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.

多发性内分泌肿瘤 1 综合征 (MEN1) 患者通常会发展为多灶性十二指肠胰腺神经内分泌肿瘤 (dpNET)。非功能性胰腺神经内分泌肿瘤（PanNET）和十二指肠胃泌素瘤是最常见的转移来源。目前的指南建议根据肿瘤功能、大小≥2 cm、分级或是否存在淋巴结转移来进行手术。然而，在多个原发性肿瘤的情况下，通常不知道哪个特定肿瘤发生了转移。本研究旨在通过研究内分泌分化来揭示 MEN1 患者原发 dpNET 与转移之间的关系。首先，研究表明内分泌分化标志物 ARX 和 PDX1 在 18 个单灶散发性神经内分泌肿瘤 (NET) 和匹配的转移瘤中表达一致。此后，在 10 名 MEN1 患者的 137 个微观和宏观 dpNET 以及 36 个匹配的转移瘤中确定了 ARX、PDX1、Ki67 和胃泌素表达以及端粒选择性延长的存在。执行 ARX 和 PDX1 H 分数聚类来推断相关性。对于多发转移的患者，相似的转移内转录因子表达表明大多数转移（29/32）起源于单一 NET，而少数患者可能具有多个转移性原发 NET。在 6 名患有 MEN1 和高胃泌素血症的患者中，十二指肠胰周淋巴结转移表达胃泌素，并与微小的十二指肠胃泌素瘤聚集在一起，而不是与较大的 PanNET 聚集。PanNET 转移通常与端粒阳性原发肿瘤的高级别或替代性延长聚集在一起。总之，对于 MEN1 相关的高胃泌素血症和 PanNET 患者，即使当前的常规和功能影像学研究未在术前揭示十二指肠肿瘤，也应考虑十二指肠胰周淋巴结转移的起源。