Management of Upper Tract Urothelial Carcinoma

Fig. 15.1

Example of ureteroscopic brush biopsy. (Permission for use granted by Cook Medical, Bloomington, Indiana)

Some clinicians would advocate that treatment can be undertaken with the diagnosis of UTUC based off of imaging, questioning the necessity of routine ureteroscopy. Some have raised the theoretical concerns of tumor spread via pyelovenous or pyelolymphatic backflow as well as the possibility of “seeding” of the bladder and points distal to the tumor by ureteroscopic manipulation, though this has largely been disproven [16, 17]. The authors of this chapter feel strongly that tissue is needed to truly diagnose a patient with UTUC and, as such, ureteroscopy is routinely performed in our practice.

Ureteroscopy is both diagnostic and potentially therapeutic when done correctly, which has the advantage of a relatively low degree of invasiveness and can be done on an outpatient basis. Refinements in optics and the technology of current endoscopes allows urologists to thoroughly examine all aspects of the upper urinary tracts with improved visualization and lesions can be biopsied and ablated at the time of diagnosis.

Ureteroscopic biopsy has significantly improved since ureteroscopic management of UTUC was introduced in the 1980s [18]. Despite these improvements, the adequacy of ureteroscopic biopsies is limited by their relatively small size which has resulted in a limited ability to accurately stage UTUC by biopsy. Vashistha et al. compared 118 biopsies with surgical tissue samples and found that ureteroscopic biopsy had a specificity of 100% and a sensitivity of 85.4%. They also found that 87.1% of specimens had concordant grade, but there was only a concordance rate of 58.6% when comparing tumor staging [19]. Because of this, UTUC grade obtained from ureteroscopic biopsy has been used as a surrogate for stage. This has been demonstrated by a number of groups when comparing ureteroscopic biopsy to nephroureterectomy specimens. Low-grade UTUC has been shown to be Ta or T1 at the time of RNU 73–86% of the time, whereas high-grade UTUC is T2 or higher 66% of the time [20, 21].

There are currently a number of options to biopsy a lesion available to the practicing urologist. Most commonly, reusable 3-F cold cup biopsy forceps represent an economic and effective option to biopsy both renal and ureteral lesions (Fig. 15.2). There is currently little data available that compares ureteroscopic biopsy techniques head to head. The best evidence currently comes from Kleinmann et al. in which they retrospectively looked at 504 ureteroscopic biopsies that were performed with either 3-F cold cup biopsy forceps or a 2.4-F stainless steel flat wire basket. They found that diagnosis was successful 63% of the time with forceps compared with 94% with the flat wire basket. These results should be interpreted with caution, however, as the study was retrospective in nature and the authors noted that forceps were preferentially used for smaller, sessile, or non-papillary lesions which by definition will provide less of a sample size and are harder to biopsy [22]. The 2.4-F flat wire basket has the advantage of being able to cut papillary lesions at their stalk and can be used to debulk large tumors. Specifically, a stainless steel flat wire basket should be used as nitinol baskets commonly used in stone procedures have a tendency to slip off of the tumor [17]. Another option available for biopsy is the BIGopsy™ forceps (Cook ®) (Fig. 15.3). The BIGopsy forceps are 4mm³ in size and provide a sample four times larger than standard 3-F cold cup biopsy forceps. Although it is touted as providing a larger specimen with less architectural distortion of the tissue, the BIGopsy forceps are quite difficult to use as they cannot pass through a standard ureteroscope’s working channel. The device has to be back-loaded into the ureteroscope and then advanced along with the ureteroscope through a ureteral access sheath while exposed out of the end of the scope. The large size of the device also takes up a large field of view and is difficult to get significant deflection [23].

../images/461848_1_En_15_Chapter/461848_1_En_15_Fig2_HTML.jpg — Fig. 15.2

Example of 3-F cold cup biopsy forceps. (Permission for use granted by Cook Medical, Bloomington, Indiana)

../images/461848_1_En_15_Chapter/461848_1_En_15_Fig3_HTML.jpg — Fig. 15.3

BIGopsy device. (Permission for use granted by Cook Medical, Bloomington, Indiana)

The following recommendations were made by the European Association of Urology (EAU) in the 2017 UTUC guidelines in regards to diagnosis (Fig. 15.4) [6]:

1.

Perform cystoscopy to rule out a concomitant bladder tumor.
2.

Perform CT urography for upper tract evaluation and staging.
3.

Use diagnostic ureteroscopy and biopsy only in cases where additional information will impact treatment options.

../images/461848_1_En_15_Chapter/461848_1_En_15_Fig4_HTML.png — Fig. 15.4

Summary of evidence and guidelines for the diagnosis of UTUC. (From Roupret et al., Figs. 2, 4, 6, with permission of Elsevier [6])

There are a number of technological advancements in development for the diagnosis and surveillance of UTUC including narrow band imaging (NBI) and photodynamic diagnosis- guided inspection (PDD). These technologies are designed to provide better visualization and improve sensitivity of ureteroscopy. In a small study, narrow band imaging improved the rate of diagnosis of UTUC by 20% [24]. PDD has been reported to have better sensitivity as high as 95.8%. PDD has also shown to have improved ability in detecting CIS and early dysplasia [25]. Despite their promise, these technologies are still in the early phases and have limited evidence, as such they have not reached mainstream popularity [26].

Management

As examined in the introduction, classically, management of UTUC was limited to radical nephroureterectomy (RNU). Historically, only patients unfit for RNU, those with a functionally or anatomically solitary kidney, or bilateral tumors were considered for minimally invasive treatment options of UTUC. However, with the advancement of technology in the urologist’s armamentarium, a number of minimally invasive options for management of UTUC have arisen [27]. These minimally invasive options (namely via ureteroscopic, segmental resections of the ureter, and percutaneous approaches) have been termed nephron-sparing or kidney-sparing surgery (KSS). KSS is an enticing management modality with the goal of preserving the renal unit without compromising oncologic outcomes. Mostly based off of data from conservative therapy of renal cell carcinoma, by preserving the renal unit one could avoid the potential long-term cardiovascular morbidity associated with chronic kidney disease (CKD) [28].

Nephron-sparing options for the treatment of UTUC are broadly separated into segmental ureterectomy, percutaneous, and ureteroscopic approaches. This chapter specifically deals with ureteroscopic management of UTUC. Under the umbrella of ureteroscopy, there are a number of options available to the practicing urologist including cauterization techniques, a variety of lasers, and ureteroscopic resectoscopes.

There is currently no level 1 evidence regarding endoscopic management of UTUC. As discussed by the EAU non-muscle invasive bladder cancer guidelines panel, the currently available data comparing KSS to RNU is both heterogenous and scarce [29]. There are five studies that report oncologic outcomes of URS versus RNU [30–34]. Patients treated with URS were younger, were more unhealthy, and had smaller size and lower-grade UTUC. Despite this heterogeneity, the EAU has released the following recommendations in its guidelines in the management of UTUC in 2017 (Fig. 15.5) [6]:

1.

KSS should be offered as primary treatment option in patients with low-risk tumors (strong strength rating).
2.

Offer KSS in patients with high-risk distal ureteral tumors (weak strength rating).
3.

As long as not compromising survival, on a case-by-case basis, KSS should be offered to patients with a solitary kidney and/or impaired renal function (strong).
4.

Use a laser for endoscopic treatment of UTUC (weak).

../images/461848_1_En_15_Chapter/461848_1_En_15_Fig5_HTML.png — Fig. 15.5

EAU Guidelines for kidney-sparing management of UTUC. (From Roupret et al., Figs. 2, 4, 6, with permission of Elsevier [6])

Specific to ureteroscopic of UTUC, the EAU guidelines state that it can be considered as long as the following criteria are met:

1.

Laser generation and biopsy forceps are available for use.
2.

Both flexible and rigid ureteroscopes are available.
3.

The patient is aware earlier second look procedures with closer and more stringent follow-up will be necessary.
4.

Complete resection and/or destruction of the tumor is possible.

Unfortunately, there are no guidelines for UTUC from the American Urological Association. There is also no consensus on the ideal nephron-sparing approach used, and the authors would suggest surgical planning on a case-by-case basis. As indicated in the EAU guidelines, patient selection is key, with KSS being ideal for patients with low-grade or low-volume disease or those too unhealthy to undergo RNU. Deciding between a distal ureterectomy, percutaneous, or ureteroscopic approach largely depends on tumor size and location. Large tumors in the renal pelvis/ calyceal collecting system are likely best managed with a percutaneous approach. Smaller-volume tumors throughout essentially the entirety of the collecting system can be managed with a ureteroscopic approach; however, if choosing a ureteroscopic approach, the surgeon must not compromise oncologic outcomes and should be able to deal with all tumors present. The inability to treat a tumor would be an indication to move onto a more aggressive approach.

One of the first ureteroscopic modalities used in the ureteroscopic management of UTUC was the use of electrocautery, including a ureteroscopic resectoscope. One advantage of ureteroscopy with electrocautery and/or the ureteroscopic resectoscope is that the tumor can largely be debulked with cold cup forceps or ureteroscopic basket and provides for a good specimen from the surgery. Electrocautery is also relatively cheap and widely available to the practicing urologists. Despite these advantages, the use of electrocautery has largely fallen out of favor because dispersion of the energy often results in a transmural injury to the urothelium resulting in postoperative stricture, particularly in the thin-walled ureter [35]. There have also been concerns raised about the systemic effects of the absorption of hypotonic irrigation solutions (glycine, sorbitol, or water) as required when using electrocautery, though the authors would argue that the volume of fluid absorbed during ureteroscopy is quite small and this complication is exceedingly rare.

The use of lasers has become a mainstay in the ureteroscopic management of UTUC. In fact, laser ablation/destruction of the tumor is part of the recommendations from the EAU guidelines. There are a number of different types of lasers available to the practicing urologist, each with its own set of advantages and disadvantages. There is no consensus on the best laser for the treatment of UTUC, but the three most commonly used lasers are the Holmium:YAG (Ho:YAG), neodymium, and thulium lasers.

The most commonly used laser in ureteroscopic management of UTUC is the holmium:YAG laser. Its popularity is likely multifactorial, but the fact that urologists are already familiar with Ho:YAG and facilities own Ho:YAG lasers because of their use in laser lithotripsy for stone is likely a large influence. The Ho:YAG laser emits energy at a wavelength of 2100 nm, which is rapidly absorbed by water. Because of this, the depth of penetration is about 0.4 mm [17]. This shallow depth of penetration allows for concentration of the energy and is believed to lower the risk of stricture and perforation associated with the use of electric coagulators. Ho:YAG can be used on a variety of settings depending on the goal of the operation. Verges et al. have published recommendations of 0.6–1.0 J at a rate of 5–10 Hz, which is similar to the settings used in our practice [17].

Some authors have advocated for the use of the neodymium:YAG (Nd:YAG) laser in the treatment of UTU, but high-quality studies are currently lacking. The Nd:YAG laser produces a wavelength of 1064 nm, which is absorbed by both water and melanin. The absorption depth of the Nd:YAG is 10+ times that of the Ho:YAG laser at about a 4–6 mm depth. Because of its deeper depth of penetration, the Nd: YAG laser is used mostly for renal pelvis tumors and can be used in conjunction with Ho:YAG with the Nd:YAG being optimally used for tumor volume coagulation and the Ho:YAG to remove/ablate the tissue [17]. Verges et al. recommend using the Nd:YAG laser on a 30 W continuous wave setting while sweeping over the tumor and avoiding circumferential usage to prevent ureteral strictures.

The thulium laser , which has widely been used in the treatment of benign prostatic hyperplasia (BPH), has demonstrated efficacy in the treatment of UTUC in a number of small studies. The thulium laser is available in a number of wattages and produces a wavelength similar to holmium at 2010 nm. This is quite close to the peak for absorption in water at 1940 nm. In contrast to the holmium laser which is a pulsed laser, the thulium laser delivers its energy in a continuous wave. While also available in a pulsed fashion, the continuous wave mode theoretically leads to more efficient vaporization and decreases absorption depth (0.2 mm vs 0.4 mm for holmium) [36, 37]. This continuous wave also creates small microbubbles in the surrounding fluid resulting in less tip vibration and, thus, better precision.

The use of thulium laser in the treatment of UTUC was first published by Defidio et al. in 2011 [38]. In their study they found recurrence-free survival to be non-inferior compared to holmium, but with the added benefit of increased precision with less bleeding and less mucosal perforation. The most recent study of the thulium laser in the treatment of UTUC comes from Musi et al. [39]. In this study, 42 consecutive patients were enrolled for conservative management of UTUC with thulium laser. The study cohort most consisted of patients with low-grade disease, but regardless, eight (19%) patients had a recurrence and four (9.5%) underwent subsequent nephroureterectomy over a median follow-up period of 26.3 months. Because they experienced no progression or upstaging of disease with no major complications, the authors contend that thulium is a safe and effective minimally invasive option for the treatment of UTUC. The authors of the above study used 150 W and 200 W lasers on a power setting of 10–20 W, which they state has optimal vapocoagulative effects. Two hundred and seventy-two micrometers were used in cases requiring a flexible ureteroscope and 365 μm for rigid ureteroscopy. The authors started at the cranial end of the lesion and worked caudal, stating that this improves visibility. Finally, the authors recommend lowering the power setting to 5 W or increasing the distance between the fiber and the target to improve coagulation.

Surveillance

Similar to bladder cancer, the recurrence rate of UTUC is quite high and requires stringent follow-up. The true recurrence rate of UTUC is difficult to assess, particularly when managed endoscopically, largely because of the lack of currently available evidence, with most studies of endoscopically UTUC not going beyond 50 months of follow-up [40]. Most recurrences happen within 2 years of initial treatment and can occur anywhere within the collecting system, with recurrence within the urinary bladder being the most common [29]. Some authors believe that if followed indefinitely, all patients with UTUC who are treated endoscopically will have a recurrence [40]. As such, it is important when selecting a patient for endoscopic management that he or she is reliable and understand the importance of close, rigorous follow-up.

In its 2017 guidelines, the EAU recommends the following surveillance for patients who underwent KSS for UTUC (Fig. 15.6) [6]: