Metastatic Patterns of Duodenopancreatic Neuroendocrine Tumors in Patients With Multiple Endocrine Neoplasia Type 1

Abstract

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.

Update on the clinical management of multiple endocrine neoplasia type 1

“…In a recent study, most patients with metastatic PanNETs and/or gastrinomas had a single NET of origin for their metastases, but multiple metastatic primaries were also seen. 71 A most clinically relevant finding was that in six patients with MEN1 and hypergastrinemia, periduodenopancreatic lymph node metastases clustered with minute duodenal gastrinomas and not with larger PanNETs. So a duodenal origin for locoregional lymph node metastases in patients with MEN1 and hypergastrinemia should always be considered.…”

“…As PanNETs and gastrinomas are often multiple in patients with MEN1, it may be challenging to attribute locoregional lymph node metastases to the correct primary NET. In a recent study, most patients with metastatic PanNETs and/or gastrinomas had a single NET of origin for their metastases, but multiple metastatic primaries were also seen 71 . A most clinically relevant finding was that in six patients with MEN1 and hypergastrinemia, periduodenopancreatic lymph node metastases clustered with minute duodenal gastrinomas and not with larger PanNETs.…”

“…So a duodenal origin for locoregional lymph node metastases in patients with MEN1 and hypergastrinemia should always be considered. 71 Gastric NETs are almost exclusively seen in patients with a gastrinoma, 72 and patients with hypergastrinemia are therefore advised to undergo EGD surveillance for gastric NETs at least every 3 years. 2 Patients with MEN1 are screened for insulinoma by yearly history taking and fasting glucose.…”

“…A most clinically relevant finding was that in six patients with MEN1 and hypergastrinemia, periduodenopancreatic lymph node metastases clustered with minute duodenal gastrinomas and not with larger PanNETs. So a duodenal origin for locoregional lymph node metastases in patients with MEN1 and hypergastrinemia should always be considered 71 …”