Department of Endocrine Oncology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.
Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, 1007 MB Amsterdam, The Netherlands.
J Clin Endocrinol Metab. 2017 Oct 1;102(10):3795-3805. doi: 10.1210/jc.2017-00372.
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.
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.
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.
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.
胰腺神经内分泌肿瘤（pNET）在多发性内分泌肿瘤 1 型（MEN1）患者中非常普遍，转移疾病是 MEN1 相关死亡的重要原因。特别是小的无功能性（NF）pNET 对治疗医生构成挑战，需要更多关于其自然病程的信息。我们评估了荷兰 MEN1 人群中小的 NF-pNET 及其修饰物的长期自然史。
对来自荷兰国家 MEN1 数据库的小（<2 厘米）NF-pNET 患者进行回顾性纵向观察队列研究，该数据库包括>90%的荷兰 MEN1 人群。使用线性混合模型分析来分析长期自然病程的修饰物。
99 例患者的 115 个小 NF-pNET 的生长速度缓慢（0.4 毫米/年；95%置信区间，0.15 至 0.59）。70%的肿瘤是稳定的，有 30%的肿瘤是生长的（1.6 毫米/年；95%置信区间，1.1 至 2.0）。生长和稳定的肿瘤之间在临床特征上没有差异。在生长肿瘤的亚组中，与无义和移码突变相比，种系错义突变与加速生长显著相关。
在长期随访中，大多数小的 NF-pNET 是稳定的，与 MEN1 基因型无关。肿瘤亚组生长缓慢，但不能根据临床依据确定。在这个亚组中，错义突变的肿瘤生长更快。pNET 进展似乎还需要其他事件。未来的研究应该旨在确定这些潜在的分子驱动事件，这些事件可能被用作潜在的生物标志物。
