IBJU.2016.0026

Pedrosa

, Masterson

, Rice

, et al. Oncologic outcomes and prognostic impact of urothelial recurrences in patients undergoing segmental and total ureterectomy for upper tract urothelial carcinoma. Can Urol Assoc J, 2015; 9:E187–E192.

Seisen

, Colin

, Roupret

. Risk-adapted strategy for the kidney-sparing management of upper tract tumours. Nat Rev Urol, 2015; 12:155–166.

Gadzinski

, Roberts

, Faerber

, et al. Long-term outcomes of immediate versus delayed nephroureterectomy for upper tract urothelial carcinoma. J Endourol, 2012; 26:566–573.

Pak

, Moskowitz

, Bagley

. What is the cost of maintaining a kidney in upper-tract transitional-cell carcinoma? An objective analysis of cost and survival. J Endourol, 2009; 23:341–346.

Collins

, Foley

, Herzog

, et al. Excerpts from the US renal data system 2009 annual data report. Am J Kidney Dis, 2010; 55:S1–S420.

Bus

, Muller

, de Bruin

, et al. Volumetric in vivo visualization of upper urinary tract tumors using optical coherence tomography: A pilot study. J Urol, 2013; 190:2236–2242.

10.

Brown

, Matin

, Busby

, et al. Ability of clinical grade to predict final pathologic stage in upper urinary tract transitional cell carcinoma: Implications for therapy. Urology, 2007; 70:252–256.

11.

Roupret

, Colin

, Yates

. A new proposal to risk stratify urothelial carcinomas of the upper urinary tract (UTUCs) in a predefinitive treatment setting: Low-risk versus high-risk UTUCs. Eur Urol, 2014; 66:181–183.

12.

Brien

, Shariat

, Herman

, et al. Preoperative hydronephrosis, ureteroscopic biopsy grade and urinary cytology can improve prediction of advanced upper tract urothelial carcinoma. J Urol, 2010; 184:69–73.

13.

Grasso

, Fishman

, Cohen

, et al. Ureteroscopic and extirpative treatment of upper urinary tract urothelial carcinoma: A 15-year comprehensive review of 160 consecutive patients. BJU Int, 2012; 110:1618–1626.

14.

Cutress

, Stewart

, Tudor

, et al. Endoscopic versus laparoscopic management of noninvasive upper tract urothelial carcinoma: 20-year single center experience. J Urol, 2013; 189:2054–2060.

15.

Motamedinia

, Keheila

, Leavitt

, et al. The expanded use of percutaneous resection for upper tract urothelial carcinoma: A 30-year comprehensive experience. J Endourol, 2015; 30:262–267.

16.

Smith

, Matin

, Jarrett

. Urolothelial tumors of the upper urinary tract. In: Wein

, ed. Campbell-Walsh Urology, 11th edn. Elsevier, Pennsylvania, PA, 2016, pp. 1365–1402.

17.

Wolf

Jr. , Bennett

, Dmochowski

, et al. Best practice policy statement on urologic surgery antimicrobial prophylaxis. J Urol, 2008; 179:1379–1390.

18.

Kleinmann

, Healy

, Hubosky

, et al. Ureteroscopic biopsy of upper tract urothelial carcinoma: Comparison of basket and forceps. J Endourol, 2013; 27:1450–1454.

19.

Guarnizo

, Pavlovich

, Seiba

, et al. Ureteroscopic biopsy of upper tract urothelial carcinoma: Improved diagnostic accuracy and histopathological considerations using a multi-biopsy approach. J Urol, 2000; 163:52–55.

20.

Wason

, Seigne

, Schned

, et al. Ureteroscopic biopsy of upper tract urothelial carcinoma using a novel ureteroscopic biopsy forceps. Can J Urol, 2012; 19:6560–6565.

21.

Auge

, Pietrow

, Lallas

, et al. Ureteral access sheath provides protection against elevated renal pressures during routine flexible ureteroscopic stone manipulation. J Endourol, 2004; 18:33–36.

22.

Gorin

, Santos Cortes

, Kyle

, et al. Initial clinical experience with use of ureteral access sheaths in the diagnosis and treatment of upper tract urothelial carcinoma. Urology, 2011; 78:523–527.

23.

Bagley

, Grasso

3rd . Ureteroscopic laser treatment of upper urinary tract neoplasms. World J Urol, 2010; 28:143–149.

24.

Weizer

, Faerber

, Wolf

Jr.

Progression of disease despite good endoscopic local control of upper tract urothelial carcinoma. Urology, 2007; 70:469–472.

25.

Elashry

, Elgamasy

, Sabaa

, et al. Ureteroscopic management of lower ureteric calculi: A 15-year single-centre experience. BJU Int, 2008; 102:1010–1017.

26.

Chen

, Bagley

. Ureteroscopic surgery for upper tract transitional-cell carcinoma: Complications and management. J Endourol, 2001; 15:399–404.

27.

Tomera

, Leary

, Zincke

. Pyeloscopy in urothelial tumors. J Urol, 1982; 127:1088–1089.

28.

Motamedinia

, Hoenig

, Okeke

, et al. A case for nephron sparing surgery in the management of upper tract urothelial carcinoma. J Endourol, 2016; 30 Suppl 1:S18–S22.

29.

Rastinehad

, Ost

, Vanderbrink

, et al. A 20-year experience with percutaneous resection of upper tract transitional carcinoma: Is there an oncologic benefit with adjuvant Bacillus Calmette Guerin therapy?. Urology, 2009; 73:27–31.

30.

Rhee

, Jarrett

. Percutaneous management of upper urinary tract transitional cell carcinoma. In: Smith

, Preminger

, Badlani

, eds. Smith's Textbook of Endourology. Wiley-Blackwell, Hoboken, NJ, 2011, vol. 1, pp. 316–326.

31.

Argyropoulos

, Tolley

. Upper urinary tract transitional cell carcinoma: Current treatment overview of minimally invasive approaches. BJU Int, 2007; 99:982–987.

32.

Jarrett

, Sweetser

, Weiss

, et al. Percutaneous management of transitional cell carcinoma of the renal collecting system: 9-year experience. J Urol, 1995; 154:1629–1635.

33.

Huang

, Low

, deVere White

. Nephrostomy tract tumor seeding following percutaneous manipulation of a ureteral carcinoma. J Urol, 1995; 153:1041–1042.

34.

Schwartzmann

, Pastore

, Sacca

, et al. Upper urinary tract urothelial carcinoma tumor seeding along percutaneous nephrostomy track: Case report and review of the literature. Urol Int, 2016; 98:115–119.

35.

Chang

, Boorjian

, Chou

, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guidelines. J Urol, 2016; 196:1021–1029.

36.

Bouffioux

, Kurth

, Bono

, et al. Intravesical adjuvant chemotherapy for superficial transitional cell bladder carcinoma: Results of 2 European organization for research and treatment of cancer randomized trials with mitomycin C and doxorubicin comparing early versus delayed instillations and short-term versus long-term treatment. European Organization for Research and Treatment of Cancer Genitourinary Group. J Urol, 1995; 153:934–941.

37.

Shapiro

, Lipsky

, Cha

, et al. Outcomes of intrarenal Bacillus Calmette-Guerin/interferon-alpha2B for biopsy-proven upper-tract carcinoma in situ. J Endourol, 2012; 26:1645–1650.

38.

Yossepowitch

, Lifshitz

, Dekel

, et al. Assessment of vesicoureteral reflux in patients with self-retaining ureteral stents: Implications for upper urinary tract instillation. J Urol, 2005; 173:890–893.

39.

Carmignani

, Bianchi

, Cozzi

, et al. Intracavitary immunotherapy and chemotherapy for upper urinary tract cancer: Current evidence. Rev Urol, 2013; 15:145–153.

40.

Giannarini

, Kessler

, Birkhauser

, et al. Antegrade perfusion with Bacillus Calmette-Guerin in patients with non-muscle-invasive urothelial carcinoma of the upper urinary tract: Who may benefit?. Eur Urol, 2011; 60:955–960.

41.

Aboumarzouk

, Somani

, Ahmad

, et al. Mitomycin C instillation following ureterorenoscopic laser ablation of upper urinary tract carcinoma. Urol Ann, 2013; 5:184–189.

42.

Eastham

, Huffman

. Technique of mitomycin C instillation in the treatment of upper urinary tract urothelial tumors. J Urol, 1993; 150:324–325.

43.

Goel

, Mahendra

, Roberts

. Percutaneous management of renal pelvic urothelial tumors: Long-term followup. J Urol, 2003; 169:925–929.

44.

Keeley

Jr. , Bagley

. Adjuvant mitomycin C following endoscopic treatment of upper tract transitional cell carcinoma. J Urol, 1997; 158:2074–2077.

45.

Cutress

, Stewart

, Zakikhani

, et al. Ureteroscopic and percutaneous management of upper tract urothelial carcinoma (UTUC): Systematic review. BJU Int, 2012; 110:614–628.

46.

Yakoubi

, Colin

, Seisen

, et al. Radical nephroureterectomy versus endoscopic procedures for the treatment of localised upper tract urothelial carcinoma: A meta-analysis and a systematic review of current evidence from comparative studies. Eur J Surg Oncol, 2014; 40:1629–1634.

47.

Margulis

, Shariat

, Matin

, et al. Outcomes of radical nephroureterectomy: A series from the upper tract urothelial carcinoma collaboration. Cancer, 2009; 115:1224–1233.

48.

Almas

, Halvorsen

, Gjengsto

, et al. Grading of urothelial carcinoma of the upper urinary tract according to the World Health Organization/International Society of Urological Pathology classification from 2004 is a valuable tool when considering whether a patient is suitable for endoscopic treatment. Scand J Urol, 2016; 50:298–304.