GLP-1 Receptor PET/CT Detects Gastrinomas That SSTR Imaging Misses

A rare but consequential diagnostic problem in neuroendocrine tumor medicine has gained a possible new answer. In a case series published in EJNMMI Reports, researchers report three patients with metastatic gastrinomas in which conventional somatostatin receptor PET/CT failed to show clear tumor uptake, while an experimental imaging agent targeting the glucagon-like peptide-1 receptor, 68Ga-exendin-4, lit up the primary tumors and their spread to lymph nodes, liver, and bone.

Gastrinomas are functional neuroendocrine tumors that secrete gastrin ectopically, producing Zollinger-Ellison syndrome, a condition marked by severe peptic ulcer disease, gastroesophageal reflux, and chronic diarrhea. These tumors most often arise in the so-called gastrinoma triangle, the anatomical region bounded by the confluence of the cystic and common bile ducts, the junction of the second and third parts of the duodenum, and the neck and body of the pancreas. The duodenal bulb and pancreatic head are the most common sites. Although many gastrinomas behave in a relatively indolent fashion, diagnosis is frequently delayed because their symptoms overlap with far more common gastrointestinal disorders, and long-term proton pump inhibitor use can itself induce hypergastrinemia that mimics the syndrome.

The biochemical diagnosis rests on elevated fasting serum gastrin in the presence of inappropriate gastric acid secretion, but interpretation is complicated by proton pump inhibitor therapy, chronic atrophic gastritis, renal insufficiency, or achlorhydria. That places heavy weight on imaging, which serves not only to localize the tumor but also to stage disease, select treatment, and assess response. Contrast-enhanced CT, MRI, and endoscopic ultrasound remain the anatomical backbone of the workup, with endoscopic ultrasound particularly sensitive for lesions in the duodenal-pancreatic area. Yet tiny gastrinomas, often submucosal and only a few millimeters across, frequently escape detection on anatomical imaging altogether.

Molecular imaging has improved matters substantially. Most well-differentiated gastrinomas overexpress somatostatin receptors, particularly the SSTR2 subtype, which is the biological basis for somatostatin receptor PET/CT. This modality has become the imaging method of choice for staging well-differentiated neuroendocrine tumors and for determining eligibility for peptide receptor radionuclide therapy. An early study cited by the authors found that 68Ga-DOTANOC PET/CT achieved an overall lesion detection rate of up to 92.8 percent in patients with CT-negative or indeterminate gastrinomas, and more recent work has reported overall diagnostic sensitivities for SSTR PET in gastrinomas ranging from 68 to 100 percent. In-vitro analysis has shown that gastrinomas express SSTR2, SSTR3, and SSTR5 at rates of 100, 79, and 76 percent respectively.

Those figures, however, describe averages, and averages hide the patients who fall outside them. Small duodenal lesions can evade detection because of partial volume effects, physiological bowel activity, or genuinely heterogeneous receptor expression. In clinical practice, some patients show absent or patchy SSTR expression across different lesions, and identifying which lesion is actually driving hormone secretion remains a stubborn clinical challenge. This is precisely the gap the new case series addresses, using a tracer developed for a different tumor type.

68Ga-exendin-4 targets the glucagon-like peptide-1 receptor and was designed primarily for detecting insulinomas, the most common functional pancreatic neuroendocrine tumors. Because insulinomas express SSTR2 in only about half of cases, SSTR PET/CT often fails to localize them, whereas exendin-4 imaging achieves roughly 95 percent sensitivity and accuracy in that disease. An immunohistochemical study previously showed that all 11 gastrinomas examined expressed both SSTR2 and GLP-1R at high levels, and a case report from Peking Union Medical College Hospital described an incidental finding in which a retroperitoneal lymph node with intense exendin-4 uptake proved on biopsy to be a gastrinoma rather than the suspected insulinoma. The three patients now reported showed the reverse pattern from typical cases: low uptake on SSTR PET but high uptake on GLP-1R PET.

The first patient was a 46-year-old man with six months of progressively worsening diarrhea, up to five or six watery stools daily, which improved when he took proton pump inhibitors and recurred when he stopped. Gastroscopy showed erythematous gastric mucosa and multiple ulcerative lesions in the duodenal bulb and descending duodenum, and contrast-enhanced CT revealed a mass adjacent to the gastric antrum. His serum gastrin was 435.0 pg/mL, well above the normal range of 13.0 to 115.0 pg/mL. 68Ga-DOTANOC PET/CT showed only mild uptake in the periantral mass, similar to normal hepatic tissue, with no abnormal liver foci. 68Ga-exendin-4 PET/CT, by contrast, showed intense uptake in the mass, with a maximum standardized uptake value of 10.9, and unexpectedly revealed a small metastatic lesion in hepatic segment 4. Surgeons resected both the primary tumor and the left-lobe hepatic metastasis; pathology confirmed a grade 2 neuroendocrine tumor positive for gastrin and negative for insulin, and serum gastrin returned to normal within a month of the operation.

The second patient, a 50-year-old man, presented in November 2021 with three months of diarrhea and was found to have a neuroendocrine tumor at the gastric angle with multiple duodenal ulcers. He underwent laparoscopic distal gastrectomy and resection of liver metastases, followed by chemotherapy with an S1 plus temozolomide regimen combined with surufatinib, which kept disease stable on three-monthly imaging. In July 2024, 68Ga-DOTANOC PET/CT showed multiple liver metastases lacking somatostatin receptor expression, prompting radiofrequency ablation with continued surufatinib maintenance. When intrahepatic progression and recurrent diarrhea appeared in July 2025, with serum gastrin elevated to 410 pg/mL, 18F-FDG PET/CT showed low glucose metabolism in the metastases while 68Ga-exendin-4 PET/CT demonstrated markedly increased uptake, with an SUVmax of 7.8. The imaging finding supported a switch to capecitabine plus temozolomide chemotherapy; by January 2026 gastrin had fallen to 316.00 pg/mL, and imaging in March 2026 showed stable disease.

The third patient, a 69-year-old man with diarrhea dating to 2018, was found in 2022 to have hepatic lesions on biopsy-proven grade 2 neuroendocrine disease and underwent right hepatectomy, pancreatic tumor resection, and lymph node dissection, with pathology confirming a pancreatic grade 2 tumor with lymph node metastases in all seven nodes examined and multiple liver metastases. Long-acting octreotide controlled his diarrhea until April 2025, when CT showed enlargement of a liver segment 2 metastasis and multiple enlarged retroperitoneal lymph nodes. In June 2025, 18F-FDG and 68Ga-DOTANOC PET/CT revealed scattered metastases in the remnant liver, lymph nodes, and bone, with striking intertumoral heterogeneity: lymph node uptake of 68Ga-DOTANOC was markedly increased at an SUVmax of 24.5, while liver and bone metastases showed only mild uptake at an SUVmax of 10.1. Serum gastrin had risen to 655.00 pg/mL. 68Ga-exendin-4 PET/CT then demonstrated high GLP-1R expression across hepatic, nodal, and osseous metastases and detected additional lesions in the left ilium and femur that the other modalities had not shown.

The authors argue that GLP-1R imaging could matter well beyond diagnosis. Because some gastrinomas arise in the setting of multiple endocrine neoplasia type 1, where roughly 30 percent of patients develop Zollinger-Ellison syndrome and tumors are commonly multifocal, distinguishing the gastrin-secreting lesion from nonfunctional ones is notoriously difficult. Their center previously reported a MEN1 patient in whom combined SSTR and exendin-4 PET/CT separated insulin-secreting from nonfunctional pancreatic lesions, allowing targeted surgery that relieved hormone-related symptoms. The same logic, they suggest, applies to gastrinomas: identifying the hormonally active lesions could guide resection, and in metastatic disease, mapping the full GLP-1R-positive tumor burden could inform individual treatment strategies. The tracer may also point toward future radionuclide therapies targeting the receptor, though that remains a research direction rather than an established option. The authors are candid about the limitations of their report: only three cases, and no immunohistochemical confirmation of GLP-1R expression in the tumors themselves. They call for prospective studies correlating 68Ga-exendin-4 uptake with pathology. For now, the conclusion is appropriately measured: for gastrinomas with no or heterogeneous somatostatin receptor expression, GLP-1 receptor PET/CT is a promising imaging modality that may help guide precise treatment decisions.

Subject of Research: GLP-1 receptor PET/CT imaging of metastatic gastrinomas with absent or heterogeneous somatostatin receptor expression

Article Title: Glucagon-like peptide-1 receptor PET/CT in gastrinomas: a case series demonstrating the precise characterization to guide surgical and medical treatment

Article References: Xu, J., Liang, Y., Chen, J., & Song, S. (2026). Glucagon-like peptide-1 receptor PET/CT in gastrinomas: a case series demonstrating the precise characterization to guide surgical and medical treatment. EJNMMI Reports, 10(1), Article 53. https://doi.org/10.1186/s41824-026-00320-9

Image Credits: AI Generated

DOI: 10.1186/s41824-026-00320-9

Keywords: gastrinoma, 68Ga-exendin-4, GLP-1 receptor, PET/CT, somatostatin receptor, Zollinger-Ellison syndrome, neuroendocrine tumor, 68Ga-DOTANOC, molecular imaging, case series, liver metastases, MEN1