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The prognostic value of preoperative neutrophil-to-lymphocyte ratio in patients with upper tract urothelial carcinoma
Clinica Chimica Acta 485 (2018) 26–32
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The prognostic value of preoperative neutrophil-to-lymphocyte ratio in patients with upper tract urothelial carcinoma
T
Ping Tana,1, Hang Xua,1, Liangren Liua,1, Jianzhong Aia, Huan Xub, Yong Jiangb, Xiaoyu Zhangc, ⁎ ⁎ Lu Yanga, , Qiang Weia, a
Department of Urology & Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China Department of Pathology, West China Hospital, Sichuan University, Chengdu, China c Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, United States b
A R T I C LE I N FO
A B S T R A C T
Keywords: Neutrophil-lymphocyte ratio Tumor grade Upper urinary tract Urothelial carcinoma Prognosis
Background: We evaluated the prognostic impact of the preoperative neutrophil-to-lymphocyte ratio (NLR) in patients with upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy treatment. Methods: A total of 717 patients were identified between 2003 and 2016. The cutoff value of NLR was set as 2.5. Kaplan–Meier method and Cox's proportional hazards regression models were utilized to analyze the association between NLR and oncological outcomes. Results: The median follow-up was 42 months. The results suggested that preoperative elevated NLR was associated with worse pathological features. Also, patients with NLR ≥ 2.5 had worse survival outcomes than those with NLR < 2.5 (all P < .001). Multivariate cox analysis revealed that NLR ≥ 2.5 was an independent predictor of worse cancer-specific survival, disease recurrence-free survival, metastasis-free survival and overall survival (HR 1.95, 95%CI: 1.42–2.69, P < .001; HR 1.70, 95%CI: 1.31–2.20, P < .001; HR 1.67, 95%CI: 1.22–2.31, P = .002; and HR 1.88, 95%CI: 1.42–2.50, P < .001; respectively). Notably, NLR was ascertained to be a useful prognostic predictor in patients with high-grade disease, but not in those with low-grade UTUC. Conclusions: Preoperative elevated NLR was associated with worse outcomes in patients with UTUC. Subgroup analysis affirmed that NLR was a useful predictor in patients with high-grade disease, but not in those with lowgrade UTUC.
1. Introduction Upper tract urothelial carcinomas (UTUCs), which include renal pelvicalyceal and ureteric urothelial carcinoma, are uncommon urothelial carcinomas (UCs) and only account for 5–10% of UCs [1]. The incidence of UTUC is approximately 2 cases per 100,000 inhabitants in western countries but higher in Asian countries due to exposure to Chinese herds and arsenic [1]. Although conservative management can be carried out in selected patients, radical nephroureterectomy (RNU) with bladder-cuff excision is the reference standard treatment for UTUC to date [1]. Despite the advancement of surgical techniques and benefits of neoadjuvant or early adjuvant intervention, the survival rates of patients with UTUC have not been improved significantly over time. Thus, the identification of the prognostic factors is of paramount importance to adapt treatment in time. Pathological features such as tumor stage, tumor grade, lymphovascular invasion (LVI), and lymph node invasion ⁎
1
have been well established as independent predictors of patients' survival, but preoperative prognostic factors are scarcely appraised. The neutrophil-to-lymphocyte ratio (NLR) is a blood-based inflammatory marker reported in the routine blood test, and it has been proved to be an independent prognostic factor in various malignancies. An increase in NLR may be a result of increased tumor-associated neutrophils and/or decreased lymphocytes, a connection that reflects an unbalanced tumor immunity and inflammation [2], which play important roles in triggering tumor genesis, promoting and/or inhibiting tumor progression in the tumor microenvironment [3]. Recently, several studies have been performed to evaluate the association of preoperative NLR with clinicopathological features as well as oncological outcomes in UTUC patients, but their results are controversial [4–8]. According to data, only 4385 UTUC patients from nine studies were included to assess the importance of NLR on outcomes of UTUC [3, 9]. Moreover, a majority of them have < 500 patients included, and utilized different cut-off values of NLR. Meanwhile, the impacts of NLR
Corresponding author at: Department of Urology & Institute of Urology, West China Hospital, Sichuan University, Number 37, Guoxue Alley, Chengdu, Sichuan 610041, China. E-mail addresses: wyclefl[email protected] (L. Yang), [email protected] (Q. Wei). Authors contributed equally to this work.
https://doi.org/10.1016/j.cca.2018.06.019 Received 25 March 2018; Received in revised form 16 May 2018; Accepted 13 June 2018 Available online 15 June 2018 0009-8981/ © 2018 Published by Elsevier B.V.
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16]. Moreover, the cutoff value of white cell count was determined according to the previous study [6]. The clinicopathological data including patients` age, gender, smoking history, surgical procedures, preoperative anemia and renal function, peri-operative blood transfusion, hydronephrosis, and tumor side as well as tumor size were also collected.
on outcomes in subsets with different disease grade or stage were rarely discussed due to the small sample size. More importantly, although, since 2016, NLR has been included into the EAU guidelines on UTUC and regarded as a preoperative prognostic factor, it still has not been applied to clinical use to date [10]. Therefore, more evidence from studies with large sample size is essential and informative to confirm NLR's importance, and can further enhance its clinical application.
2.3. Follow-up regimen 2. Material and methods Patients were followed up every 3–4 months for the first year after surgery according to the guideline. Then, semiannually for the second and third year, and annually thereafter. Alternatively as clinically indicated with urinary cytology and excretory urography of the contralateral upper urinary tract, routine check-ups were performed that included medical history, physical examination, blood laboratory tests, and chest radiography. If clinically indicated, selective bone scan and chest/abdomen CT/MRI were carried out.
2.1. Patients A total of 822 patients with UTUC who received RNU treatment from our center between 2003 and 2016 were collected with approval from our institutional review board. Patients with missing data, history of conservative surgery (such as segmental ureterectomy and endourological resection of tumor) before RNU, background of receiving neoadjuvant chemotherapy or radiotherapy before RNU, record of undergoing cystectomy prior to or concurrently with RNU, presence of concomitant tumors, as well as those with systematic diseases which could interfere NLR level at the time of RNU (such as blood malignancies, acute or chronic inflammatory diseases, active infection, or immune diseases) were excluded (n = 105). Lymph node dissection was not routinely performed. All patients received standard open or laparoscopic RNU, including extrafascial dissection of the kidney with the entire span of ureter and adjacent bladder-cuff resection, which were performed by three experienced surgeons. The surgical methods were the same as to what we have previously described [11]. Briefly, the open RNU procedures were performed through a standard double-access procedure, with a loin incision followed by an iliac incision. The laparoscopic RNU procedure was performed using retroperitoneal laparoscopic nephrectomy in combination with an open iliac incision. Lymphadenectomy was not routinely performed. Only patients with suspicious enlarged lymph nodes on preoperative radiology or with intraoperative abnormal observations received regional lymphadenectomy. The extent of and the number of lymph nodes removed in the lymphadenectomy were determined by the surgeons during the surgery.
2.4. Statistical analysis Continuous variables were analyzed using Student's t-test, and categorical variables were evaluated using the chi-squared test. The Kaplan–Meier method was used to calculate survival outcomes including overall survival (OS), cancer-specific survival (CSS), disease recurrence-free survival (RFS) and metastasis-free survival (MFS). The log-rank test was used to assess differences. Univariate and multivariate Cox's proportional hazards regression models were used to evaluate the relationship between variables and OS, CSS, RFS, and MFS. Risk factors with a P value < .1 in the univariate analysis were included in the multivariate analysis model. Hazard ratios (HRs) with their 95% CIs were used to assess the strength of the individual variables. All reported P values were 2-sided with statistical significance set at P < .05. Statistical analyses were performed using IBM SPSS Statistics ver 22.0. 3. Result The selection flowchart of patients was shown in Fig. 1. A total of 717 patients were ultimately included in the analyses; their demographic and clinicopathological features were shown in Table 1. This study was approved by the Research Ethics Committee of West China Hospital. Informed consent was not applicable for this study. The median age of the whole cohort was 67 (interquartile range, IQR: 59–74) y and the follow-up duration was 42 (range: 1–167; IQR: 18–76) months. The median preoperative NLR was 2.75 (IQR: 2.00–4.43), and median WBC count was 6.34 (IQR: 5.18–7.98) *10^9/l. Among them, 385 patients had a tumor in the renal pelvis, 205 had a tumor only in the ureter, and 127 had tumors in both sites. 221 patients (30.8%) were diagnosed with pTis/Ta/T1, 20.2% with pT2, 34.6% with pT3, and 14.4% with pT4. Positive lymph nodes were found in 71 (9.9%) patients (Table 1). Three hundred and eleven patients (43.4%) were included in NLR < 2.5 group and 406 cases were included in NLR ≥2.5 group (56.6%), respectively. There were no differences between 2 groups in age, sex, tumor side, smoking, tumor location, lymph node status, tumor size or multifocality (all P > .05); however, patients with elevated NLR were found to have higher rate of positive LVI (P < .001), worse tumor stage (P < .001) and high tumor grade (P = .021), as well as concomitant variant histology (CVH) (P = .040) (Table 1). At the time of the analysis, 209 patients (29.1%) had died from UTUC, 260 patients (36.3%) had died from all causes, and 298 patients (41.6%) had developed cancer recurrence. Kaplan-Meier curves revealed that patients with elevated preoperative NLR (≥2.5) could be accurately predicted to develop worse CSS, RFS, MFS, and OS (all P < .001). The 5-year CSS, RFS, MFS, and OS were 48.4, 37.9, 52.7, and 42.6%, respectively, in cases with NLR ≥ 2.5, and 73.3, 60.3, 72.1, and 67.3%, respectively, in their counterparts (Fig. 2. A-D; all
2.2. Data collection All RNU specimens were retrospectively reviewed by 2 experienced pathologists (HX & YJ) according to standard procedures. The 2002 American Joint Committee of Cancer TNM classification and the WHO International Society of Urological Pathology consensus classification were used to evaluate the tumor stage and grade, respectively. Lymphovascular invasion (LVI) was defined as the presence of tumor cells within an endothelium-lined space without underlying muscular walls [12]. A positive surgical margin was defined as the presence of the tumor at inked areas of soft tissue on the RNU specimen [13]. Lymph node status was categorized as negative (pN0), unknown (pNx) or positive (pN+) [14]. Tumor location was categorized as the renal pelvis, ureter or involvement of both renal pelvis and ureter [15]. Multifocality means two or more tumors were found during surgery or pathological analysis. Disease recurrence was defined as local recurrence in the operating field, as well as lymph node spread and/or distant metastasis that had not been found in the preoperative examination. Specifically, the tumor found in the urinary bladder or contralateral upper urinary tract after surgery was not regarded as tumor relapse. NLR was defined as the absolute neutrophil count divided by the absolute lymphocyte count. Preoperative serum NLR was measured within 30 days before surgery. If more than one preoperative NLR values were available, the most recent one before surgery was used. The cutoff value of NLR was defined as 2.5 by using the receiveroperating characteristic (ROC) curves and Youden Index, which were commonly used to select cutoff point for markers in clinical trials [5, 27
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Fig. 1. The patient selection flowchart.
Table 1 Demographics and clinicopathological characteristics of patients with urinary tract urothelial carcinoma included in present study. Variables
Total (N = 717)
NLR < 2.5 (n = 311, 43.4%)
NLR ≥ 2.5 (n = 406, 56.6%)
P
Sex (Male/Female) Age (≤67/ > 67 y) Tumor side (Left/Right) Smoking (Yes/No) Surgical approach (Open/Laparoscopic RNU) Hydronephrosis (Yes/No) Peri-operative blood transfusion (Yes/No) Adjuvant therapy (Yes/No) Tumor location, n (%) Pelvicalyceal Ureteric Both Tumor stage, n (%) pTis, Ta, T1 pT2 pT3 pT4 Tumor grade (Low/High) Lymph node status, n (%) pN0 pN+ pNx LVI (Negative/Positive) Tumor size (≤3 cm/ > 3 cm) Surgical margin status (Negative/Positive) Multifocality (Absent/Present) CVH (With/Without) Bladder cancer status, n (%) No Previous Concomitant
408/309 363/354 367/350 204/513 484/233 447/270 111/606 291/426
168/143 156/155 153/158 87/224 198/113 193/118 35/276 131/180
240/166 207/199 214/192 117/289 286/120 254/152 76/330 160/246
NS NS NS NS NS NS 0.007 NS NS
385 (53.7) 205 (28.6) 127 (17.7)
166 (53.4) 97 (31.2) 48 (15.4)
219 (53.9) 108 (26.6) 79 (19.5)
221 (30.8) 145 (20.2) 248 (34.6) 103 (14.4) 189/528
115 (37.0) 70 (22.5) 97 (31.2) 29 (9.3) 96/215
106 (26.1) 75 (18.5) 151 (37.2) 74 (18.2) 93/313
90 (12.6) 71 (9.9) 556 (77.5) 610/107 229/488 659/58 598/119 165/552
42 (13.5) 25 (8.0) 244 (78.5) 282/29 109/202 293/18 263/48 60/251
48 (11.9) 46 (11.3) 312 (76.8) 328/78 120/286 366/40 335/71 105/301
616 (85.9) 22 (3.1) 79 (11.0)
265 (85.2) 10 (3.2) 36 (11.6)
351 (86.5) 12 (3.0) 43 (10.6)
< 0.001
Note: CVH, concomitant variant histology; LVI, lymphovascular invasion; RNU, radical nephroureterectomy. 28
0.021 NS
< 0.001 NS NS NS 0.040 NS
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Fig. 2. Kaplan–Meier curves for CSS (A), DFS (B), MFS (C) and OS (D) stratified according to NLR value in patients undergoing RNU for UTUC.
MFS, and OS (all P < .05). Interestingly, tumor located on the ureter (HR 1.56, 95%CI: 1.09–2.24) or involved both renal pelvis and ureter (HR 1.87, 95%CI: 1.26–2.76) and adjuvant therapy (HR 1.53, 95%CI: 1.15–2.05) contributed to worse MFS in multivariate analysis. However, the LVI and margin status were not associated with CSS, RFS, MFS, and OS in multivariate models, even though they showed a strong relationship with oncological outcomes in univariate analysis. (Table 2 and Table S1). Subgroup analysis according to tumor grade found that NLR was an independent predictor of survival outcomes in patients with high-grade UTUC (OS HR 1.97, 95%CI: 1.43–2.70; CSS HR 1.97, 95%CI: 1.38–2.81; RFS HR 1.80, 95%CI: 1.34–2.43 and MFS HR 1.79, 95%CI: 1.24–2.59), but not in patients with low-grade UTUC. WBC count did not affect survival outcomes on patients with either low-grade or high-grade UTUC. Moreover, tumor involved both renal pelvis and ureter
P < .001). Univariate cox analysis showed that NLR ≥ 2.5 was associated with worse CSS, RFS, MFS, and OS (HR 2.34, 95%CI: 1.74–3.14, P < .001; HR 1.87, 95%CI: 1.47–2.37, P < .001; HR 1.88, 95%CI: 1.40–2.53, P < .001; HR 2.11, 95%CI: 1.63–2.74, P < .001; respectively) (Table S1). After controlling the impacts of clinicopathological features, multivariate cox analysis showed that NLR ≥ 2.5 was an independent predictor of worse CSS (HR 1.95, 95%CI: 1.42–2.69), RFS (HR 1.70, 95%CI: 1.31–2.20), MFS (HR 1.67, 95%CI: 1.22–2.31), and OS (HR 1.88, 95%CI: 1.42–2.50). WBC count was found to be associated with worse CSS, RFS and OS in univariate analysis, but these differences were not observed in multivariate analysis. (Table 2). Both univariate and multivariate Cox analysis suggested that tumor pT stage and grade, lymph node metastasis, tumor size, peri-operative blood transfusion were also significantly associated with CSS, RFS, 29
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Table 2 Multivariate Cox regression analyses of relationship between NLR and survival outcomes in patients with urinary tract urothelial carcinoma. Variables
Tumor site Ureteric vs. Pelvicalyceal Both vs. Pelvicalyceal Tumor stage pT2 vs. pTis, Ta, T1 pT3 vs. pTis, Ta, T1 pT4 vs. pTis, Ta, T1 Tumor grade (High vs. Low) Lymph node status pNx vs. pN0 pN+ vs. pN0 LVI (Positive vs. Negative) Size (> 3 cm vs. ≤3 cm) Margin status (Positive vs. Negative) Surgical approach (Laparoscopic vs. Open) Peri-operative blood transfusion (Yes vs. No) NLR (≥2.5 vs. < 2.5) WBC count (≥8.3 vs. < 8.3∗10^9/l) Adjuvant therapy (Yes vs. No)
Cancer-specific survival
Disease recurrence-free survival
Overall survival
HR
HR
HR
95%CI
P
– – 1.32 2.61 4.28 2.17
0.78–2.23 1.66–4.09 2.52–7.28 1.39–3.41
1.81 2.66 1.06 1.71 1.15 0.98 1.90 1.95 1.20
1.10–2.98 1.47–4.82 0.75–1.49 1.22–2.39 0.75–1.76 0.70–1.37 1.35–2.68 1.42–2.69 0.86–1.68 –
95%CI
P
– – < 0.001 NS < 0.001 < 0.001 0.001 0.005 0.021 0.001 NS 0.002 NS NS < 0.001 < 0.001 NS
0.88–1.96 1.63–3.27 2.66–6.33 1.15–2.21
1.82 2.97
1.22–2.72 1.80–4.89 – 1.21–2.09 0.72–1.56 – 1.09–2.01 1.31–2.20 0.85–1.51 –
1.48 1.70 1.13
P
– –
1.31 2.30 4.11 1.60
1.59 1.06
95%CI
Metastasis-free survival
< 0.001 NS < 0.001 < 0.001 0.005 < 0.001 0.003 < 0.001 0.001 NS 0.013 < 0.001 NS
1.38 2.51 4.24 1.91
0.89–2.17 1.70–3.72 2.65–6.78 1.31–2.78
1.80 2.49 1.04 1.68 1.11 1.00 1.74 1.88 1.11
1.17–2.79 1.46–4.24 0.75–1.43 1.25–2.28 0.75–1.66 0.74–1.36 1.26–2.50 1.42–2.50 0.82–1.51 –
< 0.001 NS < 0.001 < 0.001 0.001 0.003 0.008 0.001 NS 0.001 NS NS < 0.001 < 0.001 NS
HR
95%CI
1.56 1.87
1.09–2.24 1.26–2.76
1.34 2.95 4.86 1.59
0.78–2.31 1.84–4.75 2.73–8.65 1.05–2.41
1.67 3.58 0.94 1.76 0.92
1.01–2.75 1.97–6.51 0.65–1.38 1.23–2.52 0.57–1.51 – 1.12–2.38 1.22–2.31 0.75–1.57 1.15–2.05
1.63 1.67 1.09 1.53
P 0.003 0.015 0.002 < 0.001 NS < 0.001 < 0.001 0.028 < 0.001 0.046 < 0.001 0.765 0.002 0.751 0.011 0.002 0.650 0.004
Note: LVI, lymphovascular invasion; NLR, Neutrophil-lymphocyte ratio; WBC count, white blood cell count. Table 3 Multivariate Cox regression analysis in patients with high-grade urinary tract urothelial carcinoma. Variables
Tumor site Ureteric vs. Pelvicalyceal Both vs. Pelvicalyceal Tumor stage pT2 vs. pTis, Ta, T1 pT3 vs. pTis, Ta, T1 pT4 vs. pTis, Ta, T1 Lymph node status pNx vs. pN0 pN+ vs. pN0 LVI (Positive vs. Negative) Size (> 3 cm vs. ≤3 cm) Margin status (Positive vs. Negative) Surgical approach (Laparoscopic vs. Open) Peri-operative blood transfusion (Yes vs. No) NLR (≥2.5 vs. < 2.5) WBC count (≥8.3 vs. < 8.3*10^9/l) Adjuvant therapy (Yes vs. No)
Cancer-specific survival
Disease recurrence-free survival
Overall survival
HR
95%CI
HR
95%CI
HR
95%CI
1.29 1.63
0.88–1.90 1.05–2.53
1.19 NS
0.85–1.66 1.12–2.36
1.13 1.53
0.79–1.60 1.03–2.27
1.77 3.48 6.16
0.91–3.47 1.93–6.27 3.19–11.88
1.38 2.55 5.02
0.82–2.31 1.64–3.97 3.00–8.40
1.53 3.06 5.36
0.85–2.72 1.87–5.01 3.07–9.38
2.08 2.94 1.11 1.81 0.97 0.98 1.80 1.97 1.33
1.18–3.66 1.54–5.61 0.78–1.58 1.23–2.65 0.61–1.54 0.68–1.41 1.24–2.60 1.38–2.81 0.93–1.89 –
1.82 3.04 0.96 1.72 0.93 1.13 1.41 1.80 1.25
1.17–2.83 1.79–5.14 0.70–1.33 1.25–2.36 0.62–1.41 0.83–1.54 1.00–1.99 1.34–2.43 0.91–1.72 –
1.87 2.46 1.09 1.74 1.01 0.96 1.71 1.97 1.18
1.16–3.01 1.40–4.33 0.79–1.50 1.23–2.45 0.66–1.55 0.69–1.35 1.21–2.40 1.43–2.70 0.85–1.64 –
P NS NS 0.028 < 0.001 NS < 0.001 < 0.001 0.005 0.011 0.001 NS 0.002 NS NS 0.002 < 0.001 NS
P 0.039 NS 0.011 < 0.001 NS < 0.001 < 0.001 < 0.001 0.008 < 0.001 NS 0.001 NS NS 0.051 < 0.001 NS
Metastasis-free survival P NS NS 0.036 < 0.001 NS < 0.001 < 0.001 0.007 0.011 0.002 NS 0.002 NS NS 0.002 < 0.001 NS
HR
95%CI
1.38 2.10
0.91–2.08 1.34–3.28
1.86 3.70 6.29
0.91–3.79 1.97–6.97 3.06–12.92
1.85 4.00 0.99 1.79 0.87 1.17 1.47 1.79 1.11 1.54
1.04–3.29 2.08–7.70 0.67–1.45 1.20–2.67 0.52–1.46 0.80–1.72 0.96–2.25 1.24–2.59 0.74–1.66 1.12–2.11
P 0.005 NS 0.001 < 0.001 NS < 0.001 < 0.001 < 0.001 0.035 < 0.001 NS 0.005 NS NS NS 0.002 NS 0.009
Note: LVI, lymphovascular invasion; NLR, Neutrophil-lymphocyte ratio; WBC count, white blood cell count.
analysis with a sample size about 1700 concluded that elevated NLR (≥2.5) was not associated with worse CSS (HR 1.25; P = .77), but contributed to OS and RFS [9]. While in our study, higher NLR was observed to decrease the OS, MFS and RFS, not only CSS, in patients with UTUC after RNU. Interestingly, subgroup analysis discovered that NLR was only an independent predictor of survival outcomes in patients with high-grade UTUC, but not in patients with low-grade UTUC, which has never been reported in the past. The NLR has been suggested as a simple index of systemic inflammation and is accurate, standardized, and available from routinely test in clinical practice. Previous studies have reported that high NLR was also correlated with oncologic outcomes of urothelial cancer including UTUC, UBC, and metastatic as well as advanced urothelial cancer [9, 17, 18]. Moreover, the role of NLR in cancer progression has also been widely investigated; increasing evidence has demonstrated that high NLR is associated with worse oncological outcomes in various malignancies [19, 20]. Almost all findings reported by previous studies were in line with the results observed in our study, but the majority of
contribute the inferior survival outcomes in patients with high grade UTUC, while tumor located on the ureter contriute to worse CSS, OS, and MFS in patiens with low-grade disese. (Tables 3 and 4).
4. Discussion At present study, we retrospectively analyzed a cohort of 717 patients who underwent RNU, and the results revealed that NLR ≥ 2.5 was associated with advanced pathological tumor stage, positive lymph nodes, high tumor grade, positive LVI, positive surgical margin and the presence of CVH. Moreover, the results confirmed that NLR ≥ 2.5 was an independent predictor for worse CSS, RFS, MFS, and OS in both univariate and multivariate analysis. However, the absolute WBC count > 8.3*10^9/l did not affect the survival outcomes of UTUC after RNU in our study, which was inconsistent with the results of the previous study using the same WBC count cut-off value [6]. Additionally, another previous study reported that WBC count was not observed as an independent predictor in UTUC patients after RNU [8]. A recent meta30
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Table 4 Multivariate Cox regression analysis in patients with low-grade urinary tract urothelial carcinoma. Variables
Tumor site Ureteric vs. Pelvicalyceal Both vs. Pelvicalyceal Tumor stage pT2 vs. pTis, Ta, T1 pT3 vs. pTis, Ta, T1 pT4 vs. pTis, Ta, T1 Lymph node status pNx vs. pN0 pN+ vs. pN0 LVI (Positive vs. Negative) Size (> 3 cm vs. ≤3 cm) Margin status (Positive vs. Negative) Surgical approach (Laparoscopic vs. Open) Peri-operative blood transfusion (Yes vs. No) NLR (≥2.5 vs. < 2.5) WBC count (≥8.3 vs. < 8.3*10^9/l) Adjuvant therapy (Yes vs. No)
Cancer-specific survival
Disease recurrence-free survival
Overall survival
HR
95%CI
HR
95%CI
HR
95%CI
5.51 1.02
1.74–17.50 0.25–4.17
1.84 0.81
0.88–3.84 0.30–2.18
2.78 0.54
1.15–6.71 0.14–2.08
0.26 1.72 5.22
0.06–1.20 0.48–6.11 0.95–28.85
0.97 2.30 3.92
0.43–2.18 1.03–5.11 0.71–21.80
0.91 1.77 4.37
0.34–2.42 0.62–5.08 0.81–23.54
0.55 1.71 2.06 1.87
0.15–2.06 0.10–28.42 0.22–19.2 0.64–5.43 – 0.23–2.45 0.58–8.72 0.58–4.67 0.44–4.33 –
1.53 2.98 0.60 1.43
0.46–5.06 0.20–45.12 0.08–4.59 0.73–2.79
0.91 2.51 1.30 1.60
1.57 1.70 1.19 0.83
0.78–3.15 0.63–4.64 0.62–2.26 0.35–1.96 –
0.26–3.16 0.16–38.36 0.16–10.79 0.70–3.69 – 0.64–3.72 0.38–4.84 0.49–2.39 0.37–2.63
0.74 2.24 1.65 1.39
P 0.009 0.004 NS 0.027 NS NS 0.058 NS NS NS NS NS NS NS NS NS NS
P NS NS NS NS NS 0.041 NS NS NS NS NS NS NS NS NS NS NS
1.54 1.36 1.08 0.98
Metastasis-free survival P 0.021 0.023 NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS
HR
95%CI
3.44 0.81
1.32–8.94 0.24–2.73
0.72 3.97 7.21
0.22–2.33 1.44–10.94 1.22–42.64
0.79 1.92 0.79 1.55
0.22–2.85 0.13–27.56 0.10–6.44 0.64–3.79 – 0.67–4.20 0.92–10.10 0.56–2.99 0.61–4.41 0.88–4.81
1.67 3.04 1.29 1.64 2.05
P 0.022 0.011 NS 0.006 NS 0.008 0.029 NS NS NS NS NS NS NS NS NS NS NS
Note: LVI, lymphovascular invasion; NLR, Neutrophil-lymphocyte ratio; WBC count, white blood cell count.
diagnosed with low grade UTUC were included in this study, thus the evidence from sets with low-grade disease should be explained with cautious. At, the follow-up duration seems not long enough, so we only found few independent prognostic factors in population with low-grade disease.
them included relatively small population and were from single institutional experience; also their follow-up durations were relatively short. In addition, the cutoff value of NLR ranged widely from 2.5 to 5. Most studies used the cutoff point between 2.5 and 3 as a better subgroup point because the higher cutoff value will lead to the false exclusion of more patients who also need anti-inflammatory treatment before surgery, although higher cutoff value reflects more serious inflammation. The increasing evidence has indicated the relationship between systemic inflammation and the tumor development and progression in a variety of malignancies [21, 22]. Systemic inflammation-based factors: NLR, platelet-lymphocyte ratio (PLR), serum C-reactive protein (CRP), fibrinogen, and plasma cytokines (e.g. IL-6) or their receptors have been reported as potential markers for prognosis in various cancers including UCs [22, 23]. The potential underlying mechanisms have not been elucidated in detail. Recent studies have suggested that an inflammatory microenvironment might play an essential role in cancer development and progression [24]. The inflammatory milieu allows tumor cells to evade host responses and contributes to angiogenesis, tumor growth, invasion and metastasis. Studies suggested that the “tumor-associated neutrophils”, which are now considered as a crucial role in the tumor microenvironment, could promote the extracellular matrix modification and further activation of the epithelial-mesenchymal transition [25, 26]. In the latest European Association of Urology guidelines, NLR has been suggested as a prognostic factor for CSS in UTUC [10]. However, the NLR has not yet been regarded as a risk factor in UTUC patients due to low grade of evidence. Therefore, the current evidence is not strong enough to support its clinical application. The present study provided supporting evidence that NLR is an important prognostic factor in patients with UTUC. Meanwhile, the roles of NLR in CSS, RFS, MFS and OS were reported in detail in our cohort, but the majority of previous studies mentioned above only reported one or two primary outcomes [3]. Some limitations in the present study should be acknowledged. First, its retrospective nature may cause a selection bias. In addition, lymphadenectomy is not routinely performed, because there is no consensus on the pattern of lymphadenectomy for UTUC and its additional benefits are still unknown. Moreover, other inflammatory parameters such as CRP and cytokines were unavailable and not routinely tested, thus their association with patients` prognosis and interaction with NLR could not be evaluated in this study. At last, only 189 patients
5. Conclusions The present study revealed that preoperative elevated NLR was associated with advanced pathological features and tumor progression in RNU specimens. The results of our study enhanced the evidence that elevated NLR was an independent risk factor for worse CSS, RFS, MFS, and OS in UTUC patients after RNU treatment. Moreover, subset analyses showed this prognostic value was only valid in patients with highgrade UTUC, but not in those with low-grade disease. Due to its ease of accessibility and low cost, future studies are warranted for external validation to promote its clinical application. Supplementary data to this article can be found online at https:// doi.org/10.1016/j.cca.2018.06.019. Acknowledgement This program was supported by the National Key Research and Development Program of China (Grant No. SQ2017YFSF090096), the Prostate Cancer Foundation Young Investigator Award 2013, the National Natural Science Foundation of China (Grant No. 81300627, 81370855, 81702536, 81770756), Programs from Science and Technology Department of Sichuan Province (Grant No. 2018JY0089 and 2017HH0063), and Young Investigator Award of Sichuan University 2017. The funders had no role in study design, patient selection, data extraction, statistical analysis or interpretation, paper writing or revising, or the decision to publish. References [1] M. Roupret, M. Babjuk, E. Comperat, R. Zigeuner, R.J. Sylvester, M. Burger, N.C. Cowan, A. Bohle, B.W. Van Rhijn, E. Kaasinen, J. Palou, S.F. Shariat, European association of urology guidelines on upper urinary tract urothelial cell carcinoma: 2015 update, Eur. Urol. 68 (2015) 868–879. [2] X. Yin, Y. Xiao, F. Li, S. Qi, Z. Yin, J. Gao, Prognostic role of neutrophil-to-lymphocyte ratio in prostate cancer: a systematic review and meta-analysis, Medicine (Baltimore) 95 (2016) e2544. [3] M.D. Vartolomei, S. Kimura, M. Ferro, L. Vartolomei, B. Foerster, M. Abufaraj, S.F. Shariat, Is neutrophil-to-lymphocytes ratio a clinical relevant preoperative biomarker in upper tract urothelial carcinoma? A meta-analysis of 4385 patients,
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[14] M. Roscigno, S.F. Shariat, V. Margulis, P. Karakiewicz, M. Remzi, E. Kikuchi, R. Zigeuner, A. Weizer, A. Sagalowsky, K. Bensalah, J.D. Raman, C. Bolenz, W. Kassou, T.M. Koppie, C.G. Wood, J. Wheat, C. Langner, C.K. Ng, U. Capitanio, R. Bertini, M.I. Fernandez, S. Mikami, M. Isida, P. Strobel, F. Montorsi, The extent of lymphadenectomy seems to be associated with better survival in patients with nonmetastatic upper-tract urothelial carcinoma: how many lymph nodes should be removed? Eur. Urol. 56 (2009) 512–518. [15] F.A. Yafi, G. Novara, S.F. Shariat, A. Gupta, K. Matsumoto, T.J. Walton, H.M. Fritsche, A. El-Hakim, S. Trischler, J.I. Martinez-Salamanca, C. Seitz, V. Ficarra, F. Zattoni, P.I. Karakiewicz, W. Kassouf, Impact of tumour location versus multifocality in patients with upper tract urothelial carcinoma treated with nephroureterectomy and bladder cuff excision: a homogeneous series without perioperative chemotherapy, BJU Int. 110 (2012) E7–13. [16] T. Azuma, Y. Matayoshi, K. Odani, Y. Sato, Y. Sato, Y. Nagase, M. Oshi, Preoperative neutrophil-lymphocyte ratio as an independent prognostic marker for patients with upper urinary tract urothelial carcinoma, Clin. Genitourin. Cancer 11 (2013) 337–341. [17] Y. Luo, D.L. She, H. Xiong, S.J. Fu, L. Yang, Pretreatment neutrophil to lymphocyte ratio as a prognostic predictor of urologic tumors: a systematic review and metaanalysis, Medicine (Baltimore) 94 (2015) e1670. [18] K. Hu, L. Lou, J. Ye, S. Zhang, Prognostic role of the neutrophil-lymphocyte ratio in renal cell carcinoma: a meta-analysis, BMJ Open 5 (2015) e006404. [19] M.X. Li, X.M. Liu, X.F. Zhang, J.F. Zhang, W.L. Wang, Y. Zhu, J. Dong, J.W. Cheng, Z.W. Liu, L. Ma, Y. Lv, Prognostic role of neutrophil-to-lymphocyte ratio in colorectal cancer: a systematic review and meta-analysis, Int. J. Cancer 134 (2014) 2403–2413. [20] J.J. Yang, Z.G. Hu, W.X. Shi, T. Deng, S.Q. He, S.G. Yuan, Prognostic significance of neutrophil to lymphocyte ratio in pancreatic cancer: a meta-analysis, World J. Gastroenterol. 21 (2015) 2807–2815. [21] B.J. Laird, S. Kaasa, D.C. Mcmillan, M.T. Fallon, M.J. Hjermstad, P. Fayers, P. Klepstad, Prognostic factors in patients with advanced cancer: a comparison of clinicopathological factors and the development of an inflammation-based prognostic system, Clin. Cancer Res. 19 (2013) 5456–5464. [22] H.L. Martin, K. Ohara, A. Kiberu, T. Van Hagen, A. Davidson, M.A. Khattak, Prognostic value of systemic inflammation-based markers in advanced pancreatic cancer, Intern. Med. J. 44 (2014) 676–682. [23] N. Tanaka, E. Kikuchi, K. Matsumoto, N. Hayakawa, H. Ide, A. Miyajima, S. Nakamura, M. Oya, Prognostic value of plasma fibrinogen levels in patients with localized upper tract urothelial carcinoma, BJU Int. 111 (2013) 857–864. [24] D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation, Cell 144 (2011) 646–674. [25] B. Azab, V.R. Bhatt, J. Phookan, S. Murukutla, N. Kohn, T. Terjanian, W.D. Widmann, Usefulness of the neutrophil-to-lymphocyte ratio in predicting short- and long-term mortality in breast cancer patients, Ann. Surg. Oncol. 19 (2012) 217–224. [26] S.I. Grivennikov, F.R. Greten, M. Karin, Immunity, inflammation, and cancer, Cell 140 (2010) 883–899.
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The prognostic value of preoperative neutrophil-to-lymphocyte ratio in patients with upper tract urothelial carcinoma
T
Ping Tana,1, Hang Xua,1, Liangren Liua,1, Jianzhong Aia, Huan Xub, Yong Jiangb, Xiaoyu Zhangc, ⁎ ⁎ Lu Yanga, , Qiang Weia, a
Department of Urology & Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China Department of Pathology, West China Hospital, Sichuan University, Chengdu, China c Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, United States b
A R T I C LE I N FO
A B S T R A C T
Keywords: Neutrophil-lymphocyte ratio Tumor grade Upper urinary tract Urothelial carcinoma Prognosis
Background: We evaluated the prognostic impact of the preoperative neutrophil-to-lymphocyte ratio (NLR) in patients with upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy treatment. Methods: A total of 717 patients were identified between 2003 and 2016. The cutoff value of NLR was set as 2.5. Kaplan–Meier method and Cox's proportional hazards regression models were utilized to analyze the association between NLR and oncological outcomes. Results: The median follow-up was 42 months. The results suggested that preoperative elevated NLR was associated with worse pathological features. Also, patients with NLR ≥ 2.5 had worse survival outcomes than those with NLR < 2.5 (all P < .001). Multivariate cox analysis revealed that NLR ≥ 2.5 was an independent predictor of worse cancer-specific survival, disease recurrence-free survival, metastasis-free survival and overall survival (HR 1.95, 95%CI: 1.42–2.69, P < .001; HR 1.70, 95%CI: 1.31–2.20, P < .001; HR 1.67, 95%CI: 1.22–2.31, P = .002; and HR 1.88, 95%CI: 1.42–2.50, P < .001; respectively). Notably, NLR was ascertained to be a useful prognostic predictor in patients with high-grade disease, but not in those with low-grade UTUC. Conclusions: Preoperative elevated NLR was associated with worse outcomes in patients with UTUC. Subgroup analysis affirmed that NLR was a useful predictor in patients with high-grade disease, but not in those with lowgrade UTUC.
1. Introduction Upper tract urothelial carcinomas (UTUCs), which include renal pelvicalyceal and ureteric urothelial carcinoma, are uncommon urothelial carcinomas (UCs) and only account for 5–10% of UCs [1]. The incidence of UTUC is approximately 2 cases per 100,000 inhabitants in western countries but higher in Asian countries due to exposure to Chinese herds and arsenic [1]. Although conservative management can be carried out in selected patients, radical nephroureterectomy (RNU) with bladder-cuff excision is the reference standard treatment for UTUC to date [1]. Despite the advancement of surgical techniques and benefits of neoadjuvant or early adjuvant intervention, the survival rates of patients with UTUC have not been improved significantly over time. Thus, the identification of the prognostic factors is of paramount importance to adapt treatment in time. Pathological features such as tumor stage, tumor grade, lymphovascular invasion (LVI), and lymph node invasion ⁎
1
have been well established as independent predictors of patients' survival, but preoperative prognostic factors are scarcely appraised. The neutrophil-to-lymphocyte ratio (NLR) is a blood-based inflammatory marker reported in the routine blood test, and it has been proved to be an independent prognostic factor in various malignancies. An increase in NLR may be a result of increased tumor-associated neutrophils and/or decreased lymphocytes, a connection that reflects an unbalanced tumor immunity and inflammation [2], which play important roles in triggering tumor genesis, promoting and/or inhibiting tumor progression in the tumor microenvironment [3]. Recently, several studies have been performed to evaluate the association of preoperative NLR with clinicopathological features as well as oncological outcomes in UTUC patients, but their results are controversial [4–8]. According to data, only 4385 UTUC patients from nine studies were included to assess the importance of NLR on outcomes of UTUC [3, 9]. Moreover, a majority of them have < 500 patients included, and utilized different cut-off values of NLR. Meanwhile, the impacts of NLR
Corresponding author at: Department of Urology & Institute of Urology, West China Hospital, Sichuan University, Number 37, Guoxue Alley, Chengdu, Sichuan 610041, China. E-mail addresses: wyclefl[email protected] (L. Yang), [email protected] (Q. Wei). Authors contributed equally to this work.
https://doi.org/10.1016/j.cca.2018.06.019 Received 25 March 2018; Received in revised form 16 May 2018; Accepted 13 June 2018 Available online 15 June 2018 0009-8981/ © 2018 Published by Elsevier B.V.
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16]. Moreover, the cutoff value of white cell count was determined according to the previous study [6]. The clinicopathological data including patients` age, gender, smoking history, surgical procedures, preoperative anemia and renal function, peri-operative blood transfusion, hydronephrosis, and tumor side as well as tumor size were also collected.
on outcomes in subsets with different disease grade or stage were rarely discussed due to the small sample size. More importantly, although, since 2016, NLR has been included into the EAU guidelines on UTUC and regarded as a preoperative prognostic factor, it still has not been applied to clinical use to date [10]. Therefore, more evidence from studies with large sample size is essential and informative to confirm NLR's importance, and can further enhance its clinical application.
2.3. Follow-up regimen 2. Material and methods Patients were followed up every 3–4 months for the first year after surgery according to the guideline. Then, semiannually for the second and third year, and annually thereafter. Alternatively as clinically indicated with urinary cytology and excretory urography of the contralateral upper urinary tract, routine check-ups were performed that included medical history, physical examination, blood laboratory tests, and chest radiography. If clinically indicated, selective bone scan and chest/abdomen CT/MRI were carried out.
2.1. Patients A total of 822 patients with UTUC who received RNU treatment from our center between 2003 and 2016 were collected with approval from our institutional review board. Patients with missing data, history of conservative surgery (such as segmental ureterectomy and endourological resection of tumor) before RNU, background of receiving neoadjuvant chemotherapy or radiotherapy before RNU, record of undergoing cystectomy prior to or concurrently with RNU, presence of concomitant tumors, as well as those with systematic diseases which could interfere NLR level at the time of RNU (such as blood malignancies, acute or chronic inflammatory diseases, active infection, or immune diseases) were excluded (n = 105). Lymph node dissection was not routinely performed. All patients received standard open or laparoscopic RNU, including extrafascial dissection of the kidney with the entire span of ureter and adjacent bladder-cuff resection, which were performed by three experienced surgeons. The surgical methods were the same as to what we have previously described [11]. Briefly, the open RNU procedures were performed through a standard double-access procedure, with a loin incision followed by an iliac incision. The laparoscopic RNU procedure was performed using retroperitoneal laparoscopic nephrectomy in combination with an open iliac incision. Lymphadenectomy was not routinely performed. Only patients with suspicious enlarged lymph nodes on preoperative radiology or with intraoperative abnormal observations received regional lymphadenectomy. The extent of and the number of lymph nodes removed in the lymphadenectomy were determined by the surgeons during the surgery.
2.4. Statistical analysis Continuous variables were analyzed using Student's t-test, and categorical variables were evaluated using the chi-squared test. The Kaplan–Meier method was used to calculate survival outcomes including overall survival (OS), cancer-specific survival (CSS), disease recurrence-free survival (RFS) and metastasis-free survival (MFS). The log-rank test was used to assess differences. Univariate and multivariate Cox's proportional hazards regression models were used to evaluate the relationship between variables and OS, CSS, RFS, and MFS. Risk factors with a P value < .1 in the univariate analysis were included in the multivariate analysis model. Hazard ratios (HRs) with their 95% CIs were used to assess the strength of the individual variables. All reported P values were 2-sided with statistical significance set at P < .05. Statistical analyses were performed using IBM SPSS Statistics ver 22.0. 3. Result The selection flowchart of patients was shown in Fig. 1. A total of 717 patients were ultimately included in the analyses; their demographic and clinicopathological features were shown in Table 1. This study was approved by the Research Ethics Committee of West China Hospital. Informed consent was not applicable for this study. The median age of the whole cohort was 67 (interquartile range, IQR: 59–74) y and the follow-up duration was 42 (range: 1–167; IQR: 18–76) months. The median preoperative NLR was 2.75 (IQR: 2.00–4.43), and median WBC count was 6.34 (IQR: 5.18–7.98) *10^9/l. Among them, 385 patients had a tumor in the renal pelvis, 205 had a tumor only in the ureter, and 127 had tumors in both sites. 221 patients (30.8%) were diagnosed with pTis/Ta/T1, 20.2% with pT2, 34.6% with pT3, and 14.4% with pT4. Positive lymph nodes were found in 71 (9.9%) patients (Table 1). Three hundred and eleven patients (43.4%) were included in NLR < 2.5 group and 406 cases were included in NLR ≥2.5 group (56.6%), respectively. There were no differences between 2 groups in age, sex, tumor side, smoking, tumor location, lymph node status, tumor size or multifocality (all P > .05); however, patients with elevated NLR were found to have higher rate of positive LVI (P < .001), worse tumor stage (P < .001) and high tumor grade (P = .021), as well as concomitant variant histology (CVH) (P = .040) (Table 1). At the time of the analysis, 209 patients (29.1%) had died from UTUC, 260 patients (36.3%) had died from all causes, and 298 patients (41.6%) had developed cancer recurrence. Kaplan-Meier curves revealed that patients with elevated preoperative NLR (≥2.5) could be accurately predicted to develop worse CSS, RFS, MFS, and OS (all P < .001). The 5-year CSS, RFS, MFS, and OS were 48.4, 37.9, 52.7, and 42.6%, respectively, in cases with NLR ≥ 2.5, and 73.3, 60.3, 72.1, and 67.3%, respectively, in their counterparts (Fig. 2. A-D; all
2.2. Data collection All RNU specimens were retrospectively reviewed by 2 experienced pathologists (HX & YJ) according to standard procedures. The 2002 American Joint Committee of Cancer TNM classification and the WHO International Society of Urological Pathology consensus classification were used to evaluate the tumor stage and grade, respectively. Lymphovascular invasion (LVI) was defined as the presence of tumor cells within an endothelium-lined space without underlying muscular walls [12]. A positive surgical margin was defined as the presence of the tumor at inked areas of soft tissue on the RNU specimen [13]. Lymph node status was categorized as negative (pN0), unknown (pNx) or positive (pN+) [14]. Tumor location was categorized as the renal pelvis, ureter or involvement of both renal pelvis and ureter [15]. Multifocality means two or more tumors were found during surgery or pathological analysis. Disease recurrence was defined as local recurrence in the operating field, as well as lymph node spread and/or distant metastasis that had not been found in the preoperative examination. Specifically, the tumor found in the urinary bladder or contralateral upper urinary tract after surgery was not regarded as tumor relapse. NLR was defined as the absolute neutrophil count divided by the absolute lymphocyte count. Preoperative serum NLR was measured within 30 days before surgery. If more than one preoperative NLR values were available, the most recent one before surgery was used. The cutoff value of NLR was defined as 2.5 by using the receiveroperating characteristic (ROC) curves and Youden Index, which were commonly used to select cutoff point for markers in clinical trials [5, 27
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Fig. 1. The patient selection flowchart.
Table 1 Demographics and clinicopathological characteristics of patients with urinary tract urothelial carcinoma included in present study. Variables
Total (N = 717)
NLR < 2.5 (n = 311, 43.4%)
NLR ≥ 2.5 (n = 406, 56.6%)
P
Sex (Male/Female) Age (≤67/ > 67 y) Tumor side (Left/Right) Smoking (Yes/No) Surgical approach (Open/Laparoscopic RNU) Hydronephrosis (Yes/No) Peri-operative blood transfusion (Yes/No) Adjuvant therapy (Yes/No) Tumor location, n (%) Pelvicalyceal Ureteric Both Tumor stage, n (%) pTis, Ta, T1 pT2 pT3 pT4 Tumor grade (Low/High) Lymph node status, n (%) pN0 pN+ pNx LVI (Negative/Positive) Tumor size (≤3 cm/ > 3 cm) Surgical margin status (Negative/Positive) Multifocality (Absent/Present) CVH (With/Without) Bladder cancer status, n (%) No Previous Concomitant
408/309 363/354 367/350 204/513 484/233 447/270 111/606 291/426
168/143 156/155 153/158 87/224 198/113 193/118 35/276 131/180
240/166 207/199 214/192 117/289 286/120 254/152 76/330 160/246
NS NS NS NS NS NS 0.007 NS NS
385 (53.7) 205 (28.6) 127 (17.7)
166 (53.4) 97 (31.2) 48 (15.4)
219 (53.9) 108 (26.6) 79 (19.5)
221 (30.8) 145 (20.2) 248 (34.6) 103 (14.4) 189/528
115 (37.0) 70 (22.5) 97 (31.2) 29 (9.3) 96/215
106 (26.1) 75 (18.5) 151 (37.2) 74 (18.2) 93/313
90 (12.6) 71 (9.9) 556 (77.5) 610/107 229/488 659/58 598/119 165/552
42 (13.5) 25 (8.0) 244 (78.5) 282/29 109/202 293/18 263/48 60/251
48 (11.9) 46 (11.3) 312 (76.8) 328/78 120/286 366/40 335/71 105/301
616 (85.9) 22 (3.1) 79 (11.0)
265 (85.2) 10 (3.2) 36 (11.6)
351 (86.5) 12 (3.0) 43 (10.6)
< 0.001
Note: CVH, concomitant variant histology; LVI, lymphovascular invasion; RNU, radical nephroureterectomy. 28
0.021 NS
< 0.001 NS NS NS 0.040 NS
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Fig. 2. Kaplan–Meier curves for CSS (A), DFS (B), MFS (C) and OS (D) stratified according to NLR value in patients undergoing RNU for UTUC.
MFS, and OS (all P < .05). Interestingly, tumor located on the ureter (HR 1.56, 95%CI: 1.09–2.24) or involved both renal pelvis and ureter (HR 1.87, 95%CI: 1.26–2.76) and adjuvant therapy (HR 1.53, 95%CI: 1.15–2.05) contributed to worse MFS in multivariate analysis. However, the LVI and margin status were not associated with CSS, RFS, MFS, and OS in multivariate models, even though they showed a strong relationship with oncological outcomes in univariate analysis. (Table 2 and Table S1). Subgroup analysis according to tumor grade found that NLR was an independent predictor of survival outcomes in patients with high-grade UTUC (OS HR 1.97, 95%CI: 1.43–2.70; CSS HR 1.97, 95%CI: 1.38–2.81; RFS HR 1.80, 95%CI: 1.34–2.43 and MFS HR 1.79, 95%CI: 1.24–2.59), but not in patients with low-grade UTUC. WBC count did not affect survival outcomes on patients with either low-grade or high-grade UTUC. Moreover, tumor involved both renal pelvis and ureter
P < .001). Univariate cox analysis showed that NLR ≥ 2.5 was associated with worse CSS, RFS, MFS, and OS (HR 2.34, 95%CI: 1.74–3.14, P < .001; HR 1.87, 95%CI: 1.47–2.37, P < .001; HR 1.88, 95%CI: 1.40–2.53, P < .001; HR 2.11, 95%CI: 1.63–2.74, P < .001; respectively) (Table S1). After controlling the impacts of clinicopathological features, multivariate cox analysis showed that NLR ≥ 2.5 was an independent predictor of worse CSS (HR 1.95, 95%CI: 1.42–2.69), RFS (HR 1.70, 95%CI: 1.31–2.20), MFS (HR 1.67, 95%CI: 1.22–2.31), and OS (HR 1.88, 95%CI: 1.42–2.50). WBC count was found to be associated with worse CSS, RFS and OS in univariate analysis, but these differences were not observed in multivariate analysis. (Table 2). Both univariate and multivariate Cox analysis suggested that tumor pT stage and grade, lymph node metastasis, tumor size, peri-operative blood transfusion were also significantly associated with CSS, RFS, 29
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Table 2 Multivariate Cox regression analyses of relationship between NLR and survival outcomes in patients with urinary tract urothelial carcinoma. Variables
Tumor site Ureteric vs. Pelvicalyceal Both vs. Pelvicalyceal Tumor stage pT2 vs. pTis, Ta, T1 pT3 vs. pTis, Ta, T1 pT4 vs. pTis, Ta, T1 Tumor grade (High vs. Low) Lymph node status pNx vs. pN0 pN+ vs. pN0 LVI (Positive vs. Negative) Size (> 3 cm vs. ≤3 cm) Margin status (Positive vs. Negative) Surgical approach (Laparoscopic vs. Open) Peri-operative blood transfusion (Yes vs. No) NLR (≥2.5 vs. < 2.5) WBC count (≥8.3 vs. < 8.3∗10^9/l) Adjuvant therapy (Yes vs. No)
Cancer-specific survival
Disease recurrence-free survival
Overall survival
HR
HR
HR
95%CI
P
– – 1.32 2.61 4.28 2.17
0.78–2.23 1.66–4.09 2.52–7.28 1.39–3.41
1.81 2.66 1.06 1.71 1.15 0.98 1.90 1.95 1.20
1.10–2.98 1.47–4.82 0.75–1.49 1.22–2.39 0.75–1.76 0.70–1.37 1.35–2.68 1.42–2.69 0.86–1.68 –
95%CI
P
– – < 0.001 NS < 0.001 < 0.001 0.001 0.005 0.021 0.001 NS 0.002 NS NS < 0.001 < 0.001 NS
0.88–1.96 1.63–3.27 2.66–6.33 1.15–2.21
1.82 2.97
1.22–2.72 1.80–4.89 – 1.21–2.09 0.72–1.56 – 1.09–2.01 1.31–2.20 0.85–1.51 –
1.48 1.70 1.13
P
– –
1.31 2.30 4.11 1.60
1.59 1.06
95%CI
Metastasis-free survival
< 0.001 NS < 0.001 < 0.001 0.005 < 0.001 0.003 < 0.001 0.001 NS 0.013 < 0.001 NS
1.38 2.51 4.24 1.91
0.89–2.17 1.70–3.72 2.65–6.78 1.31–2.78
1.80 2.49 1.04 1.68 1.11 1.00 1.74 1.88 1.11
1.17–2.79 1.46–4.24 0.75–1.43 1.25–2.28 0.75–1.66 0.74–1.36 1.26–2.50 1.42–2.50 0.82–1.51 –
< 0.001 NS < 0.001 < 0.001 0.001 0.003 0.008 0.001 NS 0.001 NS NS < 0.001 < 0.001 NS
HR
95%CI
1.56 1.87
1.09–2.24 1.26–2.76
1.34 2.95 4.86 1.59
0.78–2.31 1.84–4.75 2.73–8.65 1.05–2.41
1.67 3.58 0.94 1.76 0.92
1.01–2.75 1.97–6.51 0.65–1.38 1.23–2.52 0.57–1.51 – 1.12–2.38 1.22–2.31 0.75–1.57 1.15–2.05
1.63 1.67 1.09 1.53
P 0.003 0.015 0.002 < 0.001 NS < 0.001 < 0.001 0.028 < 0.001 0.046 < 0.001 0.765 0.002 0.751 0.011 0.002 0.650 0.004
Note: LVI, lymphovascular invasion; NLR, Neutrophil-lymphocyte ratio; WBC count, white blood cell count. Table 3 Multivariate Cox regression analysis in patients with high-grade urinary tract urothelial carcinoma. Variables
Tumor site Ureteric vs. Pelvicalyceal Both vs. Pelvicalyceal Tumor stage pT2 vs. pTis, Ta, T1 pT3 vs. pTis, Ta, T1 pT4 vs. pTis, Ta, T1 Lymph node status pNx vs. pN0 pN+ vs. pN0 LVI (Positive vs. Negative) Size (> 3 cm vs. ≤3 cm) Margin status (Positive vs. Negative) Surgical approach (Laparoscopic vs. Open) Peri-operative blood transfusion (Yes vs. No) NLR (≥2.5 vs. < 2.5) WBC count (≥8.3 vs. < 8.3*10^9/l) Adjuvant therapy (Yes vs. No)
Cancer-specific survival
Disease recurrence-free survival
Overall survival
HR
95%CI
HR
95%CI
HR
95%CI
1.29 1.63
0.88–1.90 1.05–2.53
1.19 NS
0.85–1.66 1.12–2.36
1.13 1.53
0.79–1.60 1.03–2.27
1.77 3.48 6.16
0.91–3.47 1.93–6.27 3.19–11.88
1.38 2.55 5.02
0.82–2.31 1.64–3.97 3.00–8.40
1.53 3.06 5.36
0.85–2.72 1.87–5.01 3.07–9.38
2.08 2.94 1.11 1.81 0.97 0.98 1.80 1.97 1.33
1.18–3.66 1.54–5.61 0.78–1.58 1.23–2.65 0.61–1.54 0.68–1.41 1.24–2.60 1.38–2.81 0.93–1.89 –
1.82 3.04 0.96 1.72 0.93 1.13 1.41 1.80 1.25
1.17–2.83 1.79–5.14 0.70–1.33 1.25–2.36 0.62–1.41 0.83–1.54 1.00–1.99 1.34–2.43 0.91–1.72 –
1.87 2.46 1.09 1.74 1.01 0.96 1.71 1.97 1.18
1.16–3.01 1.40–4.33 0.79–1.50 1.23–2.45 0.66–1.55 0.69–1.35 1.21–2.40 1.43–2.70 0.85–1.64 –
P NS NS 0.028 < 0.001 NS < 0.001 < 0.001 0.005 0.011 0.001 NS 0.002 NS NS 0.002 < 0.001 NS
P 0.039 NS 0.011 < 0.001 NS < 0.001 < 0.001 < 0.001 0.008 < 0.001 NS 0.001 NS NS 0.051 < 0.001 NS
Metastasis-free survival P NS NS 0.036 < 0.001 NS < 0.001 < 0.001 0.007 0.011 0.002 NS 0.002 NS NS 0.002 < 0.001 NS
HR
95%CI
1.38 2.10
0.91–2.08 1.34–3.28
1.86 3.70 6.29
0.91–3.79 1.97–6.97 3.06–12.92
1.85 4.00 0.99 1.79 0.87 1.17 1.47 1.79 1.11 1.54
1.04–3.29 2.08–7.70 0.67–1.45 1.20–2.67 0.52–1.46 0.80–1.72 0.96–2.25 1.24–2.59 0.74–1.66 1.12–2.11
P 0.005 NS 0.001 < 0.001 NS < 0.001 < 0.001 < 0.001 0.035 < 0.001 NS 0.005 NS NS NS 0.002 NS 0.009
Note: LVI, lymphovascular invasion; NLR, Neutrophil-lymphocyte ratio; WBC count, white blood cell count.
analysis with a sample size about 1700 concluded that elevated NLR (≥2.5) was not associated with worse CSS (HR 1.25; P = .77), but contributed to OS and RFS [9]. While in our study, higher NLR was observed to decrease the OS, MFS and RFS, not only CSS, in patients with UTUC after RNU. Interestingly, subgroup analysis discovered that NLR was only an independent predictor of survival outcomes in patients with high-grade UTUC, but not in patients with low-grade UTUC, which has never been reported in the past. The NLR has been suggested as a simple index of systemic inflammation and is accurate, standardized, and available from routinely test in clinical practice. Previous studies have reported that high NLR was also correlated with oncologic outcomes of urothelial cancer including UTUC, UBC, and metastatic as well as advanced urothelial cancer [9, 17, 18]. Moreover, the role of NLR in cancer progression has also been widely investigated; increasing evidence has demonstrated that high NLR is associated with worse oncological outcomes in various malignancies [19, 20]. Almost all findings reported by previous studies were in line with the results observed in our study, but the majority of
contribute the inferior survival outcomes in patients with high grade UTUC, while tumor located on the ureter contriute to worse CSS, OS, and MFS in patiens with low-grade disese. (Tables 3 and 4).
4. Discussion At present study, we retrospectively analyzed a cohort of 717 patients who underwent RNU, and the results revealed that NLR ≥ 2.5 was associated with advanced pathological tumor stage, positive lymph nodes, high tumor grade, positive LVI, positive surgical margin and the presence of CVH. Moreover, the results confirmed that NLR ≥ 2.5 was an independent predictor for worse CSS, RFS, MFS, and OS in both univariate and multivariate analysis. However, the absolute WBC count > 8.3*10^9/l did not affect the survival outcomes of UTUC after RNU in our study, which was inconsistent with the results of the previous study using the same WBC count cut-off value [6]. Additionally, another previous study reported that WBC count was not observed as an independent predictor in UTUC patients after RNU [8]. A recent meta30
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Table 4 Multivariate Cox regression analysis in patients with low-grade urinary tract urothelial carcinoma. Variables
Tumor site Ureteric vs. Pelvicalyceal Both vs. Pelvicalyceal Tumor stage pT2 vs. pTis, Ta, T1 pT3 vs. pTis, Ta, T1 pT4 vs. pTis, Ta, T1 Lymph node status pNx vs. pN0 pN+ vs. pN0 LVI (Positive vs. Negative) Size (> 3 cm vs. ≤3 cm) Margin status (Positive vs. Negative) Surgical approach (Laparoscopic vs. Open) Peri-operative blood transfusion (Yes vs. No) NLR (≥2.5 vs. < 2.5) WBC count (≥8.3 vs. < 8.3*10^9/l) Adjuvant therapy (Yes vs. No)
Cancer-specific survival
Disease recurrence-free survival
Overall survival
HR
95%CI
HR
95%CI
HR
95%CI
5.51 1.02
1.74–17.50 0.25–4.17
1.84 0.81
0.88–3.84 0.30–2.18
2.78 0.54
1.15–6.71 0.14–2.08
0.26 1.72 5.22
0.06–1.20 0.48–6.11 0.95–28.85
0.97 2.30 3.92
0.43–2.18 1.03–5.11 0.71–21.80
0.91 1.77 4.37
0.34–2.42 0.62–5.08 0.81–23.54
0.55 1.71 2.06 1.87
0.15–2.06 0.10–28.42 0.22–19.2 0.64–5.43 – 0.23–2.45 0.58–8.72 0.58–4.67 0.44–4.33 –
1.53 2.98 0.60 1.43
0.46–5.06 0.20–45.12 0.08–4.59 0.73–2.79
0.91 2.51 1.30 1.60
1.57 1.70 1.19 0.83
0.78–3.15 0.63–4.64 0.62–2.26 0.35–1.96 –
0.26–3.16 0.16–38.36 0.16–10.79 0.70–3.69 – 0.64–3.72 0.38–4.84 0.49–2.39 0.37–2.63
0.74 2.24 1.65 1.39
P 0.009 0.004 NS 0.027 NS NS 0.058 NS NS NS NS NS NS NS NS NS NS
P NS NS NS NS NS 0.041 NS NS NS NS NS NS NS NS NS NS NS
1.54 1.36 1.08 0.98
Metastasis-free survival P 0.021 0.023 NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS
HR
95%CI
3.44 0.81
1.32–8.94 0.24–2.73
0.72 3.97 7.21
0.22–2.33 1.44–10.94 1.22–42.64
0.79 1.92 0.79 1.55
0.22–2.85 0.13–27.56 0.10–6.44 0.64–3.79 – 0.67–4.20 0.92–10.10 0.56–2.99 0.61–4.41 0.88–4.81
1.67 3.04 1.29 1.64 2.05
P 0.022 0.011 NS 0.006 NS 0.008 0.029 NS NS NS NS NS NS NS NS NS NS NS
Note: LVI, lymphovascular invasion; NLR, Neutrophil-lymphocyte ratio; WBC count, white blood cell count.
diagnosed with low grade UTUC were included in this study, thus the evidence from sets with low-grade disease should be explained with cautious. At, the follow-up duration seems not long enough, so we only found few independent prognostic factors in population with low-grade disease.
them included relatively small population and were from single institutional experience; also their follow-up durations were relatively short. In addition, the cutoff value of NLR ranged widely from 2.5 to 5. Most studies used the cutoff point between 2.5 and 3 as a better subgroup point because the higher cutoff value will lead to the false exclusion of more patients who also need anti-inflammatory treatment before surgery, although higher cutoff value reflects more serious inflammation. The increasing evidence has indicated the relationship between systemic inflammation and the tumor development and progression in a variety of malignancies [21, 22]. Systemic inflammation-based factors: NLR, platelet-lymphocyte ratio (PLR), serum C-reactive protein (CRP), fibrinogen, and plasma cytokines (e.g. IL-6) or their receptors have been reported as potential markers for prognosis in various cancers including UCs [22, 23]. The potential underlying mechanisms have not been elucidated in detail. Recent studies have suggested that an inflammatory microenvironment might play an essential role in cancer development and progression [24]. The inflammatory milieu allows tumor cells to evade host responses and contributes to angiogenesis, tumor growth, invasion and metastasis. Studies suggested that the “tumor-associated neutrophils”, which are now considered as a crucial role in the tumor microenvironment, could promote the extracellular matrix modification and further activation of the epithelial-mesenchymal transition [25, 26]. In the latest European Association of Urology guidelines, NLR has been suggested as a prognostic factor for CSS in UTUC [10]. However, the NLR has not yet been regarded as a risk factor in UTUC patients due to low grade of evidence. Therefore, the current evidence is not strong enough to support its clinical application. The present study provided supporting evidence that NLR is an important prognostic factor in patients with UTUC. Meanwhile, the roles of NLR in CSS, RFS, MFS and OS were reported in detail in our cohort, but the majority of previous studies mentioned above only reported one or two primary outcomes [3]. Some limitations in the present study should be acknowledged. First, its retrospective nature may cause a selection bias. In addition, lymphadenectomy is not routinely performed, because there is no consensus on the pattern of lymphadenectomy for UTUC and its additional benefits are still unknown. Moreover, other inflammatory parameters such as CRP and cytokines were unavailable and not routinely tested, thus their association with patients` prognosis and interaction with NLR could not be evaluated in this study. At last, only 189 patients
5. Conclusions The present study revealed that preoperative elevated NLR was associated with advanced pathological features and tumor progression in RNU specimens. The results of our study enhanced the evidence that elevated NLR was an independent risk factor for worse CSS, RFS, MFS, and OS in UTUC patients after RNU treatment. Moreover, subset analyses showed this prognostic value was only valid in patients with highgrade UTUC, but not in those with low-grade disease. Due to its ease of accessibility and low cost, future studies are warranted for external validation to promote its clinical application. Supplementary data to this article can be found online at https:// doi.org/10.1016/j.cca.2018.06.019. Acknowledgement This program was supported by the National Key Research and Development Program of China (Grant No. SQ2017YFSF090096), the Prostate Cancer Foundation Young Investigator Award 2013, the National Natural Science Foundation of China (Grant No. 81300627, 81370855, 81702536, 81770756), Programs from Science and Technology Department of Sichuan Province (Grant No. 2018JY0089 and 2017HH0063), and Young Investigator Award of Sichuan University 2017. The funders had no role in study design, patient selection, data extraction, statistical analysis or interpretation, paper writing or revising, or the decision to publish. References [1] M. Roupret, M. Babjuk, E. Comperat, R. Zigeuner, R.J. Sylvester, M. Burger, N.C. Cowan, A. Bohle, B.W. Van Rhijn, E. Kaasinen, J. Palou, S.F. Shariat, European association of urology guidelines on upper urinary tract urothelial cell carcinoma: 2015 update, Eur. Urol. 68 (2015) 868–879. [2] X. Yin, Y. Xiao, F. Li, S. Qi, Z. Yin, J. Gao, Prognostic role of neutrophil-to-lymphocyte ratio in prostate cancer: a systematic review and meta-analysis, Medicine (Baltimore) 95 (2016) e2544. [3] M.D. Vartolomei, S. Kimura, M. Ferro, L. Vartolomei, B. Foerster, M. Abufaraj, S.F. Shariat, Is neutrophil-to-lymphocytes ratio a clinical relevant preoperative biomarker in upper tract urothelial carcinoma? A meta-analysis of 4385 patients,
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