Sentinel lymph node detection for gastric cancer: Promise or pitfall?

Journal Pre-proof Sentinel lymph node detection for gastric cancer: promise or pitfall?

Jingtao Wei, Zhaode Bu PII:

S0960-7404(19)30393-7

DOI:

https://doi.org/10.1016/j.suronc.2019.12.005

Reference:

SO 1312

To appear in:

Surgical Oncology

Received Date:

14 August 2019

Accepted Date:

18 December 2019

Please cite this article as: Jingtao Wei, Zhaode Bu, Sentinel lymph node detection for gastric cancer: promise or pitfall?, Surgical Oncology (2019), https://doi.org/10.1016/j.suronc.2019.12.005

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Journal Pre-proof Sentinel lymph node detection for gastric cancer: promise or pitfall？ Authors: Jingtao Wei1, Zhaode Bu1 Author’s addresses: 1.Department of gastrointestinal surgery, Peking University Cancer Hospital and Institute, Beijing, 100142, China. Corresponding author: Zhaode Bu Department of gastrointestinal surgery, Peking University Cancer Hospital and Institute, Haidian District Fuchengmen Road No. 52, Beijing, 100142, China. E-mail: [email protected]

Journal Pre-proof Abstract At present, optimal surgery for gastric cancer is still under debate, especially the extent of lymph node dissection. Gastrectomy with D1/D2 lymphadenectomy is standard treatment for resectable advanced gastric cancer. However, in early gastric cancer without lymph node metastasis, gastrectomy with D1/D2 lymphadenectomy may not be unnecessary, which could increases morbidity and mortality and reduces the quality of life (QOL). Therefore, the concept of sentinel lymph node could be applied in gastric cancer. But due to the complexity of gastric lymphatic drainage, there are still many issues under debate, such as suitable tracers, the method of mapping and collecting and the oncologic safety of sentinel node navigation surgery (SNNS). In addition, skip metastasis and unreliability of intraoperative pathological diagnosis are two main reasons for false negative cases. In this review, we summarize the current status and controversy of sentinel lymph node detection in gastric cancer, attempting to help with practical application. Further, we hold opinion that we should be cautious about performing sentinel lymph node detection in gastric cancer before an accurate and effective method occurs. Keywords: sentinel lymph node; gastric cancer 1.Introduction At present, the treatment of gastric cancer is still a comprehensive therapy based on surgery. But the optimal surgery for gastric cancer is still under debate, especially the extent of lymph node dissection. However, the long-term follow-up results of the Dutch trial showed that the recurrence rate of patients after D2 lymphadenectomy was significantly lower than that of patients after D1 lymphadenectomy, which established the status of D2 lymphadenectomy in the treatment of resectable advanced gastric cancer (1). It has been reported that the lymph node metastasis rate of early gastric cancer is 2-20% (2). In other words, for most early gastric cancer patients without lymph node metastasis, D2 lymphadenectomy is too aggressive and cannot benefit

Journal Pre-proof patients while increasing the risk of surgery. Therefore, Japanese gastric cancer guidelines recommend a small lymph node dissection (D1/D1+) for early gastric cancer patients (3). Moreover, the concept of sentinel lymph node was gradually applied in gastric cancer in order to acquire more accurate preoperative diagnosis of lymph node status, avoid such excessive surgical treatment, carry out more accurate and individualized treatment. The sentinel lymph node (SLN) is defined as the first stage to receive lymphatic drainage from the primary tumor and also the first site of lymphatic metastasis. The status of sentinel lymph node can reflect the status of the remaining lymph nodes, which means if the sentinel lymph node is not infiltrated by metastasized malignant cells , there will be no metastasis of regional lymph node. In 1960, Gould et al. first described sentinel lymph nodes (sentinel node) in parotid tumors (4). In 1992, Morton et al. first advocated the concept of sentinel lymph node and applied it to melanoma (5). Moreover, SLN biopsy plays an important role in the treatment of melanoma and breast cancer. The application of the concept of SLN in gastric cancer began in the 21st century (68). In 1999, Palaia et al. had reported that sentinel lymph node biopsy using patent blue as a tracer in patients with T1-T2 gastric cancer was feasible procedure (6). In 2001, Hiratsuka et al. successfully performed sentinel lymph node biopsy with indocyanine green (ICG) in patients with gastric cancer, and then evaluated its accuracy of predicting lymph node metastasis, and achieved good sensitivity in patients with T1 gastric cancer (8). In 2002, Kitagawa et al. applied radioisotopes (99mTc-tin colloid) to sentinel lymph node detection for gastric cancer (9). The presence or absence of metastases in sentinel lymph node was proposed from the 6th edition of American Joint Committee on Cancer (AJCC) TNM Staging Classification for Carcinoma of the Stomach and the 14th edition of Japanese classification of gastric carcinoma (10). But there are still many issues under debate over application of sentinel lymph node concept in gastric cancer. 2. How to identify sentinel lymph nodes？

Journal Pre-proof First of all, sentinel node mapping requires a suitable tracer. Dye and radioisotope (RI) are two categories of commonly used tracers, both having advantages and disadvantages in the detection of sentinel lymph nodes for gastric cancer. In the radioisotope method, 99mTc-phytate, 99mTc-tin colloid, 99mTc sulfur colloid and 99mTc antimony sulfur colloid are commonly applied as a tracer (11-13). Since the half-life of 99mTc is approximately 6 h and radioisotope migrates into the SLNs within 2 h and remains there for more than 20h, the 99mTc RI tracer is usually injected into the submucosa around the lesion 1 day before surgery, and a gamma ray detector is used to detect the radioactivity of the lymph nodes during surgery (13, 14). The advantages of RI tracers are objective measurable intensity of radioactivity and the detection of SLNs even in thick intraperitoneal adipose tissues as well as the retention time within lymph nodes is relatively long. However, high cost, need for radiation protection and sophisticated instruments for detection limit their application. In addition, radioactive colloid exhibit a shine‐through effect during detection of hot nodes, thereby affecting sentinel lymph node detection around the tumor (15). On the contrary, indocyanine green (ICG), patent blue (PB) and isosulfide blue (IB) are commonly used as dye tracers (11-13). And some researchers still used classic methylene blue dye to identify sentinel lymph node in early and advanced gastric cancer (16, 17). Compared to radioisotopes, dyes have good visibility, cost effectiveness and safety. Besides, the ability of detecting both the lymphatic vessels and the lymph nodes permits an accurate visualization of the lymphatic drainage pattern of tumor. However, the dye method is not suitable for obese patients. The dense adipose tissue affects the detection rate of sentinel lymph nodes, which would cause a high false-negative rate (18, 19). On the side, ICG is less visually recognizable by the naked eye than other blue dyes (20). Furthermore, the above two types of tracers have the problem of migration to secondary lymph nodes, so the researchers developed novel tracers, such as adsorbing the nanocolloid to ICG (21). The adsorption of nanocolloid to ICG increases its

Journal Pre-proof hydrodynamic diameter, and therefore, prevents the agent from migrating to second‐tier lymph nodes (22). And other similar novel tracers that have fluorescence and colloid particle characteristics have been used in other cancer or animal models (23-26). In terms of validity, Cardoso et al. reported a systematic review evaluating the accuracy of SLN biopsy for gastric cancer showing that the detection rate, the calculated sensitivity and the calculated accuracy for dye method and radioisotope method were similar (91.5%-100% vs. 84.4%-98.5%, 40.0%-100% vs. 50.0%-100%, 72.0%-100% vs. 71.4%-100%, respectively) (27). The calculated false-negative rate (FNR) of the dye method was 34.7%, while the overall FNR of the radioisotope method was 18.5% (27). Moreover, the detection rate, the calculated sensitivity and the calculated accuracy for the dual method (both dye and radioisotope) were 54.8%-98.5%, 66.7%-100%, 90.0%-100%, respectively (27). The use of dual-tracer for identifying SLN may yield a lower FNR (13%) than either method alone, although statistical significance was not met (27). And a related meta-analysis that included 2128 patients also demonstrated that the diagnostic value of dye and radioactive isotope were similar (28). When considering the type of tracers used, dye alone got a pooled identification rate, sensitivity, accuracy and FNR of 92.1%, 72.7%, 90.1% and 27.3%, respectively, while radioactive isotope alone were 92.1%, 76.4%, 90.8% and 23.6%, respectively. Compared with dye and RI subgroups, the pooled sensitivity, negative predictive value and accuracy of dual subgroup(combine) were higher (28). At present, neither dye nor radioactive isotope alone seems to be accurate enough. Therefore, the dual tracer method is considered to be the most reliable procedure for detection of sentinel lymph node in patients with early gastric cancer and has been used in related randomized controlled trials (29). Recently, Ling et al. reported a systematic review that evaluated diagnostic performance of dual-tracer-guided SLN biopsy for gastric cancer. The results of their meta-analysis, which included 1663 patients, demonstrated that the pooled SLN identification rate and sensitivity were 97% and 89%, respectively. In the subgroup analysis, the pooled sensitivity of the 99mTc-human serum albumin and ICG

Journal Pre-proof subgroup and the 99mTc-antimony sulfur colloid and ICG subgroup were the highest (30). In order to overcome the shortcomings of dyes, the researchers attempted to use new imaging techniques, including infrared imaging and fluorescence imaging, to improve the detection rate and sensitivity of sentinel lymph node mapping using ICG. Infrared light has a wavelength of around 805nm and can penetrate adipose tissue up to a depth from 3 to 5 mm (31). In 2004, Nimura et al. first used Infrared ray electronic endoscopy (IREE) with ICG to detect sentinel lymph nodes in gastric cancer, showing a good detection rate and sensitivity (32). In this study, 84 patients with cT1-2N0 gastric cancer were enrolled, 11 of whom were confirmed with lymph node metastases. All patients with lymph node metastases could be detected by IREE with ICG, but 4 of them could not be detected by ICG alone. Kelder et al. used IREE with ICG in sentinel lymph node navigation surgery (SNNS) for 212 gastric cancer patients. The results showed that the SLN detection rate was 99.5% and the sensitivity was 97%, which was significantly better than ICG alone (33). ICG has a maximum absorption wavelength of 805 nm and emits a maximum fluorescence wavelength of 830 nm after absorbing the light. However, compared to the reflected light, the intensity of fluorescence is extremely weak. The fluorescence imaging system filters out the reflected light and then receives the light near the maximum fluorescence wavelength (10). In 2006, Soltesz et al. first used near infrared fluorescence imaging (NIFI) to detect SLNs of the gastrointestinal tract in an animal model (34). And then, Kusano et al. performed sentinel node mapping guided by indocyanine green fluorescence imaging for the first time in patients with gastric cancer, but it is necessary to maintain a dark environment during the mapping

procedure (35).

Therefore, in order to get visualization of high-definition images under conventional white light, researchers have developed new types of fluorescence imaging system, such as D-light P System, Hyper Eye Medical System and PINPOINT endoscopic fluorescence imaging System (15, 21, 36-38). Many clinical studies have demonstrated

Journal Pre-proof the safety and feasibility of fluorescence imaging, with the SLN detection rate ranging from 90.9% to 100% and the sensitivity ranging from 90.1% to 100%(15, 35, 39-41). Skubleny et al. reported a systematic review that evaluated the diagnostic utility of SLN biopsy using ICG and infrared or fluorescent imaging in gastric cancer. The pooled identification rate, diagnostic odds ratio, sensitivity and accuracy of using ICG and IREE/NIFI were 99%, 380.0, 87%, 98.3%, respectively. Further analysis showed that IREE had a higher detection rate, diagnostic odds ratio and sensitivity than NIFI (42). Another systematic review comparing infrared and fluorescence imaging, included 971 patients, also indicated that infrared imaging was more sensitive than fluorescence imaging (98% vs 70%), and diluted indocyanine green showed higher sensitivity (26). As for the injection method of tracers, most researchers considered that there was no significant difference between submucosal injection and subserosal injection (4345). On the contrary, some researchers found in the systematic review that the sensitivity of submucosal injection was higher (26, 28, 42). Furthermore, it is difficult to recognize the early gastric cancer on the serosal surface, so the majority of studies inject tracers submucosally. 3. What are the main obstacles to sentinel lymph node detection? False negative cases are a particular concern during sentinel lymph node detection for gastric cancer. At present, there are two main reasons for false negative cases. Firstly, the tracer may not enter some metastatic lymph nodes. It is known that the lymphatic drainage pattern of the stomach is complex and multidirectional. In addition, in some cases, the structure of lymphatic vessels and lymph nodes is destroyed due to metastasis. Therefore, skip metastasis occurs in gastric cancer. It had been reported that among the patients with lymph node metastases, the incidence of skip metastases was up to 11%, while among the patients with early gastric cancer, the proportion was about 2.8%. And the most of patients with skip metastases had metastatic lymph nodes at No.

Journal Pre-proof 7, 8, and 9 stations (46). Skip metastasis and multidirectional lymphatic drainage could be related to tumor size, tumor location and other factors. Relevant studies manifested that the risk of skip metastasis and multidirectional lymphatic drainage increased with the maxim tumor diameter, especially when the tumor size of early gastric cancer was greater than 4cm (46, 47). Therefore, the indications of the ongoing SENORITA study were patients with early gastric cancer less than 3cm (48). Studies had also shown that the incidence of skip metastasis was higher, up to 29%, when the tumors were located in the lower and lesser curvature of the stomach (47, 49). And the association between tumor differentiation and skip metastasis was inconsistent (46, 50). Further study found that non-SN metastasis without SN involvement were encountered in up to 3.4% of patients with cT1-2N0 gastric cancer (48). In addition, most of these non-sentinel lymph node metastases missed by SLN biopsy were located in the same lymphatic basin (48, 51). In 2003, Miwa et al. first proposed the concept of sentinel basin dissection (SBD). According to the direction of lymphatic drainage, the gastric lymphatic compartments were divided into five regions: left gastric artery basin, right gastric artery basin, left gastroepiploic artery basin, right gastroepiploic artery basin and posterior gastric artery basin (52). In general, there are two method of collecting labeled sentinel lymph nodes including pick-up method and sentinel basin dissection. The picked-up method implies the removal of the labeled SLNs only, while sentinel basin dissection implies the en bloc dissection of the basins including labeled SLNs and lymphatic vessels. Because of skip metastasis, pick-up method may result in a high false negative rate. Many studies have also compared the effectiveness of the two approaches, and the results show that sentinel basin dissection can significantly improve the sensitivity of sentinel lymph node detection compared with biopsy, from 50-54.8% to 92.3-96% (48). But there are some practical difficulties concerning SBD. Firstly, more than half of patients have two or three sentinel basins (52, 53). In these patients, SBD approximated to D1 lymph node dissection, and minimal gastric resection might not possible due to lack of blood supply. Secondly, SBD increases the number of lymph nodes that require intraoperative

Journal Pre-proof pathological examination, which prolongs operation time. Secondly, the unreliability of intraoperative diagnostic methods is another major cause of false positive cases. In order to determine whether the sentinel lymph node metastasizes, we need to establish an accurate and rapid intraoperative diagnostic method. In most of the previous studies, sentinel lymph node were evaluated intraoperatively by frozen section with HE staining, but even under the optimal conditions, the sensitivity was only about 85%, and 15-20% of metastases could not be diagnosed intraoperatively, and the false negative rate was between 11.1% and 53.8% (48, 54). The multi-center prospective study JCOG0302 conducted in Japan was also discontinued due to the high false negative rate, and further analysis suggested that the unreliability of intraoperative single-plane frozen section was one of the main reasons (55). Therefore, Multistep level sections (56), immunohistochemistry (41, 57), reverse transcription polymerase chain reaction (RT-PCR) (58-60), and the one-step nucleic acid amplification assay (OSNA) (61, 62)have been used to increase the sensitivity of intraoperative diagnosis and reduce the false negative rate. The rate of SN positive patients increases to 7.9-12.6% with serial section and IHC methods, or 40% with RTPCR methods (48). The 7th TNM classification defines micrometastases as metastatic lesions between 0.2 and 2 mm and isolate tumor cells (ITCs) are single or small clusters of tumor cells that are no larger than 0.2mm at the greatest diameter. However, the effect of micrometastases on the prognosis of gastric cancer remains controversial (63). Most of studies reported that presence of lymph node micrometastases is associated with a worse prognosis (64, 65). Hence, the use of these enhanced pathological examination may increase the false positive rate and thus increase the risk of unnecessary resection. But Huang et al. demonstrated in their study that occult lymph node metastasis (OLNM) correlated with poor prognosis for patients with nodenegative gastric cancer, and for OLNM-positive patients with node-negative gastric cancer, D2 lymph node dissection was necessary (66). Therefore, further studies about the clinical impact of micrometastases and ITCs are required.

Journal Pre-proof 4. Is sentinel lymph node detection effective and accurate ? The lymphatic drainage pattern of the stomach is complex and the application of sentinel lymph node detection to gastric cancer remains controversial. Many singlecenter studies manifested that the detection rate, sensitivity, and accuracy of the SLN mapping procedure for gastric cancer were 55%-100%, 40%-100% and 70%-100%, respectively (12). And for early-stage gastric cancer, the detection rate and accuracy of SLN mapping were 90%-100% and 85%-100%, respectively, which were comparable to melanoma and breast cancer (14). But the lymph node metastasis rate of early gastric cancer is relatively low, which could increase the accuracy. In 2002, Wang et al reported a meta-analysis of diagnostic value of SLN biopsy for gastric cancer (28). The results demonstrated that the SLN detection rate, sensitivity, negative predictive value and accuracy of prediction of lymph node metastasis based on SLN status were 93.7%, 76.9%, 90.2% and 92.0%, respectively. Besides, Subgroup analysis showed that the detection rate and sensitivity were higher in patients with early T stage and subgroups using dual tracers, submucosal injection and immunohistochemistry during sentinel lymph node mapping. On the side, the results of a meta-analysis of the feasibility of sentinel node biopsy by Ryu et al. showed that the detection rate was 97.5%, and the sensitivity was 87.7%. Further study found that the number of SLNs harvested was assicaed with the detection rate and sensitivity, and it was recommended to collect at least 4 lymph nodes during SLN biopsy or use the method of sentinel basin dissection (67). Ryu et al. also suggested that SLN biopsy in gastric cancer was not clinically applicable for limited lymphadenectomy due its unsatisfactory sensitivity and heterogeneity (67). At present, there are few multicenter prospective studies on sentinel lymph node detection of gastric cancer, mainly from Korea and Japan. In 2004, Japan Clinical Oncology Group (JCOG) conducted a multicenter prospective studies (JCOG0302) evaluate the feasibility and accuracy of sentinel lymph node biopsy in T1 gastric cancer. The study enrolled patients without indication for endoscopic resection, performing

Journal Pre-proof SLN biopsy with ICG and determining the sentinel lymph node status by intraoperative frozen section with HE staining. However, this study was suspended due to the high false negative rate (46.4%). which was mainly attributed to the unreliability of intraoperative single-plane frozen section and the insufficient learning period (55). Kitagawa et al. conducted another prospective multicenter study of sentinel node mapping for gastric cancer, in which a total of 397 patients with cT1-2 gastric adenocarcinomas < 4 cm in gross diameter were enrolled, which demonstrate that dual tracer method for SN biopsy was as safe and effective when applied to the superficial small gastric cancer (29). The 12 hospitals that participated in this multicenter prospective study had previous experience (more than 30 patients each) with SN mapping for gastric cancer using the dual tracer method (radiolabeled tin colloid and isosulfan blue dye). The results demonstrated that the SLN detection rate, sensitivity, false negative rate and accuracy of metastatic status based on SN evaluation were 97.5% (387/397), 93% (53/57), 7% (4/57), 99% (383/387), respectively (29). Moreover, the false negative rate was significantly higher in cT2 tumors than in cT1 tumors, and three of the four false negative cases had pathological lymph node metastases only in the sentinel lymphatic basin indicating the advantages of sentinel basin dissection (29). In short, more evidence of high level is required to promote the application of the sentinel node concept in gastric cancer treatment. 5. Is sentinel node navigation surgery oncologically safe？ If the concept of sentinel lymph node is appropriate for gastric cancer, sentinel lymph node detection may provide more accurate status of lymph node metastasis. Sentinel node navigation surgery(SNNS) is to determine the surgical procedure based on the status of the sentinel lymph node. If sentinel lymph node metastasis is negative, total gastrectomy or distal gastrectomy with D2 lymph node dissection could not be necessary. And the SNNS brings more possibilities for individual treatment and minimally invasive surgery. But whether the concept of sentinel lymph node is suitable for gastric cancer remains to be proved.

Journal Pre-proof In general, patients who undergo standard gastrectomy with D2 lymph node dissection often suffer a variety of complication. Therefore, in sentinel node navigation surgery, the goal of the surgeons is to achieve early postoperative recovery and preservation of QOL by reducing the extent of gastric resection and undergoing limited lymph node dissection, on the premise of oncologic safety. Compared with conventional

distal

gastrectomy,

pylorus-preserving

gastrectomy

has

fewer

complications such as weight loss, dumping syndrome, regurgitant gastritis, disturbed bowel movement, dysfunction of the gallbladder, cholecystolithiasis and so on (20). For patients with early gastric cancer, the indications for laparoscopic wedge resection, segmental resection, pylorus-preserving gastrectomy and proximal gastrectomy could be determined according to the status of sentinel lymph nodes (68, 69). The relevant researches also showed a relatively optimistic prospect. Takeuchi et al. performed sentinel lymph node detection and laparoscopic assisted proximal gastrectomy on 37 patients with cT1N0 gastric cancer, and the results showed that the sensitivity in predicting nodal metastasis, including ITCs, and diagnostic accuracy based on SN status were 100% (3/3) and 100% (37/37), respectively. All patients were free from recurrence for a median follow-up period of 26 months (70). But the performance of intraoperative pathological diagnosis was still poor. A single-center clinical trial about SNNS by Park et al. included 100 patients with cT1N0 stomach cancer. All patients underwent

SLN

mapping

using

dual

tracer,

SBD,

intraoperative

rapid

immunohistochemical staining, and those with negative SNs underwent laparoscopic limited gastric resections or ESD. The results of the study demonstrated that SLN detection rate and false negative rate were 99.0% and 2.24%, and that the 3-year relapse-free and overall survival rates were 96.0% and 98.0%, respectively (71). In addition, all recurrences occurred in the SN-negative group. The results suggested that indicate that laparoscopic SNNS might be oncologically safe in EGC, but limited gastric resections should be carefully performed to prevent local recurrence in SNnegative cases. In addition, South Korea is conducting a multicentric RCT study (SENORITA)

Journal Pre-proof comparing the oncologic safety of sentinel node navigation surgery with standard surgery, which is also the first multicentric RCT study of sentinel node navigation surgery for early gastric cancer (56). The study planned to enroll 580 patients with a single lesion of clinical stage T1N0M0 gastric adenocarcinoma, with a diameter of 3 cm or less. The patients allocated to the experimental group will undergo SLN detection with dual tracer (radiolabeled human serum albumin and ICG), SBD and intraoperative frozen section with HE staining. And then according to the status of sentinel lymph node, SLN-positive patients will undergo standard operation, and SLN-negative patients will undergo laparoscopic stomach-preserving surgery. The primary endpoint of the study is the three-year disease-free survival (DFS), whose results will be published in 2020. Although the feasibility study and quality control study demonstrated that laparoscopic SBD was a feasible and safe and procedure during SNNS for gastric cancer prior to the SENORITA study, there are still some practical difficulties (72, 73). For example, due to complicated lymphatic drainage and vascular structures, the primary tumors located at the lesser curvature were usually more difficult to deal with than those at the greater curvature. And tracers sometimes spread diffusely and quickly to the secondary lymph nodes causing difficulties in determining the exact range of sentinel basins. In the feasibility study, the median number of retrieved sentinel basins was two and the median number of sentinel basins nodes examined was nine (72). Although the article did not mention other effects of SBD, we are still concerned that excessive SBD will affect minimal gastric resection and increase intraoperative pathological examination time. On the other hand, in the SENORITA study, sentinel basin nodes thicker than 4 mm were examined intraoperatively with HE staining using serial sections at 2 mm intervals parallel to the long axis (56). And the reliability and feasibility of serial sections has yet to be studied. Theoretically, EMR/ESD seems oncologically sufficient for cT1 gastric cancer patients if all SLNs are pathologically negative for metastasis and endoscopically resectable. Therefore, the indications of EMR/ESD could be expanded. In addition, EMR/ESD does not significantly affected the sentinel lymphatic basin (74). However,

Journal Pre-proof it is still too early to combine sentinel lymph node detection with EMR/ESD, and some problems still need to be solved, such as the accuracy of intraoperative pathological diagnosis, the necessity of full-thickness resection, and the possibility of cancer cells being present in afferent lymphatic vessels leading to SLNs (14). On the side, Laparoscopic and endoscopic cooperative surgery (LECS) is also an important application area for SNNS in gastric cancer. Laparoscopic and endoscopic full-thickness resection combined with SLN detection can fully reflect the concept of minimally invasive surgery and cause minimal damage to patients (75, 76). However, traditional LECS still have the risk of risk of tumor dissemination via gastric juice and contamination of the peritoneal cavity by enterobacteria, so LECS mainly performed for gastrointestinal stromal tumors (75). To overcome this limitation and expand the indications for LECS, several modified LECS procedures have been developed, such as inverted LECS (77), nonexposed endoscopic wall-inversion surgery (NEWS) (78, 79), combination of laparoscopic and endoscopic approaches to neoplasia with a nonexposure technique (CLEAN-NET), laparoscopic transgastric surgery (80), closed LECS (81), lift-and-cut method (82). In addition, researchers had reported cases of hybrid surgery guided by fluorescence lymphangiography in animal models (83). 6.Conclusion In order to improve the quality of life of patients and provide more accurate and individualized treatment, the concept of sentinel lymph node has been gradually applied in gastric cancer. However, due to the complexity of gastric lymphatic drainage, many issues remain to be solved. First, dual tracers seem to be the most effective way, but a suitable tracer is hard to find. Secondly, although SBD can effectively improve the sensitivity of sentinel lymph node detection and reduce the false negative rate, this is only a compromise on skip metastasis. Without accurate and effective tracers, excessive SBD could affect minimal gastric resection and increase intraoperative pathological examination time. Third, frozen section with HE staining is still the most commonly used intraoperative diagnostic method with high false negative rate, and to establish an

Journal Pre-proof accurate and rapid intraoperative diagnostic method is difficult. In addition, the oncologic safety of sentinel node navigation surgery remains to be further studied. Therefore, we should be cautious about performing sentinel lymph node detection in gastric cancer before an accurate and effective method occurs. Declarations of interest None. Acknowledgements Not applicable. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Dual tracers seem to be the most effective way Skip metastasis and intraoperative diagnosis are reasons for false negative cases Sentinel basin dissection can reduce the false negative rate The oncologic safety of SNNS remains to be further studied