Introduction

Although urothelial carcinoma of the bladder is the fourth most common cancer entity in men, upper urinary tract (UTT) cancer is rare, since these tumors represent only 5–10% of urothelial tumors [1, 2]. Men are affected 3× as often as women and tumors of the renal pelvis occur about twice as frequently as tumors of the ureter [3]. Moreover, a bladder tumor exists concurrently in about 17% of cases of a UUT tumor [4]. An intravesical recurrence after UUT tumors is observed in 22–47% of cases [2]. In general, recurrences in the contralateral UUT are rare with only 2–6% [2, 5, 6].

In stark contrast to urothelial bladder tumors, 60% of newly diagnosed UUT tumors are found at an invasive tumor stage (>T1) [7]. UUT tumors invading the muscle layer are associated with a poor prognosis. The 5-year survival rate is less than 50% for pT2/3 tumors and below 10% for pT4 tumors [8, 9].

Radical nephroureterectomy (RNU) is the gold standard for operative management of larger UUT tumors. However, kidney-preserving therapy strategies are being used with increased frequency for tumors affecting the ureters only [10]. RNU is regularly performed with the inclusion of a bladder cuff resection (BCR) and surgery may be performed via an open, laparoscopic or robot-assisted approach along with a lymph-node dissection [11]. Interestingly, retrospective SEER Database analysis including T1-T3 N0 M0 patients with UUT cancer found no significant 5-year overall survival or cancer specific survival benefit utilizing bladder cuff resection, despite the observation of a growing number of guideline conform performance of bladder cuff resection, in 68% of all patients [12]. A systematic review of available, merely retrospective data confirms that laparoscopic RNU is a safe method as compared to open surgery with similar minor and major complication rates and offers beneficial effects such as reduced blood loss, transfusion rates and shorter hospital stay [13]. No differences in 5-year recurrence rates or cancer specific survival could be observed [13]. Noteworthy, longer operation time has been reported for the both the conventional and robotic minimal invasive approach [11, 13]. The issue of how an oncologically safe and surgically standardized BCR may be accomplished during a minimal invasive procedure represents a relevant question still to be answered, given the variable techniques described in the literature. BCR may be performed through a transvesical, extravesical, or endoscopic approach and currently, these methods include open excision via a Gibson incision, transurethral resection (TUR) of ureteral orifice (pluck technique), ureteric intussusception, and pure laparoscopic or pure robotic-assisted laparoscopic resection techniques [14]. Irrespective of the surgical approach, a single postoperative dose of intravesical mitomycin C appears to reduce the risk of a bladder tumor within the first year following RNU for UUT cancer. An absolute risk reduction of 11% was reported in a prospective randomized trial, while the relative risk reduction was 40%, and the number needed to treat to prevent one bladder tumor was nine [15].

Recent study results, which describe prognostic disadvantages of reduced kidney function after RNU, highlight the principle of organ-preserving therapy, also in patients without imperative indications for organ preservation [16] and have led to a more frequent utilization of endoscopic approaches in urothelial cancer. By contrast, given the paucity of published data for non-urothelial cancer of the UUT, treatment for aberrant histology usually requires radical surgery [17, 18].

Diagnostics and Imaging of Tumors of the Upper Urinary Tract

With the establishment of modern computer tomography (CT) techniques, excretory urography has finally lost its relevance in the diagnostics of UUT tumors, and it is no longer discussed in the current guidelines [2]. Nonetheless, it still represents an established diagnostic tool in the clinical routine. Retrograde ureteropyelography is frequently used for the assessment of the upper urinary tract, because of the possibility of simultaneous cystoscopic evaluation. Moreover, a selective urine sample from the renal pelvis can be obtained for cytological analysis prior to application of contrast agents.

With a sensitivity of 67–100% and a specificity of 93–99%, CT imaging is the technique with the highest diagnostic precision for UUT tumors [19, 20]. Performing a urographic phase, 10–15 min after application of contrast agents, is necessary for meaningful diagnostics. The diagnostic advantage of CT in comparison to excretory urography is the option to also detect a contrast-enhanced thickening of the wall of the renal pelvis or the ureter in the arterial or portal-venous phase, without the existence of a urographically suspicious area.

Analogously to excretory urography, the glomerular filtration rate should not fall below 45 mL/min during the i.v. application of contrast agents containing iodine [21].

In cases of intolerance of contrast agents, magnetic resonance (MR) urography is, besides retrograde pyelography, the diagnostic alternative of choice. For UUT tumors <2 cm, the sensitivity of MR urography around 75% [22]. The kidney function of the patients should be given consideration also for MR urography, since gadolinium increases the risk of renal systemic sclerosis in patients with chronic renal insufficiency or at a glomerular filtration rate <30 mL/min [23].

Endoscopy

The method of choice for the evaluation of the UUT is diagnostic (flexible) ureterorenoscopy with the option of simultaneously taking a biopsy. Tumor detection by biopsy and prediction of the grade of differentiation is successful in 90% of the cases, with a low false-negative rate [29]. Nonetheless, undergrading and understaging is possible through the use of biopsies. A reliable differentiation of invasive and non-invasive lesions is made difficult both because of the anatomical features of the upper urinary tract and also because of the technique of taking the biopsy and the size of the resulting sample. The limited size of the biopsy needle and sample does not allow for exact prediction about the wall layers, i.e. the degree of infiltration. Furthermore, the biopsy usually contains only tissue from the papillary part of the tumor. Moreover, pathological upgrading was reported to occur in up to 51% of cases when preoperative and postoperative specimen after definitive surgery were compared, indicating the need for extensive endoscopic sampling in case of an organ-sparing approach [30]. Given the recent development in molecular analysis of tissue specimen, preliminary results exist that illustrate reproducibility of mutation analyses between biopsies and RNU specimen [31]. However, no clear determination of candidate aberrations or panels have so far been established as clinical routine.

Studies on filter-based endoscopic procedures show results that are quite promising, even though preliminary, especially for the endoscopic evaluation of flat urothelial lesions [32]. In narrow-band imaging, the wavelength of white light, for example, is specifically reduced (415–540 nm). In this way, fine structural changes of the mucosa can be made identifiable more effectively. The deeper tissue layers are not reached, and the light is absorbed by blood vessels, so that the contrast of epithelial, light-reflecting areas and heavily vascularized, non-reflecting areas is intensified. With the SPIES SPECTRA™ technology, specific regions of the color spectrum are intensified through color-tone shifting, so that blood vessels and capillaries are represented more clearly. The spectral separation takes place within the camera system without the need for a special light source. Clinical investigation for the application of this technology in the bladder and upper urinary tract is under way. The use of photodynamic diagnostics (PDD) in the upper urinary tract has been evaluated in a few studies. The instillation of 5-aminolevulinic acid (5-ALA) in the urinary tract via a percutaneous nephrostomy or a ureteral stent was described as technically feasible for the preoperative evaluation of a UUT tumor and the detection of a CIS [33]. Nonetheless, the small capacity of the cavities of the renal pelvis and the ureter and the shortened duration of local exposition should be considered as a detrimental factor. Somani and colleagues have also reported on the possibility of a PDD endoscopy 3–4 h after oral administration of 5-ALA in four patients [33].

Prognostic Factors and Risk Stratification for Tumors of the Upper Urinary Tract

Besides radiological and endoscopic diagnostics, the identification of patient-associated and pathological prognostic factors in UUT cancer is highly relevant, with regard to a possible curative organ-preserving procedure. Analogous to the treatment of non-muscle invasive urothelial bladder cancer [34], preoperative risk stratification for UUT tumors is recommended, in particular addressing the question of an organ-preserving therapy. The European Association of Urology (EAU) Guidelines recommend that patients with normal contralateral kidneys are divided into the “low risk” and “high risk” categories as suggested in Table 32.1. Figure 32.1 illustrates a possible clinical algorithm for UUT tumors, based on this risk stratification [10].

Table 32.1

Risk stratification of UUT tumors with normal contralateral kidney according to EAU guidelines

High-risk	Parameter
Clinical factors	Hydronephrosis
	High-grade URS biopsy
	High-grade cytology
	Tumor size >1 cm
	Invasive aspect in cross-sectional imaging
	Multifocal lesions
	Endoscopic therapy failure for “low-risk UTUC”
Patient-related factors	Previous Urothelial carcinoma of the bladder and/or cystectomy
	Smoking
Low-risk UTUC
Clinical factors	Low-grade URS biopsy
	Low-grade cytology
	Tumor size <1 cm
	No invasive aspect in cross-sectional imaging
	Unifocal lesion
Patient-related factors	Intensive follow-up possible and accepted by the patient

Pathological tumor stage and grade, as well as the proof of an extra-nodal extension in lymph-node positive UUT tumors are relevant for prognosis [8, 9, 35]. Patient sex has not been identified as an independent prognostic factor for overall survival. A high patient age at radical nephroureterectomy has been shown to be associated with a reduced tumor-specific survival [36, 37]. The primary localization of a UUT tumor in the renal pelvis or the ureter is also relevant for prognosis: ureteral and multifocal tumors have a poor oncological outcome as compared to tumors localized in the renal pelvis, after adjusting for tumor stage [38].

Furthermore, smoking at the time of diagnosis, as well as the duration and intensity of tobacco consumption are proven prognostic factors for UUT cancer [39, 40]. An additional, important pathological risk factor is the presence of lymphovascular invasion, so the pathology analysis should be performed with particular attention to this finding [41, 42]. Although diverse molecular markers have been investigated with regard to their prognostic importance for UUT tumors, there is currently no sensible parameter included into the preoperative risk stratification. Considering the difficult classification of tumors with high or low malignant behavior, the search for suitable prognostic factors at the molecular level remains however important for tumors of the upper urinary tract. Table 32.2 summarizes patient-associated and pathological prognostic factors for UUT tumors.

Table 32.2

Prognostic factors in tumors of the upper urinary tract

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