Abstract

Introduction

Upper urinary tract urothelial carcinoma (UTUC) is a relatively rare malignant tumor of the urinary system. Its incidence rate is far lower than that of bladder cancer (BC), accounting for 5%–10% of all urothelial carcinomas (1, 2). The symptoms in the early stage of UTUC are relatively obscure, and the degree of malignancy is relatively high. Approximately 60% of the patients have UTUC that already infiltrated the muscular layer at diagnosis (3, 4). Compared with other urological tumors, the clinical progress of UTUC is faster and the prognosis is worse. Radical nephroureterectomy (RNU) with bladder sleeve resection is the standard surgical treatment of UTUC, especially for patients with high risk (5).

It is noteworthy that patients who underwent RNU still have a high rate of intravesical recurrence (IVR) and extraurothelial recurrence (EUR), leading to poor prognosis (1). A large multi-institution study of 1,363 patients treated with RNU demonstrated that 379 (28%) patients experienced EUR and the median time to EUR was 10.4 months (6). Up to now, most present studies still pay attention to the survival time or IVR of patients with UTUC after receiving RNU. Previous studies reported that pathologic tumor stage, tumor grade, lymph node (LN) status, and lymphovascular invasion (LVI) are independent risk factors for overall survival (OS) after RNU (7, 8). Some blood inflammation biomarkers including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) have also been found to be related to survival time (9, 10). However, few studies focused on the risk factors predicting the EUR.

Because EUR plays a crucial role in survival outcome, it is important to identify predictors of EUR to enable early detection and intervention to improve prognosis. In this study, we aimed to identify the risk factors of EUR in UTUC patients undergoing RNU. Additionally, we developed a grading system based on these factors to stratify risk and assist urologists in optimizing clinical decision-making.

Methods

Results

Predictors of EUR

Univariate and multivariate Cox regression models were applied to identify the prognostic risk factors related to EUR. The results were presented in Table 2 . In the univariate Cox analysis, pathologic stage, LN status, tumor grade, hydronephrosis, LVI, urine cytology, Ki-67, NLR, PLR, LMR, and LVI showed a strong association with EUR (p < 0.05). After including these relative factors, pathologic stage, LN status, LVI, Ki-67, NLR, and PLR were identified as independent risk factors for EUR based on multivariate Cox analysis. Kaplan–Meier curves were plotted to demonstrate the difference between subgroups divided by these risk factors. The results showed that patients with these risk factors had a shorter EURFS ( Figure 1 ).

Table 2

Uni- and multivariate analysis of the 220 patients for extraurothelial recurrence-free survival.

Characteristic	Univariate analysis			Multivariate analysis
	HR	95% CI	p value	HR	95% CI	p value
Age (years)	0.993	0.968-1.019	0.602
Sex
Men	Reference
Women	0.654	0.396-1.082	0.099
BMI	1.003	0.931-1.080	0.944
History of hypertension
Yes	Reference
No	0.948	0.573-1.568	0.836
History of DM
Yes	Reference
No	0.942	0.501-1.773	0.853
Tumor location
Ureter	Reference
Renal pelvis	0.833	0.251-2.765	0.765
Both	1.068	0.327-3.491	0.913
Laterality
Left	Reference
Right	1.17	0.707-1.934	0.541
Pathologic stage
pT2 or less	Reference			Reference
pT3 or greater	2.658	1.586-4.456	<0.001	2.755	1.554-4.886	<0.001
Lymph node status
pN0/pNx	Reference			Reference
pN+	2.694	1.220-5.949	0.014	2.468	1.046-5.822	0.039
Tumor grade
Low	Reference			Reference
High	4.145	1.011-16.990	0.048	2.319	0.542-9.931	0.257
Tumor size
<3cm	Reference
≥3cm	1.598	0.966-2.641	0.068
Tumor multifocality
Absent	Reference
Present	1.01	0.555-1.838	0.973
Hydronephrosis
Absent	Reference			Reference
Present	1.662	1.004-2.750	0.048	1.416	0.844-2.374	0.188
LVI
Absent	Reference			Reference
Present	2.335	1.317-4.141	0.004	1.893	1.038-3.454	0.037
Margin positivity
Negative	Reference
Positive	1.972	0.789-4.929	0.146
Urine cytology
Normal	Reference			Reference
Abnormal	1.699	0.999-2.888	0.049	1.505	0.848-2.671	0.163
eGFR
<60	Reference
≥60	0.830	0.398-1.712	0.625
Adjuvant chemotherapy
Yes	Reference
No	0.958	0.579-1.586	0.868
Ki-67
<20%	Reference			Reference
≥20%	2.283	1.360-3.832	0.002	2.000	1.160-3.449	0.013
NLR
<2.4	Reference			Reference
≥2.4	2.553	1.495-4.361	0.001	2.342	1.333-4.115	0.003
PLR
<132.6	Reference			Reference
≥132.6	1.757	1.054-2.928	0.031	2.536	1.437-4.474	0.001
LMR
<3.2	Reference			Reference
≥3.2	0.504	0.295-0.864	0.013	0.665	0.376-1.177	0.162

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BMI, body mass index; DM, diabetes mellitus; LVI, lymphovascular invasion; eGFR, estimated glomerular filtration rate; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; LMR, lymphocyte-to-monocyte ratio.

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Figure 1

Kaplan–Meier curves for EURFS grouped by risk factors in the patients with UTUC, including pathologic stage (A), lymph node status (B), LVI (C), Ki-67 (D), NLR (E), and PLR (F). EURFS, extraurothelial recurrence-free survival; UTUC, upper urinary tract urothelial carcinoma; LVI, lymphovascular invasion; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio.

Survival outcome of patients with EUR

The 3- and 5-year OS estimate was 78.0% and 65.2% in all patients, respectively. However, in patients with EUR, 3- and 5-year OS estimate was 38.8% and 22.3%, respectively. Similarly, for CSS, the survival rate for 3 and 5 years was 80.5% and 71.4% in all patients and 38.8% and 22.3% in patients with EUR, respectively. The plots revealed that patients with EUR had significantly worse OS and CSS ( Figures 2 , 3 ).

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Figure 2

Kaplan–Meier curves for OS of patients with UTUC according to EUR. OS, overall survival; UTUC, upper urinary tract urothelial carcinoma; EUR, extraurothelial recurrence.

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Figure 3

Kaplan–Meier curves for CSS of patients with UTUC according to EUR. CSS, cancer-specific survival; UTUC, upper urinary tract urothelial carcinoma; EUR, extraurothelial recurrence.

Risk stratification analysis for EUR

The multivariate Cox analysis showed that pT3–4, pN+, LVI, Ki-67 ≥20%, NLR ≥2.4, and PLR ≥132.6 were significant predictors of EUR. Combining the analysis results, we developed a risk classification model according to the number of risk factors (0, 1, or 2 and 3 or more). The low-risk group included patients with 0 or 1 risk factor. Those with two risk factors were included in the intermediate-risk group, and the high-risk group included patients with three or more risk factors. The Kaplan–Meier curves revealed a significant difference in EURFS among the three groups ( Figure 4 ). We also performed ROC analysis to evaluate the discriminatory ability of the simple model; the AUC value was 0.769, and sensitivity and specificity were 0.869 and 0.610, respectively ( Supplementary Figure S1 ).

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Figure 4

Kaplan–Meier curves for EURFS of patients with UTUC according to risk classification. EURFS, extraurothelial recurrence-free survival; UTUC, upper urinary tract urothelial carcinoma.

Discussion

Although both UTUC and BC are transitional cell carcinomas in their pathological manifestations, UTUC is more prone to local progression or recurrence after surgery compared to BC (15). Previous studies showed that 20%–30% of patients with UTUC will develop EUR, even if they underwent RNU (16–18). The most common sites of EUR are the lung, bone, and liver (19). However, despite recent advances in adjuvant chemotherapy, which can reduce the risk of EUR to a certain extent, the overall outcome benefit is still unsatisfactory (20). Prognostic models commonly used in clinical practice all cast light on survival outcome. However, patients who experience EUR face a rapid decline in their quality of life and a heavy financial burden. Therefore, accurately screening the high-risk population for postoperative EUR has become the focus and difficulty of clinical attention. Different with other literature reports (18, 21), our results show that pathologic stage, LN status, LVI, Ki-67, NLR, and PLR are independent risk factors.

For the TNM stage of UTUC, the T stage represents the depth of tumor invasion. The higher T stage suggests a higher risk of metastases and worse prognosis. The 5-year CSS rate of patients with pTa/T1 stage is usually over 90%, while that of patients with T2/T3 stage drops to less than 50%, and that of patients with T4 stage is less than 10% (22, 23). In our research, patients with a higher pT stage had a higher incidence of EUR and worse survival outcomes than those with a lower pT stage. Ouzzane et al. (24) reported that the T stage is both a risk factor of local recurrence and distant metastasis in patients with UTUC who underwent RNU. For tumors with a higher T stage, especially those located in the ureter, tumor cells are more likely to penetrate the thinner adventitia of the ureter and invade the vascular lymphatic plexus, making it easier for EUR to occur.

Currently, there is still controversy about the survival benefit and safety of lymph node dissection (LND). Therefore, RNU with concurrent LND is rarely performed in the real world. The guidelines of the European Association of Urology (EAU) recommend that LND should be performed concurrently with surgery for patients with a high risk, but this is based on a low level of evidence (1). Cha et al. (25) reported that the risk of CSS in UTUC patients with LN positivity was approximately 2.23 times higher than that in those with LN negativity. Abe et al. (26) conducted a multicenter study including 293 patients on the relationship between LN status and prognosis. The results showed that for patients with T2 or higher stage, the CSS of patients without LN metastasis (pN0) was higher than that of patients without lymphadenectomy (pNx) (26). Our results also indicate that patients with positive LNs have a worse prognosis and a higher incidence of EUR. In our center, LND was performed in 36 patients with suspected enlarged LNs detected during intraoperative inspection or preoperative images with suspected LN metastasis and only 13 patients had LN metastasis. In view of the above, how to more accurately identify preoperative LN metastases has become a problem that should be solved promptly.

Recent studies have shown that adjuvant chemotherapy could improve oncological outcomes for patients with UTUC (1, 27). Interestingly, our research suggested that adjuvant chemotherapy was not associated with EUR. We reviewed our original data and found that the results could be explained by the following reasons: first, some patients were unable to adhere to the full course of adjuvant chemotherapy due to advanced age combined with underlying diseases or financial reasons, thus affecting the effectiveness of adjuvant chemotherapy; next, some patients were not sensitive to cisplatin-based chemotherapy and develop secondary drug resistance during the course of treatment. Therefore, individualized treatment of UTUC patients after RNU should be the focus of future research.

LVI is currently recognized as an important factor affecting the clinical prognosis of patients with malignant tumors (28). The detection rate of LVI in UTUC is approximately 20% (29, 30). In our study, a total of 37 patients (16.8%) had LVI, which is slightly lower than that reported by Novara et al. (29). We speculate that this discrepancy may be related to the number of tumor tissue samples and the experience of pathologists. Studies have shown that vascular lymphatic invasion is a prerequisite for tumor LN invasion, which can further lead to tumor cells entering the blood and forming micrometastases (31). Margulis et al. (6) and Hurel et al. (32) also confirmed that LVI is an independent predictor of postoperative recurrence and distant metastasis in patients with UTUC, which is in accordance with our result.

Ki-67 is an immunostaining marker of nuclear cell proliferation, which is frequently expressed in several malignancies, such as breast, colon, and ovarian cancers (33, 34). Referring to relevant literature, we defined that Ki-67 overexpression was 20% (33–35). In our study, 43.2% of the patients showed Ki-67 overexpression, which is consistent with the percentage of Ki-67 ≥20% in previous studies (36, 37). The research by Krabbe et al. (33) demonstrated that Ki-67 was a validated independent predictor of recurrence-free survival and CSS in patients with UTUC treated with RNU. Our study also confirmed that Ki-67 overexpression was closely related to EUR. However, due to differences in race, sample size, and laboratory equipment, the results should be interpreted with caution.

The occurrence and development of tumors are known to be associated with the systemic inflammatory response (38, 39). Related cellular components such as neutrophils, lymphocytes, and platelets have been reported to have prognostic value in patients with a variety of cancers (9, 40). In this study, we analyzed some systemic inflammation biomarkers including NLR, PLR, and LMR. Although all of these markers showed significant differences in univariate Cox analysis, only NLR and PLR were identified as independent risk factors of EUR when performing multivariate Cox analysis. Neutrophils are an important component of the inflammatory response and have been found to participate in the suppression of antitumor immune monitoring and extracellular matrix remodeling, promoting the metastasis of cancer cells. Furthermore, elevated neutrophils can produce more inflammatory transmitters, such as interleukin (IL)-1, IL-6, IL-17, vascular endothelial growth factor, and other immunomodulatory transmitters, leading to angiogenesis and the progression of malignant tumors (41). Lymphocytes are also an essential part of the immune response and produce antitumor effects through humoral and cellular immunity. Activated and proliferating lymphocytes secrete interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), which inhibit the proliferation and migration of tumor cells. Therefore, low lymphocyte counts may reflect an impaired host immune function (42). Elevated NLR reflects the body’s inflammatory state and immune function abnormalities, and tumors are more likely to recur and metastasize in patients with this condition. Several studies have reported that preoperative NLR is associated with adverse clinicopathologic features and worse survival outcomes (43, 44). The EAU guidelines have suggested preoperative NLR as a prognostic factor for CSS in UTUC (1).

Platelets are generally considered to be one of the key components in physiological hemostasis. However, studies have confirmed that platelets release pro-inflammatory mediators, such as cytokines and chemokines, which can promote angiogenesis and stimulate the production of stromal growth factors and matrix remodeling enzymes, thereby promoting tumor progression and metastasis (45, 46). Therefore, an increase in PLR indicates that patients have a worse prognosis and the prognostic value of PLR has also been verified in some research (47, 48). NLR and PLR can be conveniently obtained from routine blood tests before surgery. Therefore, these biomarkers could provide potentially prognostic information without increasing costs in clinical application. It is worth mentioning that there is no consensus on the best cutoff values for these inflammation biomarkers. Most research selected the cutoff value of NLR from 2 to 5 and PLR from 120 to 200 (9). The cutoff value in this study was determined by X-tile software and also falls within this range. However, further investigations with large samples are required to define the optimal cutoff value for these inflammation biomarkers.

In order to better stratify patients for risk of EUR, we construct a grading system based on these risk factors. Interestingly, the model can also distinguish the OS and CSS of patients ( Supplementary Figures S2 , S3 ). The application of this classification model will be helpful for developing personalized treatment options and follow-up plans for UTUC patients treated with RNU. For UTUC patients with low-risk EUR, regular bladder instillation may be sufficient instead of adjuvant chemotherapy to avoid overtreatment. However, owing to worse survival outcomes, postoperative follow-up and selection of treatment options need to be more cautious for patients with high-risk EUR. It may be necessary to comprehensively consider multiple treatment options such as chemotherapy, radiotherapy, and immunotherapy to improve the prognosis as much as possible.

The present study has several strengths, as follows: first, the follow-up was relatively long compared to previous studies; in addition, this is the first research concerning the EUR of Chinese patients with UTUC to our knowledge; third, the NLR and PLR were identified as independent risk factors, which can be obtained before surgery compared to other risk factors, thereby guiding further treatment in a timely manner. However, there are several limitations in our study that should be acknowledged. First, selection bias cannot be avoided, since this is a retrospective study with a limited sample size due to the low incidence of UTUC and our strict inclusion criteria. Some variables such as performance status, molecular parameters, and genetic mutations were not collected in our cohort, which require further prospective multicenter trials to focus on. Moreover, the relative standards of blood tests, urine exfoliation cytology, and pathological examinations may have changed over the study period, further affecting the reliability of the collected data. Next, the grading system in our study is simple but does not consider the contribution of each risk factor, in which the coefficient is not applicable in this model. Finally, these results should be interpreted with caution, since the data are from a single center.

Conclusion

Our study indicates that pathologic stage, LN status, LVI, Ki-67, NLR, and PLR are independent risk factors for EUR after RNU. We have developed a prediction system based on these factors for risk stratification in patients with UTUC, which will assist urologists in making clinical decisions for better survival benefits. Further prospective multicenter trials with extensive follow-up are required to confirm our findings.

Data availability statement

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

Ethics statement

The studies involving human participants were reviewed and approved by the China-Japan Friendship Hospital. The patients/participants provided their written informed consent to participate in this study.

Author contributions

(I) study design: ZD, GZ; (II) data collection: CS, HZ, BJ; (III)data analysis and interpretation: YP, YB, ZL; (IV) Article writing: ZL, BJ, YY. All authors contributed to the article and approved the submitted version

References