Identification and Localization of Functioning Gastroenteropancreatic Neuroendocrine Tumors Using [18F]F-NOTA-octreotide PET/CT

Summary

These two case reports demonstrate the use of [¹⁸F]F-NOTA-octreotide positron emission tomography/computed tomography (PET/CT) to identify and localize functioning gastroenteropancreatic neuroendocrine tumors (F-GEP-NETs) and highlight its role in guiding clinical diagnosis and treatment planning.

Abstract

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, [¹⁸F]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 [¹⁸F]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.

Introduction

Neuroendocrine tumors (NETs) are a diverse group of neoplasms arising in neuroendocrine cells throughout the body, particularly in the gastrointestinal tract, pancreas, and lungs¹. Gastroenteropancreatic NETs (GEP-NETs) are located throughout the gastrointestinal (GI) tract or pancreas, accounting for 55-70% of NETs². Based on their ability to secrete hormones and biogenic amines, GEP-NETs are classified as functional or non-functional GEP-NETs. Although non-functional GEP-NETs (NF-GEP-NETs) account for approximately 60% of GEP-NETs, the incidence of F-GEP-NETs has surged in the last 10 years². NF-GEP-NETs often present no symptoms or nonspecific symptoms, such as abdominal pain, due to mass effect induced by an indolent growth rate³. F-GEP-NETs manifest as a spectrum of specific clinical syndromes related to the hormones they secrete, such as insulinomas, gastrinomas, VIPomas, and glucagonomas. Surgical resection is the primary treatment for F-GEP-NETs, regardless of tumor size⁴. To ensure a successful curative outcome, precise preoperative detection and localization are essential^4,5. However, these tumors are frequently diminutive in size, exhibit slow growth, and can be located anywhere within the abdomen or even at ectopic sites, rendering the diagnostic process exceedingly challenging⁵. In clinical practice, gallium-68 ([⁶⁸Ga]Ga)-labeled somatostatin analogs ([⁶⁸Ga]Ga-SSAs), including [⁶⁸Ga]Ga-DOTATATE, [⁶⁸Ga]Ga-DOTA-NOC, have been widely used for the localization of NETs^3,4. Nevertheless, Fluorine-18 ([¹⁸F]F) provides better spatial resolution in PET/CT imaging than [⁶⁸Ga]Ga, owing to its lower positron energy and shorter positron range. Detecting small GEP-NETs, especially those measuring less than 1 cm, is often difficult with CT or MRI due to limited spatial resolution. In clinical practice, [¹⁸F]F-NOTA-octreotide PET/CT should be considered when biochemical tests strongly suggest a functioning tumor that remains occult on standard imaging. However, its use is currently constrained by limited tracer availability and the need for more large-scale prospective data to establish standardized diagnostic thresholds. This study aimed to investigate the clinical value of [¹⁸F]F-NOTA-octreotide PET/CT in guiding precision management for patients with neuroendocrine tumors.

Case Presentation

Case 1
A 48-year-old female patient presented with recurrent watery diarrhea for more than 5 months (up to 20 times/day), weight loss of 5 kg, no abdominal pain or fever, and was admitted to our Department of Endocrinology. She had an unremarkable medical history with respect to trauma, cancer, tuberculosis, or surgery. Laboratory investigations were notable for a high serum gastrin of 913 pg/mL (normal range 13~115 pg/mL), and normal peripheral blood cell counts and tumor biomarker levels. Gastroscopy findings showed reflux esophagitis (LA grade B), lower esophageal ulcer, chronic non-atrophic gastritis, and multiple duodenal ulcers (Figure 1A). CE-CT revealed no abnormal findings in the gastrointestinal tract (Figure 1B). Based on the clinical presentation, the patient was suspected of having gastrinoma-related Zollinger–Ellison syndrome, and PET/CT imaging was planned for further evaluation. Endoscopic ultrasound (EUS) revealed a nodular lesion (1.15 × 0.75 cm) in the gastric antrum with abundant internal blood flow and poorly defined borders (Figure 1D). The patient underwent endoscopic ultrasound-guided needle biopsy followed by ablation therapy for the gastric antrum lesion. Histopathological and immunohistochemical examinations confirmed the diagnosis of NET (G1) (Figure 1 E–H). A final diagnosis of gastrinoma was made in the patient when the clinical data were taken into consideration.

Case 2
A 67-year-old male patient with persistent watery diarrhea, accompanied by severe hypokalemia, was admitted to our Department of Endocrinology. Laboratory tests demonstrated low levels of potassium of 2.3 mmol/L (normal range: 3.5~5.3 mmol/L), blood pH of 7.33 (7.35~7.45), bicarbonate concentration (HCO₃^-) of 9.6 mmol/L (22~27 mmol/L), partial pressure of carbon dioxide (PCO₂) of 18.4 mmHg (35~45 mmHg), serum gastrin of 9.0 pg/mL (normal range: 13~115 pg/mL), and high levels of sodium of 151 mmol/L (normal range: 137~147 mmol/L), chloride of 133 mmol/L (normal range: 99~107 mmol/L), ionized calcium of 1.7 mmol/L (normal range:1.15~1.29 mmol/L). Due to the absence of local laboratory facilities for vasoactive intestinal peptide (VIP) testing, serum VIP levels were not obtained. CE-CT showed a hyper-enhancing mass (5.2 x 3.9 cm) in the space between the pancreatic head and the portal cavity, suggesting a neuroendocrine tumor (NET) or Castleman's disease (Figure 2C). Based on the clinical presentation, the patient was suspected of having VIPoma, and [¹⁸F]F-NOTA-octreotide PET/CT was planned for further evaluation. Ultrasound-guided biopsy demonstrated a neuroendocrine tumor. The patient subsequently underwent laparoscopic pancreaticoduodenectomy, after which the clinical symptoms improved markedly. Postoperative pathological and immunohistochemical examinations confirmed a grade 2 neuroendocrine tumor (Figure 2D–F). In combination with the classic WDHA syndrome (watery diarrhea, hypokalemia, and achlorhydria), a clinical diagnosis of functional gastroenteropancreatic neuroendocrine tumor (GEP-NET) consistent with VIPoma was established.

Protocol

The protocol followed the Institutional Ethics Committee guidelines of The First Affiliated Hospital, Zhejiang University School of Medicine. Approval was obtained from the ethics committee (ClinicalTrials.gov identifier: IIT202110004C) before initiating the study procedures. Written informed consent was obtained from all enrolled patients prior to their [¹⁸F]F-NOTA-octreotide PET/CT examination.

1. Study design and participant recruitment

1. A retrospective review was conducted of patients who underwent [¹⁸F]F-NOTA-octreotide PET/CT imaging at the Department of Nuclear Medicine between November 2024 and February 2025. 
2. Two cases were confirmed as F-GEP-NETs (gastrinoma and VIPoma, respectively) through pathological examination.
3. Clinical data were collected for each patient, including gender, age, clinical symptoms, laboratory results, CT imaging findings, and pathological findings.

2. [¹⁸F]F-NOTA-octreotide PET/CT acquisition

1. Synthesis of [¹⁸F]F-NOTA-octreotide 
   NOTE: [¹⁸F]F-NOTA-octreotide was synthesized based on the Al18F complexation method previously described6,7, with the following specific optimizations for clinical production.
   1. The precursor solution was prepared by dissolving the NOTA-Octreotide precursor in 200 µL of acetic acid (pH 3.0) and 1 mL of acetonitrile.
   2. The labeling reaction was performed at 100°C for 15 min. After labeling, the reaction vial was allowed to naturally cool to room temperature under high-pressure air.
   3. The reaction mixture was diluted with water and passed through an HLB (light) column to capture the product. The column was rinsed with water to remove unreacted ¹⁸F ions and other impurities.
   4. The final product was eluted from the HLB column into a collection bottle using 2 mL of 50% ethanol. The product was diluted with 10 mL of saline.
   5. The radiochemical purity was verified to exceed 95%, and the final radioactive concentration was confirmed at approximately 370 MBq/mL before clinical use.
2. PET/CT Imaging Acquisition and Reconstruction
   1. An intravenous injection of [¹⁸F]F-NOTA-octreotide was administered at a dose of 3.7 to 4.44 MBq/kg. It was noted that for Case 1 (51 kg), the injected dose was 214.6 MBq (5.8 mCi), and for Case 2 (67 kg), it was 251.6 MBq (6.8 mCi).
   2. Radiation safety procedures were implemented. Patients were advised to increase fluid intake and void frequently for at least 4 h after injection to reduce bladder radiation exposure. Patients were observed for 30 minutes following radiotracer administration to monitor adverse reactions.
   3. An uptake period of approximately 60 to 75 min was allowed before scanning. For patients with severe clinical symptoms, the scan was performed without discontinuing subcutaneous octreotide.
   4. Imaging was performed using a Siemens Biograph Vision 600 PET/CT scanner. A low-dose CT scan (120 kV, 150 mA, Care Dose 4D) was initiated first for anatomical localization and attenuation correction.
   5. PET acquisition was conducted at 2 min per bed position, covering the range from the skull base to the mid-thigh.
   6. The data were reconstructed using the TrueX + TOF method on the VG76B software platform. Four iterations, 5 subsets, and a 4.0 mm Gaussian filter were applied. The image matrix was set to 440 × 440 with a voxel size of 1.85 × 1.85 × 3 mm.
   7. The reconstructed PET/CT images were transferred to the nuclear medical information system (MedEx) for subsequent quantitative analysis.
   8. Radioactive waste was managed in accordance with institutional and regulatory standards. All contaminated items, including syringes and needles, were collected in lead-shielded containers. They were stored in a designated decay storage area until radiation levels returned to background.

3. CE-CT acquisition

1. A 256-slice scanner (Brilliance iCT) was used for the CE-CT examination.
2. An intravenous injection of Iohexol was administered at a dose of 1.5 mL/kg.
3. CT scans were performed at three phases post-injection: arterial phase (25–35 s), portal-vein phase (55–75 s), and delayed phase (120–180 s).

4. Image interpretation

1. Two experienced nuclear medicine physicians were assigned to perform independent image analysis.
2. The physicians were blinded to the clinical data and pathological results when independently analyzing all images.
3. Any discordant results between the two physicians were resolved by consensus.
4. Positive lesions were defined as focal [¹⁸F]F-NOTA-octreotide accumulations with activity higher than the surrounding background tissue, excluding physiological uptake in normal organs and tissues.
5. The regions of interest (ROIs) were defined on the workstation, and the built-in software was used to automatically calculate the maximum standardized uptake value (SUV_max). All SUV measurements were normalized to the patient’s body weight to maintain quantitative consistency.

5. Troubleshooting 

1. The precursor pH was maintained at 3.0 if the radiochemical purity is below 95%. 
2. The uptake period was extended to at least 60 min if the tumor-to-background contrast was poor.

Results

[¹⁸F]F-NOTA-octreotide PET/CT was performed in two patients with suspected F-GEP-NETs. The clinical and imaging details of the two cases are summarized in Supplementary Table 1. Image interpretation was performed independently by two experienced nuclear medicine physicians, and concordant findings were obtained in both cases. In Case 1, no abnormal lesions were identified on CE-CT or CE-MRI. [¹⁸F]F-NOTA-octreotide PET/CT showed a focal lesion with markedly increased radiotracer upta...

Discussion

The incidence of neuroendocrine tumors (NETs), once considered rare diseases, has increased steadily worldwide in recent years in most countries and has garnered increasing attention⁸. Although F-GEP-NETs represent a minority of NETs, their incidence has increased in recent decades⁸. Since F-GEP-NETs present with a wide variety of clinical signs and symptoms related to inappropriately elevated hormonal levels secreted by the tumor, which may affect different organs, their m...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Aluminum chloride (AlCl3)	Alfa Aesar	88488.06
Biograph Vision 600 PET/CT	Siemens Healthineers	N/A
HLB Light Cartridge	Waters	186001879
Iohexol Injection	Yangtze River Pharmaceutical Group	NMPA Approval No.H10970358
Lauromacrogol Injection	Shaanxi Tianyu Pharmaceutical	NMPA Approval No.H20080445
MedEx Nuclear Medical Information System	MedEx Technology	N/A
NOTA-octreotide	Beijing PET Technology	BJA-025
QMA Cartridge	Waters	186000805
Sodium Acetate	Sigma-Aldrich	S2889-250G
Sterile Filter (0.22 μm )	Millipore	SLGV033RS
Brilliance iCT (Slice scanner)	Philips Healthcare, Germany	4535 674 80181
VG76B Reconstruction Software	Siemens Healthineers	N/A