Pancreatic and Ileal Neuroendocrine Tumors: Metastatic Disease or a Novel MEN Syndrome?

Multiple endocrine neoplasms are a feature of multiple endocrine neoplasia (MEN) syndromes types 1, 2, 4, and 5. However, the ileum is not usually involved in these disorders. We report a series of patients with neuroendocrine tumors (NETs) involving both the pancreas and the ileum. We searched the laboratory information system and personal consultation records of the authors from 2019 to 2023 for patients who had neuroendocrine tumors (NETs) involving both the pancreas and ileum. In a series of 846 patients, we identified 4 patients with pancreatic and ileal NETs, 2 female and 2 male, ages 52 to 75. Two female patients had primary EC cell tumors of the ileum with metastasis to the pancreas that showed expression of CDX2 and serotonin similar to the ileal primary tumors. Two males had primary lesions in the 2 sites with different immunoprofiles; the ileal tumors expressed CDX2 and serotonin and were negative for ARX, whereas the pancreatic tumors expressed ARX, glucagon, and pancreatic polypeptide and were negative for CDX2 and serotonin. In both male patients, the nontumorous pancreas showed preneoplastic changes in the endocrine elements, suggesting germline predisposition to endocrine neoplasia. Testing for known genetic alterations underlying MEN syndromes has not identified a genetic alteration that can be implicated in the development of NETs in both pancreas and ileum. Our series indicates the rare occurrence of NETs in both the pancreas and ileum and emphasizes the importance of using the correct biomarkers to distinguish metastasis from primary neoplasms at the different sites. The rare occurrence of primary ileal and pancreatic NETs may represent a novel MEN syndrome with as yet unknown germline predisposition.