There is currently no standardized definition for small pancreatic neuroendocrine tumors, but they are generally regarded as tumors with a diameter of 2 cm or less. Functional or symptomatic tumors are typically recommended for aggressive surgical treatment. However, there is still debate on whether to surgically treat nonfunctional tumors. The Chinese guidelines for diagnosing and treating pancreatic neuroendocrine tumors advise close monitoring, effective communication with patients and their families, and prompt surgical intervention if high-risk factors are identified [7]. Meanwhile, the European Consensus on Functional and Nonfunctional Pancreatic Neuroendocrine Tumors discourages routine surgical exploration [8]. The North American Society for Neuroendocrine Tumors suggests clinical observation for tumors less than 1 cm in diameter, while the decision to operate on tumors between 1 and 2 cm should be tailored to each individual case [9]. Similarly, the Japanese Society for Neuroendocrine Tumors advocates surgical removal of non-functioning tumors smaller than 2 cm [10]. Recent research suggests that aggressive surgical intervention can prolong patient survival. Toshitaka Sugawara and colleagues conducted a study involving 4641 patients, revealing that surgical resection did not affect survival rates for patients with tumors 1 cm or less (group 1a). However, for patients with tumors ranging from 1.1 to 2 cm (group 1b), surgical resection demonstrated a positive correlation with extended survival [11].

Laparoscopic surgery, whether regular or local pancreatic resection, is relatively straightforward. Compared to regular resection, the challenge in local resection lies in precisely locating the tumor during surgery. Pancreatic neuroendocrine tumors ≤ 2 cm can be hard to visualize with the naked eye, especially given the limited tactile feedback in laparoscopic procedures [12]. Considering the size and characteristics of the tumor, traditional methods like distal pancreatectomy or pancreaticoduodenectomy, which carry high surgical risks and potential for post-operative pancreatic secretory dysfunction, are becoming less favored. Instead, local tumor resection with preservation of the pancreatic parenchyma is preferred [13], requiring exact intraoperative lesion localization.

Currently, laparoscopic ultrasonography serves as the primary tool for intraoperative localization during laparoscopic pancreatic tumor resection. Professor Rodney J. Lane emphasized in The Lancet in 1980 that intraoperative ultrasound offers a valuable non-invasive approach for diagnosing pancreatic ailments [14]. Numerous subsequent studies have further underscored the significance of laparoscopic ultrasound in pancreatic tumor surgeries [15,16,17,18]. Nevertheless, with the evolution of laparoscopic procedures and the widespread adoption of ultrasound equipment, certain constraints have become apparent. These include the requirement for surgeons to possess ultrasound proficiency, the challenge of detecting small pancreatic tumors via ultrasound, the inability of laparoscopic ultrasound to provide real-time tumor boundaries during local resection, and limited access to intraoperative ultrasound equipment in certain facilities.

Recently, various novel intraoperative localization techniques for small pancreatic neuroendocrine tumors have emerged in clinical practice. Professor Fausto Rosa and colleagues examined 16 cases, including 8 insulinomas and 8 non-functional pancreatic neuroendocrine tumors. In their study, they utilized ultrasonic endoscopy to pinpoint the tumor location and injected a dye (Spot® ink) into the lesion using a fine needle prior to surgery. Notably, 15 patients were able to precisely identify the lesion through intraoperative ultrasound [19]. Additionally, Professor Jonaan K. Law and team experimented with placing a metal marker plate in or adjacent to the lesion, guided by ultrasound endoscopy, in two instances of small neuroendocrine tumors of the pancreas. This technique, inspired by stereotactic radiation therapy for pancreatic cancer, allowed for rapid lesion localization during surgery via the plate, thereby reducing surgical time without any complications [20].

In this study, all three patients underwent successful intraoperative fluorescence visualization, which clearly delineated the tumor boundary and offered real-time guidance for precise resection. This visualization was complemented by intraoperative frozen pathology to initially rule out malignancy, and postoperative routine pathology confirmed negative incision margins. In 2016, Paiella, an Italian scholar, introduced indocyanine green imaging technology in pancreatic neuroendocrine tumor surgery (five boli of 2 ml each were administered, 2.5 mg/ml) [21]. Kou et al. presented a case where indocyanine green fluorescence imaging was used as a safe and straightforward method for intraoperative localization of pancreatic insulinoma (intraoperative injection of 4 ml through a peripheral vein) [22]. A retrospective single-arm cohort study led by Prof. Chihua Fang et al. indicates that indocyanine green fluorescence imaging aids surgeons in effectively locating tumors during laparoscopic insulinoma resection (intraoperative injection of 1 ml through a peripheral vein) [23]. The time and dose of indocyanine green injection are not yet standardized; subject to the clinical practice of various centers, our team gradually adjusted the injection dose downward through the preliminary animal test to avoid the background fluorescence intensity which is too high, and at the same time to ensure that the injection dose is relatively safe and carried out the clinical trials of ICG injection in the first window (preoperative 24-h intravenous drip) and the second window (intraoperative intravenous), and found that patients with the first ICG injection window. It was found that patients with ICG injection in the first window might have uncomfortable reactions to the drug, such as phlebitis and allergic reactions. It was finally determined that a one-time intraoperative injection of 2.5 mg ICG was performed, and the dosage was safe and effective.

Compared to laparoscopic ultrasound and ultrasound endoscopy, indocyanine green fluorescence imaging offers distinct advantages for intraoperative localization of small pancreatic neuroendocrine tumors: 1. The procedure is straightforward and efficient, involving only an intraoperative peripheral intravenous injection of a precisely proportioned indocyanine green solution. Within approximately 1 min of the injection, the tumor’s location and boundaries become visible. Conversely, laparoscopic ultrasound’s search time for foci is unpredictable and may involve repeated searches, positioning uncertainties, and even errors. 2. Preoperative positioning is not necessary, minimizing the risks associated with ultrasound endoscopic puncture and sparing the patient the burden of a stepwise surgical approach. 3. Most importantly, fluorescence imaging continuously outlines the tumor’s boundaries, guiding the surgeon to perform a complete resection beyond the fluorescence perimeter. Additionally, it holds potential clinical value in determining surgical margins during the operation. 4. It facilitates the discovery of potential lesions Figs. 1, 2 and 3.

Patient 1: a abdominal-enhanced MRI indicates potential pancreatic neck occupancy; b laparoscopic white light mode reveals no visible lesion in the pancreatic neck; c laparoscopic fluorescence mode featuring green fluorescence imaging of the tumor; d laparoscopic fluorescence mode dissects the tumor, allowing visualization of the parenchyma while the margins of the incision remain no visualization

Patient 2: a abdominal enhanced MRI indicating potential pancreatic tail occupancy. b The laparoscopic white light mode seemingly reveals a nodular lesion located in the tail of the pancreas. c Laparoscopic fluorescence mode reveals the tumor, imaged in green fluorescence. d Laparoscopic fluorescence mode dissects the tumor, allowing visualization of the parenchyma, while the margins of the incision remain no visualization

Patient 4: a Abdominal enhanced MRI indicating possible pancreatic body occupancy. b Multiple nodular lesions appeared to be visible in the body of the pancreas under the white light mode of laparoscopy. c The tumor was fluorescently visualized in green color in the fluorescence mode of laparoscopy. d Fluorescence laparoscopy dissection revealed no visualization within the parenchyma, but fluorescent visualization was observed on the surface

In conclusion, indocyanine green fluorescence imaging proves beneficial for the intraoperative localization of small neuroendocrine tumors in the pancreas, offering excellent safety. It serves as an effective complement to laparoscopic ultrasound technology and is poised to emerge as a novel intraoperative localization modality for laparoscopic local resection of pancreatic tumors.