Several studies explored the relationship between hydronephrosis on preoperative imaging, pathologic stage, and CSS in patients with UTUC. Presence of hydronephrosis has been associated with more advanced disease stage [22–24] and CSS [25].

The presence of systemic symptoms such as pain or weight loss has been associated with presence of higher-stage and higher-grade UTUC [26] and OM in patients treated with RNU for UTUC [27]. Further multi-institutional efforts are still needed to validate this predictor. With more advanced imaging studies, most of the patients with systemic symptoms will be likely identified as metastatic.

The impact of tumor location (renal pelvicalyceal system compared with ureter) on the prognosis of patients with UTUC is controversial. Several single-institutional studies initially reported that ureteral location was associated with worse outcomes [28, 29]. A recent multi-institutional French study confirmed these findings [8]. On the contrary, several other population-based and multi-institutional studies found no association of tumor location with oncologic outcomes after RNU once adjusted for tumor stage [5, 30]. To conclude, the currently available retrospective studies do not permit a definitive conclusion regarding the impact of tumor location on UTUC prognosis. However, while there is a differential impact of tumor location on tumor stage, lymph node status and tumor stage are more powerful drivers of tumor biology and clinical behavior.

Multifocal tumors are defined as tumors with two or more distinct locations within the urinary tract. Tumor multifocality (occurring in at least 30 % of patients) in retrospective studies has been shown to be an independent predictor of CSM (Fig. 4.2) [8, 31]. Tumor presence in both the renal pelvicalyceal system and ureter is worse than either location with regard to cancer-specific outcomes [32]. Based on the current literature evidence, tumor multifocality should be routinely determined by clinicians with adequate sampling and reported by pathologists.

Tumor size is an established predictor of cancer-related outcomes in several malignancies. A cutoff of tumor diameter of 3 cm and 4 cm has been associated with occurrence of metastasis [33] and intravesical recurrence after RNU [34], respectively. Both these studies need validation in studies with larger cohorts. From clinical experience, Ta tumors can reach a large size and have a low risk of becoming invasive. Whether tumor size is an accurate predictor of biological behavior of an individual tumor remains to be determined.

Endoscopic evaluation (+/−biopsy) establishes the definitive diagnosis of UTUC and helps risk stratify patients towards conservative or radical management. Biopsy grade is accurate and can help predict pathologic findings [24]. Unlike lower tract UC, the clinical staging of UTUC is difficult because biopsies that include underlying muscle are generally not possible [35]. Imaging studies can help improve clinical staging based on the presence of hydronephrosis (see above) and invasion in soft tissue [36].

UTUC are considered part of a pan-urothelial phenomenon that can yield multifocal tumors including lower tract UC. Previous history of bladder cancer has been associated with intravesical recurrence [37, 38], DR, and CSM after RNU [37, 39].

In lower tract UC, a delay between diagnosis and radical cystectomy (≥3 months) is considered to have a negative impact on prognosis. In UTUC, a multi-institutional study investigated the prognostic impact of the time interval between diagnosis and RNU on oncologic outcomes [40]. The study showed that a longer interval (≥3 months) was also associated with advanced pathological stage, DR, and CSM in patients with invasive disease [40]. This data together with that from the lower tract indicated that once the tumor becomes invasive, which is difficult to assess clinically in UTUC, one should proceed to definite therapy in a time-sensitive fashion.

Open RNU (ONU) with excision of a bladder cuff is considered the gold standard treatment of invasive or high-risk noninvasive UTUC regardless of the location of the tumor in the urinary tract [1]. Laparoscopic RNU (LNU) has emerged as a minimally invasive alternative to ONU, with advantages in terms of lower blood loss, shorter length of hospital stay, and shorter convalescence [41, 42]. To date, only one prospective randomized trial showed no difference in terms of DR and CSM between LNU and ONU [43]. In non-organ-confined tumors LNU was inferior to ONU. This difference could be attributed to surgeon experience and other factors such as the differential use of lymph node dissection between the two groups. A population-based study (with a propensity score matched analysis) and a meta-analysis of retrospective studies confirmed the safety of LNU with regard to oncologic outcomes when compared to ONU [41, 42]. As long that one abides to the oncologic principles, there should be no difference between the different approaches.

Excision of the bladder cuff is mandatory for invasive or high-risk noninvasive UTUC [1]. Moreover the procedure must comply with oncological principles, which consist of preventing tumor seeding by avoiding entry into the urinary tract during tumor resection. Resection of the distal ureter and its orifice is performed because it is a part of the urinary tract with considerable risk of tumor recurrence. After removal of the proximal part, it is almost impossible to image or approach it by endoscopy during follow-up. Recent publications on survival after RNU have concluded that removal of the distal ureter (bladder cuff) improves prognosis after RNU [44]. Moreover, endoscopic distal ureter management has been associated with a higher risk of intravesical recurrence (Fig. 4.3) [9]. While there have been a variety of techniques described for the management of the bladder cuff, complete removal is what really matters. Techniques such as ureteral stripping lead to incomplete surgery and should be avoided [1].

Lymph node dissection (LND) during RNU allows for optimal staging of the disease and may have a therapeutic role [45]. However, the anatomical sites of LND have not yet been clearly defined. Specific LND templates are likely to have a greater impact on patient survival than the number of lymph nodes removed (Fig. 4.4) [45, 46]. The cumulative data from the literature on this subject suggest that a LND should be performed during RNU or distal ureterectomy for invasive UTUC [1, 45]. The templates for LND need to be defined through large multicenter template studies. Similarly to lower tract UCB, a pathological nodal staging score has been proposed in order to predict the probability of a patient staged as pN0 to be truly node negative (Fig. 4.5) [47]. However, all data are retrospective; consequently, underreporting of the true rate of node-positive disease is likely.

Pathologic tumor stage represents the best-established predictor of survival in patients with UTUC and should always be considered in the preoperative and postoperative counseling of these patients, specifically in the determination of the intensity of postoperative surveillance and the decision-making regarding adjuvant therapies and trials (Fig. 4.6) [39, 48].

Tumor grade represents another well-established predictor of cancer-related outcomes in patients with UTUC because it is strongly related to the single cell behavior and tumor stage (Fig. 4.7). Both the 1973 and the 2004 World Health Organization (WHO) classifications are predictive of outcomes [48, 49]. Tumor grade should always be taken into account in the preoperative and postoperative counseling of these patients. Specifically in the preoperative setting, tumor grade can help guide decision regarding RNU versus endoscopic management.

Concomitant carcinoma in situ (CIS) of the upper urinary tract represents a rare entity that is considered to be associated with DR and CSM in patients with organ-confined disease [50]. Moreover, presence of concomitant CIS is associated with intravesical recurrence after RNU [51, 52]. Therefore, the presence of concomitant CIS should always be evaluated in patients with UTUC, because they may require more aggressive surveillance regimens and strategies utilizing topical therapies.

The presence of lymph node invasion (LNI) is considered an important prognostic factor, indicating the metastatic spread of a tumor to its lymph nodes [45, 48]. In patients with LNI, lymph node density (≥30 %) may help risk stratify patients with regard to DR and CSM [53]. Extranodal extension appears to be a powerful predictor of clinical outcomes in patients with LNI [3, 53]. LNI is an important prognostic factor in patients with UTUC. Efforts are still needed to standardize the indications and LND templates.

In retrospective studies, lymphovascular invasion (LVI) is present in approximately 20 % of UTUC and it represents an independent predictor of DR and CSS specifically adding information in patients with lymph node negative UTUC [4, 54]. LVI status should be reported in the pathologic report of all UTUC specimens [4, 54]. Consensus regarding the pathologic definition of LVI needs to be reached.

Several studies have investigated the prognostic impact of tumor architecture (sessile compared with papillary) on the survival of patients with UTUC. Three multi-institutional studies found that a sessile/infiltrative growth pattern was associated with features of aggressive disease, DR, and CSM [48, 55, 56]. These findings suggest that tumor architecture should always be mentioned during the endoscopic evaluation of UTUC, as well as in the gross description of the pathological reports.

Extensive tumor necrosis (defined as >10 % of the tumor area) is an independent predictor of oncologic outcomes in patients after RNU [57]. However, a recent multicenter international study failed to confirm these findings [58]. Thus, the prognostic role of tumor necrosis in UTUC patients needs further confirmation in larger well-designed multi-institutional studies. Whether it adds to other pathologic features thereby impacting clinical decision-making remains to be proven.

The presence of positive surgical margins is reported in ≤8.5 % of RNU cases and strictly depends on the management of the bladder cuff. Presence of positive surgical margins has been associated with higher rates of DR and CSM [59]. One needs, however, to differentiate between ureteral positive margin and soft tissue positive margin. While both negatively impact outcomes of the patient, soft tissue positive margins lead to fast demise of the patient [59].

In retrospective studies, almost 25 % of patients with UTUC treated with RNU harbor histological variants [60]. Variant histology was associated with features of aggressive disease [60], but not with oncologic outcomes when adjusted for the effects of standard clinicopathological features [60]. Moreover, variant histology does not seem to affect response to adjuvant systemic chemotherapy in patients treated with RNU [61]. Future studies may allow to differentiate between the different types of variant histology.