The diagnostic ureteroscopy before radical nephroureterectomy in upper urinary tract urothelial carcinoma is not associated with higher intravesical recurrence

Upper tract urothelial carcinoma (UTUC), involving renal pelvis and ureter, is rare in western countries but presents an unusual feature in Taiwan. The US National Cancer Database identifies a ratio of bladder cancer to UTUC of 93 to 7%. The male-to-female and pyelocaliceal-to-ureter tumor ratio incidence of UTUC are both about 2–3:1 [1, 2]. However, UTUC comprises up to 30% of all UCs in Taiwan, and the male-to-female ratio incidence is approximately equal, as well as in renal pelvis and ureter [3, 4]. The standard treatment of UTUC is radical nephroureterectomy with ipsilateral bladder cuff excision. However, minimally invasive uretereorenoscopic (URS) therapy in selected cases is also considered because it can preserve renal function and reduce morbidity. It also provides effective oncologic outcomes [5]. Because URS allows direct visualization of the entire collecting system, when combined with biopsies, it can increase the detection rate of UTUC lesions [6, 7]. However, pyelolymphatic, pyelotubular, and pyelovenous backflow of irrigation can occur during diagnostic URS [8, 9]. The raising about the possibility of backflow of malignant urothelial cells and tumor seeding during URS evaluation is to be considered to induce higher risk of intravesical recurrence (IVR). Although URS has been reported to be safe [10‐12], more evidences are needed to establish that this procedure is not harmful for patients with UTUC. Besides, the impact of delay radical treatment because of previous URS biopsy is still controversial.

The primary recognized prognostic factors of survival for UTUC are tumor stage and grade. UTUC that invade the muscle layer usually have a relatively poor prognosis. The 5-year disease-specific survival of UTUC is < 50% for pT2/pT3 and < 10% for pT4 [13]. Based on the possibility of occult micrometastases before the surgery, metastases are often discovered after nephroureterectomy [14]. In addition, previous studies showed that after nephroureterectomy for UTUC, 25 to 69% of patients would develop a metachronous bladder tumor recurrence. Therefore, to figure out the potential risk factors of survival, metastasis and subsequent IVR for UTUC are important and will affect our clinical decision in further treatment and surveillance.

In this study, we evaluated the influence of URS biopsy on survival, metastasis, and especially focus on IVR and to analyze if delay of the curative treatment will cause worse survival. We aim to provide a more precise comparison and, therefore, also assess the impact by calculating our National Health Insurance (NHI) database. Besides, we attempted to identify the significant prognostic factors to predict disease-specific survival, metastasis-free survival, and intravesical recurrence-free survival for UTUC after nephroureterectomy.

Because pathological T stage and tumor grade have been established as major prognostic factors for UTUC, it is important to determine tumor architecture, grade, and stage assessment before definite treatment [15]. To compensate for the limitations of a cross-sectional image study, URS can be used as a direct visualization method for diagnosis especially combined with biopsies. Based on the analysis of previous studies, URS has been shown to have significantly higher accuracy, specificity, and positive predictive value than multiphase computed tomography urography (MCTU) [16]; however as many hospitals do not have MCTU equipment, URS evaluation is even more important. Advance in endourologic technologies improve diagnostic accuracy without severe adverse effects and have been increasingly used for treatment purposes by direct tumor ablation with laser in selected patients. However, some previous studies have raised concerns about the possibility of intraluminal tumor seeding with manipulation during ureteroscopy and an increased incidence of IVR and metastasis [17, 18]. On the other hand, delaying radical nephroureterectomy may reduce survival rate. In order to clarify these issues and the conflicting results from several previous studies, we used both our own database and the National Health Insurance Research database to analyze the impact of pre-radical nephroureterectomy ureteroscopy on survival rate, metastasis rate, and especially the IVR rate.

Our cohort study revealed that bladder cancer history was the only risk factor for IVR after nephroureterectomy on multivariate Cox regression analysis, which is similar to the results of previous studies [19, 20]. We found that diagnostic URS did not increase intravesical recurrence rate. In accordance with the treatment guidelines at our institution, we arranged for regular imaging studies for clinical staging before diagnostic procedure or radical surgery. For patients who had a large and obvious tumor, we considered performing radical surgery without URS biopsy. For pathology evaluation before radical surgery, we performed not only URS inspection but also simultaneous tumor biopsy. We further analyzed the subgroups of patients with and without a history of bladder cancer and noted no increase in the risk of IVR whether or not patients underwent URS before radical surgery. From the NHI database results, we included only patients with UTUC who had no previous or concurrent bladder cancer history, which is a well-known important predictive factor for IVR. This analysis also revealed that diagnostic URS was not significantly associated with increased IVR. In addition, we compared the duration of nephroureterectomy to bladder cancer recurrence between the groups with and without URSs and found that the URS group did not have significantly accelerated IVR.

Although the use of diagnostic URS followed by nephroureterectomy may raise concerns about delaying the course of curative treatment in patients with UTUC, no impact was noted on cancer-specific, bladder, or contralateral upper urinary tract recurrence and metastasis-free survival [21]. Similar to our findings, we still maintain a regular follow-up schedule based on standard guidelines instead of reducing the follow-up interval even when using diagnostic URS before radical surgery.

Early diagnosis of UTUC is still a challenging issue, especially for lower stage or flat growth pattern tumors. Although various imaging modalities are available including computed tomography urography which replaced intravenous urography owing to its higher detection rate, CT urography often cannot be used to identify carcinoma in situ or to localize superficial extensions of the tumor. Chronic inflammation can easily mimic urothelial cancer, leading to false-positive findings, which constitute a limitation of CT urography for the diagnosis of UTUC [22]. Liquid biopsy is also a popular continuing research target [23]. In addition, endoscopic management or kidney-sparing surgery can be considered for a specialized group of low-risk patients with impaired renal function; therefore, in order to avoid an unnecessary radical surgery, the imperative role of URS biopsy cannot be neglected. At a minimum, it should be included as one multimodality diagnostic option. Cutress et al. reported an analysis comparing endoscopic and laparoscopic management of noninvasive UTUC, and endoscopic treatment may provide non-inferior disease-free survival compared to radical surgery only in lower grade disease [24]. In their study, they found a significantly higher risk of IVR when patients received endoscopic management rather than laparoscopic management in higher grade (G2 and G3) disease but not in low-grade disease. Among our high-grade and low-grade subgroups, there was no significant difference between patients with and without URS biopsy. Moreover, in a previous study, about 3% of patients with suspected UTUC who underwent radical surgery were reported to eventually have benign pathology and that they need to be prevented from unnecessary radical surgery [25]. Therefore, careful investigation in patients with previously suspected UTUC is critical.

In previous studies, about half of patients with UTUC encountered IVR after receiving radical surgery [26], which is higher than our results (around 27% (138/502)). Although IVR was not related to an increased risk of poor survival or distant metastasis, about 5–10% of recurrent bladder tumors progressed to a muscle-invasive state that is an important risk factor for poor survival and metastasis [27]. Given the high risk of IVR, patients with UTUC after undergoing radical surgery are recommended to undergo regular endoscopic surveillance. Therefore, it is important to consider this issue to reduce the risk of IVR. Our current study indicates that bladder tumor history is the only prognostic factor for IVR. If a higher probability of IVR is suspected after radical surgery, single-dose immediate intravesical chemotherapy is reported to be a feasible and safe strategy to prevent IVR in patients with UTUC [28]. Yoo et al. hypothesized that tumor location is a key factor affecting IVR after URS with manipulation. In their assessment, the reason for bladder tumor recurrence from the ureter tumor is the previous shedding of tumor cells owing to the short distance from the ureter tumor to the bladder. They concluded that URS biopsy was an independent risk factor for IVR only in patients with a renal pelvis tumor which offsets the protective distance between the renal pelvis and the bladder [29]. Compared to our data, no matter where the tumor is located, URS biopsy before radical surgery does not increase the risk of IVR. Based on these results, the actual mechanism of IVR is still not clear; it may not be simply from tumor detachment induced by manipulation.

There are some limitations to the present study in addition to its retrospective design. However, in order to increase its accuracy, we also analyze the National Taiwan Insurance Database and included more patients with UTUC. The first limitation was that some possible prognostic factors for IVR including bladder cuff management method and concomitant carcinoma in situ were not included. Furthermore, we could not compare our patients with those receiving URS without biopsy or with laser treatment for kidney-sparing surgery. In addition, the impact of URS on the conditional survival of IVR over time needs to be assessed because Shigeta et al. concluded that the influence of most predictive factors for IVR diminish over time [30]. A recent meta-analysis comprising six studies concluded that diagnostic URS before radical surgery seems to increase the risk of IVR after radical surgery. However, all of these six studies had the same results, and they need to be considered cautiously with various limitations. As we discussed, previous analyses have reported that diagnostic URS before radical surgery has no significant effect on IVR. On the other hand, the duration required to define bladder tumor recurrence and a primary bladder tumor event is still unclear. Nevertheless, our findings indicate that a two-session approach was not an independent risk factor for increased IVR.

Diagnostic URS before radical nephroureterectomy does not significantly increase the risk of worse survival, progression, and intravesical recurrence even in patients who have no history of bladder cancer. Our data from both our institution and the NHI database indicate that diagnostic URS can be part of a diagnostic strategy especially in flat, small tumors which are difficult to identify on imaging studies and when patients plan to undergo conservative treatment.