Journal of Minimally Invasive Surgery 2024; 27(4): 185-197
Published online December 15, 2024
https://doi.org/10.7602/jmis.2024.27.4.185
© The Korean Society of Endo-Laparoscopic & Robotic Surgery
Correspondence to : Yoo Min Kim
Division of Gastrointestinal Surgery, Department of Surgery, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemungu, Seoul 03722, Korea
E-mail: ymkim@yuhs.ac
https://orcid.org/0000-0002-5176-804X
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
In recent years, indocyanine green (ICG) and near-infrared (NIR) fluorescence-guided surgery has become a versatile and well-researched tool for gastric cancer treatment. Our narrative review aims to explore the applications, benefits, and challenges that are associated with this technique. Initially used to detect sentinel lymph nodes in early gastric cancer, its scope has broadened to include several clinical applications. Its most notable advantages are the ability to guide standard lymphadenectomy, intraoperatively localize tumors and define tumor margins. Despite these advantages, there are still ongoing discussions regarding its accuracy, lack of standardized administration, and oncologic safety in sentinel node navigation surgery. The limited tumor specificity of ICG has been especially put into question, hindering its ability to accurately differentiate between malignant and healthy tissue. With ongoing innovations and its integration into newer endoscopic and robotic systems, ICG-NIR fluorescence imaging shows promise in becoming a standard tool in the surgical treatment of gastric cancer.
Keywords Indocyanine green, Near-infrared spcetroscopy, Stomach neoplasms, Fluorescence, Gastrectomy
Recent years have witnessed significant progress in the field of gastric cancer surgery, with notable advancements in intraoperative techniques. One such technique is the use of fluorescence image-guided surgery to identify the tumor margins and lymphatic spread. During the procedure, a fluorescent probe is preoperatively or intraoperatively administered, and an external light source then illuminates the tissues as a specialized camera system captures the emitted light, providing valuable optical contrast for precise surgical resection. The optimal wavelengths for this technique are typically in the near-infrared (NIR) region, particularly the first (NIR-I, 700–900 nm) and second (NIR-II, 1,000–1,700 nm) NIR windows [1]. While a variety of fluorescent probes have been employed for fluorescence-guided surgery, indocyanine green (ICG) is one of the most frequently employed NIR fluorophores due to its favorable optical properties, safety profile, and versatility [2]. With the successful integration of fluorescence imaging technology in both laparoscopic and robotic equipment, this technique has since established its place in the treatment of gastric cancer with a wide range of applications.
In this narrative review, we aim to provide a comprehensive overview of the current evidence on the role of NIR imaging with ICG in gastric cancer surgery, as well as identify existing gaps in knowledge that may guide future research efforts.
ICG is a water-soluble, tricarbocyanine dye with a molecular weight of 774.96 g/mol and a normal biological half-time of 2.5 to 3.0 minutes. It is a compound that emits a fluorescent signal when excited by NIR light at a wavelength of approximately 840 nm [3]. Once injected
ICG exhibits a low toxicity with few side effects mainly when doses exceed 0.5 mg/kg, these include shock symptoms, nausea, angialgia, and fever [8]. The safety profile, ease of use, quick detection, and ability to produce high-quality NIR images have made ICG an optimal tracer agent for intraoperative surgical guidance. These advantages have led to the broad adoption of ICG in clinical practice and the development and approval of compatible imaging systems [9]. These devices are capable of alternating between white light view and NIR imaging through a filter switch system thus permitting direct real-time intraoperative visualization of the organ lymphatic or blood flow.
The Novadaq SPY system (Stryker), which was granted U.S. Food and Drug Administration approval in 2005, became the first fluorescence imaging system used for intraoperative procedures. Since then, it has paved the way for a variety of other devices with unique features and capabilities, including fluorescence overlay on reflected light (FLARE, Curadel LLC), ergonomic and portable designs (PDE NEO, Hamamatsu Photonics K.K; Artemis/Quest, Quest Medical Imaging), 3D in 4K quality support (VISERA ELITE II, Olympus; IMAGE1S Rubina, Karl Stortz), multichannel functionality (Quest), and integration with endoscopic, and robotic approaches (Firefly, Intuitive Surgical; Pinpoint, Stryker) [10]. The incorporation of NIR fluorescence technology in current endoscopic and robotic imaging systems is a growing trend, owing to its well-established effectiveness as an intraoperative tool.
ICG-NIR fluorescence imaging has various intraoperative applications in open, endoscopic, and robotic gastric cancer surgery. Initially employed to detect sentinel lymph nodes (LNs) in early gastric cancer, its use has been extended to real-time navigation through tumor localization and perigastric LN mapping [7]. The utilization of this technique aids in determining resection margins, enhancing LN yield, identifying anatomical structures, and clarifying complex vessel anatomy [11]. It even has the capacity to improve the occurrence of postoperative complications (Clavien-Dindo grade II or higher) in gastric cancer surgery patients as evidenced in a 19-study meta-analysis [12]. The evolution and continued research on ICG-NIR fluorescence imaging has come a long way and is expected to further enhance surgical outcomes for gastric cancer patients (Fig. 1).
ICG with NIR imaging is frequently utilized as a guide for lymphadenectomy in gastric cancer [13]. The retrieval of an adequate number of LNs is critical for accurate staging. According to most guidelines, a minimum of 16 regional nodes should be collected for pathologic examination, although some studies suggest it is more desirable to remove 30 or more nodes [14–18]. While multiple studies have shown an increased LN yield with the use of ICG fluorescence imaging, variations in the type of NIR camera, ICG concentration, and injection method across studies [19–27] have led to inconsistencies in the use of ICG to visualize the lymphatic systems (Table 1 [19,20,22–24,27–43]).
Table 1 . Summary of studies on ICG-NIR fluorescence-guided lymphadenectomy
Study | Year | Country | Sample size (ICG:control) | Endpointsa) | ICG dosage (mg) | Administration route | Administration time | Imaging system | Type of gastrectomy | LN dissection |
---|---|---|---|---|---|---|---|---|---|---|
Lan et al. [31] | 2017 | China | 14:65 | 1, 3 | 6 | Subserosa | During surgery | NA | Robotic DG and TG | D1+ or D2 |
Kwon et al. [20] | 2019 | Korea | 40:40 | 1, 3 | 3 | Endoscopy; submucosal | 1 day before surgery | Firefly | Robotic DG and TG | D1+ or D2 |
Ma et al. [32] | 2019 | China | 38:44 | 1, 2, 3 | 1.25 | Endoscopy; submucosal | 12 hr before surgery | Storz | Laparoscopic DG and TG | D1+ or D2 |
Ushimaru et al. [30] | 2019 | Japan | 84:84 | 1, 3 | 0.1 | Endoscopy; submucosal | 1 day before surgery | Storz | Laparoscopic DG and TG | D1+ or D2 |
Chen et al. [19] | 2020 | China | 129:129 | 1, 2, 3 | 2.5 | Endoscopy; submucosal | 1 day before surgery | Stryker | Laparoscopic DG and TG | D2 |
Cianchi et al. [23] | 2020 | Italy | 37:37 | 1, 2, 3 | 2.5 | Endoscopy; submucosal | 1 day before surgery | Firefly | Laparoscopic DG and TG | D2 |
Jung et al. [27] | 2020 | Korea | 592 | 1, 2 | 1.5 or 3 | Endoscopy; submucosal | 1 day before surgery | Pinpoint or Firefly | Robotic or Laparoscopic PG, DG and TG | D1+ or D2 |
Liu et al. [24] | 2020 | China | 61:75 | 1, 2, 3 | 1.25 | Endoscopy; submucosal | 20–30 hr before surgery | Stryker | Laparoscopic DG | D2 |
Park et al. [33] | 2020 | Korea | 20:60 | 1, 3 | 0.5 | Endoscopy; submucosal | During surgery | Pinpoint | Laparoscopic DG | D1+ or D2 |
Huang et al. [29] | 2021 | China | 94:94 | 1, 3 | 4.5 | Subserosa | During surgery | Stryker | Laparoscopic DG and TG | D2 |
Lu et al. [22] | 2021 | China | 28:28 | 1, 3, 4 | 2.5 | Endoscopy; submucosal | During surgery | Pinpoint | Laparoscopic PG, DG and TG | D2 |
Romanzi et al. [34] | 2021 | Italy | 10:10 | 1 | 3 | Endoscopy; submucosal | 18 hr before surgery | Firefly | Robotic DG | D2 |
Zhong et al. [28] | 2021 | China | 385:129 | 1, 2 | 4.5 | Subserosa | During surgery | Stryker | Laparoscopic DG and TG | D2 |
Chen et al. [35] | 2022 | China | 18:38 | 1, 2, 3 | 1.25 | Endoscopy; submucosal | 1 day before surgery | NA | Laparoscopic PG, DG and TG | D2 |
Lee et al. [36] | 2022 | Korea | 74:94 | 1 3, 4, 5 | 1.5–3.0 | Endoscopy; submucosal | 1 day before surgery | Firefly or Pinpoint | Laparoscopic and Robotic TG | D2 |
Maruri et al. [37] | 2022 | Spain | 17:17 | 1, 2, 4 | 3 | Endoscopy; submucosal | 18–24 hr before surgery | NA | Laparoscopic DG and TG | D1+ or D2 |
Puccetti et al. [38] | 2022 | Italy | 38:64 | 1, 2 | 0.25 | Endoscopy; submucosal | 12–24 hr before surgery | NA | Laparoscopic TG | D2 |
Tian et al. [39] | 2022 | China | 27:32 | 1, 3 | 5 | Endoscopy; submucosal | 1 day before surgery | NA | Robotic DG | D2 |
Wei et al. [40] | 2022 | China | 107:88 | 1, 2, 3, 4, 5 | 2.5 | Endoscopy; submucosal | 12–24 hr before surgery | Stryker | Laparoscopic DG and TG | D2 |
Yoon et al. [41] | 2022 | Korea | 21:42 | 1, 2 | 0.4 | Endoscopy; submucosal | 1 day before surgery | NA | Laparoscopic DG | D2 |
Sposito et al. [42] | 2023 | Italy | 18 | 1, 2, 3, 4, 5 | 1.25 | Endoscopy; submucosal | 1 day before surgery | Stryker | Laparoscopic DG | D2 |
Chen et al. [43] | 2023 | China | 129:129 | 1, 2, 3, 4, 5 | 1.25 | Endoscopy; submucosal | 1 day before surgery | Stryker | Laparoscopic DG and TG | D2 |
ICG, indocyanine green; NIR, near-infrared; LN, lymph node; NA, not available; DG, distal gastrectomy; TG, total gastrectomy.
a)1, number of retrieved LNs; 2, number of metastatic LNs; 3, complication rate; 4, recurrence rate; 5, overall survival.
An increase in LN yield has been observed with this technique in both laparoscopy and robotic surgery. Chen et al. [19] conducted a randomized controlled trial to compare patients with gastric adenocarcinoma who were randomly assigned to receive either ICG tracer-guided laparoscopic gastrectomy or conventional laparoscopic gastrectomy. The study found that the ICG group had a significantly higher mean number of retrieved LNs and a lower LN noncompliance rate suggesting that ICG with NIR can be used for routine lymphatic mapping during laparoscopic gastrectomy. A prospective study by Kwon et al. [20] assessed the effectiveness of using ICG-NIR during robotic-assisted gastrectomy. The study examined the impact of fluorescent lymphography on LN yield by comparing results from two groups: with and without the use of ICG-NIR. The ICG group showed a significant increase in LN retrieval compared to historical controls, with an average of 48.9 nodes per patient vs. 35.2 nodes (
The clinical implications of ICG-NIR-guided lymphadenectomy were also analyzed in a cohort study of two large randomized controlled trials (FUGES-012 and FUGES-019). Analysis of data from 514 patients revealed an increase of 7.9 LNs per patient in the mean number of retrieved LNs when ICG was used. The ICG group demonstrated a reduced rate of noncompliance with LN detection in comparison to the non-ICG group (31.9% vs. 57.4%). In addition, fluorescence imaging exhibited a sensitivity of 86.8% for detecting all metastatic LN stations, and a negative predictive value of 92.2% for non-fluorescent stations. Diagnostic accuracy was 100% for detecting all metastatic LN stations in D1 and D2 lymphadenectomy for cT1–cT2 disease, regardless of gastrectomy type. The study recommended D1 plus selective fluorescent station-based dissection for patients with cT1–cT2 disease and D2 plus systematic fluorescent imaging-guided LN dissection for cT3–cT4a tumors [28]. Similar results have been documented for patients who underwent neoadjuvant chemotherapy. A retrospective study by Huang et al. [29] that assessed the feasibility, safety, and effectiveness of ICG in this subset of patients also reported a significant increase in the total number of LN dissections and a reduction in noncompliance rates.
A recent systematic review and meta-analysis conducted by Pang et al. [44] assessed the utility of ICG fluorescence lymphography in LN dissection during minimally invasive gastric cancer surgery. The study revealed that the ICG group retrieved a significantly higher number of LNs compared to the control group, without any increase in operative time, estimated blood loss, or postoperative complications. However, it’s worth noting that the analysis did not show a significant difference in the retrieval of metastatic nodes between the two groups stating that adequate removal of metastatic LNs can be achieved without the use of ICG fluorescence lymphography. While ICG fluorescence lymphography may increase the overall number of retrieved LNs, it lacks the specificity required to distinguish metastatic nodes from non-metastatic ones. However, a later study by Park et al. [45], showed that fluorescence guidance not only increased the number of retrieved LNs but also the number of metastatic LNs. Furthermore, their research showed that enhanced LN retrieval improved staging accuracy, resulting in a change in nodal stage distribution. This ‘stage migration effect’ they identified was a significant factor linked to improved survival outcomes, with fluorescence lymphography demonstrating higher overall survival (
The implementation of fluorescence image-guided surgery offers a way to optimize lymphadenectomy and personalize treatment for patients with gastric cancer. By enabling real-time visualization of lymphatic drainage pathways, this approach has the potential to improve the completeness of LN dissection and improve surgical outcomes. Traditional tracers for LN localization rely on physical properties and are not specific to tumors, so researchers are exploring innovative strategies to target tumor cells more successfully such as conjugating fluorophores to agents with a high affinity for specific molecular targets [46]. A 5-aminolevulinic acid tumor-specific tracer and a carcinoembryonic antigen-targeted fluorescent probe have been developed for clinical trials. Nanoparticles utilizing the Arg-Gly-Asp sequence and tumor-specific markers like HER-2 have shown promise in preclinical gastric carcinoma therapy but are still in the development phase [47]. These advancements are anticipated to facilitate greater precision and effectiveness in guiding lymphadenectomy for gastric cancer.
The first application of fluorescence imaging in gastric cancer was centered around the sentinel LN which is the hypothetical initial LN group to receive lymphatic drainage from a primary tumor [48,49]. Dyes, radiocolloids, or the dual method have been conventionally used in sentinel LN mapping. Several systematic reviews and meta-analyses have documented the use of these tracers and their respective disadvantages [50–53]. Dyes have a rapid washout time and exhibit blind sites in dense fat while radiocolloids present poor sensitivity for the detection of LNs near the injection site because of interference by gamma rays emitted from the primary tumor [54–57]. A dual method overcomes the limitations of individual methods, but its implementation necessitates a significantly longer operative time and entails more complex patient preparation [48,58]. In 2001, Hiratsuka et al. [59] proposed the use of ICG as an alternative sentinel LN tracer to address these issues. Their study, which showed a success rate of up to 99% in detecting sentinel LNs, concluded that the use of ICG can accurately predict LN status, especially in patients with T1 gastric cancer.
Skubleny et al. [58] were the first to systematically review and perform a meta-analysis on the diagnostic utility of ICG and NIR fluorescent imaging for sentinel LN surgery exclusively in gastric cancer. The researchers observed 100% specificity and 98% accuracy with the ICG-NIR method. While sensitivity was sub-optimal (87%), studies published since 2010 demonstrated increased sensitivity (93%), suggesting an improvement in technique and technology.
More recently, another meta-analysis including 54 studies, investigated the ability of different sentinel LN techniques to predict the status of LN metastasis. The available methods included blue dye, radiocolloid tracer, ICG, radiocolloid dye, and radiocolloid-ICG combinations. The results of the meta-analysis demonstrated that ICG alone and radiocolloid with ICG had higher identification rates (99% and 98%, respectively) and may be the preferred technique for sentinel LN identification. The authors suggested that given the high costs and potential biohazard of radioactive substances used in dual tracer methods, experienced surgeons should opt for sentinel LN biopsy with ICG alone [60].
ICG is usually administered at injection four sites: proximal, distal, and at both sides of the tumor for sentinel LN navigation. While this method of peritumoral administration is sufficient for most neoplasms, additional injections may be required for larger tumors [61]. Most authors inject ICG submucosal during an endoscopy, but the procedure may be done subserosal. Previous studies have found, however, that lymph travels via the submucosal plexus and communicates freely with the intermuscular and subserosal networks [62,63].
The use of sentinel node navigation surgery in gastric cancer has been a topic of debate due to concerns about its accuracy in intraoperative pathological diagnosis and its potential impact on oncologic safety [64]. False-negative results and unreliability of intraoperative diagnostic methods may compromise the oncologic safety of this technique, emphasizing the need for improved detection methods and further research. Factors that contribute to these results include the complex and multidirectional lymphatic drainage pattern of the stomach and the possibility of skip metastases. Skip metastasis is thought to occur when the structure of lymphatic vessels and nodes is compromised due to obstruction caused by extensive cancerous infiltration, leading to some metastatic LNs not being reached by the tracer [65]. So far, studies have reported false negative rates ranging from 23.5% to 60% [66–69]. Several factors, including tumor stage, location, and the number of detected sentinel nodes, significantly affect detection and false negative rates [66]. Early gastric cancers larger than 4cm are more likely to result in false negatives [68]. In addition, these rates have been demonstrated to progressively increase from T1 to T3 gastric cancer [67]. Tumors located in the lower and lesser curvature of the stomach have a higher incidence of skip metastasis, up to 29% [70,71]. Various techniques have been employed to improve the sensitivity of intraoperative diagnosis and reduce the false negative rate, including complete serial sectioning, immunohistochemistry [72,73], reverse transcription polymerase chain reaction [74,75], and nucleic acid amplification assay [76–78].
An intercontinental Delphi survey was conducted to standardize the use of fluorescence imaging and ICG for sentinel node mapping during gastric cancer surgery. The survey covered several topics, including patient preparation, ICG administration, as well as indications and contraindications. One important outcome of the survey was the consensus that ICG-NIR is a viable single-agent modality for identifying sentinel LNs, and that the sentinel LN basin method is preferred. However, the survey also recommended that sentinel LN dissection be limited to T1 gastric cancers and tumors with a diameter of ≤4 cm [64]. Nevertheless, further research is needed to optimize the technique and establish fluorescence-guided sentinel LN dissection as a viable approach for routine clinical use.
The diminished tactile sense during minimal access surgery can make it difficult to accurately identify the position of a gastric tumor intraoperatively. Additionally, the rise of early gastric cancer diagnosis has made localization even more challenging as these tumors are difficult to see with the naked eye [79]. Various other detection methods for tumor localization include dye or autologous blood tattooing, intraoperative visualization through endoscopy, ultrasonography or gastrofibroscopy, and radio-frequency identification detection clipping [80–85].
Tumor localization via ICG-NIR imaging fluoroscopy has been used to evaluate resection margins and achieve R0 resections. Liu et al. [24] used injection points for lymphography as landmarks to locate early gastric cancer during evaluation of the resection margin in partial gastrectomy. In their study, an endoscopist performed a submucosal injection of 0.5 mL of ICG, diluted to 0.625 mg/mL, at four points around the tumor the day before the procedure. This allowed them to effectively confirm intraoperative surgical margins, demonstrating the advantages of this approach in terms of the quality and safety of surgery.
Ushimaru et al. [30] also conducted a study to determine the feasibility and safety of using ICG fluorescence marking to determine tumor location. The study compared two groups, which were categorized as the ICG or non-ICG groups based on whether they underwent preoperative endoscopic mucosal ICG injection. The ICG group had a shorter operative time, lower estimated blood loss, and significantly shorter postoperative hospital stay. Positive resection margins were confirmed in 6.0% of the non-ICG group, whereas none were found in the ICG group.
Endoscopic application of resin-conjugated ICG marking clips is a promising new technique for visualizing precise tumor localization. Studies by Namikawa et al. [86,87] demonstrated that the fluorescence signal of preoperatively applied marking clips could be visualized on the serosal surface and could clearly indicate the tumor location.
The drawbacks of ICG in tumor localization include concentration-dependent aggregation, weak aqueous stability, rapid elimination, and the absence of target specificity. To address these limitations researchers have incorporated polymeric nanoparticles into ICG dye. These biocompatible and biodegradable nanoparticles have potential applications in tumor diagnosis and targeted imaging due to their strong aqueous stability, excellent NIR optical properties, and significantly improved targeting property
ICG has the potential to facilitate vessel navigation during gastric surgery by enabling the real-time identification of vessels that may have been missed during preoperative work-up. This technology can assist surgeons in determining which vessels can be safely ligated and which must be preserved to prevent morbidity.
Kim et al. [89] conducted a study to assess the feasibility of using ICG fluorescence imaging in identifying the infrapyloric artery (IPA) type, which is critical to the success of a pylorus-preserving laparoscopic or robotic gastrectomy. The study also aimed to determine whether the technique could help identify an accessory splenic artery to minimize inferior splenic infarction after ligation of the left gastroepiploic artery. The authors reported the IPA type was correctly identified in 80% of cases within a procedural time of less than one minute and that the accessory splenic artery was easily identifiable. They suggested that the real-time use of ICG fluorescence imaging could be beneficial for inexperienced surgeons with minimal complexity, potentially reducing operative time, blood loss, and inadvertent injury.
In another study, Lee et al. [90] used ICG and NIR fluorescence imaging to visualize areas perfused by an aberrant left hepatic artery (ALHA) during minimally invasive gastrectomy. The authors applied an endo-clamp to the ALHA near the left hepatic lobe and intravenously administered 5 mg of ICG dissolved in 2 mL of sterile water. Strong, uniform fluorescence excitation on the entire liver surface demonstrated that ALHAs were accessory arteries and could be safely ligated, while an absence of or faint fluorescence indicated ALHAs were replacement arteries critical to hepatic function, thus warranting preservation. In 32% of patients, the artery was safely preserved and in 65% of the patients, fluorescence across the entire liver surface was observed, indicating that the ALHA could be ligated. Ligation of ALHAs guided by NIR fluorescence imaging did not result in significant changes in postoperative liver function indicating that this technique could be beneficial to limiting potential liver-related complications in minimally invasive gastrectomy.
The versatile potential of real-time vessel navigation using ICG and NIR fluorescence imaging can be used to suit the specific needs of individual patients. A case study by Kamada et al. [91] described the application of ICG and NIR fluorescence imaging during robotic-assisted gastrectomy in a patient who had undergone coronary artery bypass grafting to preserve the right gastroepiploic artery graft.
Despite the current lack of large-scale data on the technique’s application for vessel navigation in gastric surgery, its low incidence of adverse effects, easy implementation, and versatility across surgical procedures and patients suggest that further studies may not be necessary.
In the past, surgeons have relied on visual and manual examination for the assessment of anastomotic perfusion, such as evaluating color, bleeding, and pulsation, following an esophagectomy. However, this clinical risk assessment has proven to have a low predictive value for anastomotic leak (AL) in gastrointestinal surgery and may not accurately detect hypoperfusion [92]. The efficacy of ICG-NIR fluorescence imaging in evaluating the anastomosis of the gastric conduit has been the focus of numerous studies [93–98].
However, a recent systematic review and meta-analysis examining patients who underwent esophagectomy with intrathoracic anastomosis found no significant differences in the risk of AL, AL rate, and mortality rate between those who received ICG fluorescence imaging and those who did not. Given the subjective nature of ICG ‘coloration’ assessment, the authors of the study also suggested the need for more objective fluorescence assessment methods [99].
The application of ICG-NIR fluorescence as an evaluation tool for perfusion in gastric cancer surgery, on the other hand, has been limited to only a few studies. Huh et al. [100] conducted a prospective study on 30 patients who underwent various types of gastric surgeries, including distal, total, and pylorus-preserving gastrectomy, to assess anastomotic vascular perfusion using ICG-NIR fluorescence imaging. Each anastomosis was assigned a clinical score using conventional anastomotic evaluation and a fluorescence score based on ICG uptake. Although perfusion status was confirmed in only 76.7% of cases, fluorescence was detected in all patients. The study also documented one patient with leakage that showed reduced focal ICG intensity on fluorescence imaging.
Similarly, Mori et al. [101] conducted a study that examined anastomosis during gastrectomy using ICG-NIR fluorescence. Like the previous study, the authors used fluorescence intensity but included chronological assessment of ICG as parameters. Their findings suggested that weaker fluorescence intensity and a longer ICG fluorescence transit time may serve as useful predictors of AL. While the feasibility of this method was confirmed in both studies, further investigation is required to establish its effectiveness.
ICG-NIR fluorescence angiography has been effective in surgeries where the anastomotic blood supply plays a critical role, such as in esophageal or colorectal resections [92,102]. As a result, there have been more studies evaluating its application in these procedures. In contrast, its utility in gastrectomy is less clear since the blood supply is less of a concern. Nevertheless, this procedure may still serve as a valuable adjunct in the prevention of ALs.
Our review demonstrates that ICG-NIR fluorescence imaging is a safe and versatile technique that enhances gastric cancer surgery. Its ability to precisely guide lymphadenectomy has been the focus of numerous studies. It has had satisfactory results in increasing LN yield, despite the lack of an established standard for its administration. This increase has led to more precise staging and better surgical outcomes, making this application its primary advantage in the field of gastric cancer surgery. Furthermore, because of the shift toward minimally invasive surgery and increasing diagnosis of early gastric cancer, its capacity to identify tumor location and establish resection margins is becoming just as crucial.
Debates about ICG’s oncologic safety and accuracy in detecting sentinel and metastatic LNs are expected to continue unless researchers find an answer for its inability to specifically target cancer cells. Our review suggests that future research could focus on conjugating ICG with tumor-specific markers while reviewing more precise fluorophores to address this issue. As for vessel navigation and anastomosis evaluation, this is where the flexibility of ICG-NIR imaging stands out because it enables individualized treatment to each patient’s unique anatomy or specific case circumstances. Coupled with the evidence that fluorescence imaging can mitigate complications of Clavien-Dindo grade II and higher, this technique is poised to become a standard in gastric cancer surgery.
Authors’ contributions
Conceptualization, Validation, Supervision: YKM
Data curation, Investigation, Visualization, Formal Analysis, Methodology: KAT
Writing–original draft: KAT
Writing–review & editing: YKM
All authors read and approved the final manuscript.
Conflict of interest
All authors have no conflicts of interest to declare.
Funding/support
None.
Data availability
The data presented in this study are available upon reasonable request to the corresponding author.
Journal of Minimally Invasive Surgery 2024; 27(4): 185-197
Published online December 15, 2024 https://doi.org/10.7602/jmis.2024.27.4.185
Copyright © The Korean Society of Endo-Laparoscopic & Robotic Surgery.
Kristoff Armand Tan1,2, Yoo Min Kim1
1Division of Gastrointestinal Surgery, Department of Surgery, Severance Hospital, Seoul, Korea
2Department of Surgery, Chong Hua Hospital, Cebu, Philippines
Correspondence to:Yoo Min Kim
Division of Gastrointestinal Surgery, Department of Surgery, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemungu, Seoul 03722, Korea
E-mail: ymkim@yuhs.ac
https://orcid.org/0000-0002-5176-804X
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
In recent years, indocyanine green (ICG) and near-infrared (NIR) fluorescence-guided surgery has become a versatile and well-researched tool for gastric cancer treatment. Our narrative review aims to explore the applications, benefits, and challenges that are associated with this technique. Initially used to detect sentinel lymph nodes in early gastric cancer, its scope has broadened to include several clinical applications. Its most notable advantages are the ability to guide standard lymphadenectomy, intraoperatively localize tumors and define tumor margins. Despite these advantages, there are still ongoing discussions regarding its accuracy, lack of standardized administration, and oncologic safety in sentinel node navigation surgery. The limited tumor specificity of ICG has been especially put into question, hindering its ability to accurately differentiate between malignant and healthy tissue. With ongoing innovations and its integration into newer endoscopic and robotic systems, ICG-NIR fluorescence imaging shows promise in becoming a standard tool in the surgical treatment of gastric cancer.
Keywords: Indocyanine green, Near-infrared spcetroscopy, Stomach neoplasms, Fluorescence, Gastrectomy
Recent years have witnessed significant progress in the field of gastric cancer surgery, with notable advancements in intraoperative techniques. One such technique is the use of fluorescence image-guided surgery to identify the tumor margins and lymphatic spread. During the procedure, a fluorescent probe is preoperatively or intraoperatively administered, and an external light source then illuminates the tissues as a specialized camera system captures the emitted light, providing valuable optical contrast for precise surgical resection. The optimal wavelengths for this technique are typically in the near-infrared (NIR) region, particularly the first (NIR-I, 700–900 nm) and second (NIR-II, 1,000–1,700 nm) NIR windows [1]. While a variety of fluorescent probes have been employed for fluorescence-guided surgery, indocyanine green (ICG) is one of the most frequently employed NIR fluorophores due to its favorable optical properties, safety profile, and versatility [2]. With the successful integration of fluorescence imaging technology in both laparoscopic and robotic equipment, this technique has since established its place in the treatment of gastric cancer with a wide range of applications.
In this narrative review, we aim to provide a comprehensive overview of the current evidence on the role of NIR imaging with ICG in gastric cancer surgery, as well as identify existing gaps in knowledge that may guide future research efforts.
ICG is a water-soluble, tricarbocyanine dye with a molecular weight of 774.96 g/mol and a normal biological half-time of 2.5 to 3.0 minutes. It is a compound that emits a fluorescent signal when excited by NIR light at a wavelength of approximately 840 nm [3]. Once injected
ICG exhibits a low toxicity with few side effects mainly when doses exceed 0.5 mg/kg, these include shock symptoms, nausea, angialgia, and fever [8]. The safety profile, ease of use, quick detection, and ability to produce high-quality NIR images have made ICG an optimal tracer agent for intraoperative surgical guidance. These advantages have led to the broad adoption of ICG in clinical practice and the development and approval of compatible imaging systems [9]. These devices are capable of alternating between white light view and NIR imaging through a filter switch system thus permitting direct real-time intraoperative visualization of the organ lymphatic or blood flow.
The Novadaq SPY system (Stryker), which was granted U.S. Food and Drug Administration approval in 2005, became the first fluorescence imaging system used for intraoperative procedures. Since then, it has paved the way for a variety of other devices with unique features and capabilities, including fluorescence overlay on reflected light (FLARE, Curadel LLC), ergonomic and portable designs (PDE NEO, Hamamatsu Photonics K.K; Artemis/Quest, Quest Medical Imaging), 3D in 4K quality support (VISERA ELITE II, Olympus; IMAGE1S Rubina, Karl Stortz), multichannel functionality (Quest), and integration with endoscopic, and robotic approaches (Firefly, Intuitive Surgical; Pinpoint, Stryker) [10]. The incorporation of NIR fluorescence technology in current endoscopic and robotic imaging systems is a growing trend, owing to its well-established effectiveness as an intraoperative tool.
ICG-NIR fluorescence imaging has various intraoperative applications in open, endoscopic, and robotic gastric cancer surgery. Initially employed to detect sentinel lymph nodes (LNs) in early gastric cancer, its use has been extended to real-time navigation through tumor localization and perigastric LN mapping [7]. The utilization of this technique aids in determining resection margins, enhancing LN yield, identifying anatomical structures, and clarifying complex vessel anatomy [11]. It even has the capacity to improve the occurrence of postoperative complications (Clavien-Dindo grade II or higher) in gastric cancer surgery patients as evidenced in a 19-study meta-analysis [12]. The evolution and continued research on ICG-NIR fluorescence imaging has come a long way and is expected to further enhance surgical outcomes for gastric cancer patients (Fig. 1).
ICG with NIR imaging is frequently utilized as a guide for lymphadenectomy in gastric cancer [13]. The retrieval of an adequate number of LNs is critical for accurate staging. According to most guidelines, a minimum of 16 regional nodes should be collected for pathologic examination, although some studies suggest it is more desirable to remove 30 or more nodes [14–18]. While multiple studies have shown an increased LN yield with the use of ICG fluorescence imaging, variations in the type of NIR camera, ICG concentration, and injection method across studies [19–27] have led to inconsistencies in the use of ICG to visualize the lymphatic systems (Table 1 [19,20,22–24,27–43]).
Table 1 . Summary of studies on ICG-NIR fluorescence-guided lymphadenectomy.
Study | Year | Country | Sample size (ICG:control) | Endpointsa) | ICG dosage (mg) | Administration route | Administration time | Imaging system | Type of gastrectomy | LN dissection |
---|---|---|---|---|---|---|---|---|---|---|
Lan et al. [31] | 2017 | China | 14:65 | 1, 3 | 6 | Subserosa | During surgery | NA | Robotic DG and TG | D1+ or D2 |
Kwon et al. [20] | 2019 | Korea | 40:40 | 1, 3 | 3 | Endoscopy; submucosal | 1 day before surgery | Firefly | Robotic DG and TG | D1+ or D2 |
Ma et al. [32] | 2019 | China | 38:44 | 1, 2, 3 | 1.25 | Endoscopy; submucosal | 12 hr before surgery | Storz | Laparoscopic DG and TG | D1+ or D2 |
Ushimaru et al. [30] | 2019 | Japan | 84:84 | 1, 3 | 0.1 | Endoscopy; submucosal | 1 day before surgery | Storz | Laparoscopic DG and TG | D1+ or D2 |
Chen et al. [19] | 2020 | China | 129:129 | 1, 2, 3 | 2.5 | Endoscopy; submucosal | 1 day before surgery | Stryker | Laparoscopic DG and TG | D2 |
Cianchi et al. [23] | 2020 | Italy | 37:37 | 1, 2, 3 | 2.5 | Endoscopy; submucosal | 1 day before surgery | Firefly | Laparoscopic DG and TG | D2 |
Jung et al. [27] | 2020 | Korea | 592 | 1, 2 | 1.5 or 3 | Endoscopy; submucosal | 1 day before surgery | Pinpoint or Firefly | Robotic or Laparoscopic PG, DG and TG | D1+ or D2 |
Liu et al. [24] | 2020 | China | 61:75 | 1, 2, 3 | 1.25 | Endoscopy; submucosal | 20–30 hr before surgery | Stryker | Laparoscopic DG | D2 |
Park et al. [33] | 2020 | Korea | 20:60 | 1, 3 | 0.5 | Endoscopy; submucosal | During surgery | Pinpoint | Laparoscopic DG | D1+ or D2 |
Huang et al. [29] | 2021 | China | 94:94 | 1, 3 | 4.5 | Subserosa | During surgery | Stryker | Laparoscopic DG and TG | D2 |
Lu et al. [22] | 2021 | China | 28:28 | 1, 3, 4 | 2.5 | Endoscopy; submucosal | During surgery | Pinpoint | Laparoscopic PG, DG and TG | D2 |
Romanzi et al. [34] | 2021 | Italy | 10:10 | 1 | 3 | Endoscopy; submucosal | 18 hr before surgery | Firefly | Robotic DG | D2 |
Zhong et al. [28] | 2021 | China | 385:129 | 1, 2 | 4.5 | Subserosa | During surgery | Stryker | Laparoscopic DG and TG | D2 |
Chen et al. [35] | 2022 | China | 18:38 | 1, 2, 3 | 1.25 | Endoscopy; submucosal | 1 day before surgery | NA | Laparoscopic PG, DG and TG | D2 |
Lee et al. [36] | 2022 | Korea | 74:94 | 1 3, 4, 5 | 1.5–3.0 | Endoscopy; submucosal | 1 day before surgery | Firefly or Pinpoint | Laparoscopic and Robotic TG | D2 |
Maruri et al. [37] | 2022 | Spain | 17:17 | 1, 2, 4 | 3 | Endoscopy; submucosal | 18–24 hr before surgery | NA | Laparoscopic DG and TG | D1+ or D2 |
Puccetti et al. [38] | 2022 | Italy | 38:64 | 1, 2 | 0.25 | Endoscopy; submucosal | 12–24 hr before surgery | NA | Laparoscopic TG | D2 |
Tian et al. [39] | 2022 | China | 27:32 | 1, 3 | 5 | Endoscopy; submucosal | 1 day before surgery | NA | Robotic DG | D2 |
Wei et al. [40] | 2022 | China | 107:88 | 1, 2, 3, 4, 5 | 2.5 | Endoscopy; submucosal | 12–24 hr before surgery | Stryker | Laparoscopic DG and TG | D2 |
Yoon et al. [41] | 2022 | Korea | 21:42 | 1, 2 | 0.4 | Endoscopy; submucosal | 1 day before surgery | NA | Laparoscopic DG | D2 |
Sposito et al. [42] | 2023 | Italy | 18 | 1, 2, 3, 4, 5 | 1.25 | Endoscopy; submucosal | 1 day before surgery | Stryker | Laparoscopic DG | D2 |
Chen et al. [43] | 2023 | China | 129:129 | 1, 2, 3, 4, 5 | 1.25 | Endoscopy; submucosal | 1 day before surgery | Stryker | Laparoscopic DG and TG | D2 |
ICG, indocyanine green; NIR, near-infrared; LN, lymph node; NA, not available; DG, distal gastrectomy; TG, total gastrectomy..
a)1, number of retrieved LNs; 2, number of metastatic LNs; 3, complication rate; 4, recurrence rate; 5, overall survival..
An increase in LN yield has been observed with this technique in both laparoscopy and robotic surgery. Chen et al. [19] conducted a randomized controlled trial to compare patients with gastric adenocarcinoma who were randomly assigned to receive either ICG tracer-guided laparoscopic gastrectomy or conventional laparoscopic gastrectomy. The study found that the ICG group had a significantly higher mean number of retrieved LNs and a lower LN noncompliance rate suggesting that ICG with NIR can be used for routine lymphatic mapping during laparoscopic gastrectomy. A prospective study by Kwon et al. [20] assessed the effectiveness of using ICG-NIR during robotic-assisted gastrectomy. The study examined the impact of fluorescent lymphography on LN yield by comparing results from two groups: with and without the use of ICG-NIR. The ICG group showed a significant increase in LN retrieval compared to historical controls, with an average of 48.9 nodes per patient vs. 35.2 nodes (
The clinical implications of ICG-NIR-guided lymphadenectomy were also analyzed in a cohort study of two large randomized controlled trials (FUGES-012 and FUGES-019). Analysis of data from 514 patients revealed an increase of 7.9 LNs per patient in the mean number of retrieved LNs when ICG was used. The ICG group demonstrated a reduced rate of noncompliance with LN detection in comparison to the non-ICG group (31.9% vs. 57.4%). In addition, fluorescence imaging exhibited a sensitivity of 86.8% for detecting all metastatic LN stations, and a negative predictive value of 92.2% for non-fluorescent stations. Diagnostic accuracy was 100% for detecting all metastatic LN stations in D1 and D2 lymphadenectomy for cT1–cT2 disease, regardless of gastrectomy type. The study recommended D1 plus selective fluorescent station-based dissection for patients with cT1–cT2 disease and D2 plus systematic fluorescent imaging-guided LN dissection for cT3–cT4a tumors [28]. Similar results have been documented for patients who underwent neoadjuvant chemotherapy. A retrospective study by Huang et al. [29] that assessed the feasibility, safety, and effectiveness of ICG in this subset of patients also reported a significant increase in the total number of LN dissections and a reduction in noncompliance rates.
A recent systematic review and meta-analysis conducted by Pang et al. [44] assessed the utility of ICG fluorescence lymphography in LN dissection during minimally invasive gastric cancer surgery. The study revealed that the ICG group retrieved a significantly higher number of LNs compared to the control group, without any increase in operative time, estimated blood loss, or postoperative complications. However, it’s worth noting that the analysis did not show a significant difference in the retrieval of metastatic nodes between the two groups stating that adequate removal of metastatic LNs can be achieved without the use of ICG fluorescence lymphography. While ICG fluorescence lymphography may increase the overall number of retrieved LNs, it lacks the specificity required to distinguish metastatic nodes from non-metastatic ones. However, a later study by Park et al. [45], showed that fluorescence guidance not only increased the number of retrieved LNs but also the number of metastatic LNs. Furthermore, their research showed that enhanced LN retrieval improved staging accuracy, resulting in a change in nodal stage distribution. This ‘stage migration effect’ they identified was a significant factor linked to improved survival outcomes, with fluorescence lymphography demonstrating higher overall survival (
The implementation of fluorescence image-guided surgery offers a way to optimize lymphadenectomy and personalize treatment for patients with gastric cancer. By enabling real-time visualization of lymphatic drainage pathways, this approach has the potential to improve the completeness of LN dissection and improve surgical outcomes. Traditional tracers for LN localization rely on physical properties and are not specific to tumors, so researchers are exploring innovative strategies to target tumor cells more successfully such as conjugating fluorophores to agents with a high affinity for specific molecular targets [46]. A 5-aminolevulinic acid tumor-specific tracer and a carcinoembryonic antigen-targeted fluorescent probe have been developed for clinical trials. Nanoparticles utilizing the Arg-Gly-Asp sequence and tumor-specific markers like HER-2 have shown promise in preclinical gastric carcinoma therapy but are still in the development phase [47]. These advancements are anticipated to facilitate greater precision and effectiveness in guiding lymphadenectomy for gastric cancer.
The first application of fluorescence imaging in gastric cancer was centered around the sentinel LN which is the hypothetical initial LN group to receive lymphatic drainage from a primary tumor [48,49]. Dyes, radiocolloids, or the dual method have been conventionally used in sentinel LN mapping. Several systematic reviews and meta-analyses have documented the use of these tracers and their respective disadvantages [50–53]. Dyes have a rapid washout time and exhibit blind sites in dense fat while radiocolloids present poor sensitivity for the detection of LNs near the injection site because of interference by gamma rays emitted from the primary tumor [54–57]. A dual method overcomes the limitations of individual methods, but its implementation necessitates a significantly longer operative time and entails more complex patient preparation [48,58]. In 2001, Hiratsuka et al. [59] proposed the use of ICG as an alternative sentinel LN tracer to address these issues. Their study, which showed a success rate of up to 99% in detecting sentinel LNs, concluded that the use of ICG can accurately predict LN status, especially in patients with T1 gastric cancer.
Skubleny et al. [58] were the first to systematically review and perform a meta-analysis on the diagnostic utility of ICG and NIR fluorescent imaging for sentinel LN surgery exclusively in gastric cancer. The researchers observed 100% specificity and 98% accuracy with the ICG-NIR method. While sensitivity was sub-optimal (87%), studies published since 2010 demonstrated increased sensitivity (93%), suggesting an improvement in technique and technology.
More recently, another meta-analysis including 54 studies, investigated the ability of different sentinel LN techniques to predict the status of LN metastasis. The available methods included blue dye, radiocolloid tracer, ICG, radiocolloid dye, and radiocolloid-ICG combinations. The results of the meta-analysis demonstrated that ICG alone and radiocolloid with ICG had higher identification rates (99% and 98%, respectively) and may be the preferred technique for sentinel LN identification. The authors suggested that given the high costs and potential biohazard of radioactive substances used in dual tracer methods, experienced surgeons should opt for sentinel LN biopsy with ICG alone [60].
ICG is usually administered at injection four sites: proximal, distal, and at both sides of the tumor for sentinel LN navigation. While this method of peritumoral administration is sufficient for most neoplasms, additional injections may be required for larger tumors [61]. Most authors inject ICG submucosal during an endoscopy, but the procedure may be done subserosal. Previous studies have found, however, that lymph travels via the submucosal plexus and communicates freely with the intermuscular and subserosal networks [62,63].
The use of sentinel node navigation surgery in gastric cancer has been a topic of debate due to concerns about its accuracy in intraoperative pathological diagnosis and its potential impact on oncologic safety [64]. False-negative results and unreliability of intraoperative diagnostic methods may compromise the oncologic safety of this technique, emphasizing the need for improved detection methods and further research. Factors that contribute to these results include the complex and multidirectional lymphatic drainage pattern of the stomach and the possibility of skip metastases. Skip metastasis is thought to occur when the structure of lymphatic vessels and nodes is compromised due to obstruction caused by extensive cancerous infiltration, leading to some metastatic LNs not being reached by the tracer [65]. So far, studies have reported false negative rates ranging from 23.5% to 60% [66–69]. Several factors, including tumor stage, location, and the number of detected sentinel nodes, significantly affect detection and false negative rates [66]. Early gastric cancers larger than 4cm are more likely to result in false negatives [68]. In addition, these rates have been demonstrated to progressively increase from T1 to T3 gastric cancer [67]. Tumors located in the lower and lesser curvature of the stomach have a higher incidence of skip metastasis, up to 29% [70,71]. Various techniques have been employed to improve the sensitivity of intraoperative diagnosis and reduce the false negative rate, including complete serial sectioning, immunohistochemistry [72,73], reverse transcription polymerase chain reaction [74,75], and nucleic acid amplification assay [76–78].
An intercontinental Delphi survey was conducted to standardize the use of fluorescence imaging and ICG for sentinel node mapping during gastric cancer surgery. The survey covered several topics, including patient preparation, ICG administration, as well as indications and contraindications. One important outcome of the survey was the consensus that ICG-NIR is a viable single-agent modality for identifying sentinel LNs, and that the sentinel LN basin method is preferred. However, the survey also recommended that sentinel LN dissection be limited to T1 gastric cancers and tumors with a diameter of ≤4 cm [64]. Nevertheless, further research is needed to optimize the technique and establish fluorescence-guided sentinel LN dissection as a viable approach for routine clinical use.
The diminished tactile sense during minimal access surgery can make it difficult to accurately identify the position of a gastric tumor intraoperatively. Additionally, the rise of early gastric cancer diagnosis has made localization even more challenging as these tumors are difficult to see with the naked eye [79]. Various other detection methods for tumor localization include dye or autologous blood tattooing, intraoperative visualization through endoscopy, ultrasonography or gastrofibroscopy, and radio-frequency identification detection clipping [80–85].
Tumor localization via ICG-NIR imaging fluoroscopy has been used to evaluate resection margins and achieve R0 resections. Liu et al. [24] used injection points for lymphography as landmarks to locate early gastric cancer during evaluation of the resection margin in partial gastrectomy. In their study, an endoscopist performed a submucosal injection of 0.5 mL of ICG, diluted to 0.625 mg/mL, at four points around the tumor the day before the procedure. This allowed them to effectively confirm intraoperative surgical margins, demonstrating the advantages of this approach in terms of the quality and safety of surgery.
Ushimaru et al. [30] also conducted a study to determine the feasibility and safety of using ICG fluorescence marking to determine tumor location. The study compared two groups, which were categorized as the ICG or non-ICG groups based on whether they underwent preoperative endoscopic mucosal ICG injection. The ICG group had a shorter operative time, lower estimated blood loss, and significantly shorter postoperative hospital stay. Positive resection margins were confirmed in 6.0% of the non-ICG group, whereas none were found in the ICG group.
Endoscopic application of resin-conjugated ICG marking clips is a promising new technique for visualizing precise tumor localization. Studies by Namikawa et al. [86,87] demonstrated that the fluorescence signal of preoperatively applied marking clips could be visualized on the serosal surface and could clearly indicate the tumor location.
The drawbacks of ICG in tumor localization include concentration-dependent aggregation, weak aqueous stability, rapid elimination, and the absence of target specificity. To address these limitations researchers have incorporated polymeric nanoparticles into ICG dye. These biocompatible and biodegradable nanoparticles have potential applications in tumor diagnosis and targeted imaging due to their strong aqueous stability, excellent NIR optical properties, and significantly improved targeting property
ICG has the potential to facilitate vessel navigation during gastric surgery by enabling the real-time identification of vessels that may have been missed during preoperative work-up. This technology can assist surgeons in determining which vessels can be safely ligated and which must be preserved to prevent morbidity.
Kim et al. [89] conducted a study to assess the feasibility of using ICG fluorescence imaging in identifying the infrapyloric artery (IPA) type, which is critical to the success of a pylorus-preserving laparoscopic or robotic gastrectomy. The study also aimed to determine whether the technique could help identify an accessory splenic artery to minimize inferior splenic infarction after ligation of the left gastroepiploic artery. The authors reported the IPA type was correctly identified in 80% of cases within a procedural time of less than one minute and that the accessory splenic artery was easily identifiable. They suggested that the real-time use of ICG fluorescence imaging could be beneficial for inexperienced surgeons with minimal complexity, potentially reducing operative time, blood loss, and inadvertent injury.
In another study, Lee et al. [90] used ICG and NIR fluorescence imaging to visualize areas perfused by an aberrant left hepatic artery (ALHA) during minimally invasive gastrectomy. The authors applied an endo-clamp to the ALHA near the left hepatic lobe and intravenously administered 5 mg of ICG dissolved in 2 mL of sterile water. Strong, uniform fluorescence excitation on the entire liver surface demonstrated that ALHAs were accessory arteries and could be safely ligated, while an absence of or faint fluorescence indicated ALHAs were replacement arteries critical to hepatic function, thus warranting preservation. In 32% of patients, the artery was safely preserved and in 65% of the patients, fluorescence across the entire liver surface was observed, indicating that the ALHA could be ligated. Ligation of ALHAs guided by NIR fluorescence imaging did not result in significant changes in postoperative liver function indicating that this technique could be beneficial to limiting potential liver-related complications in minimally invasive gastrectomy.
The versatile potential of real-time vessel navigation using ICG and NIR fluorescence imaging can be used to suit the specific needs of individual patients. A case study by Kamada et al. [91] described the application of ICG and NIR fluorescence imaging during robotic-assisted gastrectomy in a patient who had undergone coronary artery bypass grafting to preserve the right gastroepiploic artery graft.
Despite the current lack of large-scale data on the technique’s application for vessel navigation in gastric surgery, its low incidence of adverse effects, easy implementation, and versatility across surgical procedures and patients suggest that further studies may not be necessary.
In the past, surgeons have relied on visual and manual examination for the assessment of anastomotic perfusion, such as evaluating color, bleeding, and pulsation, following an esophagectomy. However, this clinical risk assessment has proven to have a low predictive value for anastomotic leak (AL) in gastrointestinal surgery and may not accurately detect hypoperfusion [92]. The efficacy of ICG-NIR fluorescence imaging in evaluating the anastomosis of the gastric conduit has been the focus of numerous studies [93–98].
However, a recent systematic review and meta-analysis examining patients who underwent esophagectomy with intrathoracic anastomosis found no significant differences in the risk of AL, AL rate, and mortality rate between those who received ICG fluorescence imaging and those who did not. Given the subjective nature of ICG ‘coloration’ assessment, the authors of the study also suggested the need for more objective fluorescence assessment methods [99].
The application of ICG-NIR fluorescence as an evaluation tool for perfusion in gastric cancer surgery, on the other hand, has been limited to only a few studies. Huh et al. [100] conducted a prospective study on 30 patients who underwent various types of gastric surgeries, including distal, total, and pylorus-preserving gastrectomy, to assess anastomotic vascular perfusion using ICG-NIR fluorescence imaging. Each anastomosis was assigned a clinical score using conventional anastomotic evaluation and a fluorescence score based on ICG uptake. Although perfusion status was confirmed in only 76.7% of cases, fluorescence was detected in all patients. The study also documented one patient with leakage that showed reduced focal ICG intensity on fluorescence imaging.
Similarly, Mori et al. [101] conducted a study that examined anastomosis during gastrectomy using ICG-NIR fluorescence. Like the previous study, the authors used fluorescence intensity but included chronological assessment of ICG as parameters. Their findings suggested that weaker fluorescence intensity and a longer ICG fluorescence transit time may serve as useful predictors of AL. While the feasibility of this method was confirmed in both studies, further investigation is required to establish its effectiveness.
ICG-NIR fluorescence angiography has been effective in surgeries where the anastomotic blood supply plays a critical role, such as in esophageal or colorectal resections [92,102]. As a result, there have been more studies evaluating its application in these procedures. In contrast, its utility in gastrectomy is less clear since the blood supply is less of a concern. Nevertheless, this procedure may still serve as a valuable adjunct in the prevention of ALs.
Our review demonstrates that ICG-NIR fluorescence imaging is a safe and versatile technique that enhances gastric cancer surgery. Its ability to precisely guide lymphadenectomy has been the focus of numerous studies. It has had satisfactory results in increasing LN yield, despite the lack of an established standard for its administration. This increase has led to more precise staging and better surgical outcomes, making this application its primary advantage in the field of gastric cancer surgery. Furthermore, because of the shift toward minimally invasive surgery and increasing diagnosis of early gastric cancer, its capacity to identify tumor location and establish resection margins is becoming just as crucial.
Debates about ICG’s oncologic safety and accuracy in detecting sentinel and metastatic LNs are expected to continue unless researchers find an answer for its inability to specifically target cancer cells. Our review suggests that future research could focus on conjugating ICG with tumor-specific markers while reviewing more precise fluorophores to address this issue. As for vessel navigation and anastomosis evaluation, this is where the flexibility of ICG-NIR imaging stands out because it enables individualized treatment to each patient’s unique anatomy or specific case circumstances. Coupled with the evidence that fluorescence imaging can mitigate complications of Clavien-Dindo grade II and higher, this technique is poised to become a standard in gastric cancer surgery.
Authors’ contributions
Conceptualization, Validation, Supervision: YKM
Data curation, Investigation, Visualization, Formal Analysis, Methodology: KAT
Writing–original draft: KAT
Writing–review & editing: YKM
All authors read and approved the final manuscript.
Conflict of interest
All authors have no conflicts of interest to declare.
Funding/support
None.
Data availability
The data presented in this study are available upon reasonable request to the corresponding author.
Table 1 . Summary of studies on ICG-NIR fluorescence-guided lymphadenectomy.
Study | Year | Country | Sample size (ICG:control) | Endpointsa) | ICG dosage (mg) | Administration route | Administration time | Imaging system | Type of gastrectomy | LN dissection |
---|---|---|---|---|---|---|---|---|---|---|
Lan et al. [31] | 2017 | China | 14:65 | 1, 3 | 6 | Subserosa | During surgery | NA | Robotic DG and TG | D1+ or D2 |
Kwon et al. [20] | 2019 | Korea | 40:40 | 1, 3 | 3 | Endoscopy; submucosal | 1 day before surgery | Firefly | Robotic DG and TG | D1+ or D2 |
Ma et al. [32] | 2019 | China | 38:44 | 1, 2, 3 | 1.25 | Endoscopy; submucosal | 12 hr before surgery | Storz | Laparoscopic DG and TG | D1+ or D2 |
Ushimaru et al. [30] | 2019 | Japan | 84:84 | 1, 3 | 0.1 | Endoscopy; submucosal | 1 day before surgery | Storz | Laparoscopic DG and TG | D1+ or D2 |
Chen et al. [19] | 2020 | China | 129:129 | 1, 2, 3 | 2.5 | Endoscopy; submucosal | 1 day before surgery | Stryker | Laparoscopic DG and TG | D2 |
Cianchi et al. [23] | 2020 | Italy | 37:37 | 1, 2, 3 | 2.5 | Endoscopy; submucosal | 1 day before surgery | Firefly | Laparoscopic DG and TG | D2 |
Jung et al. [27] | 2020 | Korea | 592 | 1, 2 | 1.5 or 3 | Endoscopy; submucosal | 1 day before surgery | Pinpoint or Firefly | Robotic or Laparoscopic PG, DG and TG | D1+ or D2 |
Liu et al. [24] | 2020 | China | 61:75 | 1, 2, 3 | 1.25 | Endoscopy; submucosal | 20–30 hr before surgery | Stryker | Laparoscopic DG | D2 |
Park et al. [33] | 2020 | Korea | 20:60 | 1, 3 | 0.5 | Endoscopy; submucosal | During surgery | Pinpoint | Laparoscopic DG | D1+ or D2 |
Huang et al. [29] | 2021 | China | 94:94 | 1, 3 | 4.5 | Subserosa | During surgery | Stryker | Laparoscopic DG and TG | D2 |
Lu et al. [22] | 2021 | China | 28:28 | 1, 3, 4 | 2.5 | Endoscopy; submucosal | During surgery | Pinpoint | Laparoscopic PG, DG and TG | D2 |
Romanzi et al. [34] | 2021 | Italy | 10:10 | 1 | 3 | Endoscopy; submucosal | 18 hr before surgery | Firefly | Robotic DG | D2 |
Zhong et al. [28] | 2021 | China | 385:129 | 1, 2 | 4.5 | Subserosa | During surgery | Stryker | Laparoscopic DG and TG | D2 |
Chen et al. [35] | 2022 | China | 18:38 | 1, 2, 3 | 1.25 | Endoscopy; submucosal | 1 day before surgery | NA | Laparoscopic PG, DG and TG | D2 |
Lee et al. [36] | 2022 | Korea | 74:94 | 1 3, 4, 5 | 1.5–3.0 | Endoscopy; submucosal | 1 day before surgery | Firefly or Pinpoint | Laparoscopic and Robotic TG | D2 |
Maruri et al. [37] | 2022 | Spain | 17:17 | 1, 2, 4 | 3 | Endoscopy; submucosal | 18–24 hr before surgery | NA | Laparoscopic DG and TG | D1+ or D2 |
Puccetti et al. [38] | 2022 | Italy | 38:64 | 1, 2 | 0.25 | Endoscopy; submucosal | 12–24 hr before surgery | NA | Laparoscopic TG | D2 |
Tian et al. [39] | 2022 | China | 27:32 | 1, 3 | 5 | Endoscopy; submucosal | 1 day before surgery | NA | Robotic DG | D2 |
Wei et al. [40] | 2022 | China | 107:88 | 1, 2, 3, 4, 5 | 2.5 | Endoscopy; submucosal | 12–24 hr before surgery | Stryker | Laparoscopic DG and TG | D2 |
Yoon et al. [41] | 2022 | Korea | 21:42 | 1, 2 | 0.4 | Endoscopy; submucosal | 1 day before surgery | NA | Laparoscopic DG | D2 |
Sposito et al. [42] | 2023 | Italy | 18 | 1, 2, 3, 4, 5 | 1.25 | Endoscopy; submucosal | 1 day before surgery | Stryker | Laparoscopic DG | D2 |
Chen et al. [43] | 2023 | China | 129:129 | 1, 2, 3, 4, 5 | 1.25 | Endoscopy; submucosal | 1 day before surgery | Stryker | Laparoscopic DG and TG | D2 |
ICG, indocyanine green; NIR, near-infrared; LN, lymph node; NA, not available; DG, distal gastrectomy; TG, total gastrectomy..
a)1, number of retrieved LNs; 2, number of metastatic LNs; 3, complication rate; 4, recurrence rate; 5, overall survival..
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