Urothelial carcinoma (UC) is a malignant tumor of the lining of the urinary tract. While the majority of UCs arise in the bladder, upper tract UC (UTUC) is less common (1, 2). Unlike bladder UC, almost 60% of UTUCs are invasive at diagnosis (3–5). The standard treatment for invasive UTUC is radical nephroureterectomy (RNU) with bladder cuff excision, but the cancer often recurs after surgical intervention (2, 3). Therefore, it is important to select candidates who require adjunctive therapy in the perioperative period. Identifying useful prognostic markers for UTUC is one way to aid patient selection. Previous studies have demonstrated the prognostic significance of pathological features such as tumor stage and lymphovascular invasion (2). However, these characteristics are only obtained after RNU and cannot be incorporated into preoperative assessment. Preoperative prognostic factors are more conducive to make up for the inadequacy of clinical staging of UTUC.

UTUC is usually initially diagnosed by examination after seeking medical attention for clinical symptoms. The most common symptom of UTUC is hematuria, which occurs in approximately 70%–80% of patients (2, 6). Flank pain is the second most common symptom (20%), usually caused by obstruction of urine flow, and is closely related to hydronephrosis (7–9). Other systemic symptoms, including weight loss, general malaise, fatigue, and cachexia, may be associated with worse prognosis and should be treated promptly (2, 8, 9). Although local symptoms are common, their impact on survival outcomes in patients with UTUC remains questionable (7–14). This study aimed to evaluate the value of preoperative local symptoms on the prognosis of UTUC after nephroureterectomy.

Studies have shown that systemic symptoms such as weight loss, general malaise, and fatigue are associated with poor prognosis in UTUC (2, 8, 9). However, the prognostic significance of local symptoms directly attributable to the tumor, such as hematuria and symptomatic hydronephrosis, have been poorly studied. This is the largest multicenter study investigating the prognostic value of preoperative local symptoms in UTUC, showing that hematuria and symptomatic hydronephrosis independently lead to better and worse survival, respectively. These findings suggest that hematuria and symptomatic hydronephrosis are not only helpful in disease detection, but also have prognostic value.

Although hematuria is the most common symptom of UC, few studies have investigated the prognostic role of hematuria. Ramirez et al. showed that the severity of hematuria was associated with more advanced pathological stages of bladder UC (18). However, inherent anatomical differences between the bladder and upper urinary tract may prevent extrapolation of this result to UTUC (4). Bladder UC is almost impossible to block the urinary tract before hematuria occurs. In contrast, UTUC is prone to urinary obstruction due to the small diameter of the upper urinary tract and may not present with hematuria. In the absence of hematuria, accurate diagnosis may be delayed, leading to tumor upstaging. As our results showed, the pathological tumor stage was significantly higher in patients without hematuria than in patients with hematuria (p = 0.001).

Previous studies have not established the protective effect of hematuria on UTUC (10–13, 19). Of these studies, some of them showed that hematuria was associated with better prognosis in patients with UTUC (12, 13), but not others (10, 11, 19). In the present study, the significance of hematuria in OS and CSS remained after adjustment for various clinicopathological variables. With three times the number of patients compared to the largest previous study (11), we believe that patients presenting with hematuria have better survival rates. Notably, the results were very similar if only gross hematuria was defined as hematuria ( Supplementary Table ).

Another key finding of the study was that symptomatic hydronephrosis predicted worse outcomes. Similar to the results of hematuria, not all previous studies showed that flank pain (11–13) or hydronephrosis (20–24) was unfavorable for the prognosis of UTUC. In current guidelines and in a recent meta-analysis, hydronephrosis is considered a high-risk feature (2, 25), but its prognostic significance is greatly reduced after multivariate adjustment (20, 21). Although high-grade hydronephrosis may be a better indicator of poor prognosis (22–24), interobserver variability and how severe hydronephrosis is significant are problematic. Symptomatic hydronephrosis was described as co-occurring flank pain and hydronephrosis, which was clearly defined and confirmed as an important prognostic factor for UTUC in a previous study (10). Notably, neither flank pain nor hydronephrosis alone was significant in multivariate analysis. Our results also supported the prognostic value of symptomatic hydronephrosis in UTUC.

Some previous studies grouped all local symptoms as a whole to assess their impact on prognosis. For example, in patients with renal cell carcinoma (RCC), those with flank pain, hematuria, and palpable tumors had a worse prognosis than those without these symptoms (26–28). Raman et al. used the same criteria, but local symptoms failed to predict outcomes in patients with UTUC (8). Although the etiology of flank pain can differ between RCC and UTUC (local mass effect and urinary tract obstruction, respectively), pain is probably related to tumor aggressiveness. On the contrary, hematuria generally represents the invasion of advanced RCC into the collecting system, but is a warning symptom for early diagnosis and prompt treatment of UTUC. In addition, Ataus et al. showed that in UTUC, patients with flank pain had lower survival than those with hematuria (13). Taken together, we believe that dissecting local symptoms in detail is important to obtain additional prognostic information.

Zhao et al. found that UTUC patients with hydronephrosis should have a shorter waiting time for surgery (13), otherwise the increased intraluminal pressure may lead to wall thinning and a greater chance of peripheral invasion of tumor cells (29). Since symptomatic hydronephrosis was a more reliable predictor of cancer invasiveness than hydronephrosis alone (10), we supposed that these patients may require more timely treatment to avoid upstaging. Another potential clinical application is for monitoring treatment efficacy. In the study by Miyake et al., down-grading of hydronephrosis after neoadjuvant chemotherapy was associated with favorable oncological outcomes (30). Likewise, relief of flank pain could reflect a favorable response to therapy and a proxy for downstaging.

This study has some limitations. First, this is a retrospective study. Second, we were unable to determine the exact extent of the patient’s local symptoms. Third, several important factors, such as surgical margins, histological variants, and tumor necrosis, were not included in the analysis because information on many patients was not available. We performed a sensitivity analysis in a limited subgroup and found similar results. To provide more information to those who may be wondering, we analyzed the effect of positive surgical margins on survival at different pT stages. As shown in the Supplementary Figure , positive surgical margins appeared to have the greatest impact on pT3 disease. Fourth, data collection was performed by collaborating with multiple medical centers, so surgical specimens were reviewed by different genitourinary pathologists and operated by different surgeons. To our knowledge, there is no consensus on the impact of local symptoms on the prognosis of UTUC. We have included most of the recognized clinicopathological variables in our comprehensive survival analysis, and this is the largest multicenter study to date evaluating the effect of preoperative symptoms on UTUC outcomes. We demonstrate that preoperative local symptoms are important prognostic factors, and our promising results support further prospective studies for validation.

In conclusion, symptomatic hydronephrosis was an independent prognostic factor for worse disease outcomes, while the presence of hematuria was associated with better survival. Preoperative local symptoms could be a novel variable to risk stratify patients with UTUC and help physicians make better treatment decisions.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by Kaohsiung Medical University Hospital [KMUHIRB-E(I)-20180214]. The patients/participants provided their written informed consent to participate in this study.

H-CY and W-JW conceived the project. All authors collected the data. H-CY analyzed the results. T-WL and H-CY drafted the manuscript. H-CY and W-JW edited the manuscript. All authors contributed to the article and approved the submitted version.

This study was supported by Kaohsiung Municipal Ta-Tung Hospital (kmtth-110-015) and supported partially by the Ministry of Science and Technology (MOST 109-2314-B-037-095), Ministry of Health and Welfare (MOHW111-TDU-B-212-134006), Kaohsiung Medical University Hospital (KMUH-DK-111007C), Kaohsiung Medical University Regenerative Medicine and Cell Therapy Research Center (KMU-TC109A02), and Kaohsiung Medical University Center for Liquid Biopsy and Cohort Research (KMU-TC109B05).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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