Since the original discovery of the Pacak-Zhuang syndrome (PZS) in 2012, defined by the clinical triad of pheochromocytoma/paraganglioma (PPGL) and/or duodenal ampullar somatostatinoma with erythrocytosis, multiple multisystemic phenotypes have been identified in patients with somatic mosaic pathogenic variants in EPAS1/HIF2A. Deep phenotyping of patients along with evaluation of a transgenic murine model has led to the understanding of the role of HIF-2α in developmental processes, including tumor development. Interestingly, pancreatic NETs occur in von Hippel-Lindau disease and the VHL gene product regulates HIF-2α expression. and results: Herein, we describe a novel series from two institutions of patients with EPAS1 associated pancreatic neuroendocrine tumors including a case of a nonfunctioning pancreatic neuroendocrine tumor (NET) in association with an EPAS1 somatic mosaic variant. This case study extends our current understanding of the phenotypic spectrum in PZS and links pancreatic NETs to an additional hypoxia-associated gene, namely EPAS1.

Background: Functional pancreatic neuroendocrine tumors (FpNETs) are extremely rare in childhood and adolescence, with an incidence of less than 0.1 per million. Since there is currently no systematic review of the literature on FpNETs in children, this study aims to summarize findings from studies focusing on clinical characteristics, diagnostics, treatment modalities, and outcomes. Methods: A systematic review was conducted following the PRISMA guidelines. A literature search was performed using three electronic databases: PubMed, Scopus, and Web of Science. An age filter was used during the search to limit results to childhood and adolescence. There was no limit set in relation to the type and the language of the article. Results: Out of 80,742 records identified, 91 studies met the inclusion criteria and were included in the review. Two studies included patients with insulinoma and gastrinomas, that is, insulinomas and glucagonoma. Of the included studies, 71 were insulinomas, 10 were gastrinomas, 3 were glucagonomas, 6 were VIPomas, and 3 were mixed FpNETs. A total of 163 children with FpNETs were analyzed, with a median age of 12 years. A total of 48 cases were reported in childhood, while 115 cases were reported in adolescence. The results indicate that FpNETs were more prevalent in males. Almost all patients presented with symptoms appropriate to the type of tumor. A significant proportion of tumors were associated with MEN1. In almost all patients, the symptomatology was accompanied by elevated levels of specific hormones. US, CT, PET-CT, MRI, and EUS were the dominant imaging modalities. Surgical approaches and types of resections, depending on the type, association with the syndrome, location, and size of the tumor, were quite heterogeneous. Grade 1 and Grade 2 tumors were nearly equally represented. There was no recurrence in most patients. Conclusions: Early suspicion based on specific clinical symptomatology is essential for timely diagnosis. Accurate localization and size based on modern radiological diagnostics, accompanied by biochemical and genetic testing, are essential for optimal management. Adequate surgical resection offers the best chance of cure, with the lowest risk of recurrence. Additional multicenter registries and studies are needed in the future to better understand tumor behavior, optimal management, and outcomes of FpNETs.

Composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET, previously "gangliocytic paraganglioma"), is a rare tumor type of uncertain pathogenesis in the ampulla/periampullary duodenum. Here, we present 11 CoGNETs in 6 females (55%) and 5 males (median age: 55 years; range: 28-69 years), all in the ampulla or duodenum. Tumors were triphasic with variable proportions of (1) neuroendocrine nests, (2) spindle cell nerve sheath regions, and (3) ganglion-like cells. By immunohistochemistry, ganglion-like cells expressed broad-spectrum keratins, somatostatin, NFP, and islet-1, and they lacked expression of PHOX2B. Neuroendocrine nests diffusely expressed ARX, islet-1, pancreatic polypeptide, and somatostatin, and they lacked expression of CDX2 and PDX1. Spindle cells expressed NFP and S-100. Targeted DNA sequencing of four tumors demonstrated 15q loss in two and multiple copy number alterations in one. Whole-exome DNA sequencing of five tumors showed borderline evidence of an NF1 frameshift mutation in one. Clinical follow-up was available for 8 patients (73%; median length: 7.0 years; range: 1.3 months-13.9 years). One Whipple resection showed regional lymph node metastases in a patient who remained disease-free 12.3 years later. No patients experienced recurrence or metastasis following surgery. The expression pattern of endocrine hormones and transcription factors distinguished CoGNET from other pancreatic and duodenal neuroendocrine tumor subtypes. The ganglion-like cells expressed keratins and not PHOX2B, demonstrating immunophenotypic divergence from true ganglion cells. Therefore, we propose that alternative nomenclature "gangliocytoid neuroendocrine neoplasm" or "composite gangliocytoid neuroendocrine neoplasm" be considered. The relative lack of pathogenic mutations raises the possibility that these tumors might harbor epigenetic drivers.

Functioning gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare tumors that secrete biologically active hormones, leading to complex clinical syndromes such as carcinoid syndrome, VIPoma, glucagonoma, gastrinoma, insulinoma, and somatostatinoma. These syndromes frequently induce profound metabolic, gastrointestinal, and nutritional disturbances. This review aims to provide a comprehensive overview of the physiopathology of malnutrition in functioning GEP-NENs and to highlight nutritional and supportive care strategies, including how medical, surgical, and locoregional treatments can indirectly improve nutritional outcomes. We analyzed the current literature and clinical guidelines to identify key mechanisms of malnutrition across different functioning syndromes and their clinical manifestations. Nutritional recommendations and the impact of treatment modalities on nutritional status were summarized. The pathophysiology of malnutrition in functioning NENs is multifactorial and syndrome-specific. Hormonal hypersecretion may cause diarrhea, electrolyte imbalances, catabolic states, steatorrhea, or hypoglycemia, among other effects. These lead to nutrient loss, malabsorption, or altered intake. Tailored dietary interventions, micronutrient supplementation (e.g., niacin, calcium, vitamin B12), and symptom-guided nutritional support are essential. Somatostatin analogs, PRRT, and cytoreductive approaches often contribute to symptom control, thereby enhancing nutritional status and patient quality of life. Malnutrition in functioning GEP-NENs is a significant clinical issue that requires early recognition and a multidisciplinary, individualized management plan. Integrating nutrition into the comprehensive care of these patients is essential to improve outcomes and quality of life. Somatostatinoma is a rare functional NET part of a heterogeneous group of tumors that range from well-differentiated NETs to poorly differentiated NECs. These tumors produce somatostatin, a cyclic peptide hormone that inhibits the function of multiple organs and hormones. Somatostatin reduces gastrointestinal motility and gallbladder contraction, and inhibits the secretion of growth hormone, insulin, glucagon, thyroid-stimulating hormone (TSH), secretin, and other hormones. The classic symptoms of somatostatinoma include diabetes mellitus, cholelithiasis, and steatorrhea. The incidence of NETs has been increasing, likely due to advancements in imaging techniques and endoscopy. However, pancreatic NETs account for only 1% to 3% of all pancreatic cancers. Of these tumors, approximately 15% are functional, producing symptoms based on the hormones they secrete, with somatostatinomas accounting for less than 5% of all functional pancreatic NETs. The first somatostatinoma was identified in the pancreas in 1977. These tumors are most commonly located in the head of the pancreas but can also be found in the periampullary region, ampulla, and duodenum. Reports of somatostatinomas in other extraintestinal sites have also been documented. The evaluation of somatostatinoma requires a combination of clinical suspicion, biochemical testing, imaging studies, and histopathologic confirmation. Localization and staging rely on cross-sectional imaging studies, eg, computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), and somatostatin receptor-based positron emission tomography (PET) scans. Surgical resection is the primary treatment for localized disease, while unresectable or metastatic cases are managed with somatostatin analogs, peptide receptor radionuclide therapy (PRRT), and targeted therapies. Prognosis depends on tumor grade, stage, and resectability, with better outcomes in localized, well-differentiated tumors.