Routine Diagnostic Ureteroscopy for Suspected Upper Tract Transitional-Cell Carcinoma

Introduction

Upper tract transitional-cell carcinoma (utTCC) is relatively uncommon, but its incidence has been on the rise in the past decades and it represents today about 7% of all kidney cancers. ¹ Nephroureterectomy (NU) with ipsilateral bladder cuff excision remains the gold standard treatment for utTCC regardless of tumor location, whereas in selected patients, endoscopic treatment may be appropriate. ² NU has been shown to offer good oncologic outcomes; however, morbidity and mortality are considerable, even in centers of excellence. ^3,4 In addition, the impact of NU on renal function is substantial, and new onset of chronic kidney disease after NU in not uncommon. ^5,6 Population-based studies indicate that NU may have almost 2% 30-day and as high as 4.4% 90-day mortality rates. ^7,8 The majority of deaths occurred because of renal insufficiency and cardiovascular disease. ⁸

It is well known that several other pathologies, both malignant and benign, can mimic utTCC on imaging studies, ^{9 –11} but the extent of misdiagnoses is not known. Current indications for NU include suspicion of infiltrating utTCC on imaging and high-grade tumor cells on urinary cytologic evaluation. Cytology, however, has less than optimal sensitivity, particularly for utTCC.

Ureteroscopy (URS) is a valuable diagnostic tool that allows for better determination of the extent of the lesion as well as tissue sampling that may aid in determining whether a nephron-sparing approach can be used. To date, the routine application of diagnostic URS in the evaluation of suspected utTCC is debated with conflicting and low-grade evidence to support either view. ^12,13 At our institution, since 2010, URS has been incorporated into the routine practice when evaluating patients with suspected utTCC based on imaging, cytology, and cystoscopy.

In this study, we compare our experience with and without routine URS evaluation in the setting of suspected utTCC. We assess the value of URS in helping establish the correct diagnosis preoperatively and evaluate the ability of routine URS to shift the procedure choice from NU to less morbid treatment options.

Patients and Methods

After approval form the Institutional Review Board, records of patients undergoing evaluation for suspected utTCC at our institution between 2002 and 2013 were reviewed. Demographic, clinical, radiographic, and pathologic data were retrieved. The patients were then divided into two groups based on our changed clinical practice patterns. Since 2010, diagnostic URS has been incorporated into the evaluation protocol for patients with suspected utTCC along with physical examination, laboratory studies, urine cytology, and imaging (CT and retrograde pyelography). Before 2010, URS was used in selected cases.

Demographic, clinical, and pathologic characteristics were summarized for this cohort and compared between the groups. Patient management strategies were summarized and compared between the groups to assess changes in the management plans with routine use of URS. NU was considered the baseline option, and any other procedure was considered a change in patient management. In a subset of patients with suspected TCC after complete workup, the rates of misdiagnosis were compared based on implementation of URS in the evaluation. Number needed to treat (NNT) was calculated to estimate the impact of URS on management strategies and correct diagnosis.

Statistical analyses were performed using R software version 3.0 with Hmisc, gmodels, and epicalc packages (The R Foundation for Statistical Computing, Vienna, Austria). All tests were two-sided; P values <0.05 were considered statistically significant.

Results

A total of 118 patients were evaluated for suspected utTCC. Of those, 63 (55%) were seen before the introduction of routine URS (group 1) and 55 (47%) after (group 2). Patient characteristics and comparisons between the groups are summarized in Table 1. Overall, the rates of TCC on final diagnosis were comparable between the groups (77.8% vs 85.5% in groups 1 and 2, respectively; P=0.347). Patient demographic characteristics were comparable between the groups (Table 1). Six (9.5%) patients in group 1 underwent URS, compared with 41 (74.5%) in group 2, P<0.001.

While the rates of pathologically confirmed TCC were similar between the groups, NU was performed in 56 (89%) of patients in groups 1compared with 38 (69%) in group 2, P=0.011. The resulting NNT was 5.05 (3.0–20.3) indicating that approximately every five patients undergoing routine URS would avoid a NU shifting the management options toward either nephron-sparing (distal ureterectomy, endoscopic treatment or partial nephrectomy) or less morbid procedures (e.g., radical nephrectomy).

Subsequently, in a subset of patients with suspected TCC after complete preoperative evaluation (with or without URS evaluation), we assessed the rates of discrepancies with final pathologic findings. A total of 58 and 48 patients from groups 1 and 2, respectively, were included. In this subset, the overall rate of misdiagnosis (not TCC on final pathologic findings) was 10/106 (9.4%). Before routine URS evaluation, the misdiagnosis rate was 9/58 (15.5%) whereas with routine URS use, misdiagnosis occurred in 1/48 (2.1%), P=0.021. The estimated NNT was 7.44, indicating that approximately seven URS evaluations performed would potentially avoid one misdiagnosis of TCC.

One URS procedure was aborted because of a kinking ureter. Sepsis developed in two patients after URS. No other URS complications have been observed in this series.

Discussion

utTCC is relatively uncommon, and the gold standard treatment is represented by NU. Evaluation of suspected utTCC includes imaging, urine cytology, and cystoscopy to rule out concomitant bladder tumors. ¹³ In the case of utTCC, however, cytology sensitivity is suboptimal at best, and a wide range of both benign and malignant conditions can mimic utTCC on imaging. ^{9 –11} The value of application of routine diagnostic URS in evaluation of suspected upper tract TCC, however, is debated. ^12,13 Indeed, while the European Association of Urology guidelines recommend diagnostic URS at a grade C level, textbooks state that routine URS should not be perfomed. ^12,13 In this study, we suggest that routine use of URS in the setting of suspected utTCC may be of clinical benefit, increasing the use of treatment options with less morbidity as well as reducing the rates of misdiagnoses.

We believe that the goals of diagnostic URS in this setting are that of confirm or rule out (visually and pathologically) utTCC, enable same session endoscopic treatment in selected cases, and enable consideration of nephron-sparing treatment options. In our current practice, URS evaluation is considered for every patient with suspected upper tract TCC by imaging and laboratory studies. In the presence of imaging suspicion of utTCC, however, we refrain from URS in the following scenarios: (1) Nonfunctioning kidney; (2) history of ipsilateral utTCC; (3) positive biopsy results of regional lymph nodes; or (4) positive cytology with multifocal imaging findings. All the analyses in the present study were performed on an “intention to treat” basis—i.e., comparing practice patterns rather than by actual receipt of diagnostic URS in the workup.

The overall rates of pathology-confirmed utTCC were comparable with and without routine URS. We observed a marked change in the choice of surgical treatment with URS, however. In fact, our results suggest that in roughly one third of patients with suspected utTCC, URS evaluation may enable organ-preserving treatment options with less morbidity. In our series, one third of the patients who had undergone URS were treated either endoscopically, with distal ureterectomy, or simply followed because of benign endoscopic findings. We estimate that every five routine URS procedures may avoid NU.

When comparing preoperative with final pathologic diagnosis, we noted that while the rate of misdiagnoses (non-TCC by final pathologic findings) was reduced from 15.5% to 2.1% by using routine URS evaluation. We estimate that including diagnostic URS as part of the workup could potentially avoid mislabeling one disease as TCC for every seven patients evaluated. Endoscopic evaluation of the upper tract can identify other conditions mimicking TCC such as strictures, hematomas, blood clots, foreign bodies, and so on. Moreover, the ability to obtain tissue for pathologic analysis can help define the nature of malignancy and differentiate TCC from other neoplasms (e.g., renal-cell carcinoma, oncocytoma, etc,) before performing NU.

With the aforementioned findings in favor of URS, the other side of the coin is URS complication rate. In this cohort, in one patient, URS could not be completed because of a kinking ureter and resulted in sepsis in this and another patient. The potential benefits of URS need to be weighed against the potential increase in morbidity.

The findings of this study should be evaluated in light of its limitations. First, the retrospective nature of the study has to be taken into account. In addition, this is a single institution study, and results will need to be confirmed in other, potentially larger cohorts. Finally, the sample size may have limited the statistical power of the analyses, preventing us from reaching an accurate estimate of effect magnitudes. These results would need to be confirmed in prospective randomized studies.

Despite the aforementioned limitations, to the best of our knowledge, this is the first study to assess the value of introducing URS as part of a routine protocol in evaluation of suspected utTCC. The results indicate that URS not only increases preoperative diagnostic confidence but also may enable less invasive, nephron-sparing treatments in a large proportion of patients with suspected utTCC. If these findings are confirmed in other studies, we think URS should be considered to be routinely included into the protocols of evaluation for patients with suspected utTCC.

Conclusions

In this study, routine URS study for patients presenting with suspected utTCC based on clinical findings, imaging, and cytology appears to enable an increased use of other treatment choices rather then radical NU. It is estimated that every five URS studies may avoid one NU. Moreover, URS increased the diagnostic accuracy and reduced the rates of misdiagnosis of TCC. Complications associated with URS, however, may add an additional morbidity burden that needs to be considered. Further studies are needed to confirm these initial results.