Abstract
Background/Aim: Little is known regarding the impact of lymph node dissection on survival benefit after curative resection for pancreatic neuroendocrine tumor (PNET). This study aimed to evaluate the efficacy of lymph node dissection based on tumor location of PNET. Patients and Methods: A retrospective study, including 50 patients with surgical resection for PNET between 2004 and 2020, was performed. The efficacy index (EI) was calculated by multiplication of the incidence of lymph node metastasis (LNM) at the station and the 5-year survival rate of patients with LNM at the station. Results: In the pancreatic head tumors, the peri-pancreatic head and superior mesenteric artery lymph node stations had high EI of 13.3 and 25, respectively. In contrast, other stations, including stations 8 and 12, had zero EI. In the pancreatic body and tail tumors, only the splenic artery lymph node station had a survival benefit from lymph node dissection with an EI of 6.7. Conclusion: The extent of lymph node dissection for PNET should be decided based on the efficacy of lymph node dissection in accordance with tumor location. Our findings may be helpful in determining the extent of lymph node dissection required.
Although pancreatic neuroendocrine tumor (PNET) is a rare potentially malignant tumor, the incidence of PNETs has been increasing due to the development of radiological imaging (1, 2). Radical resection is the only curative treatment for PNET; however, the optimal treatment strategy for PNET is still under debate. The Clinical Practice Guidelines for Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NEN) 2019 has recommended surgical resection with lymphadenectomy for nonfunctional PNET regardless of tumor size (3). However, the impact of lymphadenectomy on survival benefit following curative resection for PNET based on tumor location remains unknown.
The efficacy index (EI) has been developed as a predictor to estimate the prognostic value of lymph node dissection (4). To date, the impact of the EI has been investigated as a useful index of survival benefit in the field of gastrointestinal and hepato-pancreato-biliary surgical oncology (5-7). However, no study has investigated the effect of the EI in patients undergoing curative resection for PNET.
In this study, we aimed to examine the incidence of lymph node metastasis (LNM) as well as the efficacy of lymph node dissection using the EI in patients with curative resection for PNET. Furthermore, long-term survival after curative resection for PNET was investigated.
Patients and Methods
Study design. A retrospective review was performed using a database of 50 consecutive patients who underwent curative resection for PNET at the Okayama University Hospital (Okayama, Japan) between January 2004 and December 2020. The study protocol was approved by the Ethics Committee at our institution (approval no. 2111-011), and conducted according to the Declaration of Helsinki.
Clinicopathological data. The collected data from the database were as follows: age, sex, procedure (pancreatoduodenectomy, distal pancreatectomy, or central pancreatectomy), tumor size, tumor location (pancreatic head, or pancreatic body and tail), tumor function (functional or non-functional), 2019 World Health Organization (WHO) classification (G1, G2, or G3), LNM (presence or absence), recurrence (presence or absence), recurrence pattern, and outcomes at the last follow-up (survival or death). Pathological factors were evaluated by pathologists.
Regarding regional LNM, the location and number of harvested lymph nodes in a lymph node station were recorded. In this study, lymph node stations included the peri-gastric lymph node (stations 5 and 6), common hepatic artery (CHA) lymph node (station 8), splenic hilum lymph node (station 10), splenic artery (SpA) lymph node (station 11), liver hilum lymph node (station 12), peri-pancreatic head lymph node (stations 13 and 17), and superior mesenteric artery (SMA) lymph node (station 14).
Efficacy index for each lymph node station. Incidence of LNM was calculated as the number of patients with LNM at the station divided by the number of patients at the station being dissected (6). The EI for each lymph node station according to tumor location was examined by multiplication of the incidence of LNM at the station and the 5-year survival rate of patients with LNM (4).
Protocol for treatment strategy and the follow-up. The treatment strategy for PNET was in accordance with the Clinical Practice Guidelines for GEP-NEN 2019 (3). Endoscopic biopsy for diagnosis was performed when a tumor was suspected as PNET. Thereafter, radical resection with lymphadenectomy was considered for resectable PNET regardless of the tumor size. The extent of lymph node dissection was decided by the multidisciplinary team according to the tumor characteristics. Pancreatoduodenectomy was the first option for the pancreatic head PNET. The pancreatic body and tail tumor were resected with distal pancreatectomy, or central pancreatectomy. After surgery, all patients received postoperative screening with computed tomography or magnetic resonance imaging for the investigation of recurrence, every 3 to 6 months. Recurrence pattern investigated included liver metastasis, lung metastasis, peritoneal dissemination, and local recurrence such as abdominal lymph node metastasis.
Statistical analysis. Data are presented as mean with standard deviation for continuous variables, and proportions for categorical data. Overall (OS), recurrence-free (RFS), and post-recurrence (PRS) survival rates were calculated using the Kaplan–Meier method. RFS was defined as the length of time from the date of surgery to the date of recurrence or death. JMP version 11 software (SAS Institute, Cary, NC, USA) was used for statistical analysis.
Results
Patient characteristics. The clinicopathological characteristics are demonstrated in Table I. The mean tumor size was 2.0 cm. Out of 50 patients, 20 (40%) had a tumor in the pancreatic head requiring pancreatoduodenectomy, and 39 (78%) had non-functional tumors. According to the 2010 WHO classification, G1 was found in 38 patients (76%), G2 in 11 (22%), and G3 in 1 (2%). LNM was found in 7 patients (14%).
Characteristics of patients with curative resection for pancreatic neuroendocrine tumor.
The Kaplan–Meier curves for OS and RFS are demonstrated in Figure 1. Following a mean follow-up of 6.6 years, the 1-, 5-, and 10-year OS rates were 100%, 94.4%, and 89.5%, and the 1-, 5-, 10-year RFS rates were 95.9%, 90.4%, and 68.4%, respectively.
Overall (OS) and recurrence-free survival (RFS) following curative resection for pancreatic neuroendocrine tumor.
Frequency of lymph node metastasis and survival benefit at each node station. Incidence of LNM at each lymph node station as well as the EI according to the tumor location are depicted in Table II.
Efficacy index of estimated survival benefit from dissected lymph nodes.
In the pancreatic head tumors, LNM was found in the CHA lymph node (station 8), peri-pancreatic head lymph node (stations 13 and 17), and SMA lymph node (station 14) with an incidence of LNM of 7.1%, 20%, and 50%, respectively. However, there was no LNM in the peri-gastric (stations 5 and 6) and liver hilum (station 12) lymph node. With respect to survival benefit, the peri-pancreatic head and SMA lymph node stations had high EI of 13.3 and 25, respectively. In contrast, other stations, including stations 8 and 12, had zero EI.
In the pancreatic body and tail tumors, LNM was found only in the SpA lymph node (station 11) with an incidence of 6.7%. No LNM was found in the CHA lymph node (station 8) and splenic hilum lymph node (station 10). Regarding the EI assessment, only station 11 had a survival benefit from lymph node dissection with an EI of 6.7.
Recurrence patterns after curative resection. During the follow-up, eight patients (16%) out of 50 had recurrences after curative resection: seven for liver metastases; and one for multiple-site metastases including liver and abdominal lymph node metastasis (Table III). The mean interval from surgery to recurrence was 5.3 years. The 1-, 3-, and 5-year PRS were 100%, 100%, and 80%, respectively.
Recurrence patterns after curative resection for pancreatic neuroendocrine tumor.
The detailed characteristics of the patients with recurrence are summarized in Table IV. The mean tumor size in patients with recurrence was 3.6 cm, all being over 2 cm. Most of the patients with recurrence had non-functional tumors, and three patients had G1 tumor. LNM was found in four patients out of eight; however, the other patients had no LNM. Treatment for recurrence included local therapies such as resection, transcatheter arterial embolization, and radiofrequency ablation, as well as systemic therapy with chemotherapy.
Characteristics of patients with recurrence.
Discussion
This study analyzed the distribution on LNM and prognostic value of lymph node dissection based on tumor location in patients undergoing curative resection for PNET. Using the EI, survival benefit of lymph node dissection was clarified in pancreatic head and pancreatic body and tail tumors, respectively. Furthermore, survival and recurrence patterns after curative resection were examined. Our findings found that good long-term survival including OS, RFS and even PRS, compared to previous studies (8, 9).
With respect to treatment strategy for PNET, our indication for surgery included all resectable PNET regardless of the tumor size as well as tumor function according to the Clinical Practice Guidelines for GEP-NEN 2019 (3). Although the National Comprehensive Cancer Network (NCCN) guidelines and European Neuroendocrine Tumor Society (ENETS) guideline for treatment of nonfunctional PNET have recommended surgical resection with lymphadenectomy for tumors over 2 cm and conditional surveillance for tumors with a size of 1-2 cm (10, 11), surgical resection should be considered for all resectable PNETs considering the fact that no recurrence is observed after resection in patients with tumors less than 2 cm.
As the extent of lymph node dissection for PNET according to the tumor location should be determined by tumor characteristics, it is important to understand the distribution of LNM and survival benefit of lymph node dissection for PNET. Therefore, the results of the EI assessment based on tumor location should be unique and helpful to estimate the efficacy of lymph node dissection of a certain lymph node station.
In the pancreatic head tumors, radical resection with pancreatoduodenectomy should be applied to perform complete lymph node dissection of the peri-pancreatic head lymph node (stations 13 and 17), which has high incidence of LNM and high EI. In contrast, lymph node dissection of the peri-gastric (stations 5 and 6) and liver hilum (station 12) lymph nodes might be omitted due to no incidence of LNM and zero EI in these stations. Lymph node dissection of the CHA and SMA lymph nodes can be decided by considering tumor characteristics. In fact, the SMA lymph node station had high EI, although the SMA lymph node dissection was performed in limited patients in our cohort.
In the pancreatic body and tail tumors, the complete lymph node dissection of the SpA lymph node (station 11) with the EI of 6.7 is essential. In contrast, lymph node dissection of the CHA and splenic hilum lymph nodes could be waived based on the results demonstrating no incidence of LNM and zero EI.
Regarding recurrence patterns after resection, liver metastases were found in all patients with recurrence. The liver should be recognized as the main recurrent site following resection for PNET (12). In patients with solitary PNET liver metastasis, local therapies including surgery and interventional radiology may be effective as curative therapies (13, 14). In patients with multiple or unresectable PNET liver metastases, the role of systemic therapy with chemotherapy may be indicated as palliative treatments (14). Moreover, liver transplantation could be a viable treatment option for limited patients with unresectable PNET liver metastases (15, 16). In this study, patients with recurrence received various treatments with combination of local and systemic therapy based on a decision during multidisciplinary meetings, providing good PRS.
The present study has several limitations. This is a single-center, retrospective study with a small sample size due to the rarity of the disease. Furthermore, the incidence of LNM and EI might be overestimated. This is because the extent of lymph node dissection was decided based on tumor characteristics. In fact, there seems to be a low frequency of lymph node dissection of the SMA lymph node during pancreatoduodenectomy, as well as the splenic hilum lymph node during distal pancreatectomy. Accordingly, a multi-center study with a larger sample size is necessary to determine the optimal extent of lymph node dissection based on tumor location.
Conclusion
This study investigated the incidence of LNM and the efficacy of lymph node dissection in each lymph node station using the EI in accordance with tumor location in patients undergoing curative resection for PNET. Our findings may be helpful in deciding the extent of lymph node dissection and surgical procedure.
Footnotes
Authors’ Contributions
K.T. contributed to the study conception and design, acquisition of data, development of the protocol, and drafting of the manuscript. Y.U., R.Y., K.Y., T.F., K.K. and K.Y contributed to the analysis and interpretation of the quantitative data. T.Y. and T.F. contributed to the development of the protocol and the critical revision of the final draft. All Authors have approved the final version.
Conflicts of Interest
The Authors declare no conflicts of interest regarding this study.
- Received March 14, 2022.
- Revision received March 31, 2022.
- Accepted April 1, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.