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BMC Endocrine Disorders

, 19:123 | Cite as

Clinical significance of the preoperative main pancreatic duct dilation and neutrophil-to-lymphocyte ratio in pancreatic neuroendocrine tumors (PNETs) of the head after curative resection

  • Bo ZhouEmail author
  • Canyang Zhan
  • Jie Xiang
  • Yuan Ding
  • Sheng Yan
Open Access
Research article
  • 151 Downloads
Part of the following topical collections:
  1. Cancer and Endocrine Tumors

Abstract

Background

The present study aimed to investigate the prognostic significance of preoperative main pancreatic duct dilation and the neutrophil-to-lymphocyte ratio (PD-NLR) in pancreatic neuroendocrine tumors (PNETs) of the head after curative resection.

Methods

Sixty-four consecutive PNETs of the head that underwent curative resection were included in the study. Preoperative main pancreatic duct dilation (PD) was defined as a pancreatic duct dilation greater than 3 mm before surgery. Patients with both PD and an elevated NLR (> 3.13), with PD or elevated NLR, or neither of these characteristics were allocated a PD-NLR score of 2, 1, or 0, respectively. Univariate, multivariate and Kaplan-Meier analyses were used to calculate overall survival (OS) and disease-free survival (DFS).

Results

Preoperative PD-NLR score was correlated with tumor size (P = 0.005), T-stage (P = 0.016), lymph node metastasis (P <  0.001), distant metastasis (P = 0.005), type of hormone production (P = 0.006), perineural invasion (P = 0.014), and WHO classification (P <  0.001). Patients with a high PD-NLR score had a significantly poor OS and DFS relative to those with a low PD-NLR score (P <  0.001). In the multivariate analysis, PD-NLR score was an independent predictor of OS and DFS for PNET of the head (both P <  0.05). In the analyses of the various subgroups, preoperative PD-NLR score was also a predictor of OS and DFS. Additionally, the survival predictive capability of PD-NLR score was superior to that of WHO classification.

Conclusions

Despite the retrospective nature and small sample size of the present study, the results suggest that preoperative PD-NLR score can serve as an independent prognostic marker of early survival in patients with PNETs of the head undergoing curative resection. Further large prospective studies are necessary to validate our findings.

Keywords

Pancreatic neuroendocrine tumors Neutrophil-to-lymphocyte ratio Main pancreatic duct dilation WHO classification Prediction 

Abbreviations

AJCC

American Joint Committee on Cancer criteria

DFS

Disease-free survival

MRCP

Magnetic resonance cholangiopancreatography

NLR

Neutrophil-to-lymphocyte ratio

OS

Overall survival

PD

Main pancreatic duct dilation

PNET

Pancreatic neuroendocrine tumor

ROC

Receiver operating characteristic

WHO

World Health Organization

Background

Pancreatic neuroendocrine tumors (PNETs) are a heterogeneous group of neoplasms and account for approximately 1–2% of all pancreatic neoplasms and 7.0% of all neuroendocrine tumors [1]. PNETs can be classified as either functional or nonfunctional. The majority of PNETs, ranging from 60 to 90% of all PNETs, are nonfunctional. Complete surgical resection of a PNET has been suggested to be the only potentially curative treatment. In particular, for PNETs localized to the head of the pancreas, resectability criteria are stricter than are those for the body or tail, indicating that an inoperable tumor invades the celiac axis, superior mesenteric artery or the retroperitoneum extensively [2]. However, PNETs are considered more indolent tumors than are tumors of the exocrine pancreas and are associated with better long-term survival rates [3, 4, 5]. The clinical course of the disease is usually characterized by an indolent history with a 5-year survival rate exceeding 60% [6].

Several studies have found that multiple host-related factors are associated with survival in PNETs. Intrinsic tumor characteristics used to predict disease progression include tumor size, stage and grade, Ki-67 indices, and lymph node involvement [7, 8, 9]. Information regarding these factors is generally useful, but most of these factors are determined only after surgery. Therefore, it is necessary to identify potential prognostic indicators available before surgery. Increasing amounts of evidence suggest that inflammatory cells are an essential component of the tumor microenvironment and play a role in tumor progression [10, 11]. An elevated neutrophil-to-lymphocyte ratio (NLR) has been shown to be correlated with advanced stages and poor prognoses in a variety of human tumors, including PNET [12], hepatocellular carcinoma [13], breast cancer [14], and pancreatic cancer [15]. Moreover, recent studies have reported that the earliest consistent imaging finding of pancreatic cancer is main pancreatic duct dilation [16, 17]. In addition, Gupta N reported an association between final histologic diagnosis of pancreatic malignancy and main pancreatic duct diameter as determined by endoscopic ultrasound [18]. Nanno Y et al. observed that patients with PNET who presented with main pancreatic duct dilation (PD) showed an aggressive clinical course [19].

When considered together, main pancreatic duct dilation and the neutrophil-to-lymphocyte ratio (PD-NLR) may represent a potential predictor of clinical survival. The aim of the present study was to investigate the prognostic significance of PD-NLR score in PNETs of the head after curative resection. Furthermore, we aimed to compare the predictive capability of PD-NLR score for survival with that of other predictive models.

Methods

Study population

A total of 64 patients who underwent curative resection for PNET of the head were retrospectively reviewed from September 2002 to July 2016 at the First Affiliated Hospital, Zhejiang University School of Medicine. The diagnosis of PNET was made based on standard histologic criteria. Information on the following characteristics was collected for each patient: pathologic features including tumor size, lymph nodes and stage, gender, surgical approach, symptoms, and patient age. Tumor stage was classified according to the 8th edition of the American Joint Committee on Cancer (AJCC) staging system, and the grade of each PNET was determined based on the 2010 WHO classification of NETs of the GEP system. The retrospective measurement data on the main pancreatic duct were obtained through magnetic resonance cholangiopancreatography (MRCP) or enhanced CT by at least two experienced radiologists. According to the literature, main pancreatic duct dilatation (PD) was defined as a main pancreatic duct with a maximal diameter greater than 3 mm [18, 20]. PD was observed in 19 of 64 patients (29.7%). The NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. Receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) of NLR was 0.776 and that the optimal cut-off value was 3.13. These values indicated that NLR showed high sensitivity and high specificity in predicting overall survival. As a result, the NLR values were categorized into two groups: ≤ 3.13 and > 3.13. High NLR (> 3.13) was observed in 16 of 64 patients (25%). Patients with both PD and an elevated NLR (> 3.13), PD or an elevated NLR, or neither were allocated a PD-NLR score of 2, 1, or 0, respectively. The study was approved by the Ethics Committee of First Affiliated Hospital of Zhejiang University School of Medicine.

Follow-up

The patients were monitored after surgery by outpatient visits or telephone calls. Overall survival (OS) was calculated as the time from the date of surgery to the date of death from any cause or the date of last known contact. Disease-free survival (DFS) was calculated as the time from initial diagnosis until relapse. Follow-up was routinely carried out every 6 months for the first 5 years and yearly thereafter. Follow-up examinations included laboratory tests and imaging techniques [12].

Statistical analysis

All of the statistical analyses were performed using SPSS software, version 16.0 for Windows (SPSS, Chicago, IL, USA). Area under the curve values, obtained from ROC curve analysis, were used to compare the predictive efficacies of PD-NLR score and those of other predictive models. Differences between groups were analysed using Pearson’s chi-square test, Fisher’s exact test or the Mann-Whitney U test as appropriate. Cox proportional hazard models were used to estimate hazard ratios for OS and DFS and to determine independent risk factors. All p values were two sided and considered significant when less than 0.05.

Results

Patients’ clinicopathological characteristics

Among the 64 patients with PNETs, 29 (45.3%) were men and 35 (54.7%) were women. These patients were diagnosed at a mean age of 53.0 ± 12.17 years and were evaluated over a mean follow-up period of 46.28 ± 38.53 months. The median size of the PNETs was 2.5 (range, 0.8–19.0) cm. Forty-five of 64 patients (70.3%) underwent standard surgical procedures with regional lymph node dissection, including pancreatoduodenectomy (n = 43) and total pancreatectomy (n = 2). Patients with small tumors (< 2 cm) without any signs of metastasis underwent enucleation (n = 19). At the time of the last follow-up visit, 20 patients had relapsed, and 15 patients had died. The numbers of patients classified into grades 1, 2 and 3 were 28, 26 and 10, respectively. The 1-, 3-, and 5-year OS rates were 95, 81, and 67%, respectively, and the 1-, 3-, and 5-year DFS rates were 81, 65, and 65%, respectively.

Associations of PD, NLR, and PD-NLR score with survival

PD was predictive of inferior OS for PNETs (HR = 9.229, 95% CI 2.879–29.585, P <  0.001), whereas patients with a high NLR had shorter OS than patients with a low NLR (HR = 8.837, 95% CI 2.990–26.117, P <  0.001). Given the predictive ability of PD and NLR for survival, we analysed the prognostic significance of PD-NLR score. Patients with a PD-NLR score of 1 had shorter OS (HR = 20.055, 95% CI 2.444–164.556, P = 0.005) and DFS (HR =14.132, 95% CI 3.083–64.774, P = 0.001) than patients with a PD-NLR score of 0 (Fig. 1). Furthermore, a high tumor grade, the presence of lymph node (LN) metastasis and perineural invasion, a large tumor and a high T stage tumor were prognostic factors for poor OS (P <  0.05 for all), whereas a symptomatic tumor; a high tumor grade; the presence of LN metastasis, distant metastasis or perineural invasion; a large tumor and a high T stage tumor were associated with poor DFS (P <  0.05 for all).
Fig. 1

Kaplan-Meier survival curves showing OS (a) and DFS (b) stratified by PD-NLR in PNET patients undergoing curative resection. High PD-NLR score was significantly correlated with shorter OS and DFS in PNET of the head undergoing curative resection

In the multivariate analysis, PD-NLR score remained significantly associated with OS (HR = 16.159, 95% CI 1.902–137.304, P = 0.011) and DFS (HR = 7.356, 95% CI 1.495–36.194, P = 0.014) (Tables 1 and 2). Furthermore, WHO grade was an independent predictive factor for OS (P <  0.05, Table 1), whereas WHO grade and tumor size were independent predictive factors for DFS (P <  0.05 for all, Table 2).
Table 1

Variables associated with OS according to the Cox proportional hazards regression model

Variable

Univariate analysis

Multivariate analysis

HR

95% CI

P

HR

95% CI

P

Age (years)

  ≤ 60

Reference

     

  > 60

2.074

0.721–5.966

0.176

   

Gender

 Female

Reference

     

 Male

1.064

0.385–2.939

0.905

   

Tumor size (cm)

  ≤ 2.5

Reference

  

Reference

  

  > 2.5

7.336

1.655–32.514

0.009

NA

NA

0.249

Symptoms

 Absent

Reference

     

 Present

3.223

0.727–14.292

0.123

   

PD-NLR

 0

Reference

  

Reference

  

 1

20.055

2.444–164.556

0.005

16.159

1.902–137.304

0.011

 2

56.819

6.874–469.680

<  0.001

32.737

3.561–300.966

0.002

Type of hormone production

 Functioning

Reference

     

 Non-functioning

33.418

0.265–4211.462

0.155

   

T-stage

 T1–2

Reference

  

Reference

  

 T3–4

3.602

1.303–9.953

0.013

NA

NA

0.567

LN metastasis

 Absent

Reference

  

Reference

  

 Present

6.896

2.359–20.157

<  0.001

NA

NA

0.608

Distant metastasis

 Absent

Reference

     

 Present

3.438

0.426–27.722

0.246

   

Perineural invasion

 Absent

Reference

  

Reference

  

 Present

6.453

2.247–18.537

0.001

NA

NA

0.118

WHO classification

 Grade 1–2

Reference

  

Reference

  

 Grade 3

19.191

4.735–77.784

<  0.001

5.222

1.227–22.218

0.025

OS Overall survival, PD Main pancreatic duct dilation, NLR Neutrophil-to-lymphocyte ratio, LN Lymph node. P-values < 0.05, marked in bold font, indicate statistical significance

Table 2

Variables associated with DFS according to the Cox proportional hazards regression model

Variable

Univariate analysis

Multivariate analysis

HR

95% CI

P

HR

95% CI

P

Age (years)

  ≤ 60

Reference

     

  > 60

1.321

0.525–3.324

0.554

   

Gender

 Female

Reference

     

 Male

1.481

0.613–3.577

0.382

   

tumor size (cm)

  ≤ 2.5

Reference

  

Reference

  

  > 2.5

7.449

2.177–25.491

0.001

4.109

1.054–16.023

0.042

Symptoms

 Absent

Reference

  

Reference

  

 Present

4.935

1.143–21.302

0.032

NA

NA

0.185

PD-NLR

 0

Reference

     

 1

14.132

3.083–64.774

0.001

7.356

1.495–36.194

0.014

 2

41.928

8.731–201.359

<  0.001

15.144

2.762–83.020

0.002

Type of hormone production

 Functioning

Reference

     

 Non-functioning

34.588

0.572–2090.521

0.09

   

T-stage

 T1–2

Reference

  

Reference

  

 T3–4

2.539

1.034–6.234

0.042

NA

NA

0.222

LN metastasis

 Absent

Reference

  

Reference

  

 Present

5.789

2.368–14.152

<  0.001

NA

NA

0.394

Distant metastasis

 Absent

Reference

  

Reference

  

 Present

17.364

4.136–72.889

<  0.001

NA

NA

0.271

Perineural invasion

 Absent

Reference

  

Reference

  

 Present

4.419

1.681–11.620

0.003

NA

NA

0.287

WHO classification

 Grade 1–2

Reference

     

 Grade 3

14.287

5.321–38.358

<  0.001

6.595

1.846–23.565

0.004

DFS Disease-free survival, PD Main pancreatic duct dilation, NLR Neutrophil-to-lymphocyte ratio, LN Lymph node. P-values < 0.05, marked in bold font, indicate statistical significance

Relationships between PD-NLR and clinicopathological characteristics

Preoperative PD-NLR score was associated with tumor size (P = 0.005), T-stage (P = 0.016), distant metastasis (P = 0.005), LN metastasis (P <  0.001), type of hormone production (P = 0.006), perineural invasion (P = 0.014), and WHO classification (P <  0.001). There were no significant associations between preoperative PD-NLR score and the remaining clinicopathological parameters, such as age, gender and symptoms (all P > 0.05, Table 3).
Table 3

Relationships between PD-NLR and clinicopathological characteristics in patients with surgically resected neuroendocrine tumors in the head of the pancreas

Variable

No. of cases

PD-NLR

P

(n = 64)

0

(n = 37, %)

1

(n = 19, %)

2

(n = 8, %)

Age (years)

  ≤ 60

44

27 (73)

13 (68.4)

4 (50)

0.245

  > 60

20

10 (27)

6 (31.6)

4 (50)

 

Gender

 Female

35

22 (59.5)

8 (42.1)

5 (62.5)

0.687

 Male

29

15 (40.5)

11 (57.9)

3 (37.5)

 

tumor size (cm)

  ≤ 2.5

33

24 (64.9)

8 (42.1)

1 (12.5)

0.005

  > 2.5

31

13 (35.1)

11 (57.9)

7 (87.5)

 

Symptoms

 Absent

20

14 (37.8)

6 (31.6)

0

0.061

 Present

44

23 (62.2)

13 (68.4)

8 (100)

 

T-stage

 T1–2

49

32 (86.5)

13 (68.4)

4 (50)

0.016

 T3–4

15

5 (13.5)

6 (31.6)

4 (50)

 

LN metastasis

 Absent

49

34 (91.9)

13 (68.4)

2 (25)

<  0.001

 Present

15

3 (8.1)

6 (31.6)

6 (75)

 

Distant metastasis

 Absent

61

37 (100)

18 (94.7)

6 (75)

0.005

 Present

3

0

1 (5.3)

2 (25)

 

Type of hormone production

 Non-functioning

48

23 (62.2)

17 (89.5)

8 (100)

0.006

 Functioning

16

14 (37.8)

2 (10.5)

0

 

Perineural invasion

 Absent

56

35 (94.6)

16 (84.2)

5 (87.5)

0.014

 Present

8

2 (5.4)

3 (15.8)

3 (12.5)

 

WHO classification

 Grade 1

28

25 (67.6)

3 (15.8)

0

<  0.001

 Grade 2

26

12 (32.4)

11 (57.9)

3 (37.5)

 

 Grade 3

10

0

5 (26.3)

5 (62.5)

 

PD Main pancreatic duct dilation, NLR Neutrophil-to-lymphocyte ratio, LN Lymph node. P-values < 0.05, marked in bold font, indicate statistical significance

Prognostic value of preoperative PD-NLR in different PNET subgroups

As WHO classification, tumor size, type of hormone production and perineural invasion have been identified as prognostic factors for PNET, we next investigated the prognostic value of preoperative PD-NLR score in different subgroups of PNET patients to exclude these factors. Patients with a low PD-NLR (score 0) showed better OS and DFS than those in the high PD-NLR group (score 1 or 2) among patients with grade 1 or 2 tumor (both P <  0.001) (Fig. 2a and b). Furthermore, in the patients with tumor size > 2.5 cm, high PD-NLR score was significantly associated with decreased OS (P = 0.001) and DFS (P <  0.001) (Fig. 2c and d), and the prognostic value of OS (P <  0.001) and DFS (P <  0.001) was maintained in patients with nonfunctional PNETs (Fig. 3a and b). In addition, high PD-NLR score was a prognostic factor for poor OS and DFS in those patients without perineural invasion (both P <  0.001) (Fig. 3c and d).
Fig. 2

Kaplan-Meier survival curves for the different PNET subgroups. High PD-NLR score was significantly correlated with shorter OS and DFS in subgroups with grade 1–2 (a and b) and tumor size > 2.5 cm (c and d)

Fig. 3

Kaplan-Meier survival curves for the different PNET subgroups. High PD-NLR score was significantly correlated with shorter OS and DFS in subgroups with nonfunctional PNETs (a and b) and without perineural invasion (c and d)

Comparative performance of PD-NLR and other predictive models

To further evaluate the prognostic value of PD-NLR, PD, NLR and WHO classification, ROC analysis was performed, and AUC values were compared. PD-NLR had a higher AUC value for OS and DFS (0.886 and 0.889) than PD or NLR (Fig. 4). In addition, the discriminatory capability of PD-NLR was superior to that of the WHO classification in both OS (AUC value: 0.886 vs 0.818) and DFS (AUC value: 0.889 vs 0.858) prediction (Table 4).
Fig. 4

Comparison of the area under the receiver operating characteristic curve (AUC) in different predictive models. The discriminatory capability of PD-NLR was superior to that of other predictive models in OS (a) and DFS (b) prediction

Table 4

Areas under the ROC curve for WHO classification and PD-NLR for predicting OS and DFS in patients with surgically resected neuroendocrine tumors in the head of the pancreas

Variable

OS

DFS

Area under the ROC curve (95% CI)

P

Area under the ROC curve (95% CI)

P

PD-NLR

0.886 (0.788–0.985)

< 0.001

0.889 (0.795–0.983)

< 0.001

PD

0.785 (0.641–0.929)

0.001

0.757 (0.618–0.896)

0.001

NLR (≤ 3.1/ > 3.1)

0.772 (0.619–0.925)

0.002

0.791 (0.655–0.927)

< 0.001

WHO classification

0.818 (0.699–0.938)

< 0.001

0.858 (0.761–0.955)

< 0.001

ROC Receiver operating characteristic, OS Overall survival, DFS Disease-free survival, PD Main pancreatic duct dilation, NLR Neutrophil-to-lymphocyte ratio. P-values < 0.05, marked in bold font, indicate statistical significance

Discussion

The present study showed that preoperative PD-NLR score, a novel and easily accessible inflammation-based score derived from main pancreatic duct dilation and the neutrophil-to-lymphocyte ratio, was an independent prognostic factor for PNET of the head undergoing curative resection. Furthermore, high preoperative PD-NLR score was associated with high tumor grade, large tumor size, LN metastasis, distant metastasis and perineural invasion. In addition, we found that the predictive capability of PD-NLR score was superior to that of other predictive models, including PD, NLR and WHO classification.

Recently, there has been accumulating evidence that PD is associated with a high risk for pancreatic tumors, including pancreatic cancer or PNETs [17, 18, 19, 20]. Concerning the mechanism of PD in pancreatic tumors, mechanical compression by the tumor or cancer cell invasion may cause segmental obstruction and upstream dilatation in the main pancreatic duct. Compared with classic PNETs, which have scant stroma and proliferation of medullary pattern, PNETs with PD are more fibrotic and show greater infiltration into adjacent structures, resulting in the entrapment of the main pancreatic duct inside the tumor mass [19, 21, 22]. In addition, the pancreas with PD may be the site where pancreatic cancer originates. Tanaka S et al. reported that main pancreatic duct dilatation (> 2.5 mm) and presence of a pancreatic cyst (> 5 mm) were both strong independent predictors of the subsequent development of pancreatic cancer [23]. Nanno Y et al. found that PNET patients with main pancreatic duct involvement and dilation showed significantly worse recurrence-free survival than did those without ductal involvement (P <  0.001), with a 5-year recurrence-free rate of 41% [19]. Therefore, PD can act as a significant prognostic biomarker in pancreatic tumors.

Systemic inflammation is correlated with worse survival in cancer patients in a variety of cancer types [24, 25]. The NLR, which can reflect the systemic inflammation status, has been shown to be a reliable predictive marker for different types of cancer, such as PNET [12], pancreatic ductal adenocarcinoma [15], renal cell carcinoma [26], breast cancer [14] and liver cancer [13]. Salman T et al. revealed that an advanced stage was accompanied by significantly higher NLR and platelet-to-lymphocyte ratio (PLR) in patients with NETs [27]. Recently, Luo G et al. conducted a retrospective analysis of 165 PNETs and reported that NLR was an independent predictor of overall survival for patients with PNETs [28]. Tong Z et al. demonstrated that increased NLR was related with advanced T stage, LN metastasis, tumor thrombus formation, and advanced grade in patients with PNETs [29]. Additionally, our previous study found that NLR and PLR were significantly higher in patients with PNETs than in matched healthy volunteers. Furthermore, NLR, but not PLR, is an independent prognostic factor of both OS and DFS in patients with PNET [30]. In general, preoperative NLR, a prognosis-related serum biomarker, can be useful for predicting disease prognosis in patients with surgically resected PNETs.

In our study, we found that high PD-NLR score was correlated with tumor size, T-stage, lymph node metastasis, type of hormone production, perineural invasion, and WHO classification. Moreover, patients with high PD-NLR score were more likely to have distant metastasis than patients with low PD-NLR score. All of these findings indicate that PD-NLR can reflect the tumor progression and tumor burden. Further analysis revealed that PD-NLR score was an independent predictive factor for patients with surgically resected PNETs of the head. Patients with a high PD-NLR score had significantly poorer OS and DFS than did those with a low PD-NLR score. For the subgroups of patients with grade 1 or 2 tumor or tumor size > 2.5 cm, we similarly found that high PD-NLR score was significantly associated with decreased OS and DFS. Furthermore, the predictive capability of PD-NLR score for survival was superior to that of WHO classification. All of these findings confirm that preoperative PD-NLR score can predict the outcomes of patients with PNET of the head undergoing curative resection.

The major limitations of the present study are its retrospective nature and single-center design. A further limitation is the small sample size. Therefore, large prospective studies are necessary to validate our findings. Another limitation was the short study duration of 46 months, as PNETs generally have an indolent disease course. In addition, only patients who underwent curative resection were included in the study. Despite these limitations, the present study is valuable as it identifies PD-NLR score as a potential prognostic marker to predict survival in patients with PNET of the head undergoing curative resection.

Conclusions

Based on the PD-NLR scoring system, patients with PNETs of the head after curative resection were classified into three groups based on their prognosis. As a novel and easily accessible inflammation-based biomarker, preoperative PD-NLR score can serve as an independent prognostic marker of early survival in patients with PNETs of the head undergoing curative resection. Prospective and independent studies are warranted to verify our findings.

Notes

Acknowledgements

Not applicable.

Authors’ contributions

BZ and CY contributed to the study concept, design and drafting of the manuscript. JX and CY contributed to the collection and analysis of the data. YD and SY contributed to the supervision and interpretation of the data. BZ was the main investigator and was responsible for the overall study concept and design as well as the revision and final drafting of the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by grants from the General Research Projects of the Department of Education of Zhejiang Province (No. Y201737812), Zhejiang Province Department of Laboratory Animal Science and Technology Plan Projects (No. 2018C37115). The funder of Y201737812 and 2018C37115 was Bo Zhou who was the first and corresponding author, responsible for the overall study concept and design as well as the revision and final drafting of the manuscript.

Ethics approval and consent to participate

Our study was approved by the Ethics Committee of First Affiliated Hospital of Zhejiang University School of Medicine. Written informed consent was obtained from all subjects in our study. All the raw data are available from the corresponding author on reasonable request.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

  1. 1.
    Bilimoria KY, Talamonti MS, Tomlinson JS, Stewart AK, Winchester DP, Ko CY, et al. Prognostic score predicting survival after resection of pancreatic neuroendocrine tumors: analysis of 3851 patients. Ann Surg. 2008;247:490–500.CrossRefGoogle Scholar
  2. 2.
    Bertani E, Fazio N, Radice D, Zardini C, Spinoglio G, Chiappa A, et al. Assessing the role of primary tumour resection in patients with synchronous unresectable liver metastases from pancreatic neuroendocrine tumour of the body and tail. A propensity score survival evaluation. Eur J Surg Oncol. 2017;43:372–9.CrossRefGoogle Scholar
  3. 3.
    Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas. 2010;39(6):707–12.CrossRefGoogle Scholar
  4. 4.
    Fischer L, Kleeff J, Esposito I, Hinz U, Zimmermann A, Friess H, et al. Clinical outcome and long-term survival in 118 consecutive patients with neuroendocrine tumours of the pancreas. Br J Surg. 2008;95:627–35.CrossRefGoogle Scholar
  5. 5.
    Niederle MB, Hackl M, Kaserer K, Niederle B. Gastroenteropancreatic neuroendocrine tumours: the current incidence and staging based on the WHO and European neuroendocrine tumour society classification: an analysis based on prospectively collected parameters. Endocr Relat Cancer. 2010;17:909–18.CrossRefGoogle Scholar
  6. 6.
    Panzuto F, Nasoni S, Falconi M, Corleto VD, Capurso G, Cassetta S, et al. Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocr Relat Cancer. 2005;12:1083–92.CrossRefGoogle Scholar
  7. 7.
    Strosberg JR, Cheema A, Weber JM, Ghayouri M, Han G, Hodul PJ, et al. Relapse-free survival in patients with nonmetastatic, surgically resected pancreatic neuroendocrine tumors: an analysis of the AJCC and ENETS staging classifications. Ann Surg. 2012;256:321–5.CrossRefGoogle Scholar
  8. 8.
    Strosberg JR, Cheema A, Weber J, Han G, Coppola D, Kvols LK. Prognostic validity of a novel American joint committee on Cancer staging classification for pancreatic neuroendocrine tumors. J Clin Oncol. 2011;29(22):3044–9.CrossRefGoogle Scholar
  9. 9.
    Bettini R, Boninsegna L, Mantovani W, Capelli P, Bassi C, Pederzoli P, et al. Prognostic factors at diagnosis and value of WHO classification in a mono-institutional series of 180 non-functioning pancreatic endocrine tumours. Ann Oncol. 2008;19:903–8.CrossRefGoogle Scholar
  10. 10.
    Liao J, Hwang SH, Li H, Liu JY, Hammock BD, Yang GY. Inhibition of chronic pancreatitis and murine pancreatic intraepithelial neoplasia by a dual inhibitor of c-RAF and soluble epoxide hydrolase in LSL-KrasG12D/Pdx-1-Cre mice. Anticancer Res. 2016;36:27–37.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Stark AP, Chang HH, Jung X, Moro A, Hertzer K, Xu M, et al. E-cadherin expression in obesity-associated, Kras-initiated pancreatic ductal adenocarcinoma in mice. Surgery. 2015;158:1564–72.CrossRefGoogle Scholar
  12. 12.
    Zhou B, Zhan C, Wu J, Liu J, Zhou J, Zheng S. Prognostic significance of preoperative gamma-glutamyltransferase to lymphocyte ratio index in nonfunctional pancreatic neuroendocrine tumors after curative resection. Sci Rep. 2017;7:13372.CrossRefGoogle Scholar
  13. 13.
    Mano Y, Shirabe K, Yamashita Y, Harimoto N, Tsujita E, Takeishi K, et al. Preoperative neutrophil-to-lymphocyte ratio is a predictor of survival after hepatectomy for hepatocellular carcinoma: a retrospective analysis. Ann Surg. 2013;258:301–5.CrossRefGoogle Scholar
  14. 14.
    Azab B, Bhatt VR, Phookan J, Murukutla S, Kohn N, Terjanian T, et al. Usefulness of the neutrophil-to-lymphocyte ratio in predicting short- and long-term mortality in breast cancer patients. Ann Surg Oncol. 2012;19:217–24.CrossRefGoogle Scholar
  15. 15.
    Paramanathan A, Saxena A, Morris DL. A systematic review and meta-analysis on the impact of pre-operative neutrophil lymphocyte ratio on long term outcomes after curative intent resection of solid tumours. Surg Oncol. 2014;23:31–9.CrossRefGoogle Scholar
  16. 16.
    Gangi S, Fletcher JG, Nathan MA, Christensen JA, Harmsen WS, Crownhart BS, et al. Time interval between abnormalities seen on CT and the clinical diagnosis of pancreatic cancer: retrospective review of CT scans obtained before diagnosis. AJR Am J Roentgenol. 2004;182:897–903.CrossRefGoogle Scholar
  17. 17.
    Tanaka S, Nakaizumi A, Ioka T, Oshikawa O, Uehara H, Nakao M, et al. Main pancreatic duct dilatation: a sign of high risk for pancreatic cancer. Jpn J Clin Oncol. 2002;32:407–11.CrossRefGoogle Scholar
  18. 18.
    Gupta N, Kankotia R, Sahakian A, Jayaram P, Shindel A, Dong E, et al. Endoscopic ultrasound assessment of pancreatic duct diameter predicts neuroendocrine tumors and other pancreas masses. Pancreas. 2019;48:66–9.CrossRefGoogle Scholar
  19. 19.
    Nanno Y, Matsumoto I, Zen Y, Otani K, Uemura J, Toyama H, et al. Pancreatic duct involvement in well-differentiated neuroendocrine tumors is an independent poor prognostic factor. Ann Surg Oncol. 2017;24:1127–33.CrossRefGoogle Scholar
  20. 20.
    Edge MD, Hoteit M, Patel AP, Wang X, Baumgarten DA, Cai Q. Clinical significance of main pancreatic duct dilation on computed tomography: single and double duct dilation. World J Gastroenterol. 2007;13:1701–5.CrossRefGoogle Scholar
  21. 21.
    Chaudhry A, Funa K, Oberg K. Expression of growth factor peptides and their receptors in neuroendocrine tumors of the digestive system. Acta Oncol. 1993;32:107–14.CrossRefGoogle Scholar
  22. 22.
    Chaudhry A, Papanicolaou V, Oberg K, Heldin CH, Funa K. Expression of platelet-derived growth factor and its receptors in neuroendocrine tumors of the digestive system. Cancer Res. 1992;52:1006–12.PubMedGoogle Scholar
  23. 23.
    Tanaka S, Nakao M, Ioka T, Takakura R, Takano Y, Tsukuma H, et al. Slight dilatation of the main pancreatic duct and presence of pancreatic cysts as predictive signs of pancreatic cancer: a prospective study. Radiology. 2010;254:965–72.CrossRefGoogle Scholar
  24. 24.
    Li MX, Liu XM, Zhang XF, Zhang JF, Wang WL, Zhu Y, et al. Prognostic role of neutrophil-to-lymphocyte ratio in colorectal cancer: a systematic review and meta-analysis. Int J Cancer. 2014;134:2403–13.CrossRefGoogle Scholar
  25. 25.
    Pan QX, Su ZJ, Zhang JH, Wang CR, Ke SY. A comparison of the prognostic value of preoperative inflammation-based scores and TNM stage in patients with gastric cancer. Onco Targets Ther. 2015;8:1375–85.CrossRefGoogle Scholar
  26. 26.
    Pichler M, Hutterer GC, Stoeckigt C, Chromecki TF, Stojakovic T, Golbeck S, et al. Validation of the pre-treatment neutrophil-lymphocyte ratio as a prognostic factor in a large European cohort of renal cell carcinoma patients. Br J Cancer. 2013;108:901–7.CrossRefGoogle Scholar
  27. 27.
    Salman T, Kazaz SN, Varol U, Oflazoglu U, Unek IT, Kucukzeybek Y, et al. Prognostic value of the pretreatment neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for patients with neuroendocrine tumors: an Izmir oncology group study. Chemotherapy. 2016;61:281–6.CrossRefGoogle Scholar
  28. 28.
    Luo G, Liu C, Cheng H, Jin K, Guo M, Lu Y, et al. Neutrophil-lymphocyte ratio predicts survival in pancreatic neuroendocrine tumors. Oncol Lett. 2017;13:2454–8.CrossRefGoogle Scholar
  29. 29.
    Tong Z, Liu L, Zheng Y, Jiang W, Zhao P, Fang W, et al. Predictive value of preoperative peripheral blood neutrophil/lymphocyte ratio for lymph node metastasis in patients of resectable pancreatic neuroendocrine tumors: a nomogram-based study. World J Surg Oncol. 2017;15:108.CrossRefGoogle Scholar
  30. 30.
    Zhou B, Zhan C, Wu J, Liu J, Zhou J, Zheng S. Prognostic significance of preoperative neutrophil-to-lymphocyte ratio in surgically resectable pancreatic neuroendocrine tumors. Med Sci Monit. 2017;23:5574–88.CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
  2. 2.Department of Neonatology, Children’s Hospital, School of MedicineZhejiang UniversityHangzhouChina
  3. 3.Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina

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