Gastroenteropancreatic neuroendocrine tumors in 2025: From molecular profiling to artificial intelligence-driven therapy

Table 1 Clinical manifestations and diagnostic considerations of gastroenteropancreatic neuroendocrine tumors

Tumor type/syndrome	Hormone secreted	Key clinical manifestations	Diagnostic pearls and challenges	Ref.
Insulinoma	Insulin	Fasting hypoglycemia, neuroglycopenic symptoms (confusion, seizures), autonomic symptoms (tremor, diaphoresis), weight gain	Symptoms relieved by glucose intake; tumors often small; diagnosis frequently delayed	[40,43]
Glucagonoma	Glucagon	Weight loss, diabetes mellitus, necrolytic migratory erythema, diarrhea, stomatitis	Dermatologic findings may precede diagnosis; often metastatic at presentation	[42,45,46]
Somatostatinoma	Somatostatin	Diabetes mellitus, steatorrhea, cholelithiasis, hypochlorhydria, weight loss	Subtle or incomplete syndrome; diagnosis commonly incidental	[43,44]
PPoma	Pancreatic polypeptide	Nonspecific symptoms, abdominal discomfort, weight loss; mass-effect manifestations	Lacks a distinctive hormonal syndrome; frequently associated with MEN1	[45,49]
Carcinoid syndrome	Serotonin	Episodic flushing, secretory diarrhea, bronchospasm, right-sided heart disease, pellagra	Typically requires hepatic metastases; cardiac involvement impacts prognosis	[58-60]
Zollinger-Ellison syndrome	Gastrin	Refractory peptic ulcers, severe GERD, chronic diarrhea	MEN1 association; hypergastrinemia-driven acid hypersecretion	[59-62]
Nonfunctional NETs	None	Abdominal pain, jaundice, obstruction, constitutional symptoms	Frequently advanced at diagnosis; symptoms reflect tumor burden	[40,63-65]
Bone metastases		Localized bone pain, pathological fractures	Marker of advanced systemic disease	[67-71]

NET: Neuroendocrine tumor; GERD: Gastroesophageal reflux disease; MEN1: Multiple endocrine neoplasia type 1.

Table 2 Diagnostic modalities for gastroenteropancreatic neuroendocrine tumors

Diagnostic tool	Clinical use	Limitations	Key clinical indications/strengths
Chromogranin A	General NET marker	Low specificity; elevated in benign conditions	Broadly available; useful for disease monitoring and prognosis
5-HIAA (urine)	Detects serotonin-secreting NETs	Diet-dependent; limited for non-serotonin tumors	Specific for carcinoid syndrome and metastatic midgut NETs
Hormonal assays	Confirms functional NETs (e.g., insulinoma)	Not useful in non-functional NETs	Essential for diagnosis of functioning tumors (insulinoma, gastrinoma, VIPoma)
68Ga-DOTATATE PET/CT	First-line imaging for well-differentiated NETs	Requires PET facilities; limited for SSTR-negative tumors	High sensitivity and specificity for staging, PRRT selection, and follow-up
18F-FDG PET/CT	For high-grade/aggressive NETs	Poor sensitivity in low-grade NETs	Prognostic stratification and detection of dedifferentiation
CT/MRI	Anatomic localization	Radiation (CT); MRI less available	Widely accessible; useful for surveillance and surgical planning
Endoscopic ultrasound	Detects small PanNETs, allows biopsy	Invasive, operator-dependent	Best for pancreatic and duodenal NETs < 2 cm; enables tissue acquisition
NGS panel	Identifies mutations, guides treatment	Not always actionable; cost	Enables precision therapy (e.g., mTOR-pathway, DNA-repair alterations)
CtDNA	Detects tumor DNA in blood	Still experimental; low ctDNA in indolent NETs	Non-invasive molecular profiling and disease monitoring
NETest	Monitors disease activity non-invasively	Limited availability; high cost	Early detection of recurrence and therapy response prediction

5-HIAA: 5-hydroxyindoleacetic acid; PET/CT: Positron emission tomography/computed tomography; MRI: Magnetic resonance imaging; NGS: Next generation sequencing; ctDNA: Circulating tumor DNA; SSTR: Somatostatin receptor; PRRT: Peptide receptor radionuclide therapy; mTOR: Mammalian target of rapamycin.