Introduction: Lymph node metastasis of nonfunctioning pancreatic neuroendocrine neoplasms (pNENs) potentially leads to poor survival. Given the contradictory results in the literature regarding factors associated with lymph node metastasis of nonfunctioning pNENs, we conducted a systematic review and meta-analysis to determine the preoperative predictors of lymph node metastasis. Methods: Original studies reporting factors associated with lymph node metastasis in patients with nonfunctioning pNENs were identified in PubMed, EMBASE, and Cochrane Library databases, and data from eligible studies were analyzed using random-effects meta-analysis to obtain pooled estimates of odds ratios (ORs) and their 95% confidence intervals (CIs). Results: Eleven studies were included. Tumor size (>2 cm or >2.5 cm; OR, 5.80 [95% CI, 4.07–8.25]) and pancreatic head location (OR, 1.75 [95% CI, 1.05–2.94]) were significant preoperative predictors of lymph node metastasis. Old age (OR, 1.07 [95% CI, 0.68–1.68]) and male sex (OR, 1.12 [95% CI, 0.74–1.70]) were not significantly associated with lymph node metastasis. Conclusions: A large tumor size and pancreatic head location can be useful for planning optimal treatment in patients with nonfunctioning pNENs.

1.
Milan SA, Yeo CJ. Neuroendocrine tumors of the pancreas. Curr Opin Oncol. 2012 Jan;24(1):46–55.
2.
Sonbol MB, Mazza GL, Mi L, Oliver T, Starr J, Gudmundsdottir H, et al. Survival and incidence patterns of pancreatic neuroendocrine tumors over the last 2 decades: a SEER database analysis. Oncologist. 2022 Jul 5;27(7):573–8.
3.
Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008 Jun 20;26(18):3063–72.
4.
Falconi M, Eriksson B, Kaltsas G, Bartsch DK, Capdevila J, Caplin M, et al. ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology. 2016;103(2):153–71.
5.
National Comprehensive Cancer Network. Neuroendocrine and adrenal tumors, version 1. 2021. NCCN clinical practice guidelines in oncology. 2021.
6.
Hashim YM, Trinkaus KM, Linehan DC, Strasberg SS, Fields RC, Cao D, et al. Regional lymphadenectomy is indicated in the surgical treatment of Pancreatic Neuroendocrine Tumors (PNETs). Ann Surg. 2014;259(2):197–203.
7.
Jutric Z, Grendar J, Hoen HM, Cho SW, Cassera MA, Newell PH, et al. Regional metastatic behavior of nonfunctional pancreatic neuroendocrine tumors: impact of lymph node positivity on survival. Pancreas. 2017;46(7):898–903.
8.
Gao Y, Gao H, Wang G, Yin L, Xu W, Peng Y, et al. A meta-analysis of Prognostic factor of Pancreatic neuroendocrine neoplasms. Sci Rep. 2018 May 8;8(1):7271.
9.
Tanaka M, Heckler M, Mihaljevic AL, Probst P, Klaiber U, Heger U, et al. Systematic review and metaanalysis of lymph node metastases of resected pancreatic neuroendocrine tumors. Ann Surg Oncol. 2021 Mar;28(3):1614–24.
10.
Partelli S, Gaujoux S, Boninsegna L, Cherif R, Crippa S, Couvelard A, et al. Pattern and clinical predictors of lymph node involvement in nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs). JAMA Surg. 2013 Oct;148(10):932–9.
11.
Jiang Y, Jin JB, Zhan Q, Deng XX, Shen BY. Impact and clinical predictors of lymph node metastases in nonfunctional pancreatic neuroendocrine tumors. Chin Med J. 2015 Dec 20;128(24):3335–44.
12.
Choi SH, Kim HJ, Kim SY, Byun JH, Kim KW, Song KB, et al. Computed tomography features predictive of lymph node involvement in patients with a nonfunctioning pancreatic neuroendocrine tumor. Pancreas. 2017 Sep;46(8):1056–63.
13.
Zhou B, Deng J, Chen L, Zheng S. Preoperative neutrophil-to-lymphocyte ratio and tumor-related factors to predict lymph node metastasis in nonfunctioning pancreatic neuroendocrine tumors. Sci Rep. 2017 Dec 13;7(1):17506.
14.
Lopez-Aguiar AG, Zaidi MY, Beal EW, Dillhoff M, Cannon JGD, Poultsides GA, 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 Aug;26(8):2517–24.
15.
Masui T, Sato A, Nakano K, Uchida Y, Yogo A, Anazawa T, et al. Predictive value of the Ki67 index for lymph node metastasis of small non-functioning pancreatic neuroendocrine neoplasms. Surg Today. 2019 Jul;49(7):593–600.
16.
Guarneri G, de Mestier L, Landoni L, Partelli S, Gaujoux S, Andreasi V, et al. Prognostic role of examined and positive lymph nodes after distal pancreatectomy for non-functioning neuroendocrine neoplasms. Neuroendocrinology. 2021;111(8):728–38.
17.
Kasai Y, Masui T, Nakakura EK, Nakano K, Sato A, Uchida Y, et al. Preoperative risk stratification of lymph node metastasis for non-functional pancreatic neuroendocrine neoplasm: an international dual-institutional study. Pancreatology. 2022 Jan;22(1):123–9.
18.
Partelli S, Muffatti F, Andreasi V, Giannone F, Rossi G, Palumbo D, et al. A single-center prospective observational study investigating the accuracy of preoperative diagnostic procedures in the assessment of lymph node metastases in nonfunctioning pancreatic neuroendocrine tumors. Ann Surg. 2022 Nov 1;276(5):921–8.
19.
Perinel J, Nappo G, Zerbi A, Heidsma CM, Nieveen van Dijkum EJM, Han HS, et al. Sporadic nonfunctional pancreatic neuroendocrine tumors: risk of lymph node metastases and aggressiveness according to tumor size: a multicenter international study. Surgery. 2022 Sep;172(3):975–81.
20.
Nanno Y, Toyama H, Matsumoto I, Uemura J, Asari S, Goto T, et al. Reappraisal of malignant risk assessment for small (≤20 mm) non-functioning pancreatic neuroendocrine tumors. Ann Surg Oncol. 2023 Jun;30(6):3493–500.
21.
Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000 Apr 19;283(15):2008–12.
22.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Bmj. 2021 Mar 29;372:n71.
23.
Wells GASB, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. 2011.
24.
Jackson D, Turner R. Power analysis for random-effects meta-analysis. Res Synth Methods. 2017;8(3):290–302.
25.
Borenstein M, Hedges LV, Higgins JP, Rothstein HR. A basic introduction to fixed-effect and random-effects models for meta-analysis. Res Synth Methods. 2010 Apr;1(2):97–111.
26.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003 Sep 6;327(7414):557–60.
27.
9.5.2 Identifying and measuring heterogeneity. In: Higgins J, Green S, editors. Cochrane handbook for systematic reviews of interventions version 510. The Cochrane Collaboration; 2011.
28.
Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. Bmj. 1997 Sep 13;315(7109):629–34.
29.
Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000 Jun;56(2):455–63.
30.
Tadokoro H, Kozu T, Toki F, Kobayashi M, Hayashi N. Embryological fusion between the ducts of the ventral and dorsal primordia of the pancreas occurs in two manners. Pancreas. 1997 May;14(4):407–14.
31.
Moore KL, Persaud TVN, Torchia MG. The developing human: clinically oriented embryology. 11 ed.Elsevier Health Sciences; 2018.
32.
Kitagawa H, Ohta T, Makino I, Tani T, Tajima H, Nakagawara H, et al. Carcinomas of the ventral and dorsal pancreas exhibit different patterns of lymphatic spread. Front Biosci. 2008 Jan 1;13:2728–35.
33.
Mei W, Ding Y, Wang S, Jia Y, Cao F, Li F. Head and body/tail pancreatic neuroendocrine tumors have different biological characteristics and clinical outcomes. J Cancer Res Clin Oncol. 2020 Nov;146(11):3049–61.
34.
van Erning FN, Mackay TM, van der Geest LGM, Groot Koerkamp B, van Laarhoven HWM, Bonsing BA, et al. Association of the location of pancreatic ductal adenocarcinoma (head, body, tail) with tumor stage, treatment, and survival: a population-based analysis. Acta Oncol. 2018 Dec;57(12):1655–62.
35.
Birnbaum DJ, Bertucci F, Finetti P, Birnbaum D, Mamessier E. Head and body/tail pancreatic carcinomas are not the same tumors. Cancers. 2019 Apr 8;11(4):497.
36.
Blakely AM, Lafaro KJ, Li D, Kessler J, Chang S, Ituarte PHG, et al. Lymphovascular invasion predicts lymph node involvement in small pancreatic neuroendocrine tumors. Neuroendocrinology. 2020;110(5):384–92.
37.
Dreyer SB, Jamieson NB, Upstill-Goddard R, Bailey PJ, McKay CJ; Australian Pancreatic Cancer Genome Initiative, et al. Defining the molecular pathology of pancreatic body and tail adenocarcinoma. Br J Surg. 2018 Jan;105(2):e183–91.
38.
Kanda M, Fujii T, Nagai S, Kodera Y, Kanzaki A, Sahin TT, et al. Pattern of lymph node metastasis spread in pancreatic cancer. Pancreas. 2011 Aug;40(6):951–5.
39.
Cesmebasi A, Malefant J, Patel SD, Du Plessis M, Renna S, Tubbs RS, et al. The surgical anatomy of the lymphatic system of the pancreas. Clin Anat. 2015 May;28(4):527–37.
40.
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 Apr;24(4):1127–33.
41.
Zhou B, Zhan C, Xiang J, Ding Y, Yan S. 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. BMC Endocr Disord. 2019 Nov 12;19(1):123.
42.
Parekh JR, Wang SC, Bergsland EK, Venook AP, Warren RS, Kim GE, et al. Lymph node sampling rates and predictors of nodal metastasis in pancreatic neuroendocrine tumor resections: the ucsf experience with 149 patients. Pancreas. 2012;41(6):840–4.
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