Carolina R C Pieterman1, Joanne M de Laat1, Jos W R Twisk2,3, Rachel S van Leeuwaarde1, Wouter W de Herder4, Koen M A Dreijerink1, Ad R M M Hermus5, Olaf M Dekkers6, Anouk N A van der Horst-Schrivers7, Madeleine L Drent8, Peter H Bisschop9, Bastiaan Havekes10, Inne H M Borel Rinkes11, Menno R Vriens11, Gerlof D Valk1. 1. Department of Endocrine Oncology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands. 2. Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, 1007 MB Amsterdam, The Netherlands. 3. Department of Health Sciences, VU University, 1007 MB Amsterdam, The Netherlands. 4. Department of Internal Medicine, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands. 5. Department of Endocrinology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands. 6. Departments of Endocrinology and Metabolism and Clinical Epidemiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. 7. Department of Endocrinology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands. 8. Department of Internal Medicine, Section of Endocrinology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands. 9. Department of Endocrinology and Metabolism, Academic Medical Center, 1100 DD Amsterdam, The Netherlands. 10. Department of Internal Medicine, Division of Endocrinology, Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands. 11. Department of Endocrine Surgical Oncology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.
Abstract
Background: Pancreatic 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 Methods: Retrospective 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. Results: Growth 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. Conclusion: The 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.
Background: Pancreatic 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 Methods: Retrospective 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. Results: Growth 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. Conclusion: The 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.
Authors: Dirk-Jan van Beek; Helena M Verkooijen; Sjoerd Nell; Bert A Bonsing; Casper H van Eijck; Harry van Goor; Frederik J H Hoogwater; Elisabeth J M Nieveen van Dijkum; Geert Kazemier; Cornelis H C Dejong; Lodewijk A A Brosens; Frank J Wessels; Inne H M Borel Rinkes; Gerlof D Valk; Menno R Vriens Journal: Neuroendocrinology Date: 2020-07-28 Impact factor: 4.914
Authors: Maria Luisa Brandi; Sunita K Agarwal; Nancy D Perrier; Kate E Lines; Gerlof D Valk; Rajesh V Thakker Journal: Endocr Rev Date: 2021-03-15 Impact factor: 19.871