Predicting pathological upstaging after radical nephroureterectomy in patients with upper tract urothelial carcinoma: results from a multicenter cohort study

Introduction

Upper tract urothelial carcinoma (UTUC) is staged using the tumor-node-metastasis (TNM) classification system of malignant tumors. Lymph node dissection has been associated with better outcomes in muscle-invasive upper UTUC categorized at T2 or higher (1). However, it is challenging to distinguish T2 from T1 or lower using the current imaging modalities (2,3). Therefore, accurately preoperatively differentiating between T2 or lower and T3 or higher stages is important when considering the indication for lymph node dissection. Additionally, adjuvant chemotherapy has become widely adopted following the results of the POUT trial (4). Considering the postoperative decrease in renal function in cases of advanced UTUC of stage T3 or higher, with or without lymph node involvement, urologists may recommend neoadjuvant chemotherapy before surgery (5-7). Thus, this study focused on risk factors to differentiate between T2 or lower and T3 or higher disease stages.

Computed tomography urography (CTU) and magnetic resonance urography (MRU) are primarily used for preoperative UTUC staging (8,9). MRU has a lower spatial resolution than CTU and has been less used for imaging of UTUC. Due to its high diagnostic accuracy, CTU has become widely adopted for clinical assessments of UTUC. CTU offers the advantage of evaluating the renal pelvis, ureter, bladder, lymph nodes, and distant metastases simultaneously, which has popularized its use. Several guidelines, including the European Urology Association guidelines, recommend CTU as the first-line imaging modality to evaluate UTUC (10). However, despite the availability of advanced imaging technologies, it remains difficult to achieve sufficient staging accuracy to ensure a tailored treatment strategy for patients with UTUC (11).

Treatment strategies vary according to the preoperative clinical T stage, making precise prediction of the pathological T stage crucial. While a computed tomography (CT)-based grading system has been proposed, relying solely on preoperative imaging to determine the T stage remains inadequate (3,12,13). Additionally, there is a scarcity of data regarding preoperative risk factors linked to tumor upstaging in patients with UTUC. Thus, in this study, we identified cases initially staged as cT2 or lower, which were subsequently upstaged to pT3 or higher, and analyzed the risk factors associated with this upstaging. UTUC was divided into renal pelvic cancer and ureteral cancer for further subgroup analysis, and the risk factors associated with upstaging in each subgroup were analyzed. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-24-357/rc).

Methods

Patient demographics

We analyzed the data from patients who underwent nephroureterectomy at The Jikei University Hospital (Tokyo, Japan) and its 12 affiliated institutions, known collectively as the JIKEI-YAYOI Collaborative Group, between January 2012 and December 2021 (14-16). We excluded patients for a lack of detailed clinical information (73 patients), indeterminate pathology results (2 patients), and diagnoses of non-urothelial carcinoma (38 patients). After further excluding 78 patients who had received neoadjuvant chemotherapy, those who had undergone preoperative imaging other than CTU [simple CT: 119 cases, magnetic resonance imaging (MRI): 110 cases], and 12 patients in whom more than 90 days had elapsed from the preoperative imaging evaluation to surgery, the study cohort included 496 patients (Figure 1). The surgeries were performed by specialized genitourinary surgeons who chose between open or laparoscopic methods based on the preferences of the patient and surgeon. All patients underwent cystoscopy before radical nephroureterectomy to confirm the absence of bladder tumors. At each of the participating institutions, the standard procedure involved a radical nephroureterectomy, including the removal of the bladder cuff. The attending genitourinary surgeons determined the extent and execution of lymph node dissection and there was no strict protocol for the lymph node dissection. Board-certified radiologists independently evaluated the CTU data, without awareness of the final pathological findings, and categorized tumor stages as T2 or lower, T3, or T4. Initially, we selected patients diagnosed with clinical stage T2 or lower. We assessed various preoperative factors, including sex, age at surgery, Charlson comorbidity index score, cytology from voided urine, tumor location, tumor size, tumor multifocality, presence of hydronephrosis, and the interval between the CT scan and surgery. This evaluation was aimed at identifying factors associated with an increase in tumor stage at pathology compared to the initial clinical assessment. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by institutional ethics board of the Jikei University School of Medicine {No. 36-005[12104]} and individual consent for this retrospective analysis was waived due to the retrospective nature. All participating hospitals were informed and agreed the study.

Figure 1 Flow diagram illustrating the inclusion of patients in the study. UTUC, upper tract urothelial carcinoma; UC, urothelial carcinoma; NAC, neoadjuvant chemotherapy; CTU, computed tomography urography.

Clinical and pathological evaluation

Clinical and pathological tumor staging was conducted using the guidelines from the 8th edition [2017] of the American Joint Committee on Cancer. Tumor grading followed the classification system of the 1973 World Health Organization. Lymphovascular invasion (LVI) was identified by the presence of tumor cells within the endothelial lining of vascular or lymphatic channels. Board-certified radiologists assessed and categorized tumor stages as T2 or lower, T3, or T4. Meanwhile, board-certified pathologists determined the pathological stage, tumor grade, and the presence or absence of LVI to ensure diagnostic consistency. Studies have indicated that the surgical wait time for UTUC should be less than 1 month for nephroureterectomy (17). Consequently, we set the cut-off time at 30 days. Similarly, based on previous studies (18-20), we established a cut-off tumor size of 30 mm. Tumor multifocality was defined as the simultaneous presence of two or more confirmed tumors in any location (renal pelvis or ureter) as identified by CTU. Papanicolaou classification was used for the urine results. Positive urine cytology was defined as malignant or atypical cells highly suggestive of urothelial carcinoma. We conducted multivariate analysis to identify the factors predictive of upstaging. The variables examined included gender, age, Charlson comorbidity index score, voided urine cytology, tumor size, tumor location, hydronephrosis, tumor multifocality, and the interval from the CT scan to surgery.

Statistical analysis

Data for continuous variables were reported as medians with interquartile ranges (IQRs), and categorical variables were presented as frequencies. The Chi-squared test and Mann-Whitney U test were used for the statistical comparisons between groups depending on the data characteristics. Multivariate logistic regression analyses were conducted to predict upstaging. A P value <0.05 was considered significant. All statistical analyses were conducted using Stata software (version 13.1, Stata Corp., College Station, TX, USA).

Results

Patient characteristics

In total, 496 patients were included in the analysis; their characteristics are shown in Table 1. The median follow-up was 22 (IQR, 9–42) months. Among the 496 patients, 392 (79.0%) were diagnosed with cT2 or lower, 89 (17.9%) with cT3, and 15 (3.0%) with cT4 by CTU. Of the 392 patients diagnosed with cT2 or lower, 125 (31.9%) were diagnosed with tumors upstaged to pT3 or T4; their characteristics are shown in Table 2. The clinical N status was negative in all cases diagnosed as cT2 or lower. The median age was 74 years and 70.7% of the cohort was male. No significant difference was observed between the number of patients who had renal pelvic cancer and those who had ureteral cancer (P=0.50). Voided urine cytology (P<0.001) and preoperative tumor size (P=0.006) were correlated with pathological tumor upstaging (Table 2).

Risk factors for upstaging

A multivariate logistic regression analysis was conducted to identify factors independently associated with pathological tumor upstaging (Table 3). Positive voided urine cytology [hazard ratio (HR) =2.94, P<0.001] and tumor size ≥30 mm (HR =1.90, P=0.008) emerged as independent predictors of tumor upstaging (Table 3).

Among the 392 patients with a clinical stage of cT2 or lower, 35.5% (139/392) had positive voided urine cytology. Of those, 45.3% (63/139) were pathologically upstaged, compared to only 24.5% (62/253) of patients with negative voided urine cytology. A total of 45.9% of patients (180/392) had a tumor size ≥30 mm, and 37.8% of patients (68/180) with a tumor size ≥30 mm were pathologically upstaged, in contrast to only 26.9% (57/212) of those with a tumor size <30 mm.

Subgroup analysis

UTUC comprises renal pelvic cancer and ureteral cancer, each with distinct anatomical characteristics that may result in different risk factors. Therefore, for the subgroup analysis, we divided UTUC into renal pelvic cancer (n=193) and ureteral cancer (n=181) and re-evaluated the risk factors for upstaging. Cases with tumors in the pelvis and ureter (n=18) were excluded from the analysis; their characteristics are shown in Table S1. Multivariate logistic regression analyses were conducted to investigate the factors independently associated with pathological tumor upstaging (Table 4). In renal pelvic cancer, voided urine cytology (HR =2.71, P=0.004) and tumor size ≥30 mm (HR =3.39, P=0.001) were independent predictors of pathological tumor upstaging. In contrast, voided urine cytology (HR =3.11, P=0.003) and hydronephrosis (HR =2.69, P=0.03) were independent predictors in ureteral cancer.

Discussion

We explored the variables that contributed to the upstaging of tumors pathologically in UTUC patients. Our findings revealed that voided urine cytology and a tumor size ≥30 mm were independent predictors of pathological tumor upstaging. Furthermore, when stratifying UTUC into renal pelvic cancer and ureteral cancer, voided urine cytology and tumor size were significant factors for renal pelvic cancer. In contrast, significant factors for ureteral cancer included voided urine cytology and hydronephrosis.

Staging UTUC preoperatively using imaging techniques is challenging. However, the importance of perioperative management centered on radical nephroureterectomy is increasingly recognized, particularly considering the recommendations for adjuvant chemotherapy in cases of pT2 or higher as demonstrated in the POUT trial (4), and the recommendation for adjuvant nivolumab in pT3 (ypT2) or higher urothelial carcinoma patients from the CheckMate 274 trial (21). Shojo et al. reported on factors contributing to pathological upstaging at the time of radical nephroureterectomy (20), and their results were consistent with ours. However, that study was a relatively small-scale analysis that examined UTUC as a whole and did not conduct detailed analyses of renal pelvic cancer or ureteral cancer, which have distinct anatomical characteristics. Our current analysis included the largest cohort to date and separately examined renal pelvic cancer and ureteral cancer, thereby enhancing the significance of our findings.

Upper tract urinary cytology obtained from the renal cavity and ureteral lumen is effective for diagnosing, but not staging, UTUC (22). Similarly, cytology from voided urine does not aid in staging (23); however, it was correlated with higher pathological staging in this study. Positive results from voided urine cytology have been previously associated with poor oncological outcomes (24) and are considered indicative of high-risk UTUC as per the European Association of Urology guidelines (10), suggesting that positive urine cytology could serve as a significant predictor of adverse pathological outcomes. In contrast, no established cut-off for tumor size currently exists to accurately predict the pathological stage. Although a threshold of 20 mm has been reported as predictive of ≥ pT2 UTUC (25), cut-off values specifically for pT3 have not been reported. In our analysis, tumors measuring ≥30 mm significantly contributed to upstaging from cT2 or lower to pT3 or greater. Our findings suggest that tumors initially classified as cT2 or lower on imaging that measure ≥30 mm are likely to be upstaged to pT3, highlighting the prognostic importance of tumor size in evaluating UTUC severity.

Furthermore, we conducted a sub-analysis by dividing the cases into renal pelvic cancer and ureteral cancer. Voided urine cytology and tumor size were identified as significant factors in renal pelvic cancer. Conversely, voided urine cytology and hydronephrosis were more significant factors for upstaging than tumor size in ureteral cancer. Comparing the tumor sizes (median; IQR) in the upstaged group revealed that renal pelvic cancer (34 mm; 27–45 mm) had significantly larger tumors than ureteral cancer (20 mm; 14.5–35 mm) (P=0.002). This may reflect the tendency of ureteral tumors to invade more readily before reaching a larger size. Additionally, the anatomical distinctions between renal pelvic cancer and ureteral cancer contribute to differences in pathological staging and diagnostic criteria. Specifically, the pT3 pathological diagnosis criteria differ between these two cancer types: pT3 renal pelvic cancer encompasses invasion of the renal parenchyma and peri-pelvic fat, whereas pT3 ureteral cancer includes only invasion of periureteral fat. These differences underscore the unique diagnostic challenges associated with each type of cancer. Previous reports have highlighted the significant diagnostic challenges of UTUC compared to bladder cancer (26); however, to our knowledge, this is the first study to investigate the differences in upstaging risk by further subdividing UTUC.

The limitations of this study include its retrospective design, so further accumulation of cases is necessary to reach a definitive conclusion. Additionally, the cohort was restricted to patients who had undergone preoperative CTU, potentially introducing selection bias. Another constraint was the lack of an evaluation for other influential factors, such as the biopsy tumor grade or the tumor architecture assessed via diagnostic ureteroscopy. Furthermore, the preoperative imaging evaluations in this study were conducted by certified radiologists, but without a central review process.

Conclusions

Positive voided urine cytology and tumor size ≥30 mm were confirmed as independent predictors for advancing tumor stages from cT2 or lower to pT3. Furthermore, after examining renal pelvic cancer and ureteral cancer separately, voided urine cytology and tumor size were risk factors for renal pelvic cancer, whereas voided urine cytology and hydronephrosis were significant factors in ureteral cancer. Patients who present with these preoperative indicators should be advised about their heightened risk of tumor upstaging.

Acknowledgments

The authors thank Textcheck for providing English language editing service for this manuscript.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-24-357/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-357/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-357/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-357/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Institutional Ethics Board of the Jikei University School of Medicine {No. 36-005[12104]} and individual consent for this retrospective analysis was waived due to the retrospective nature. All participating hospitals were informed and agreed the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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