A woman in her 60s presented to the emergency department with an 18-month history of chronic secretory diarrhoea and 8 kg weight loss. She had multiple previous presentations to healthcare for dehydration, weakness and severe hypokalaemia (serum potassium <2.5 mmol/L) over the preceding 18 months. Previous colonoscopy and workup for infectious and inflammatory causes had not yielded a diagnosis. At presentation, her serum potassium was 2.1 mmol/L (reference 3.5-5 mmol/L) with evidence of muscle weakness and volume depletion. A CT of the abdomen and pelvis demonstrated an 8 cm mass in the pancreatic tail. Endoscopic biopsy demonstrated well-differentiated pancreatic neuroendocrine tumour. Serum vasoactive intestinal peptide (VIP) was elevated eightfold above the upper limit of normal, in keeping with the diagnosis of VIPoma. Long-acting somatostatin analogue (SSA) was initiated. The patient underwent surgical resection of the primary tumour for symptom control. Following surgery and ongoing SSA use, diarrhoea and hypokalaemia have resolved.

Pancreatic neuroendocrine tumors (PanNETs) are typically characterized by low tumor mutational burden and limited responsiveness to immune checkpoint inhibitors. Emerging evidence suggests that prior exposure to alkylating chemotherapeutic agents may be associated with a hypermutated phenotype (along with DNA mismatch repair dysfunction or DNA damage response gene alterations), potentially sensitizing tumors to immunotherapy. We present a case of a 68-year-old woman with metastatic functional PanNET (VIPoma) who developed a treatment-associated hypermutated, microsatellite instability-high phenotype following capecitabine-temozolomide therapy. Treatment with pembrolizumab resulted in a robust clinical, biochemical, and radiographic response. This case highlights dynamic genomic evolution in PanNETs and underscores the importance of serial molecular profiling in guiding therapeutic decisions.

Accurate identification and localization are crucial for determining surgical strategies in patients with F-GEP-NETs, as these tumors often cause specific clinical syndromes due to hormone overproduction. However, conventional anatomical imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), exhibit low sensitivity and accuracy in detecting and localizing F-GEP-NETs. This limitation stems from the frequent small size and inherent imaging heterogeneity of such tumors, which often lead to inconclusive or false-negative results. Herein, we present two illustrative cases of F-GEP-NETs (one gastrinoma and one VIPoma) that were either not visualized or yielded undefined findings on contrast-enhanced CT (CE-CT). In both instances, [[18]F]F-NOTA-octreotide PET/CT subsequently enabled precise identification and anatomical localization of the primary tumors. This molecular imaging technique leverages the overexpression of somatostatin receptors on the surface of most neuroendocrine tumor cells, providing superior functional characterization. These cases underscore the potential diagnostic value of [[18]F]F-NOTA-octreotide PET/CT in the clinical workup of patients with biochemically confirmed F-GEP-NETs in whom conventional imaging is non-diagnostic, thereby aiding in the formulation of optimal treatment strategies and personalized management plans.

A reduction in serum calcium can stimulate parathyroid hormone (PTH) release which may then increase bone resorption, enhance renal calcium reabsorption, and stimulate renal conversion of 25-hydroxyvitamin D, to the active moiety 1,25-dihydroxyvitamin D [1,25(OH)2D] which then will enhance intestinal calcium absorption. These mechanisms restore the serum calcium to normal and inhibit further production of PTH and 1,25(OH)2D. Normal serum concentrations of total calcium generally range between 8.5 and 10.5 mg/dL (2.12 to 2.62 mM) and ionized calcium between 4.65-5.30 mg/dL (1.16-1.31 mM). Decreased PTH and decreased 1,25(OH)2D should accompany hypercalcemia unless PTH or 1,25(OH)2D is causal. Hypercalcemia may be caused by: Endocrine Disorders with Excess PTH including primary sporadic and familial hyperparathyroidism, and tertiary hyperparathyroidism; Endocrine Disorders Without Excess PTH including hyperthyroidism, pheochromocytoma, VIPoma, hypoadrenalism, and Jansen's Metaphyseal Chondrodysplasia; Malignancy-Associated Hypercalcemia, which can be caused by elevated PTH-related protein (PTHrP), or other factors (e.g. increased 1,25(OH)2D in lymphomas); Inflammatory Disorders including Granulomatous Diseases, where excess 1,25(OH)2D production may be causal, and HIV/AIDS; Pediatric Syndromes including Williams Syndrome and Idiopathic Infantile Hypercalcemia, where inappropriate levels of 1,25(OH)2D may occur due to a mutation in the 25-hydroxyvitamin D-24-hydroxylase gene (CYP24A1); Medication, including thiazide diuretics, lithium, vitamin D, vitamin A, estrogens and antiestrogens, theophylline, and prolonged immobilization, particularly in states of high bone turnover. Treatment should be aimed at the underlying disorder, however, if serum calcium exceeds 12 to 14mg/dL (3 to 3.5mM), acute hydration and agents that inhibit bone resorption are required. Under selected conditions, calcimimetics, calciuresis, glucocorticoids, or dialysis may be needed. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

VIPoma is a rare neuroendocrine tumor (NET) that is challenging to diagnose. While VIP concentrations are elevated in VIPoma, the optimal threshold for diagnostic purposes is not well defined. We aimed to study this in a single-institution population. We obtained results from vasoactive intestinal peptide (VIP) tests from 2011 to 2023 and reviewed the medical record of patients who had concentrations greater than our established assay-specific reference limit of 75 pg/mL. We compared plasma VIP concentrations between patient cohorts with and without VIPoma and determined the optimal threshold for VIP concentrations to predict a VIPoma in this population. Seventy-six patients met the selection criteria. Of these, nine cases of VIPoma were diagnosed. All patients had chronic diarrhea, and five patients had a previous diagnosis of a pancreatic neuroendocrine tumor (PNET). VIP concentrations drawn for acute/episodic diarrhea or flushing/diaphoresis did not lead to a diagnosis of a VIPoma. Mean VIP concentration was increased in patients with a VIPoma relative to those without, but the difference was not statistically significant (508 pg/mL vs 223 pg/mL, P = 0.31). Using the threshold of 75 pg/mL, the positive predictive value for a VIPoma was 12%. The optimal VIP threshold was 442 pg/mL (OR: 11.96, 95% CI: 2.00-79.69, P = 0.01), with statistically significant odds ratios starting at 200 pg/mL. Our findings suggest that elevated VIP concentrations are not predictive for a VIPoma and most patients with elevated VIP do not have a VIPoma. We recommend that VIP only be drawn in certain clinical scenarios to avoid unnecessary medical investigations.

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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.

BACKGROUND Treatment of metastatic vasoactive intestinal peptide tumors (VIPoma) is challenging and requires a careful multidisciplinary approach to achieve optimal disease control. We present a case of metastatic VIPoma with recurring episodes of life-threatening diarrhea necessitating multiple intensive care unit (ICU) admissions. CASE REPORT A 54-year-old man presented with severe watery diarrhea and metabolic acidosis with MRI showing a necrotic pancreatic body mass, and multiple liver lesions. Histopathologic and biochemical findings were consistent with VIPoma. Due to the multifocal liver lesions, he was deemed unsuitable for curative surgical intervention, shifting focus to other therapies. Initial treatments over 7 months included octreotide, transarterial chemoembolization, yttrium-90 radioembolization, and systemic therapy with everolimus, with decreases in serum vasoactive intestinal peptide (VIP) levels from a peak of 3180 pg/mL to undetectable levels corresponding to temporary relief of diarrhea. However, the temporary relief was followed by a rapid increase in VIP levels into the 200s and 300s and recurrence of 3-11 liters of diarrhea per day. He had multiple ICU admissions due to severe diarrhea/hypovolemic shock until he was treated with stereotactic body radiation therapy (SBRT). SBRT of the pancreatic site immediately yielded long-term hemodynamic stability, prevented further ICU admissions, and enabled the patient to receive debulking surgery. CONCLUSIONS Although radiation is not typically a primary treatment modality for VIPoma, in this case, the high dose per fraction delivered with stereotactic technique to a pancreatic mass played a crucial role in alleviating his catastrophic volume loss through intravenous octreotide-refractory diarrhea, making the patient a suitable candidate for debulking surgery. This case highlights the importance of considering all available treatment options, even those not traditionally employed, when managing complex cases with refractory symptoms.

Vasoactive intestinal peptide tumors (VIPoma) are neuroendocrine tumors secreting vasoactive intestinal peptide (VIP) in an unregulated manner. Werner and Morrison first described them in 1958 as a pancreatic tumor resulting in watery diarrhea and hypokalemia [1]. In 1973, the team of Bloom, Polak, and Pearse confirmed that the mediator was VIP [2]. The VIPoma syndrome is also known as Verner-Morrison syndrome, watery diarrhea, hypokalemia, and hypochlorhydria or achlorhydria (WDHA) syndrome, and pancreatic cholera syndrome [3]. This review highlights the clinical presentation, diagnosis, and management.

Functioning pancreatic neuroendocrine tumors (PanNETs) represent a subset of PanNETs that cause symptoms due to hormonal activity. Insulinoma is the most common functioning PanNET type. Mutations in the alpha thalassemia/mental retardation X-linked (ATRX) and death domain-associated protein (DAXX) genes result in genomic instability. ATRX/DAXX mutations and associated alternative lengthening of telomeres (ALT) are common in non-functioning PanNETs and associated with aggressive tumor behavior. Recent reports have shown that ATRX/DAXX mutations and ALT are also present in functioning PanNETs. In this review, we summarize the literature addressing ATRX/DAXX mutations and ALT in functioning PanNETs and discuss the clinical relevance with regard to distinguishing aggressive and indolent functioning tumors. ATRX/DAXX gene mutations and/or ALT have been reported in insulinoma, glucagonoma, gastrinoma, VIPoma and calcitoninoma. In insulinoma, the presence of ATRX/DAXX mutations and ALT are associated with aggressive behavior and could therefore be used as prognostic biomarkers. Although ATRX/DAXX mutation and ALT assessment may currently not be the standard of care in routine diagnostic pathology practice, the use of DAXX/ATRX immunohistochemistry at least can be encouraged not only for non-functioning but also for functioning PanNETs.