. 2021 Apr;169(4):963-973.

doi: 10.1016/j.surg.2020.09.037. Epub 2020 Nov 19.

Prognosis after surgery for multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors: Functionality matters

Dirk-Jan van Beek¹, Sjoerd Nell², Helena M Verkooijen³, Inne H M Borel Rinkes¹, Gerlof D Valk⁴; DutchMEN Study Group (DMSG); Menno R Vriens¹; International MEN1 Insulinoma Study Group; DutchMEN Surgery Study Group

Collaborators, Affiliations

Collaborators

Pierre Goudet⁵, Nicolas Santucci⁶, Detlef K Bartsch⁷, Jerena Manoharan⁷, Nancy D Perrier⁸, Jonathan Zagzag⁸, Maria Luisa Brandi⁹, Francesca Giusti⁹, Naris Nilubol¹⁰, Laurent Brunaud¹¹, Jesse D Pasternak¹², Ralph Hsiao¹², Cord Sturgeon¹³, Sneha Giri¹³, Elfi B Conemans¹⁴, Lodewijk A Brosens¹⁵, Bert A Bonsing¹⁶, Casper H van Eijck¹⁷, Harry van Goor¹⁸, Ruben H J de Kleine¹⁹, Elisabeth J Nieveen van Dijkum²⁰, Geert Kazemier²¹, Cornelis H C Dejong²²

Affiliations

¹ Department of Endocrine Surgical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands.
² Department of Endocrine Surgical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, the Netherlands.
³ Imaging Division, University Medical Center Utrecht, Utrecht, the Netherlands.
⁴ Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, the Netherlands.
⁵ INSERM, CIC1432, Clinical Epidemiology Unit, Dijon, France; Dijon-Bourgogne University Hospital, Clinical Investigation Center, Clinical Epidemiology/Clinical trial unit, Dijon, France.
⁶ Dijon-Bourgogne University Hospital, Department of Digestive and Endocrine Surgery, Dijon, France; INSERM U1231, EPICAD, Dijon, France; University of Burgundy-Franche-Comte, UMR1231 Lipids, Nutrition, Cancer, epidemiology and clinical research in Digestive Oncology, Dijon, France.
⁷ Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, Marburg, Germany.
⁸ Department of Surgical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America.
⁹ Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.
¹⁰ Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
¹¹ Department of Digestive, Hepatobiliary and Endocrine Surgery, Université de Lorraine, Hôpital Brabois Adultes, CHU Nancy, France.
¹² Department of Surgery, University Health Network, Toronto, ON, Canada.
¹³ Department of Surgery, Northwestern University, Chicago, Illinois, United States of America.
¹⁴ Imaging Division, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Endocrinology, Amsterdam University Medical Center location VUmc University Medical Center, Amsterdam, The Netherlands; Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
¹⁵ Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁶ Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.
¹⁷ Department of Surgery, Erasmus Medical Center, Rotterdam, the Netherlands.
¹⁸ Department of Surgery, Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁹ Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
²⁰ Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Center location Academic Medical Center, Amsterdam, the Netherlands.
²¹ Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Center location VUmc University Medical Center, Amsterdam, the Netherlands.
²² Department of Surgery, Maastricht University Medical Center, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht, the Netherlands; Department of Surgery, Universitätsklinikum Aachen, Aachen, Germany.

PMID: 33220975
PMCID: PMC9263962
DOI: 10.1016/j.surg.2020.09.037

Prognosis after surgery for multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors: Functionality matters

Dirk-Jan van Beek et al. Surgery. 2021 Apr.

. 2021 Apr;169(4):963-973.

doi: 10.1016/j.surg.2020.09.037. Epub 2020 Nov 19.

Authors

Collaborators

Pierre Goudet⁵, Nicolas Santucci⁶, Detlef K Bartsch⁷, Jerena Manoharan⁷, Nancy D Perrier⁸, Jonathan Zagzag⁸, Maria Luisa Brandi⁹, Francesca Giusti⁹, Naris Nilubol¹⁰, Laurent Brunaud¹¹, Jesse D Pasternak¹², Ralph Hsiao¹², Cord Sturgeon¹³, Sneha Giri¹³, Elfi B Conemans¹⁴, Lodewijk A Brosens¹⁵, Bert A Bonsing¹⁶, Casper H van Eijck¹⁷, Harry van Goor¹⁸, Ruben H J de Kleine¹⁹, Elisabeth J Nieveen van Dijkum²⁰, Geert Kazemier²¹, Cornelis H C Dejong²²

Affiliations

¹ Department of Endocrine Surgical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands.
² Department of Endocrine Surgical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, the Netherlands.
³ Imaging Division, University Medical Center Utrecht, Utrecht, the Netherlands.
⁴ Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, the Netherlands.
⁵ INSERM, CIC1432, Clinical Epidemiology Unit, Dijon, France; Dijon-Bourgogne University Hospital, Clinical Investigation Center, Clinical Epidemiology/Clinical trial unit, Dijon, France.
⁶ Dijon-Bourgogne University Hospital, Department of Digestive and Endocrine Surgery, Dijon, France; INSERM U1231, EPICAD, Dijon, France; University of Burgundy-Franche-Comte, UMR1231 Lipids, Nutrition, Cancer, epidemiology and clinical research in Digestive Oncology, Dijon, France.
⁷ Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, Marburg, Germany.
⁸ Department of Surgical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America.
⁹ Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.
¹⁰ Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
¹¹ Department of Digestive, Hepatobiliary and Endocrine Surgery, Université de Lorraine, Hôpital Brabois Adultes, CHU Nancy, France.
¹² Department of Surgery, University Health Network, Toronto, ON, Canada.
¹³ Department of Surgery, Northwestern University, Chicago, Illinois, United States of America.
¹⁴ Imaging Division, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Endocrinology, Amsterdam University Medical Center location VUmc University Medical Center, Amsterdam, The Netherlands; Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
¹⁵ Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁶ Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.
¹⁷ Department of Surgery, Erasmus Medical Center, Rotterdam, the Netherlands.
¹⁸ Department of Surgery, Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁹ Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
²⁰ Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Center location Academic Medical Center, Amsterdam, the Netherlands.
²¹ Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Center location VUmc University Medical Center, Amsterdam, the Netherlands.
²² Department of Surgery, Maastricht University Medical Center, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht, the Netherlands; Department of Surgery, Universitätsklinikum Aachen, Aachen, Germany.

PMID: 33220975
PMCID: PMC9263962
DOI: 10.1016/j.surg.2020.09.037

Abstract

Background: Metastasized pancreatic neuroendocrine tumors are the leading cause of death in patients with multiple endocrine neoplasia type 1. Aside from tumor size, prognostic factors of pancreatic neuroendocrine tumors are largely unknown. The present study aimed to assess whether the prognosis of patients with resected multiple endocrine neoplasia type 1-related nonfunctioning pancreatic neuroendocrine tumors differs from those with resected multiple endocrine neoplasia type 1-related insulinomas and assessed factors associated with prognosis.

Methods: Patients who underwent resection of a multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors between 1990 and 2016 were identified in 2 databases: the DutchMEN Study Group and the International MEN1 Insulinoma Study Group databases. Cox regression was performed to compare liver metastases-free survival of patients with a nonfunctioning pancreatic neuroendocrine tumors versus those with an insulinoma and to identify factors associated with liver metastases-free survival.

Results: Out of 153 patients with multiple endocrine neoplasia type 1, 61 underwent resection for a nonfunctioning pancreatic neuroendocrine tumor and 92 for an insulinoma. Of the patients with resected lymph nodes, 56% (18/32) of nonfunctioning pancreatic neuroendocrine tumors had lymph node metastases compared to 10% (4/41) of insulinomas (P = .001). Estimated 10-year liver metastases-free survival was 63% (95% confidence interval 42%-76%) for nonfunctioning pancreatic neuroendocrine tumors and 87% (72%-91%) for insulinomas. After adjustment for size, World Health Organization tumor grade, and age, nonfunctioning pancreatic neuroendocrine tumors had an increased risk for liver metastases or death (hazard ratio 3.04 [1.47-6.30]). In pancreatic neuroendocrine tumors ≥2 cm, nonfunctioning pancreatic neuroendocrine tumors (2.99 [1.22-7.33]) and World Health Organization grade 2 (2.95 [1.02-8.50]) were associated with liver metastases-free survival.

Conclusion: Patients with resected multiple endocrine neoplasia type 1-related nonfunctioning pancreatic neuroendocrine tumors had a significantly lower liver metastases-free survival than patients with insulinomas. Postoperative counseling and follow-up regimens should be tumor type specific and at least consider size and World Health Organization grade.

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Conflict of interest statement

Conflict of interest/Disclosure

The authors have nothing to disclose.

Figures

**Fig 1.**
Flowchart of patient inclusion. *GHRH*, growth hormone-releasing hormone.

**Fig 2.**
(A) LMFS of patients with resected MEN1-related pancreatic neuroendocrine tumors. (B) LMFS of patients with resected MEN1-related pancreatic neuroendocrine tumors <2 cm. (C) LMFS of patients with resected MEN1-related pancreatic neuroendocrine tumors ≥2 cm.

**Fig 3.**
(A) Occurrence of liver metastases or death stratified by pNET size and pNET functionality in total cohort. (B) Occurrence of liver metastases or death stratified by pNET size for patients with a resected NF-pNET. (C) Occurrence of liver metastases or death stratified by pNET size for patients with a resected insulinoma.

**Fig 4.**
LMFS of patients with resected MEN1-related pancreatic neuroendocrine tumors stratified by tumor size (<2 cm, 2–3 cm, and ≥3 cm).

**Fig 5.**
LMFS according to pathology. n, number.

See this image and copyright information in PMC

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Prognosis after surgery for multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors: Functionality matters

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Prognosis after surgery for multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors: Functionality matters

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