• PietermanCarolina R CCRCDepartment of Endocrine Oncology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands., Joanne M de Laat, TwiskJos W RJWRDepartment of Clinical Epidemiology and Biostatistics, VU University Medical Center, 1007 MB Amsterdam, The Netherlands.Department of Health Sciences, VU University, 1007 MB Amsterdam, The Netherlands., Rachel S van Leeuwaarde, Wouter W de Herder, DreijerinkKoen M AKMADepartment of Endocrine Oncology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands., HermusAd R M MARMMDepartment of Endocrinology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands., Olaf M Dekkers, van der Horst-SchriversAnouk N AANADepartment of Endocrinology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands., Madeleine L Drent, Peter H Bisschop, Bastiaan Havekes, Borel RinkesInne H MIHMDepartment of Endocrine Surgical Oncology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands., Menno R Vriens, and Gerlof D Valk.
• Department of Endocrine Oncology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.
• J. Clin. Endocrinol. Metab. 2017 Oct 1; 102 (10): 3795-3805.

BackgroundPancreatic neuroendocrine tumors (pNETs) are highly prevalent in patients with multiple endocrine neoplasia type 1 (MEN1), and metastatic disease is an important cause of MEN1-related mortality. Especially small nonfunctional (NF) pNETs pose a challenge to the treating physician and more information is needed regarding their natural course. We assessed long-term natural history of small NF-pNETs and its modifiers in the Dutch MEN1 population.Patients And MethodsRetrospective longitudinal observational cohort study of patients with small (<2 cm) NF-pNETs from the Dutch national MEN1 database, which includes >90% of the Dutch MEN1 population. Modifiers of long-term natural course were analyzed using linear mixed-models analysis.ResultsGrowth rate of the 115 included small NF-pNETs from 99 patients was slow (0.4 mm/y; 95% confidence interval, 0.15 to 0.59). Seventy percent of the tumors was stable and a subgroup of 30% of the tumors was growing (1.6 mm/y; 95% confidence interval, 1.1 to 2.0). No differences in clinical characteristics were identified between growing and stable tumors. Within the subgroup of growing tumors, germline missense mutations were significantly associated with accelerated growth compared with nonsense and frameshift mutations.ConclusionThe majority of small NF-pNETs are stable at long-term follow-up, irrespective of the underlying MEN1 genotype. A subgroup of tumors is slowly growing but cannot be identified on clinical grounds. In this subgroup, tumors with missense mutations exhibited faster growth. Additional events appear necessary for pNETs to progress. Future studies should be aimed at identifying these molecular driving events, which could be used as potential biomarkers.Copyright © 2017 Endocrine Society

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