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A novel tool to predict nodal metastasis in small pancreatic neuroendocrine tumors: A multicenter study

Published:September 30, 2022DOI:https://doi.org/10.1016/j.surg.2022.08.022

      Abstract

      Background

      Nonfunctional pancreatic neuroendocrine tumors display a wide range of biological behavior, and nodal disease is associated with metastatic disease and poorer survival. The aim of this study was to develop a tool to predict nodal disease in patients with small (≤2 cm) nonfunctional pancreatic neuroendocrine tumors.

      Methods

      A multicenter retrospective study was performed on patients undergoing resection for small nonfunctional pancreatic neuroendocrine tumors. Patients with genetic syndromes, metastatic disease at diagnosis, neoadjuvant therapy, or positive resection margin were excluded. Factors associated with nodal disease were identified to develop a predictive model. Internal validation was performed using bootstrap with 1,000 resamples.

      Results

      Nodal disease was observed in 39 (11.1%) of the 353 patients included. Presence of nodal disease was significantly associated with lower 5-year disease-free survival (71.6% vs 96.2%, P < .001). Two predictors were strongly associated with nodal disease: G2 grade (odds ratio: 3.51, 95% confidence interval: 1.71–7.22, P = .001) and tumor size (per mm increase, odds ratio: 1.14, 95% confidence interval: 1.03–1.25, P = .009). Adequate discrimination was observed with an area under the curve of 0.71 (95% confidence interval: 0.63–0.80). Based on risk distribution, 3 risk groups of nodal disease were identified; low (<5%), intermediate (≥5% to <20%), and high (≥20%) risk. The observed mean risk of nodal disease was 3.7% in the low-risk patients, 9.6% in the intermediate-risk patients, and 30.4% in the high-risk patients (P < .001). The 10-year disease-free survival in the low, intermediate, and high-risk groups was 100%, 88.8%, and 50.1%, respectively.

      Conclusion

      Our model using tumor grade and size can predict nodal disease in small nonfunctional pancreatic neuroendocrine tumors. Integration of this tool into clinical practice could help guide management of these patients.
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      References

        • Andreasi V.
        • Muffatti F.
        • Guarneri G.
        • Falconi M.
        • Partelli S.
        Surgical principles in the management of pancreatic neuroendocrine neoplasms.
        Curr Treat Options Oncol. 2020; 21: 48
        • Cui Y.
        • Khanna L.G.
        • Saqi A.
        • et al.
        The role of endoscopic ultrasound-guided Ki67 in the management of non-functioning pancreatic neuroendocrine tumors.
        Clin Endosc. 2020; 53: 213-220
        • 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
        • Yang G.
        • Ji M.
        • Chen J.
        • et al.
        Surgery management for sporadic small (</=2 cm), non-functioning pancreatic neuroendocrine tumors: a consensus statement by the Chinese Study Group for Neuroendocrine Tumors (CSNET).
        Int J Oncol. 2017; 50: 567-574
        • Partelli S.
        • Cirocchi R.
        • Crippa S.
        • et al.
        Systematic review of active surveillance versus surgical management of asymptomatic small non-functioning pancreatic neuroendocrine neoplasms.
        Br J Surg. 2017; 104: 34-41
        • Ricci C.
        • Casadei R.
        • Taffurelli G.
        • et al.
        Sporadic small (</=20 mm) nonfunctioning pancreatic neuroendocrine neoplasm: is the risk of malignancy negligible when adopting a more conservative strategy? A systematic review and meta-analysis.
        Ann Surg Oncol. 2017; 24: 2603-2610
        • Cives M.
        • Partelli S.
        • Palmirotta R.
        • et al.
        DAXX mutations as potential genomic markers of malignant evolution in small nonfunctioning pancreatic neuroendocrine tumors.
        Sci Rep. 2019; 918614
        • Assi H.A.
        • Mukherjee S.
        • Kunz P.L.
        • et al.
        Surgery versus surveillance for well-differentiated, nonfunctional pancreatic neuroendocrine tumors: an 11-year analysis of the National Cancer Database.
        Oncologist. 2020; 25: e276-e283
        • Barenboim A.
        • Lahat G.
        • Nachmany I.
        • et al.
        Resection versus observation of small asymptomatic nonfunctioning pancreatic neuroendocrine tumors.
        J Gastrointest Surg. 2020; 24: 1366-1374
        • 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
        • Partelli S.
        • Mazza M.
        • Andreasi V.
        • et al.
        Management of small asymptomatic nonfunctioning pancreatic neuroendocrine tumors: limitations to apply guidelines into real life.
        Surgery. 2019; 166: 157-163
        • Powers B.D.
        • Rothermel L.D.
        • Fleming J.B.
        • Strosberg J.R.
        • Anaya D.A.
        A survival analysis of patients with localized, asymptomatic pancreatic neuroendocrine tumors: no surgical survival benefit when examining appropriately selected outcomes.
        J Gastrointest Surg. 2020; 24: 2773-2779
        • Halfdanarson T.R.
        • Strosberg J.R.
        • Tang L.
        • et al.
        The North American Neuroendocrine Tumor Society Consensus guidelines for surveillance and medical management of pancreatic neuroendocrine tumors.
        Pancreas. 2020; 49: 863-881
        • Inzani F.
        • Petrone G.
        • Rindi G.
        The new World Health Organization classification for pancreatic neuroendocrine neoplasia.
        Endocrinol Metab Clin North Am. 2018; 47: 463-470
        • Steyerberg E.W.
        • Vickers A.J.
        • Cook N.R.
        • et al.
        Assessing the performance of prediction models: a framework for traditional and novel measures.
        Epidemiology. 2010; 21: 128-138
        • DeLong E.R.
        • DeLong D.M.
        • Clarke-Pearson D.L.
        Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach.
        Biometrics. 1988; 44: 837-845
        • Youden W.J.
        Index for rating diagnostic tests.
        Cancer. 1950; 3: 32-35
        • Ding D.
        • Javed A.A.
        • Yuan C.
        • et al.
        Role of lymph node resection and histopathological evaluation in accurate staging of nonfunctional pancreatic neuroendocrine tumors: how many are enough?.
        J Gastrointest Surg. 2021; 25: 428-435
        • Lombardi M.
        • De Lio N.
        • Funel N.
        • et al.
        Prognostic factors for pancreatic neuroendocrine neoplasms (pNET) and the risk of small non-functioning pNET.
        J Endocrinol Invest. 2015; 38: 605-613
        • Cherenfant J.
        • Stocker S.J.
        • Gage M.K.
        • et al.
        Predicting aggressive behavior in nonfunctioning pancreatic neuroendocrine tumors.
        Surgery. 2013; 154 (; discussion 91–93): 785-791
        • Gaujoux S.
        • Partelli S.
        • Maire F.
        • et al.
        Observational study of natural history of small sporadic nonfunctioning pancreatic neuroendocrine tumors.
        J Clin Endocrinol Metab. 2013; 98: 4784-4789
        • Haynes A.B.
        • Deshpande V.
        • Ingkakul T.
        • et al.
        Implications of incidentally discovered, nonfunctioning pancreatic endocrine tumors: short-term and long-term patient outcomes.
        Arch Surg. 2011; 146: 534-538
        • Sallinen V.
        • Le Large T.Y.
        • Galeev S.
        • et al.
        Surveillance strategy for small asymptomatic non-functional pancreatic neuroendocrine tumors: a systematic review and meta-analysis.
        HPB (Oxford). 2017; 19: 310-320
        • 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
        • 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
        • Falconi M.
        • Zerbi A.
        • Crippa S.
        • et al.
        Parenchyma-preserving resections for small nonfunctioning pancreatic endocrine tumors.
        Ann Surg Oncol. 2010; 17: 1621-1627
        • Bettini R.
        • Boninsegna L.
        • Mantovani W.
        • et al.
        Prognostic factors at diagnosis and value of WHO classification in a mono-institutional series of 180 non-functioning pancreatic endocrine tumours.
        Ann Oncol. 2008; 19: 903-908
        • Dong D.H.
        • Zhang X.F.
        • Poultsides G.
        • 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: 1071-1079
        • Parekh J.R.
        • Wang S.C.
        • Bergsland E.K.
        • 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: 840-844
        • Tomassetti P.
        • Campana D.
        • Piscitelli L.
        • et al.
        Endocrine pancreatic tumors: factors correlated with survival.
        Ann Oncol. 2005; 16: 1806-1810
        • Pulvirenti A.
        • Javed A.A.
        • Landoni L.
        • et al.
        Multi-institutional development and external validation of a nomogram to predict recurrence after curative resection of pancreatic neuroendocrine tumors.
        Ann Surg. 2021; 274: 1051-1057
        • Kazanjian K.K.
        • Reber H.A.
        • Hines O.J.
        Resection of pancreatic neuroendocrine tumors: results of 70 cases.
        Arch Surg. 2006; 141 (; discussion 9–70): 765-769
        • 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
        • Toste P.A.
        • Kadera B.E.
        • Tatishchev S.F.
        • 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: 2105-2113
        • 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
        • 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
        • Ende A.R.
        • Sedarat A.
        • Shah P.
        • et al.
        Risk factors for aggressive nonfunctional pancreatic neuroendocrine tumors and the role of endoscopic ultrasound guided fine-needle aspiration.
        Endosc Ultrasound. 2016; 5: 49-54
        • Jung J.G.
        • Lee K.T.
        • Woo Y.S.
        • et al.
        Behavior of small, asymptomatic, nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs).
        Medicine (Baltimore). 2015; 94: e983
        • Kishi Y.
        • Shimada K.
        • Nara S.
        • Esaki M.
        • Hiraoka N.
        • Kosuge T.
        Basing treatment strategy for non-functional pancreatic neuroendocrine tumors on tumor size.
        Ann Surg Oncol. 2014; 21: 2882-2888
        • Regenet N.
        • Carrere N.
        • Boulanger G.
        • et al.
        Is the 2-cm size cutoff relevant for small nonfunctioning pancreatic neuroendocrine tumors: a French multicenter study.
        Surgery. 2016; 159: 901-907
        • Zhang I.Y.
        • Zhao J.
        • Fernandez-Del Castillo C.
        • et al.
        Operative versus nonoperative management of nonfunctioning pancreatic neuroendocrine tumors.
        J Gastrointest Surg. 2016; 20: 277-283
        • Paik W.H.
        • Lee H.S.
        • Lee K.J.
        • et al.
        Malignant potential of small pancreatic neuroendocrine neoplasm and its risk factors: a multicenter nationwide study.
        Pancreatology. 2021; 21: 208-214
        • 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
        • Brunner S.M.
        • Weber F.
        • Werner J.M.
        • et al.
        Neuroendocrine tumors of the pancreas: a retrospective single-center analysis using the ENETS TNM-classification and immunohistochemical markers for risk stratification.
        BMC Surg. 2015; 15: 49
        • Wang Z.
        • Cao F.
        • Zhang Y.
        • Fang Y.
        • Li F.
        Risk factors of lymph node metastasis in patients with pancreatic neuroendocrine tumors (PNETs).
        Gastroenterol Res Pract. 2020; (2020)1946156
        • Lopez-Aguiar A.G.
        • Ethun C.G.
        • Zaidi M.Y.
        • 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: 15-21
        • Kyriakopoulos G.
        • Mavroeidi V.
        • Chatzellis E.
        • Kaltsas G.A.
        • Alexandraki K.I.
        Histopathological, immunohistochemical, genetic and molecular markers of neuroendocrine neoplasms.
        Ann Transl Med. 2018; 6: 252
        • Primavesi F.
        • Andreasi V.
        • Hoogwater F.J.H.
        • et al.
        A preoperative clinical risk score including C-reactive protein predicts histological tumor characteristics and patient survival after surgery for sporadic non-functional pancreatic neuroendocrine neoplasms: an international multicenter cohort study.
        Cancers (Basel). 2020; 12: 1235
        • Oversoe S.K.
        • Sorensen B.S.
        • Tabaksblat E.M.
        • Gronbaek H.
        • Kelsen J.
        Cell-free DNA and clinical characteristics in patients with small intestinal or pancreatic neuroendocrine tumors.
        Neuroendocrinology. 2022; 112: 43-50
        • Pulvirenti A.
        • Yamashita R.
        • Chakraborty J.
        • et al.
        Quantitative computed tomography image analysis to predict pancreatic neuroendocrine tumor grade.
        JCO Clin Cancer Inform. 2021; 5: 679-694
        • Carlinfante G.
        • Baccarini P.
        • Berretti D.
        • et al.
        Ki-67 cytological index can distinguish well-differentiated from poorly differentiated pancreatic neuroendocrine tumors: a comparative cytohistological study of 53 cases.
        Virchows Arch. 2014; 465: 49-55
        • Kalantri S.
        • Bakshi P.
        • Verma K.
        Grading of pancreatic neuroendocrine tumors on endoscopic ultrasound-guided fine-needle aspiration using Ki-67 index and 2017 World Health Organization criteria: an analysis of 32 cases.
        Cytojournal. 2020; 17: 21
        • Rebours V.
        • Cordova J.
        • Couvelard A.
        • et al.
        Can pancreatic neuroendocrine tumour biopsy accurately determine pathological characteristics?.
        Dig Liver Dis. 2015; 47: 973-977
        • Unno J.
        • Kanno A.
        • Masamune A.
        • et al.
        The usefulness of endoscopic ultrasound-guided fine-needle aspiration for the diagnosis of pancreatic neuroendocrine tumors based on the World Health Organization classification.
        Scand J Gastroenterol. 2014; 49: 1367-1374