Duodenopancreatic Neuroendocrine Tumors Research Articles

A Rare Case of Co-occurrence of Multiple Endocrine Neoplasia Syndrome and Congenital Adrenal Hyperplasia

Multiple endocrine neoplasia type 1 (MEN1) and congenital adrenal hyperplasia (CAH) are rare monogenic hereditary endocrinopathies with a prevalence of 1–9 cases per 100,000 and 9–15 cases per 100,000, respectively. MEN1 is characterized by the development of multiple endocrine and nonendocrine organ tumors, including parathyroid, pituitary, and duodenopancreatic neuroendocrine tumors (NETs), which constitute the classical triad of the disease. CAH is associated with genetic defects in enzymes and transport proteins involved in the synthesis of adrenal cortical steroid hormones. Overall, cases of the combination of two hereditary diseases in one patient are extremely rare. In this article, we describe a clinical case of the combination of MEN-1 with all three classical components and CAH, which, taking into account the low prevalence of both diseases, represents scientific interest. To date, only one similar case has been described in the literature. In addition, the paper discusses the pathogenetically determined combination of CAH and Ehlers-Danlos syndrome, known as the CAH-X syndrome.

Blood-based Proteomic Signatures Associated With MEN1-related Duodenopancreatic Neuroendocrine Tumor Progression.

Patients with multiple endocrine neoplasia type 1 (MEN1) are predisposed to develop duodenopancreatic neuroendocrine tumors (dpNETs), and metastatic dpNET is the primary cause of disease-related mortality. Presently, there is a paucity of prognostic factors that can reliably identify patients with MEN1-related dpNETS who are at high risk of distant metastasis. In the current study, we aimed to establish novel circulating molecular protein signatures associated with disease progression. Mass spectrometry-based proteomic profiling was conducted on plasmas procured through an international collaboration between MD Anderson Cancer Center, the National Institutes of Health, and the University Medical Center Utrecht from a cohort of 56 patients with MEN1 [14 with distant metastasis dpNETs (cases) and 42 with either indolent dpNETs or no dpNETs (controls)]. Findings were compared to proteomic profiles generated from serially collected plasmas from a mouse model of Men1-pancreatic neuroendocrine tumors (Men1fl/flPdx1-CreTg) and control mice (Men1fl/fl). A total of 187 proteins were found to be elevated in MEN1 patients with distant metastasis compared to controls, including 9 proteins previously associated with pancreatic cancer and other neuronal proteins. Analyses of mouse plasmas revealed 196 proteins enriched for transcriptional targets of oncogenic MYCN, YAP1, POU5F1, and SMAD that were associated with disease progression in Men1fl/flPdx1-CreTg mice. Cross-species intersection revealed 19 proteins positively associated with disease progression in both human patients and in Men1fl/flPdx1-CreTg mice. Our integrated analyses identified novel circulating protein markers associated with disease progression in MEN1-related dpNET.

Abstract P066: Blood-based proteomic signatures associated with MEN1-related duodenopancreatic neuroendocrine tumor progression

Abstract Multiple Endocine Neoplasia Type 1 (MEN1) is associated with duodenopancreatic neuroendocrine tumors (dpNETs) and metastatic dpNET is the primary cause of disease-related mortality for this condition. Currently, there is a paucity of prognostic factors that can reliably identify patients with MEN1-related dpNETS who are at high risk of distant metastasis. Previously, we uncovered a blood-based polyamine metabolite signature that was associated with MEN1-dpNET disease progression. In the current study, we aimed to build upon our prior findings, by exploring the contributions of proteomics for identifying circulating protein markers associated with tumor progression. We performed in-depth proteomic analysis of serially collected plasmas from a genetically engineered mouse model of Men1-pNET, Men1fl/flPdx1-CreTg, and Men1fl/fl control mice to assess dynamic changes in the plasma proteome that associated with disease progression. Findings were compared to plasma proteomic profiles from a cohort of 56 patients with MEN1 (14 with distant metastasis dpNETs (cases) and 42 with either indolent dpNETs or no dpNETs (controls)). Analyses revealed 196 proteins related to oncogenic N-MYC, YAP1, POU5F1, and SMAD that were positively associated with pNET disease progression in Men1fl/flPdx1-CreTg mice. Similarly, 187 proteins were elevated in MEN1 patients with distant metastasis compared controls. Proteins with increased levels in metastatic cases included AMY2B, CELA3B, RNASE1, IGFBP2, CHI3L1, LYZ, TIMP1, LRG1, and COL18A1 previously associated with pancreatic cancer and other neuronal proteins. Cross-species intersection revealed 19 proteins including NDC80, DEF8, SPAG17, ATM, IMMT, DNAH6, DSP, CIT, HRG, CD79A, BDP1, SERPINA11, TARBP1, and SERPIND1 that were positively associated with disease progression in Men1fl/flPdx1-CreTg mice and human subjects. Our integrated analyses identified novel circulating protein features associated with disease progression in MEN1-related dpNET. Citation Format: Johannes F. Fahrmann, Amanda R. Wasylishen, Carolina R.C. Pieterman, Ehsan Irajizad, Jody Vykoukal, Ranran Wu, Jennifer D. Dennison, Christine B. Peterson, Guillermina Lozano, Hua Zhao, Kim-Ahn Do, Daniel M. Halperin, Sunita K. Agarwal, Jenny E. Blau, Jaydira D. Rivero, Naris Nilubol, Mary F. Walter, James M. Welch, Lee S. Weinstein, Menno R. Vriens, Rachel S. van Leeuwaarde, Mark J.C. van Treijen, Gerlof D. Valk, Nancy D. Perrier, Sam M Hanash, Hiroyuki Katayama. Blood-based proteomic signatures associated with MEN1-related duodenopancreatic neuroendocrine tumor progression. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P066.

Lanreotide as maintenance therapy after first-line treatment in patients with non-resectable duodeno-pancreatic neuroendocrine tumours: An international double-blind, placebo-controlled randomised phase II trial – Prodige 31 REMINET: An FFCD study

BackgroundFollowing European guidelines, patients with aggressive metastatic or locally advanced, non-resectable, duodeno-pancreatic (DP) neuroendocrine tumours (NETs) should receive systemic combination chemotherapy until progression. Aggressive disease is defined as progressive and/or symptomatic metastases with or without significant hepatic invasion (>30–50%), and/or bone metastases. MethodsThis academic randomised, double-blind, placebo-controlled phase II study aims to evaluate lanreotide autogel 120 mg (LAN) as maintenance treatment after at least 2 months of first-line treatment (L1) in aggressive G1-G2 DP-NET. Patients were randomly assigned in a 1:1 ratio to receive LAN or placebo (PBO), every 28 days, until progression or toxicity. The primary end-point was progression-free survival (PFS) at 6 months. ResultsAmong the 118 planned patients, 53 were included. Of these, 81.1% had a G2 tumour, and 90.6% had metastatic disease. L1 therapy consisted of chemotherapy (96.8%). Median duration of L1 was 4.6 months (range: 2.0–7.7). At the time of randomisation, 81.1% of patients had stable disease. Median follow-up was 27.0 months (95% CI: 19.5; 31.2). PFS at 6 months was 73.1% (90% CI: 55.3; 86.6) in LAN versus 54.2% (90% CI: 35.8; 71.8) in PBO. Median PFS was 19.4 months (95% CI: 7.6; 32.6) and 7.6 months (95% CI: 3.0; 9.0), respectively. Median overall survival was 41.9 months in PBO and was not reached in LAN. The toxicity profile was mainly grade 1–2 expected toxicities. ConclusionsThe encouraging results of lanreotide autogel 120 mg as a maintenance treatment after L1 in aggressive G1/2 DP-NET should be confirmed. Trial registrationNCT02288377 (clinicaltrials.gov).

Update on the clinical management of multiple endocrine neoplasia type 1.

This review provides an overview of novel insights in the clinical management of patients with Multiple Endocrine Neoplasia Type 1, focusing on the last decade since the last update of the MEN1 guidelines. With regard to Diagnosis: Mutation‐negative patients with 2/3 main manifestations have a different clinical course compared to mutation‐positive patients. As for primary hyperparathyroidism: subtotal parathyroidectomy is the initial procedure of choice. Current debate centres around the timing of initial parathyroidectomy as well as the controversial topic of unilateral clearance in young patients. For duodenopancreatic neuroendocrine tumours (NETs), the main challenge is accurate and individualized risk stratification to enable personalized surveillance and treatment. Thymus NETs remain one of the most aggressive MEN1‐related tumours. Lung NETs are more frequent than previously thought, generally indolent, but rare aggressive cases do occur. Pituitary adenomas are most often prolactinomas and nonfunctioning microadenomas with an excellent prognosis and good response to therapy. Breast cancer is recognized as part of the MEN1 syndrome in women and periodical screening is advised. Clinically relevant manifestations are already seen at the paediatric age and initiating screening in the second decade is advisable. MEN1 has a significant impact on quality of life and US data show a significant financial burden. In conclusion, patient outcomes have improved, but much is still to be achieved. For care tailored to the needs of the individual patient and improving outcomes on an individual basis, studies are now needed to define predictors of tumour behaviour and effects of more individualized interventions.

The Importance of Periodical Screening for Primary Hyperparathyroidism in a Pituitary Tumor Cohort in Searching Patients With MEN1 and Its Genetic Profile

ObjectiveMultiple endocrine neoplasia type 1 (MEN1) is a rare genetic syndrome characterized by parathyroid, anterior pituitary, and/or duodenopancreatic neuroendocrine tumors. Studies have indicated that investigating primary hyperparathyroidism (pHPT) with subsequent genetic screening may be an essential tool for the early diagnosis of MEN1 in patients with pituitary tumors (PTs). This study aimed to investigate the presence of pHPT in patients with PTs and, subsequently, to screen for genetic mutations and related tumors in patients with MEN1 syndrome. MethodsThis study included 255 patients with PTs who were assessed for the presence of MEN1 by serum calcium and parathyroid hormone measurements. Mutation screening of the MEN1, CDKN1B, and AIP genes was performed in the index cases showing the MEN1 phenotype. ResultsFive patients with PTs presented a clinical condition compatible with MEN1. These patients had a younger age of onset and a more severe clinical condition. Genetic analysis identified a frameshift mutation in the MEN1 gene in one of the cases with the MEN1 phenotype, but point mutations in CDKN1B and AIP were not detected in any of these patients. ConclusionOur results show that periodic screening for pHPT in patients with PTs may be useful to detect MEN1 syndrome; thus, it is recommended in those patients with both findings a genetic analysis of MEN1 gene and an additional search of related tumors. By contrast, our data suggest that CDKN1B and AIP mutations do not seem to play a relevant role in the pathogenesis of MEN1.

Clinical Features, Genotype-Phenotype Correlations and Treatment Outcomes in Children and Adolescents with Multiple Endocrine Neoplasia Type 1: An International Cohort Study

Omair A. Shariq1,2, Kate E. Lines3, Katherine A. English3, Bahram Jafar-Mohammadi3, PhilippaPrentrice3, Ruth Casey5, Benjamin G. Challis5, Andreas Selberherr6, Fiona J. Ryan3, Ultan Healy3,Tom Kurzawinski7, Mehul T Dattani7, Irina Bancos8, Duncan Richards9, Benzon M. Dy2, Melanie L.Lyden2, William F. Young, Jr.8, Travis J. McKenzie2, Rajesh V. Thakker3
 1Nuffield Department of Surgical Sciences, University of Oxford, UK2Department of Surgery, Mayo Clinic, Rochester, MN3Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK4Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK5Department of Endocrinology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK.6Department of Surgery, Medical University of Vienna, Vienna, Austria.7Centre for Endocrine Surgery, Great Ormond Street Hospital for Children, London, UK8Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN9Oxford Clinical Trials Research Unit, Botnar Research Centre, Oxford, UK
 
 Background: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by parathyroid, pituitary and duodenopancreatic neuroendocrine tumours (DP-NETs). Knowledge regarding manifestations and outcomes is largely derived from adult cohorts. Thus, we investigated the occurrence and treatment of MEN1 manifestations in children and adolescents, and also explored potential genotype-phenotype correlations.
 Methods Eighty MEN1 patients who underwent childhood/adolescent tumour surveillance at 5 international referral centres were included. Fisher’s exact, Wilcoxon rank-sum and Kaplan-Meier tests were used to compare proportions, continuous variables and recurrence-free survival, respectively.
 Results Fifty-six patients (70%) developed an MEN1 manifestation before 19 years, at a median age of 14 years (range: 6-18 years). Primary hyperparathyroidism occurred in 46/56 patients (82.1%), 33 (72%) of whom underwent parathyroidectomy. Less-than-subtotal (<3-gland) parathyroidectomy resulted in worse recurrence/persistence-free survival vs subtotal (3-3.5-gland) or total (4-gland) parathyroidectomy (median 27 months vs not reached; P=0.005). Twenty-one patients (37.5%) developed DP-NETs (non-functioning [n=15], insulinomas [n=8], and gastrinoma [n=1]), 12 (57.1%) underwent surgery and 3 (14.3%) had metastases (hepatic [n=2] and lymph node [n=1]). Compared to patients without DP-NETs, those with DP-NETs at <19 years were more likely to harbour MEN1 mutations disrupting the menin-JunD interaction domain (80% vs 51.9%; P=0.0459). Pituitary tumours developed in 18/56 patients (32%) and were mostly dopamine agonist-responsive prolactinomas.
 Conclusions Morbidity from MEN1 manifestations occurs during childhood and adolescence in 70% of patients. Less-than-subtotal parathyroidectomy leads to high failure rates. DP-NETs are the second most common manifestation in this age group and may be more frequent in patients with mutations that disrupt menin-JunD binding.

Metastatic Patterns of Duodenopancreatic Neuroendocrine Tumors in Patients With Multiple Endocrine Neoplasia Type 1.

Patients with multiple endocrine neoplasia 1 syndrome (MEN1) often develop multifocal duodenopancreatic neuroendocrine tumors (dpNETs). Nonfunctional pancreatic neuroendocrine tumors (PanNETs) and duodenal gastrinomas are the most frequent origins of metastasis. Current guidelines recommend surgery based on tumor functionality, size ≥2 cm, grade or presence of lymph node metastases. However, in case of multiple primary tumors it is often unknown which specific tumor metastasized. This study aims to unravel the relationship between primary dpNETs and metastases in patients with MEN1 by studying endocrine differentiation. First, it was shown that expression of the endocrine differentiation markers ARX and PDX1 was concordant in 18 unifocal sporadic neuroendocrine tumors (NETs) and matched metastases. Thereafter, ARX, PDX1, Ki67 and gastrin expression, and the presence of alternative lengthening of telomeres were determined in 137 microscopic and macroscopic dpNETs and 36 matched metastases in 10 patients with MEN1. ARX and PDX1 H-score clustering was performed to infer relatedness. For patients with multiple metastases, similar intrametastases transcription factor expression suggests that most metastases (29/32) originated from a single NET of origin, while few patients may have multiple metastatic primary NETs. In 6 patients with MEN1 and hypergastrinemia, periduodenopancreatic lymph node metastases expressed gastrin, and clustered with minute duodenal gastrinomas, not with larger PanNETs. PanNET metastases often clustered with high grade or alternative lengthening of telomeres-positive primary tumors. In conclusion, for patients with MEN1-related hypergastrinemia and PanNETs, a duodenal origin of periduodenopancreatic lymph node metastases should be considered, even when current conventional and functional imaging studies do not reveal duodenal tumors preoperatively.

Prognostic transcriptome classes of duodenopancreatic neuroendocrine tumors.

Duodenopancreatic neuroendocrine tumors (DPNETs) aggressiveness is heterogeneous. Tumor grade and extension are commonly used for prognostic determination. Yet, grade classes are empirically defined, with regular updates changing the definition of classes. Genomic screening may provide more objective classes and reflect tumor biology. The aim of this study was to provide a transcriptome classification of DPNETs. We included 66 DPNETs, covering the entire clinical spectrum of the disease in terms of secretion, grade, and stage. Three distinct molecular groups were identified, associated with distinct outcomes (log-rank P < 0.01): (i) better-outcome DPNETs with pancreatic beta-cell signature. This group was mainly composed of well-differentiated, grade 1 insulinomas; (ii) poor-outcome DPNETs with pancreatic alpha-cell and hepatic signature. This group included all neuroendocrine carcinomas and grade 3 DPNETs, but also some grade 1 and grade 2 DPNETs and (iii) intermediate-outcome DPNETs with pancreatic exocrine and progenitor signature. This group included grade 1 and grade 2 DPNETs, with some insulinomas. Fibrinogen gene FGA expression was one of the topmost expressed liver genes. FGA expression was associated with disease-free survival (HR = 1.13, P = 0.005) and could be validated on two independent cohorts. This original pathophysiologic insight provides new prognostic classification perspectives.

Do Not Miss MEN 1 Screening When Patients Are Newly Diagnosed With Pancreatic Neuroendocrine Tumor

Abstract Background: Multiple endocrine neoplasia type 1(MEN 1) is a rare genetic disorder characterized by the combined occurrence of parathyroid, pituitary, and duodeno-pancreatic neuroendocrine tumors (NETs) along with other characteristic tumors. Here, we present a patient with history of pancreatic NET who presented 2 years after her initial diagnosis with primary hyperparathyroidism and prolactinoma, consistent with MEN 1. Case Report: A 60-year-old African American woman was admitted to our hospital with nausea, vomiting and headache for a week. On presentation, she was found to be hypotensive and tachycardic, both responded to IV fluids. Workup for infectious etiology came back negative. Her physical exam was benign except for dry oral mucosa, dry skin and epigastric tenderness. Laboratory evaluation showed serum calcium 11.8 mg/dL (8.4 - 10.2 mg/dL), which prompted further work up. Her PTH level was 1,079 pg/ml (8.5 - 72.5 pg/ml), Phosphorus 2.1 mg/dL (2.3 - 4.7 mg/dL), and 25 Hydroxy Vitamin D 10.2 ng/ml (7.4 - 44.0 ng/ml). Additional history and review of her records revealed she was hospitalized 2 years earlier with nausea, vomiting and abdominal pain. Then she was found to have esophageal and gastric ulcers on EGD. Endoscopic ultrasound revealed an 8 mm hypoechoic lesion in the body of pancreas found to be a pancreatic NET on biopsy. She had elevated gastrin level of 470 pg/ml (0 - 115 pg/ml) and was diagnosed with a gastrinoma. She was discharged on a PPI and was lost to follow up. Patient had no significant family history. Given her past history and current presentation, we assessed her pituitary hormonal function which was unremarkable except for prolactin level of &amp;gt;1,000 ng/ml (post-menopausal 1.8 - 20.3 ng/ml). Pituitary MRI showed a 1.8 cm macroadenoma. The optic nerve and optic chiasm were normal. Based on her clinical presentation and radiologic findings, she was diagnosed with MEN 1. Her Calcium level trended down with IV hydration, and her presenting symptoms resolved. She was started on bromocriptine, pantoprazole and vitamin D and was discharged with out-patient appointments scheduled with gastroenterology and endocrinology clinics. Conclusion: This case highlights the importance of having a high index of suspicion to prompt screening for MEN 1 in patients newly diagnosed with a pancreatic NET. Early diagnosis and timely treatment of the associated disease conditions in MEN 1 can prevent significant morbidity and mortality associated with these conditions.

A Blood-Based Polyamine Signature Associated With Disease Progression in Patients With Multiple Endocrine Neoplasia Type 1-Related Duodenopancreatic Neuroendocrine Tumors

Background: Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare inherited autosomal dominant disease predisposing patients to endocrine tumors. MEN1 can be genetically diagnosed at an early age. Patients are prone to develop benign parathyroid tumors then multifocal duodenopancreatic neuroendocrine tumors (dpNETs), which have a penetrance of >80% by age 80. Although they can be identified at an early stage, preventive measures do not exist, and one fifth of patients develop distant metastases, which is the most significant cause of mortality. Currently, no biomarkers can reliably predict which patients with MEN1-related dpNETs are at high risk of developing metastatic disease. Polyamines are naturally occurring polycationic alkylamines that have been implicated to play functional roles in promoting neoplastic transformation and growth. We have previously demonstrated a plasma polyamine signature that associates with pancreatic cancer development and that also offers value for predicting future distant metastasis in patients with triple-negative breast cancer. We hypothesized that such a plasma polyamine signature may similarly associate with disease progression in subjects with MEN1-related dpNET. Methods: As part of an international collaboration, we measured plasma polyamine levels using mass spectrometry from 14 MEN1 patients with distant metastatic dpNET (cases), 28 MEN1 patients with indolent dpNETs without distant metastases (control-1), and 14 MEN1 patients without dpNETs (control-2). Five circulating plasma polyamines were quantified in this initial test set. A combination rule was developed using logistic regression models. Findings were validated in an independent set of plasma from 6 cases and 22 controls (n=13 control-1 and n=9 control-2). Results: Area under the Receiver Operating Characteristic Curve (AUC) of individual polyamines delineating cases from controls ranged from 0.50-0.75 in the test set. A polyamine signature consisting of 3 polyamines developed in the test set yielded an AUC of 0.84 (95% CI: 0.63-1.00) with 67% sensitivity at 95% specificity in the validation set for distinguishing cases from controls. The predictive performance of the polyamine signature for distinguishing cases from MEN1 patients with indolent dpNETS without distant metastasis or MEN1 patients without dpNETS in the validation set was 0.79 (95% CI: 0.53-1.00) and 0.91 (95% CI: 0.75-1.00) with respective resultant sensitivity at 95% specificity of 50% and 67%. Conclusion: Our findings reveal a plasma polyamine signature associated with disease progression in subjects with MEN1-related dpNETs. This polyamine signature may provide a potential breakthrough for predicting progression and distant metastasis in MEN1 patients. Further prospective studies are warranted.

Pancreatoduodenectomy for Neuroendocrine Tumors in Patients with Multiple Endocrine Neoplasia Type 1: An AFCE (Association Francophone de Chirurgie Endocrinienne) and GTE (Groupe d\u2019\xe9tude des Tumeurs Endocrines) Study

AimTo assess postoperative complications and control of hormone secretions following pancreatoduodenectomy (PD) performed on multiple endocrine neoplasia type 1 (MEN1) patients with duodenopancreatic neuroendocrine tumors (DP-NETs).BackgroundThe use of PD to treat MEN1 remains controversial, and evaluating the right place of PD in MEN1 disease makes sense.MethodsThirty-one MEN1 patients from the Groupe d’étude des Tumeurs Endocrines MEN1 cohort who underwent PD for DP-NETs between 1971 and 2013 were included. Early and late postoperative complications, secretory control and overall survival were analyzed.ResultsIndication for surgery was: Zollinger–Ellison syndrome (n = 18; 58%), nonfunctioning tumor (n = 9; 29%), insulinoma (n = 2; 7%), VIPoma (n = 1; 3%) and glucagonoma (n = 1; 3%). Mean follow-up was 141 months (range 0–433). Pancreatic fistulas occurred in 5 patients (16.1%), distant metastases in 6 (mean onset of 43 months; range 13–110 months), postoperative diabetes mellitus in 7 (22%), and pancreatic exocrine insufficiency in 6 (19%). Five-year overall survival was 93.3% [CI 75.8–98.3] and ten-year overall survival was 89.1% [CI 69.6–96.4]. After a mean follow-up of 151 months (range 0–433), the biochemical cure rate for MEN-1 related gastrinomas was 61%.ConclusionIn MEN1 patients, pancreatoduodenectomy can be used to control hormone secretions (gastrin, glucagon, VIP) and to remove large NETs. PD was found to control gastrin secretions in about 60% of cases.

Clinical aspects of multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN1) is a rare syndrome characterized by the co-occurrence of primary hyperparathyroidism, duodenopancreatic neuroendocrine tumours (NETs) and/or pituitary adenomas. MEN1 can predispose patients to other endocrine and non-endocrine tumours, such as cutaneous tumours, central nervous system tumours and breast cancer. Endocrine tumours in patients with MEN1 differ from sporadic tumours in that they have a younger age at onset, present as multiple tumours in the same organ and have a different clinical course. Therefore, patients with overt MEN1 and those who carry a MEN1 mutation should be offered tailored biochemical and imaging screening to detect tumours and evaluate their progression over time. Fortunately, over the past 10 years, knowledge about the clinical phenotype of these tumours has markedly progressed, thanks to the implementation of national registries, particularly in France and the Netherlands. This Review provides an update on the clinical management of MEN1-related tumours. Epidemiology, the clinical picture, diagnostic work-up and the main lines of treatment for MEN1-related tumours are summarized. Controversial therapeutic aspects and issues that still need to be addressed are also discussed. Moreover, special attention is given to MEN1 manifestations in children and adolescents.

Complications After Major Surgery for Duodenopancreatic Neuroendocrine Tumors in Patients with MEN1: Results from a Nationwide Cohort

BackgroundLittle is known about complications after major duodenopancreatic surgery for duodenopancreatic neuroendocrine tumors (dpNETs) in multiple endocrine neoplasia type 1 (MEN1). Therefore, the incidence and severity of complications after major surgery for MEN1-related dpNETs were assessed.MethodsPatients were selected from the population-based Dutch MEN1 database if they had undergone a Whipple procedure or total pancreatectomy from 2003 to 2017. Complications were graded according to the Clavien–Dindo classification (grade III or higher complications were considered a severe complication) and definitions from the International Study Group of Pancreatic Surgery. The Cumulative Complication Index (CCI®) was calculated as the sum of all complications weighted for their severity. Univariable logistic regression was performed to assess potential associations between predictor candidates and a severe complication.ResultsTwenty-seven patients (median age 43 years) underwent a major duodenopancreatic resection, including 14 Whipple procedures and 13 total pancreatectomies. Morbidity and mortality were 100% (27/27) and 4% (1/27), respectively. A severe complication occurred in 17/27 (63%) patients. The median CCI® was 47.8 [range 8.7–100]. Grade B/C pancreatic fistulas, delayed gastric emptying, bile leakage, hemorrhage, and chyle leakage occurred in 7/14 (50%), 10/27 (37%), 1/27 (4%), 7/27 (26%), 3/27 (11%) patients, respectively. Patients with a severe complication had longer operative time and higher blood loss. After Whipple, new-onset endocrine and exocrine insufficiency occurred in 1/13 and 9/14 patients, respectively.ConclusionsMajor duodenopancreatic surgery in MEN1 is associated with a very high risk of severe complications and cumulative burden of complications and should therefore be reserved for a select subgroup of patients with MEN1-related dpNETs.

1163P Lanreotide as maintenance therapy after first-line treatment in patients with non-resectable duodeno-pancreatic neuroendocrine tumours (NETs): An international double-blind, placebo-controlled randomized phase II trial

Patients (pts) with aggressive metastatic or locally advanced, non-resectable, grade 1-2 well-differentiated duodeno-pancreatic (WDDP) NETs should receive a combination of systemic chemotherapy until progression. Aggressive disease is defined as progressive and/or symptomatic metastases and/or with significant hepatic invasion (>30-50%), and/or bone metastases.

Understanding the clinical course of genotype-negative MEN1 patients can inform management strategies

BackgroundIt is unclear whether genotype-negative clinical multiple endocrine neoplasia type 1 patients derive equal benefit from prospective surveillance as genotype-positive patients. MethodsIn this retrospective cohort study, we compared genotype-negative patients with clinical multiple endocrine neoplasia type 1 with genotype-positive index cases. Primary outcome was age-related penetrance of manifestations; secondary outcomes were disease-specific survival and clinical course of endocrine tumors. ResultsWe included 39 genotype-negative patients with clinical multiple endocrine neoplasia type 1 (Male: 33%) and 63 genotype-positive multiple endocrine neoplasia type 1 index cases (Male: 59%). Genotype-negative patients with clinical multiple endocrine neoplasia type 1 were 65 years old at last follow-up; genotype-positive multiple endocrine neoplasia type 1 index cases were 50 (P < .001). Genotype-negative patients with clinical multiple endocrine neoplasia type 1 were significantly older at their first and second primary manifestation. Only 1 developed a third primary manifestation. No genotype-negative patients with clinical multiple endocrine neoplasia type 1 with primary hyperparathyroidism and a pituitary adenoma developed a duodenopancreatic neuroendocrine tumor. Disease-specific survival was significantly better in genotype-negative patients with clinical multiple endocrine neoplasia type 1. In genotype-negative patients with clinical multiple endocrine neoplasia type 1, primary hyperparathyroidism was single-gland disease in 47% of parathyroidectomies versus 0% in genotype-positive multiple endocrine neoplasia type 1 index cases. In genotype-negative patients with clinical multiple endocrine neoplasia type 1, 17% of duodenopancreatic neuroendocrine tumors were multifocal versus 68% in genotype-positive multiple endocrine neoplasia type 1 index cases. Genotype-negative patients with clinical multiple endocrine neoplasia type 1 had more pituitary macroadenomas, fewer prolactinomas, and more somatotroph adenomas. ConclusionGenotype-negative patients with clinical multiple endocrine neoplasia type 1 have a different clinical course than genotype-positive multiple endocrine neoplasia type 1 index cases. This may support a separate classification and a tailored surveillance regimen. Of the genotype-negative patients with clinical multiple endocrine neoplasia type 1 who had parathyroidectomy, almost half had no evidence of multigland disease and may be potential candidates for a more targeted single-gland approach.

Prognostic factors for the outcome of nonfunctioning pancreatic neuroendocrine tumors in MEN1: a systematic review of literature.

Metastatic duodenopancreatic neuro-endocrine tumors (dpNETs) are the most important disease-related cause of death in patients with multiple endocrine neoplasia type 1 (MEN1). Nonfunctioning pNETs (NF-pNETs) are highly prevalent in MEN1 and clinically heterogeneous. Therefore, management is controversial. Data on prognostic factors for risk stratification are limited. This systematic review aims to establish the current state of evidence regarding prognostic factors in MEN1-related NF-pNETs. We systematically searched four databases for studies assessing prognostic value of any factor on NF-pNET progression, development of distant metastases, and/or overall survival. In- and exclusion, critical appraisal and data-extraction were performed independently by two authors according to pre-defined criteria. Thirteen studies (370 unique patients) were included. Prognostic factors investigated were tumor size, timing of surgical resection, WHO grade, methylation, p27/p18 expression by immunohistochemistry (IHC), ARX/PDX1 IHC and alternative lengthening of telomeres. Results were complemented with evidence from studies in MEN1-related pNET for which data could not be separately extracted for NF-pNET and data from sporadic NF-pNET. We found that the most important prognostic factors used in clinical decision making in MEN1-related NF-pNETs are tumor size and grade. NF-pNETs <2 cm may be managed with watchful waiting, while surgical resection is advised for NF-pNETs ≥2 cm. Grade 2 NF-pNETs should be considered high risk. The most promising and MEN1-relevant avenues of prognostic research are multi-analyte circulating biomarkers, tissue-based molecular factors and imaging-based prognostication. Multi-institutional collaboration between clinical, translation and basic scientists with uniform data and biospecimen collection in prospective cohorts should advance the field.

Clues For Genetic Anticipation In Multiple Endocrine Neoplasia Type 1.

Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary disease caused by the loss of function of the MEN1 gene, a tumor-suppressor gene that encodes the protein menin. It is characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumors (dpNET), pituitary tumors (PIT), adrenal adenomas, and bronchopulmonary (bp-NET), thymic, and gastric neuroendocrine tumors. More insight into factors influencing the age-related penetrance of MEN1 manifestations could provide clues for more personalized screening programs. To investigate whether genetic anticipation plays a role in the largest known MEN1 families in the Netherlands. All Dutch MEN1 families with ≥ 10 affected members in ≥ 2 successive generations were identified. Age at detection of the different MEN1-related manifestations were compared among generations using regression analyses adjusted for competing risks. To correct for the beneficial effect of being under surveillance, manifestations occurring during surveillance were also separately compared. A total of 152 MEN1 patients from 10 families were included. A significantly decreased age at detection of pHPT, dpNET, PIT, and bp-NET was found in successive generations (P < 0.0001). Adjusted analyses led to the same results. These results suggest the presence of genetic anticipation. However, due to a risk of residual bias, the results must be interpreted with caution. After independent validation in other cohorts and further translational research investigating the molecular mechanisms explaining this phenomenon in MEN1, the results might add to future, more personalized, screening protocols and earlier screening for future generations of MEN1 patients.

Health-Related Quality of Life in Patients with Multiple Endocrine Neoplasia Type 1

Introduction: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary endocrine tumor syndrome characterized by the triad of primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors (pNETs), and pituitary tumors. Patients are confronted with substantial morbidity and are consequently at risk for an impaired quality of life (QOL). Meticulous assessment of QOL and associated factors in a representative population is needed to understand the full spectrum of the burden of the disease. Patients and Methods: A cross-sectional study was performed using the national Dutch MEN1 cohort. Patients with a confirmed MEN1 mutation received the SF-36 Health Related Quality of Life questionnaire and questions regarding sociodemographic and medical history. Results: A total of 227 of 285 (80%) eligible MEN1 patients returned the questionnaires. Health-related QOL scores (HRQOL) in MEN1 patients were significantly lower for the majority of subscales of the SF-36 in comparison with the general Dutch population. The most consistent predictor for HRQOL was employment status, followed by the presence of a pituitary tumor. 16% of patients harboring a pNET and 29% of patients with a pituitary tumor according to the medical records, reported that they were unaware of such a tumor. These subgroups of patients had several significant better QOL scores than patients who were aware of their pNET or pituitary tumors. Conclusion: Patients with MEN1 have an impaired QOL in comparison with the general Dutch population warranting special attention within routine care. For daily practice, physicians should be aware of their patients’ impaired QOL and of the impact of unemployment on QOL.

One-Year Postoperative Mortality in MEN1 Patients Operated on Gastric and Duodenopancreatic Neuroendocrine Tumors: An AFCE and GTE Cohort Study.

In MEN1 patients with gastric and duodenopancreatic neuroendocrine tumors (GPD-NET), surgery aims to control secretions or to prevent metastatic spread, but after GPD-NET resection, postoperative mortality may be related to the surgery itself or to other associated MEN1 lesions with their own uncontrolled secretions or metastatic behavior. To analyze the causes of death within 1year following a GPD-NET resection in MEN1 patients. An observational study collecting data from the Groupe d'étude des Tumeurs Endocrines (GTE) database. The analysis considered the time between surgery and death (early deaths [<1month after surgery] versus delayed deaths [beyond 1month after surgery]) and the period (before 1990 vs after 1990). Causes of death were classified as related to GDP surgery, related to surgery for other MEN1 lesions or not related to MEN1 causes. GTE database which includes 1220 MEN1 patients and 441 GPD-NET resections. Four hundred and forty-one GPD-NET resections. The primary end point was postoperative mortality within 1year after surgery. Twenty-four patients met the inclusion criteria (2%). Median age at death was 50.5years. Sixteen deaths occurred in the 30-day postoperative period (76%). Among the 8 delayed deaths, 3 occurred as a result of medical complications between 30 and 90 postoperative days. After 1990, mean age at death increased from 48 to 58years (p = 0.09), deaths related to uncontrolled acid secretion disappeared (p < 0.001) and deaths related to associated MEN1 lesions increased from 8 to 54% (p = 0.16). Surgery and uncontrolled secretions remain the two main causes of death in MEN1 patients operated for a GPD-NET tumor. Improving the prognosis of these patients requires a strict evaluation of the secretory syndrome and MEN1 aggressiveness before GDP surgery.