Medical Management of Secreting Syndromes in Functioning Pancreatic Neuroendocrine Tumors: A Scoping Review and Evidence Map

Background: Functioning pancreatic neuroendocrine tumors (pan-NETs) cause syndromes that can be life-threatening. Current guidelines recommend syndrome-directed drugs, but the primary evidence for hormonal control has never been mapped separately from the evidence for antitumor activity. We described how much evidence exists, how it is distributed, what outcomes were measured, and how completely the studies were reported across the ten functioning pan-NET syndromes recognized by the European Neuroendocrine Tumor Society (ENETS). Methods: We followed JBI methodology and PRISMA-ScR. PubMed/MEDLINE, Embase and Cochrane CENTRAL were searched from 1970 onward. Guideline-reference reconciliation, targeted syndrome-by-drug searches, backward citation checking and a date-sliced PubMed update with a clinical-series arm supplemented database searching. Eligible studies included at least three patients with a pancreatic-primary functioning neuroendocrine tumor and an extractable outcome of medical syndrome control. Evidence was charted by syndrome, therapy, design and reporting domain; formal certainty grading and meta-analysis were not undertaken. Results: Sixty-five studies formed the primary corpus. Fifty-three were single-cohort retrospective studies or case series, seven were prospective and five were comparative or multicenter retrospective studies. The median eligible sample was 13 patients among 55 studies with an exact denominator; 25/55 enrolled ten or fewer patients. Insulinoma accounted for 33 studies, followed by VIPoma (13), gastrinoma/Zollinger–Ellison syndrome (12) and glucagonoma (11). PTHrP-mediated hypercalcemia was represented by four studies and the combined ectopic ACTH/CRH category by two, both concerning ACTH secretion; no eligible primary study was identified for calcitoninoma or pancreatic carcinoid syndrome, which indicates the absence of eligible evidence rather than evidence of absent clinical experience. Forty-five out of 80 syndrome-by-therapy cells were empty. Biochemical or physiological outcomes were reported in 58/65 studies and clinical outcomes in 44/65, but definitions varied and the outcomes were not pooled; treatment line was reported in 41/65 and tumor grade in 25/65. A separate inventory contained 321 contextual and secondary records. Conclusions: Medical management of functioning pan-NETs looks well established in daily practice, but the primary evidence behind it is uneven and incompletely reported. The amount of evidence differs sharply between syndromes, and it does not support any comparative treatment sequence. Future studies should measure hormonal control separately from antitumor activity, adopt a core outcome set and a minimum reporting dataset, and use prospective multicenter networks for the rarest syndromes and for the treatment sequences that remain unstudied.