Advertisement

Lymph node metastases and recurrence in pancreatic neuroendocrine neoplasms

Published:September 27, 2022DOI:https://doi.org/10.1016/j.surg.2022.08.020

      Abstract

      Background

      The impact of lymph node metastasis on survival in pancreatic neuroendocrine neoplasms as well as their best surgical treatment is controversial. We aimed to determine the frequency and prognostic impact of lymph node involvement in pancreatic neuroendocrine neoplasms.

      Methods

      Patients undergoing pancreatic resections for pancreatic neuroendocrine neoplasms between 2001 and 2019 were retrospectively analyzed based on a prospective database. Clinicopathological parameters and perioperative outcome were assessed. Overall and disease-free survival was analyzed. Subgroup analysis was performed for sporadic, nonfunctional pancreatic neuroendocrine neoplasms without distant metastases and ≥4 analyzed lymph nodes.

      Results

      Of 605 surgically resected pancreatic neuroendocrine neoplasms, 55% were G1, 36% were G2, and 9% were G3 differentiated. At the time of resection, 34% of patients had lymph node metastasis, and 16% had distant metastases. For subgroup analysis, 314 patients were analyzed. Lymph node metastases occurred in 36% of patients and were most frequent in G3 patients (67%). An increase in tumor size and advancement was associated with higher rates of lymph node metastasis, and disease-free survival was significantly impaired. Significant differences in disease-free survival were observed between 1 and 3 (5-year disease-free survival 52%) and ≥4 positive lymph nodes (5-year disease-free survival 28%), as well as when G3 tumors were excluded. In multivariable analysis, grading, tumor stage, and especially lymph node metastases as well as the proposed pN1 and pN2 categories were confirmed as independent predictors of recurrence.

      Conclusion

      The presence and extent of lymph node involvement has considerable prognostic impact in pancreatic neuroendocrine neoplasms. This study, for the first time, validated the proposed pN2 stage for well-differentiated pancreatic neuroendocrine neoplasms.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Yao J.C.
        • Hassan M.
        • Phan A.
        • 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; 26: 3063-3072
        • Modlin I.M.
        • Oberg K.
        • Chung D.C.
        • et al.
        Gastroenteropancreatic neuroendocrine tumours.
        Lancet Oncol. 2008; 9: 61-72
        • Lawrence B.
        • Gustafsson B.I.
        • Chan A.
        • Svejda B.
        • Kidd M.
        • Modlin I.M.
        The epidemiology of gastroenteropancreatic neuroendocrine tumors.
        Endocrinol Metab Clin North Am. 2011; 40 (vii): 1-18
        • Bilimoria K.Y.
        • Tomlinson J.S.
        • Merkow R.P.
        • et al.
        Clinicopathologic features and treatment trends of pancreatic neuroendocrine tumors: analysis of 9,821 patients.
        J Gastrointest Surg. 2007; 11 (discussion 7–9): 1460-1467
        • Kuo E.J.
        • Salem R.R.
        Population-level analysis of pancreatic neuroendocrine tumors 2 cm or less in size.
        Ann Surg Oncol. 2013; 20: 2815-2821
        • Bilimoria K.Y.
        • Talamonti M.S.
        • Tomlinson J.S.
        • et al.
        Prognostic score predicting survival after resection of pancreatic neuroendocrine tumors: analysis of 3851 patients.
        Ann Surg. 2008; 247: 490-500
        • Fischer L.
        • Bergmann F.
        • Schimmack S.
        • et al.
        Outcome of surgery for pancreatic neuroendocrine neoplasms.
        BJS. 2014; 101: 1405-1412
        • Zhang Z.
        • Liu M.
        • Ji S.
        • et al.
        Prognostic value and clinical predictors of lymph node metastases in pancreatic neuroendocrine tumors.
        Pancreas. 2020; 49: 381-386
        • Heidsma C.M.
        • Tsilimigras D.I.
        • van Dieren S.
        • et al.
        Indications and outcomes of enucleation versus formal pancreatectomy for pancreatic neuroendocrine tumors.
        HPB (Oxford). 2021; 23: 413-421
        • Teo R.
        • Goh B.K.P.
        • Tai D.W.M.
        • et al.
        Validation and comparison between current prognostication systems for pancreatic neuroendocrine neoplasms: a single-institution experience with 176 patients.
        Surgery. 2017; 161: 1235-1245
        • Falconi M.
        • Eriksson B.
        • Kaltsas G.
        • 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: 153-171
        • Brierley J.
        • Gospodarowicz M.K.
        • Wittekind C.
        • Union for International Cancer Control
        TNM classification of malignant tumours. 8th ed. Wiley Blackwell, 2017
        • Krampitz G.W.
        • Norton J.A.
        • Poultsides G.A.
        • Visser B.C.
        • Sun L.
        • Jensen R.T.
        Lymph nodes and survival in pancreatic neuroendocrine tumors.
        Arch Surg. 2012; 147: 820-827
        • Hashim Y.M.
        • Trinkaus K.M.
        • Linehan D.C.
        • et al.
        Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs).
        Ann Surg. 2014; 259: 197-203
        • Partelli S.
        • Gaujoux S.
        • Boninsegna L.
        • et al.
        Pattern and clinical predictors of lymph node involvement in nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs).
        JAMA Surg. 2013; 148: 932-939
        • Curran T.
        • Pockaj B.A.
        • Gray R.J.
        • Halfdanarson T.R.
        • Wasif N.
        Importance of lymph node involvement in pancreatic neuroendocrine tumors: impact on survival and implications for surgical resection.
        J Gastrointest Surg. 2015; 19 (discussion 60): 152-160
        • Conrad C.
        • Kutlu O.C.
        • Dasari A.
        • 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: 1966-1974
        • Tanaka M.
        • Heckler M.
        • Mihaljevic A.L.
        • et al.
        Systematic review and metaanalysis of lymph node metastases of resected pancreatic neuroendocrine tumors.
        Ann Surg Oncol. 2021; 28: 1614-1624
        • Gratian L.
        • Pura J.
        • Dinan M.
        • Roman S.
        • Reed S.
        • Sosa J.A.
        Impact of extent of surgery on survival in patients with small nonfunctional pancreatic neuroendocrine tumors in the United States.
        Ann Surg Oncol. 2014; 21: 3515-3521
        • Grenacher L.
        • Klauss M.
        [Computed tomography of pancreatic tumors].
        Der Radiologe. 2009; 49: 107-123
        • Falconi M.
        • Bartsch D.K.
        • Eriksson B.
        • et al.
        ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors.
        Neuroendocrinology. 2012; 95: 120-134
        • Bassi C.
        • Dervenis C.
        • Butturini G.
        • et al.
        Postoperative pancreatic fistula: an international study group (ISGPF) definition.
        Surgery. 2005; 138: 8-13
        • Bassi C.
        • Marchegiani G.
        • Dervenis C.
        • et al.
        The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 years after.
        Surgery. 2017; 161: 584-591
        • Dindo D.
        • Demartines N.
        • Clavien P.A.
        Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.
        Ann Surg. 2004; 240: 205-213
        • Bosman FT, World Health Organization, International Agency for Research on Cancer
        WHO Classification of Tumours of the Digestive System.
        4th ed. International Agency for Research on Cancer, Lyon (France)2010
        • Knigge U.
        • Capdevila J.
        • Bartsch D.K.
        • et al.
        ENETS consensus recommendations for the standards of care in neuroendocrine neoplasms: follow-up and documentation.
        Neuroendocrinology. 2017; 105: 310-319
        • Strobel O.
        • Hinz U.
        • Gluth A.
        • et al.
        Pancreatic adenocarcinoma: number of positive nodes allows to distinguish several N categories.
        Ann Surg. 2015; 261: 961-969
        • Liu P.
        • Zhang X.
        • Shang Y.
        • 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: 89245-89255
        • Partelli S.
        • Javed A.A.
        • Andreasi V.
        • et al.
        The number of positive nodes accurately predicts recurrence after pancreaticoduodenectomy for nonfunctioning neuroendocrine neoplasms.
        Eur J Surg Oncol. 2018; 44: 778-783
        • Zhang X.F.
        • Xue F.
        • Dong D.H.
        • al
        New nodal staging for primary pancreatic neuroendocrine tumors: a multi-institutional and national data analysis.
        Ann Surg. 2021; 274: e28-e35
        • Mao R.
        • Zhao H.
        • Li K.
        • et al.
        Outcomes of lymph node dissection for non-metastatic pancreatic neuroendocrine tumors: a propensity score-weighted analysis of the National Cancer Database.
        Ann Surg Oncol. 2019; 26: 2722-2729
        • Strobel O.
        • Buchler M.W.
        Pancreatic ductal adenocarcinoma: a new TNM staging system is needed.
        Ann Surg. 2017; 266: e109-e110
        • Beane J.D.
        • Borrebach J.D.
        • Billderback A.
        • et al.
        Small pancreatic neuroendocrine tumors: resect or enucleate?.
        Am J Surg. 2021; 222: 29-34
        • Altimari M.
        • Abad J.
        • Chawla A.
        The role of oncologic resection and enucleation for small pancreatic neuroendocrine tumors.
        HPB (Oxford). 2021; 23: 1533-1540
        • Tsuchikawa T.
        • Tanaka K.
        • Nakanishi Y.
        • et al.
        Clinical impact of organ-preserving surgery for pancreatic neuroendocrine neoplasms: a single-center experience.
        Pancreas. 2021; 50: 196-200
        • Niessen A.
        • Bechtiger F.A.
        • Hinz U.
        • et al.
        Enucleation is a feasible procedure for well-differentiated pNEN: a matched pair analysis.
        Cancers (Basel). 2022; 14: 2570
        • Wu L.
        • Sahara K.
        • Tsilimigras D.I.
        • et al.
        Therapeutic index of lymphadenectomy among patients with pancreatic neuroendocrine tumors: a multi-institutional analysis.
        J Surg Oncol. 2019; 120: 1080-1086