Predictive factors affecting lymph node metastasis in patients of resectable pancreatic neuroendocrine neoplasms：a single-center retrospective study

doi:10.21203/rs.3.rs-5001922/v1

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Research Article

Predictive factors affecting lymph node metastasis in patients of resectable pancreatic neuroendocrine neoplasms：a single-center retrospective study

https://doi.org/10.21203/rs.3.rs-5001922/v1

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BACKGROUND

Pancreatic neuroendocrine neoplasms (pNENs) present great heterogeneity in biological behavior, histological characteristics and clinical manifestations. Monocyte-to-lymphocyte ratio (MLR) is a non-invasive and easy to obtain indicator, which can reflect disease severity in multiple tumors. Lymph node metastasis (LNM) has a great impact on patient's surgical approach and prognosis. Predicting LNM before surgery has a guiding significance for clinical treatment.

AIM

We aimed to evaluate the predictive factors including MLR associated with LNM of patients with resectable pNEN in our center.

METHODS

A total of 64 patients who underwent pNEN resection and lymph nodes dissection in our hospital from July 2014 until June 2023 were included in this study. Univariate and multivariate analyses were applied to identify predictive factors for LNM by analyzing clinical data, inflammatory markers, and pathological features.

RESULTS

Among the 64 patients, 15 (23.4%) patients were node positive. Univariate analysis showed that vascular invasion, peripheral nerve invasion, bilirubin level, tumor grade, tumor size and MLR (p<0.05 for all) were risk factor for LNM. Multivariate logistic analysis demonstrated that tumor size was the only independent risk factor for LNM in our research. Multivariate ROC analysis had better predictive performance than univariate analysis.

CONCLUSION

The preoperative MLR, vascular invasion, peripheral nerve invasion, bilirubin level, tumor grade and tumor size are potential predictors for LNM, especially during the initial diagnosis for resectable pNENs. Multivariate ROC analysis had better predictive performance than univariate analysis.

Resectable pancreatic neuroendocrine neoplasms

Lymph node metastasis

Predictive factors

Retrospective study

Inflammatory molecular markers

Monocyte-to-lymphocyte ratio

Pancreatic neuroendocrine neoplasm (pNEN) is a common gastrointestinal and pancreatic neuroendocrine neoplasm (GEP-NEN) in China, accounting for about 2%-5% of all pancreatic neoplasms. These tumors originate from pancreatic multifunctional neuroendocrine stem cells^[1–3]. The biological behaviour, histological characteristics and clinical manifestations of PNENs are highly heterogeneous. These tumors can grow independently or aggressively and even metastasize at an early stage. Their biological characteristics may also change as the disease progresses^[4].

Patients with G1 and G2 grade have a 10-year overall survival rate of 60–70%. Due to the possibility of recurrence or metastasis of pNENs, the median survival of G3 patients is less than 2 years^[5]. Surgery is the main treatment for pNENs .The incidence of lymph node metastasis (LNM) in nonfunctional pNENs with a maximum diameter ≤ 2 cm ranged from 17–27.3%^{[6, 7]}.The TNM stage of the tumor was correlated with LNM. In patients without distant metastases, tumor size and LNM have a strong impact on prognosis and the patient's surgical approach ^[8].The routine dissection of lymph nodes increases the difficulty of surgery, prolongs the operation time and increases postoperative complications ^[9]. To reduce patients' pain and postoperative complications, it is necessary to fully evaluate LNM before surgery. Some researchers have found that tumor size, T stage and tumor grade are related to LNM ^[10].

Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR) and platelet-to-lymphocyte ratio (PLR) are non-invasive, rapid, easy-to-obtain and inexpensive indicators, that can reflect the balance of inflammation and immune activity in the body. They have proven to be important indicators of prognosis and disease severity in a variety of tumors^[11–15]. These parameters have promising clinical applications.

Some researchers have shown that hepatocellular carcinoma patients with a low MLR have longer recurrence-free survival (RFS)^[16]. MLR in adult lymphoma patients with peripheral lymph node enlargement is significantly higher than that in nonlymphoma patients. MLR is a good diagnostic marker for lymphoma ^[17].

When neuroendocrine cells are overactivated by chronic inflammation, they may develop atypical or neoplastic lesions^[18].NLR and PLR are independent factors affecting the prognosis of pNEN patients ^{[10, 19–21]}. A high NLR is often associated with a poor prognosis^[22].

LNM is related to the prognosis of patients and influences the mode of surgery. Due to the heterogeneity of pNENs, predicting LNM before surgery is valuable for guiding the clinical treatment. Patients with the potential for LNM are screened, and lymph node dissection is recommended during tumor resection. However, there are limitations in deciding whether to perform lymph node dissection based only on tumor size. More risk factors need to be discovered to comprehensively evaluate LNM to determine the appropriate timing for lymph node dissection.

Hence, we performed this retrospective study to explore the risk factors associated with LNM in patients with resectable pNEN in our center by analyzing clinical data, inflammatory markers, and pathological features.

Study design and patients

A retrospective analysis of the clinical and pathological data of adult patients diagnosed with pNEN in our hospital from July 2014 until June 2023 was performed. In accordance with the Declaration of Helsinki, ethical approval for the study was obtained from the Ethics Committee of Zhejiang Provincial People's Hospital（IRB No. QT2024150）.

Inclusion criteria

1. PNEN was confirmed by postoperative pathology.

2.The lesion could be treated surgically according to preoperative evaluation.

3. Lymph nodes were dissected during the operation.

Exclusion criteria

1. The patient only underwent biopsy, but no surgical treatment was performed at our hospital.

2. Lymph nodes were not dissected during the operation.

3. Multiple endocrine neoplasia type 1(MEN1), Von Hippel–Lindau disease, neurofibromatosis type 1（NF1 ),or tuberous sclerosis was diagnosed.

Gender, age of onset, functional status, clinical symptoms and preoperative haematological indicators, such as routine blood parameters (neutrophil count, platelet count, lymphocyte count, monocyte count), bilirubin, tumor markers (NSE, CEA, CA199, AFP), tumor site, tumor size and pathological data (pathological type, pathological grade, immunohistochemical results, vascular or peripheral nerve invasion, LNM) were collected.

Data analysis

All statistical analyses and graphics in this study were calculated and demonstrated by using the IBM SPSS Statistics software 20.0. Chi-square tests were used to compare detection rates between groups. Mann–Whitney U test was utilized to evaluate ranked variables. Multivariate logistic regression analyses were performed to analyze risk factors for LN metastasis. The ROC curve was used to estimate the performance of each factor to LN metastasis. Differences with two-sided p value <0.05 was considered statistically significant.

Patient’s characteristics, preoperative peripheral blood test results and pathological results

From July 2014 to June 2023, a total of 64 patients underwent pNEN resection and lymph nodes dissection in our hospital. The characteristics and results were summarized in Table 1. The age at diagnosis was 53.50 years (range 16-max 73; 47.25–62.75). Among them, 38 (59.4%) were males. Seven people had functional pNEN (10.9%) and 62 had single NEN. Forty-three patients had no obvious discomfort at the time of visit, and 21 patients were found to have abdominal pain, abdominal distension, poor appetite, hypoglycaemia and other symptoms upon physical examination. A total of 14.1% (9/64) of patients had elevated bilirubin, 3.2% (2/63) had elevated CEA, 4.8% (3/63) had elevated CA199, and 8.3% (3/36) had elevated NSE. The preoperative MLR was 0.185 (0.132–0.246), NLR was 1.906 (1.434–2.771) and PLR was 116.32 (94.80-159.01). The lesions of 38 patients were located in the head and neck of the pancreas, the others were located in the tail of the body of the pancreas. The average tumor size was 3.00 cm (min 0.15cm, max 10cm; interquartile 1.85-4.50cm). Thirty-six (56.3%) patients were diagnosed as G1 neuroendocrine tumor (NET),21 (32.8%) as G2 NET, 4 (6.3%) as G3 NET, 1 (1.6%) as neuroendocrine cancer (NEC) and 1 (1.6%) as mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN). We found that 76.6% (49/64) of patients were lymph node negative and the other 23.4% (15/64) of patients were node positive. Pathology revealed that 23.4% (15/64) of patients had vascular invasion, 23.4% (15/64) had peripheral nerve invasion, 93.5% of patients were positive for CgA (58/62) and 100% were positive for Syn (61/61).

Table 1

Patients characteristics, preoperative peripheral blood test results and pathological results and univariate and multivariate analyses of clinical characteristics according to lymph node metastasis
Factors	Total number (64)	Lymph node status		Univariate P-value	Multivariate P-value
Factors	Total number (64)	Negative (49)	Positive (15)	Univariate P-value	Multivariate P-value
Age	53.50(47.25–62.75)	55.00(47.50–63.00)	52.00(45.00–60.00)	0.669
Gender				0.563
Male	38	28	10
Femael	26	21	5
Functional status				0.545
Functional	7	6	1
Nonfunctional	57	43	14
Numbers of NENs				0.427
Single	62	47	15
Mutiple	2	2	0
Symptoms				0.755
Yes	21	17	4
No	43	32	11
Tumor size (cm )	3.00(1.85–4.50)	2.50(1.70-4.00)	4.50(3.00–7.00)	0.013	0.033
Tumor location				0.563
Head and neck	38	28	10
Body and tail	26	21	5
Tumor grade				0.017	>0.05
G1	36	32	4
G2	21	12	9
G3	4	3	1
NEC	2	1	1
MiNEN	1	1	0
Vascular invasion				<0.05	0.755
Yes	15	6	9
No	49	43	6
Peripheral nerve invasion				0.015	0.250
Yes	15	8	7
No	49	41	8
CgA				0.969
Positive	58	44	14
Negative	4	3	1
Syn				-
Positive	61	46	15
Negative	0	0	0
Bilirubin level	64			0.027	0.484
Normal	55	45	10
Abnormal	9	4	5
CEA	63			0.442
Normal	61	47	14
Abnormal	2	2	0
CA199	63			0.058
Normal	60	48	12
Abnormal	3	1	2
NSE	36
Normal	33	25	8
Abnormal	3	2	1
MLR	0.185(0.132–0.246)	0.179(0.128–0.225)	0.200(0.167-0.500)	0.040	0.164
NLR	1.906(1.434–2.771)	1.800(1.413–2.740)	2.041(1.583–3.875)	0.425
PLR	116.32(94.80-159.01)	115.663(91.862-151.379)	130.833(96.250-180.233)	0.264

Relationships between LN metastasis and MLR and other clinicopathologic characteristics

The χ² test revealed significant differences in vascular invasion(P < 0.05)、peripheral nerve invasion༈P = 0.015༉、bilirubin level༈P = 0.027༉between patients with and without LNM. Tumor grade (P = 0.017),tumor size༈P = 0.013༉,MLR༈P = 0.040༉in patients with LNM were significantly higher than those in patients without LNM. These six variables were selected as potential independent risk factors for ROC curve and multivariate analysis. Multivariate logistic regression indicated that tumor size༈P = 0.033༉ was the only independent risk factor for LNM (Table 1).

The ROC curve analysis for single-factor prediction of LNM showed that the NEN grade had an AUC of 0.679 (95% CI [0.528, 0.830], P = 0.037), tumor size had an AUC of 0.710༈95% CI [0.564,0.857], P = 0.014༉, MLR had an AUC of 0.676༈95% CI [0.521,0.830], P = 0.041༉, vascular invasion had an AUC of 0.739༈P = 0.005༉(Fig. 1, Table 2). These variables predicted LNM. The AUC of the combination of the four significant factors༈0.898, 95% CI [0.815,0.981], P < 0.05༉ was higher than the AUC of any individual factor.

Table 2

The ROC curve analysis for prediction of LNM
Factors	ACU	P-value	95% CI
Tumor grade	0.679	0.037	0.528–0.830
Tumor size	0.710	0.014	0.564–0.857
Vascular invasion	0.739	0.005	0.578–0.899
Nerve invasion	0.652	0.077	0.481–0.822
MLR	0.676	0.041	0.521–0.830
Bilirubin level	0.626	0.143	0.450–0.802

The incidence of pNENs is low, ranging from 0.1/100,000 to 0.48/100,000^{[23, 24]} .However, with improvements in diagnostic equipment, pathological classification systems, and doctor knowledge, the incidence of pNENs in Europe, America, Japan, and China is increasing yearly ^[25–27]. More and more studies have been investigating the factors affecting the prognosis of pNENs. A previous literature review revealed that age, gender, race, tumor size, tumor marker levels, histological pathology, LNM and tumor staging are associated with the prognosis of pNENs. At present, LNM is considered one of the most important factors for poor prognosis ^{[8, 28]}. Multiple studies based on the SEER database have shown that tumor location (pancreatic head), tumor grade, tumor size, T stage, Ki-67, vascular invasion and nerve invasion are associated with LNM. Patients with a higher risk of LNM have a worse prognosis ^{[29, 30]}.Our study also found that tumor grade, tumor size, vascular invasion, nerve invasion, and bilirubin level were associated with LNM, and tumor size was an independent risk factor for LNM, which was consistent with the results of previous studies based on databases. In our study, the level of bilirubin was associated with LNM. We speculate that tumors located in the head of the pancreas are more likely to compress the bile duct and cause increased bilirubin.

According to the National Cancer Database (NCDB) (2004–2014), in a retrospective study of 2664 patients with pNEN, 2132 patients underwent lymph node dissection, 28% of whom had lymph node metastases, and the overall survival of patients with and without lymph node dissection were 152.8 and 147.3 months, respectively (p = 0.61) ^[31].Krampitz et al. also found no significant difference in 10-year overall survival between patients with and without LNM ^[32],However, neither study suggested that lymph node dissection should be routinely avoided in all pNEN patients.

Although well-differentiated, low-grade pNENs are often considered relatively indolent tumors, patients with LNM have a recurrence rate as high as 40–50% ^[33]. The recurrence rate of patients with liver metastases after surgery is as high as 95% ^[34] .Therefore, we should be cautious about detecting LNM.

Inflammatory molecular markers have been widely used in the diagnosis and prognosis of various tumors. Long-term inflammation can promote tumorigenesis, and various cells in the tumor microenvironment can also secrete a variety of inflammatory factors. The systemic inflammatory response is closely related to the occurrence, development and metastasis of tumors^[11].

Monocytes are innate immune cells of the mononuclear phagocyte system and have become important regulators of cancer occurrence and progression ^[35].Monocytes promote the release of inflammatory mediators after pathogen invasion, and then transform into macrophages to participate in the immune response ^[36].Increased monocyte numbers and decreased lymphocyte numbers in inflammatory diseases lead to an imbalanced MLR ^[37].

Some studies have also shown that pNEN patients with a low MLR at baseline have a better prognosis, and their MLR has been an independent predictor of tumor recurrence ^{[38, 39]} .Few studies have investigated the relationships between NLR, PLR, MLR and LNM. A study involving 95 patients with resectable pNEN found that RFS was higher in patients without LNM. The preoperative NLR level was an independent risk factor for LNM. The higher the NLR was, the higher the risk of LNM ^[10].PLR and MLR were not included. In our study, NLR and PLR were not associated with LNM, while MLR was a risk factor for LNM and had a predictive effect on LNM. The ability to predict the risk of LNM from tumor size alone was weaker than that of the multivariate combination.

Our study had some limitations. First, there may be some selection biases since our study was a retrospective single-center study. In the future, a multicenter study could be performed to verify of our findings. Second, due to the low incidence of pNEN, the sample size of our study that met the inclusion criteria was limited.

The preoperative MLR, vascular invasion, peripheral nerve invasion, bilirubin level, tumor grade and tumor size are potential predictors for LNM, especially during the initial diagnosis for resectable pNENs. Tumor size was the only independent risk factor for LNM in our research. Multivariate ROC analysis had better predictive performance than univariate analysis.

Pancreatic neuroendocrine neoplasms : pNENs

Gastrointestinal and pancreatic neuroendocrine neoplasm : GEP-NEN)

Monocyte-to-lymphocyte ratio : MLR

Neutrophil-to-lymphocyte ratio : NLR

Platelet-to-lymphocyte ratio : PLR

Lymph node metastasis : LNM

Recurrence-free survival : RFS

Institutional review board statement: This investigation was approved by the Ethics Committee of Zhejiang Provincial People's Hospital（IRB No. QT2024150）.

Informed consent statement: The need for patient consent was waived due to the retrospective nature of the study.

Conflict-of-interest statement: The authors declare that they have no conflict of interest.

Data sharing statement: No additional data are available.

Supported by: This work was supported by Chinese Medical Science and Technology Project of Zhejiang Province (No.2024ZL278) and Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (No. 2021KY527).

FUNDING DECLARATION

The authors appreciated the financial support from Chinese Medical Science and Technology Project of Zhejiang Province (No.2024ZL278) and Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (No. 2021KY527).

Author Contribution

Jie Dong reviewed literature, designed the study, and drafting the paper. Jing Du, Xue-yang Chen and You-wei Chen did the literature review and was responsible for collecting medical data. Tao Li and Lei Wang reviewed literature and analyzed data. Juan-juan Cai was the pathologist who gave the pathological results. Wei-quan Wu designed the study with Jie Dong and made contribution to revise the manuscript. All authors issued final approval for the version to be submitted.

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No competing interests reported.

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Predictive factors affecting lymph node metastasis in patients of resectable pancreatic neuroendocrine neoplasms：a single-center retrospective study

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Abstract

Figures

INTRODUCTION

MATERIALS AND METHODS

RESULTS

Patient’s characteristics, preoperative peripheral blood test results and pathological results

Relationships between LN metastasis and MLR and other clinicopathologic characteristics

DISCUSSION

CONCLUSION

Abbreviations

Declarations

Author Contribution

Acknowledgement

References

Additional Declarations

Status:

Version 1