Multiple endocrine neoplasia type 1 (MEN1) is a hereditary autosomal dominant disorder associated with numerous neuroendocrine tumors (NETs). Recent advances in the management of MEN1 have led to a decrease in mortality due to excess hormones; however, they have also led to an increase in mortality from malignancy, particularly NETs. The main challenges are to localize these tumors, to select those that need therapy because of the risk of aggressive behavior and to select the appropriate therapy associated with minimal morbidity. This must be applied to a hereditary disease with a high risk of recurrence. The overall aim of management in MEN1 is to ensure that the patient remains disease- and symptom-free for as long as possible and maintains a good quality of life. Herein, we review the changes that occurred in the last 20 years in the surgical management of MEN1-associated functional and non-functional pancreatico-duodenal NETs and thymic and bronchial NETs.
S M Sadowski, G Cadiot, E Dansin, P Goudet and F Triponez
S M Sadowski, C R C Pieterman, N D Perrier, F Triponez and G D Valk
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.
C R C Pieterman, S M Sadowski, J E Maxwell, M H G Katz, K E Lines, C M Heaphy, A Tirosh, J E Blau, N D Perrier, M A Lewis, J P Metzcar, D M Halperin, R V Thakker and G D Valk
The PanNET Working Group of the 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) convened in Houston, TX, USA, 27–29 March 2019 to discuss key unmet clinical needs related to PanNET in the context of MEN1, with a special focus on non-functioning (nf)-PanNETs. The participants represented a broad range of medical scientists as well as representatives from patient organizations, pharmaceutical industry and research societies. In a case-based approach, participants addressed early detection, surveillance, prognostic factors and management of localized and advanced disease. For each topic, after a review of current evidence, key unmet clinical needs and future research directives to make meaningful progress for MEN1 patients with nf-PanNETs were identified. International multi-institutional collaboration is needed for adequately sized studies and validation of findings in independent datasets. Collaboration between basic, translational and clinical scientists is paramount to establishing a translational science approach. In addition, bringing clinicians, scientists and patients together improves the prioritization of research goals, assures a patient-centered approach and maximizes patient involvement. It was concluded that collaboration, research infrastructure, methodologic and reporting rigor are essential to any translational science effort. The highest priority for nf-PanNETs in MEN1 syndrome are (1) the development of a data and biospecimen collection architecture that is uniform across all MEN1 centers, (2) unified strategies for diagnosis and follow-up of incident and prevalent nf-PanNETs, (3) non-invasive detection of individual nf-PanNETs that have an increased risk of metastasis, (4) chemoprevention clinical trials driven by basic research studies and (5) therapeutic targets for advanced disease based on biologically plausible mechanisms.