Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Annals of Surgical Oncology

23-04-2024 | Neuroendocrine Tumor | Pancreatic Tumors

Impact of Regional Metastasis on Survival for Patients with Nonfunctional Pancreatic Neuroendocrine Tumors: A Systematic Review

Authors: Callisia N. Clarke, MD, MS, FACS, Erin Ward, MD, Valencia Henry, BS, Kaitlyn Nimmer, BA, Alexandria Phan, MD, Doug B. Evans, MD

Published in: Annals of Surgical Oncology

Login to get access

Abstract

Background

Controversy exists regarding the benefit of lymphadenectomy for nonfunctional pancreatic neuroendocrine tumors (NF-PNET).

Patients and Methods

MEDLINE/PubMed, EMBASE, and the Cochrane Library were searched for studies of pancreatic neuroendocrine tumors (PNET) published between 1990 and 2021. Studies of functional PNET were excluded. Reported incidence of lymph node metastasis (LNM) and survival analysis of either disease-free survival (DFS) or overall survival (OS) were required for inclusion.

Results

Overall, 52 studies analyzing 24,608 PNET met the inclusion criteria. The reported LNM rate for NF-PNET ranged from 7 to 64 % (median 24.5%). Reported LNM rates ranged from 7 to 51% (median 11%) for NF-PNET< 2 cm in 14 studies and 29–47% (median 38%) in NF-PNET > 2 cm. In total, 19 studies (66%) reported LNM to have a negative impact on DFS. Additionally, 21 studies (60%) reported LNM to have a negative impact on OS. Two studies investigating the impact of lymphadenectomy (LND) found LND had the greatest impact for large, high-grade tumors. The overall quality of available evidence was low as assessed by the Grading of Recommendations, Assessment, Development, and Evaluation System.

Conclusions

Published literature evaluating the impact of regional LNM and LND in PNET is confounded by heterogeneity in practice patterns and the retrospective nature of these cohort studies. Most studies suggest high rates of LNM in NF-PNET that negatively impact DFS and OS. Given the high rate of LNM in NF-PNET and its potential detrimental effect on DFS and OS, we recommend lymphadenectomy be completed for NF-PNET > 2 cm and strongly considered for NF-PNET < 2 cm.
Literature
1.
Halfdanarson TR, Rabe KG, Rubin J, Petersen GM. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Surg Oncol. 2008;19(10):1727–33.CrossRef
2.
Bilimoria KY, et al. Prognostic score predicting survival after resection of pancreatic neuroendocrine tumors: analysis of 3851 patients. Ann Surg. 2008;247(3):490–500.PubMedCrossRef
3.
4.
Tsutsumi K, et al. Analysis of lymph node metastasis in pancreatic neuroendocrine tumors (PNETs) based on the tumor size and hormonal production. J Gastroenterol. 2012;47(6):678–85.PubMedCrossRef
5.
Chua TC, Yang TX, Gill AJ, Samra JS. Systematic review and meta-analysis of enucleation versus standardized resection for small pancreatic lesions. Ann Surg Oncol. 2016;23(2):592–9.PubMedCrossRef
6.
Partelli S, et al. Management of small asymptomatic nonfunctioning pancreatic neuroendocrine tumors: limitations to apply guidelines into real life. Surgery. 2019;166(2):157–63.PubMedCrossRef
7.
Haynes AB, et al. Implications of incidentally discovered, nonfunctioning pancreatic endocrine tumors: short-term and long-term patient outcomes. Arch Surg. 2011;146(5):534–8.PubMedPubMedCentralCrossRef
8.
Cherenfant J, et al. Predicting aggressive behavior in nonfunctioning pancreatic neuroendocrine tumors. Surgery. 2013;154(4):785–91.PubMedCrossRef
9.
Hashim YM, et al. Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs). Ann Surg. 2014;259(2):197–203.PubMedCrossRef
10.
Tomassetti P, et al. Endocrine pancreatic tumors: factors correlated with survival. Ann Oncol. 2005;16(11):1806–10.PubMedCrossRef
11.
Ellison TA, et al. A single institution’s 26-year experience with nonfunctional pancreatic neuroendocrine tumors: a validation of current staging systems and a new prognostic nomogram. Ann Surg. 2014;259(2):204–12.PubMedCrossRef
12.
13.
Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Br Med J. 2009;339:b2535.CrossRef
14.
15.
Li G, et al. Clinicopathological features and prognosis factors for survival in elderly patients with pancreatic neuroendocrine tumor: a STROBE-compliant article. Med (Baltimore). 2019;98(11):e14576.CrossRef
16.
Harimoto N, et al. Significance of lymph node metastasis in resectable well-differentiated pancreatic neuroendocrine tumor. Pancreas. 2019;48(7):943–7.PubMedCrossRef
17.
Dima SO, et al. Prognostic factors in patients with surgical resection of pancreatic neuroendocrine tumours. Acta Endocrinol (Buchar). 2018;14(3):389–93.PubMedCrossRef
18.
Masui T, et al. Predictive value of the Ki67 index for lymph node metastasis of small non-functioning pancreatic neuroendocrine neoplasms. Surg Today. 2019;49(7):593–600.PubMedCrossRef
19.
Genc CG, et al. A new scoring system to predict recurrent disease in grade 1 and 2 nonfunctional pancreatic neuroendocrine tumors. Ann Surg. 2018;267(6):1148–54.PubMedCrossRef
20.
Ge W, et al. Surveillance and comparison of surgical prognosis for asymptomatic and symptomatic non-functioning pancreatic neuroendocrine tumors. Int J Surg. 2017;39:127–34.PubMedCrossRef
21.
Wong J, et al. Predictors of lymph node metastases and impact on survival in resected pancreatic neuroendocrine tumors: a single-center experience. Am J Surg. 2014;208(5):775–80.PubMedCrossRef
22.
Demir R, et al. Necrosis and angioinvasion predict adverse outcome in pancreatic neuroendocrine tumors after curative surgical resection: results of a single-center series. World J Surg. 2011;35(12):2764–72.PubMedCrossRef
23.
Chung JC, et al. Malignant nonfunctioning endocrine tumors of the pancreas: predictive factors for survival after surgical treatment. World J Surg. 2007;31(3):579–85.PubMedCrossRef
24.
Schurr PG, et al. Aggressive surgery improves long-term survival in neuroendocrine pancreatic tumors: an institutional experience. Ann Surg. 2007;245(2):273–81.PubMedPubMedCentralCrossRef
25.
Kazanjian KK, Reber HA, Hines OJ. Resection of pancreatic neuroendocrine tumors: results of 70 cases. Arch Surg. 2006;141(8):765–9.PubMedCrossRef
26.
27.
Wu L, et al. Therapeutic index of lymphadenectomy among patients with pancreatic neuroendocrine tumors: a multi-institutional analysis. J Surg Oncol. 2019;120(7):1080–6.PubMedPubMedCentralCrossRef
28.
Toste PA, et al. Nonfunctional pancreatic neuroendocrine tumors < 2 cm on preoperative imaging are associated with a low incidence of nodal metastasis and an excellent overall survival. J Gastrointest Surg. 2013;17(12):2105–13.PubMedCrossRef
29.
Sarmiento JM, Farnell MB, Que FG, Nagorney DM. Pancreaticoduodenectomy for islet cell tumors of the head of the pancreas: long-term survival analysis. World J Surg. 2002;26(10):1267–71.PubMedCrossRef
30.
Sharpe SM, et al. Surgical resection provides an overall survival benefit for patients with small pancreatic neuroendocrine tumors. J Gastrointest Surg. 2015;19(1):117–23.PubMedCrossRef
31.
Ha S, et al. The clinicopathologic and operative characteristics of patients with small nonfunctioning pancreatic neuroendocrine tumors. ANZ J Surg. 2021;91(7–8):E484-e492.PubMed
32.
33.
Lopez-Aguiar AG, et al. Redefining the Ki-67 index stratification for low-grade pancreatic neuroendocrine tumors: improving its prognostic value for recurrence of disease. Ann Surg Oncol. 2018;25(1):290–8.PubMedCrossRef
34.
Zaidi MY, et al. A novel validated recurrence risk score to guide a pragmatic surveillance strategy after resection of pancreatic neuroendocrine tumors: an international study of 1006 patients. Ann Surg. 2019;270(3):422–33.PubMedCrossRef
35.
NCCN: National Comprehensive Cancer Network. NCCN guidelines version 1.2015 neuroendocrine tumors.
36.
Amin MB, et al. The Eighth Edition AJCC Cancer Staging Manual continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. 2017;67(2):93–9.PubMedCrossRef
37.
38.
Falconi M, et al. Parenchyma-preserving resections for small nonfunctioning pancreatic endocrine tumors. Ann Surg Oncol. 2010;17(6):1621–7.PubMedCrossRef
39.
Yang Z, et al. Comparison of clinical outcomes between enucleation and regular pancreatectomy in patients with non-functional pancreatic neuroendocrine tumors: a retrospective multicenter and propensity score-matched study. Jpn J Clin Oncol. 2020;51(4):595–603.CrossRef
40.
Pitt SC, et al. Small pancreatic and periampullary neuroendocrine tumors: resect or enucleate? J Gastro Intest Surg. 2009;13(9):1692–8.CrossRef
41.
Tanaka M, et al. Systematic review and metaanalysis of lymph node metastases of resected pancreatic neuroendocrine tumors. Ann Surg Oncol. 2021;28(3):1614–24.PubMedCrossRef
42.
Durczyński A, et al. Sentinel lymph node mapping in tumors of the pancreatic body: preliminary report. Contemp Oncol (Pozn). 2012;16(3):206–9.PubMed
43.
Gratian L, et al. Impact of extent of surgery on survival in patients with small nonfunctional pancreatic neuroendocrine tumors in the United States. Ann Surg Oncol. 2014;21(11):3515–21.PubMedPubMedCentralCrossRef
44.
Zhang X-F, et al. New nodal staging for primary pancreatic neuroendocrine tumors: a multi-institutional and national data analysis. Ann Surg. 2021;274(1):e28–35.PubMedCrossRef
45.
Dong DH, et al. Impact of tumor size and nodal status on recurrence of nonfunctional pancreatic neuroendocrine tumors </=2 cm after curative resection: a multi-institutional study of 392 cases. J Surg Oncol. 2019;120(7):1071–9.PubMedPubMedCentralCrossRef
46.
Harimoto N, et al. Prognostic significance of neutrophil-lymphocyte ratio in resectable pancreatic neuroendocrine tumors with special reference to tumor-associated macrophages. Pancreatology. 2019;19(6):897–902.PubMedCrossRef
47.
48.
Lopez-Aguiar AG, et al. The conundrum of < 2-cm pancreatic neuroendocrine tumors: a preoperative risk score to predict lymph node metastases and guide surgical management. Surgery. 2019;166(1):15–21.PubMedCrossRef
49.
Lopez-Aguiar AG, et al. Defining the role of lymphadenectomy for pancreatic neuroendocrine tumors: an eight-institution study of 695 patients from the US neuroendocrine tumor study group. Ann Surg Oncol. 2019;26(8):2517–24.PubMedPubMedCentralCrossRef
50.
Sho S, et al. A prognostic scoring system for the prediction of metastatic recurrence following curative resection of pancreatic neuroendocrine tumors. J Gastrointest Surg. 2019;23(7):1392–400.PubMedCrossRef
51.
Sallinen VJ, et al. Prognosis of sporadic resected small (</=2 cm) nonfunctional pancreatic neuroendocrine tumors—A multi-institutional study. HPB (Oxford). 2018;20(3):251–9.PubMedCrossRef
52.
Taki K, et al. Significance of lymph node metastasis in pancreatic neuroendocrine tumor. Surg Today. 2017;47(9):1104–10.PubMedCrossRef
53.
Postlewait LM, et al. Pancreatic neuroendocrine tumors: preoperative factors that predict lymph node metastases to guide operative strategy. J Surg Oncol. 2016;114(4):440–5.PubMedCrossRef
54.
Kaltenborn A, et al. Prediction of survival and tumor recurrence in patients undergoing surgery for pancreatic neuroendocrine neoplasms. J Surg Oncol. 2016;113(2):194–202.PubMedCrossRef
55.
Jiang Y, et al. Impact and clinical predictors of lymph node metastases in nonfunctional pancreatic neuroendocrine tumors. Chin Med J (Engl). 2015;128(24):3335–44.PubMedCrossRef
56.
Yoo YJ, et al. Overestimated oncologic significance of lymph node metastasis in G1 nonfunctioning neuroendocrine tumor in the left side of the pancreas. Medicine (Baltimore). 2015;94(36):e1404.PubMedCrossRef
57.
Furukori M, et al. Clinicopathological features of small nonfunctioning pancreatic neuroendocrine tumors. World J Gastroenterol. 2014;20(47):17949–54.PubMedPubMedCentralCrossRef
58.
Tsutsumi K, et al. Analysis of risk factors for recurrence after curative resection of well-differentiated pancreatic neuroendocrine tumors based on the new grading classification. J Hepatobiliary Pancreat Sci. 2014;21(6):418–25.PubMedCrossRef
59.
Partelli S, et al. Pattern and clinical predictors of lymph node involvement in nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs). JAMA Surg. 2013;148(10):932–9.PubMedCrossRef
60.
Lee LC, et al. Small, nonfunctioning, asymptomatic pancreatic neuroendocrine tumors (PNETs): role for nonoperative management. Surgery. 2012;152(6):965–74.PubMedCrossRef
61.
Wang SE, et al. Comparison of functional and nonfunctional neuroendocrine tumors in the pancreas and peripancreatic region. Pancreas. 2011;40(2):253–9.PubMedCrossRef
62.
Watzka FM, et al. Prognostic assessment of non-functioning neuroendocrine pancreatic neoplasms as a basis for risk-adapted resection strategies. World J Surg. 2020;44(2):594–603.PubMedCrossRef
63.
Liu P, et al. Lymph node ratio, but not the total number of examined lymph nodes or lymph node metastasis, is a predictor of overall survival for pancreatic neuroendocrine neoplasms after surgical resection. Oncotarget. 2017;8(51):89245–55.PubMedPubMedCentralCrossRef
64.
Jutric Z, et al. Regional metastatic behavior of nonfunctional pancreatic neuroendocrine tumors: impact of lymph node positivity on survival. Pancreas. 2017;46(7):898–903.PubMedCrossRef
65.
Jin K, et al. Clinical outcomes and prognostic factors of resected pancreatic neuroendocrine neoplasms: a single-center experience in China. Oncol Lett. 2017;13(5):3163–8.PubMedPubMedCentralCrossRef
66.
Conrad C, et al. Prognostic value of lymph node status and extent of lymphadenectomy in pancreatic neuroendocrine tumors confined to and extending beyond the pancreas. J Gastrointest Surg. 2016;20(12):1966–74.PubMedCrossRef
67.
Fitzgerald TL, et al. Indications for surgical resection in low-grade pancreatic neuroendocrine tumors. Am Surg. 2016;82(8):737–42.PubMedCrossRef
68.
Curran T, et al. Importance of lymph node involvement in pancreatic neuroendocrine tumors: impact on survival and implications for surgical resection. J Gastrointest Surg. 2015;19(1):152–60.PubMedCrossRef
69.
Song KB, et al. Prognostic factors in 151 patients with surgically resected non-functioning pancreatic neuroendocrine tumours. ANZ J Surg. 2016;86(7–8):563–7.PubMedCrossRef
70.
Han X, et al. Clinicopathological characteristics and prognosis-related factors of resectable pancreatic neuroendocrine tumors: a retrospective study of 104 cases in a single Chinese center. Pancreas. 2014;43(4):526–31.PubMedPubMedCentralCrossRef
71.
Matthews BD, et al. Surgical experience with nonfunctioning neuroendocrine tumors of the pancreas. Am Surg. 2000;66(12):1116–22.PubMedCrossRef
Metadata
Title
Impact of Regional Metastasis on Survival for Patients with Nonfunctional Pancreatic Neuroendocrine Tumors: A Systematic Review
Authors
Callisia N. Clarke, MD, MS, FACS
Erin Ward, MD
Valencia Henry, BS
Kaitlyn Nimmer, BA
Alexandria Phan, MD
Doug B. Evans, MD
Publication date
23-04-2024
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-024-15249-1