Novel surgical approach based on the sentinel node concept in patients with early gastric cancer

Abstract Recent prospective multicenter trials have demonstrated the clinical safety and efficacy of sentinel node navigation surgery (SNNS) in patients with early gastric cancer. Further, development of an intraoperative imaging system and an indocyanine green fluorescence imaging approach has been attracting attention as a novel tool for detection of the sentinel node (SN). The greatest advantage of an in vivo imaging system is that it visualizes SN and afferent lymphatic vessels from the primary tumor site more clearly than the conventional dye approach. Besides visualization of the SN, it is also essential to accurately assess the presence or absence of lymph node metastasis in the intraoperative management of SNNS. However, the clinical significance of lymph node micrometastasis (LNM) in patients with gastric cancer remains controversial. Reverse transcription‐polymerase chain reaction (RT‐PCR) is one of the representative assays used to identify LNM. A rapid RT‐PCR assay that completes the detection of LNM within approximately 40 minutes has recently been produced and applied in the clinical management of SNNS. From the viewpoint of surgical methods, modified laparoscopic and endoscopic cooperative surgery with non‐exposed approaches has recently been highlighted as a promising technique to prevent tumor dissemination caused by surgical procedures, and is likely to be clinically applied to SNNS in the future. When carrying out SNNS as a minimally invasive surgery, it is important to consider the balance between post‐surgical quality of life and curability. Future prospective studies on SNNS will greatly contribute to furthering its establishment as a beneficial procedure for patients with early gastric cancer.

patients with early gastric tumors without lymph node metastasis have been clinically discussed. 3,4 According to these guidelines, standard gastrectomy with lymphadenectomy is still recommended for patients with tumors and no indications for ESD. 3 In clinical practice, therapeutic strategies need to be designed in order to prevent lymph node recurrence after ESD.
Surgical gastrectomy with lymphadenectomy is currently regarded as a standard treatment for gastric cancer, even for some patients with early gastric cancer. However, conventional surgical procedures are defined based on the stomach volume to be resected. 3 However, when planning function-preserving gastrectomy, limited lymphadenectomy is a key concern from the viewpoint of disease curability. Moreover, the accuracy of detecting lymph node metastasis using preoperative examinations is clinically inadequate in patients with gastric cancer. 5 The sentinel node (SN) concept was initially proposed by Morton et al. 6 for patients with melanoma. SN are defined as the first lymph nodes to receive lymphatic flow from primary tumor sites. Many investigators have already demonstrated the clinical utility of sentinel node navigation surgery (SNNS) for patients with gastric cancer, [7][8][9][10][11] and the current technical procedures for SNNS have been gradually advancing over time. Furthermore, intraoperative methods have been developed for the accurate diagnosis of lymph node metastasis, including micrometastasis. 12 This review will focus on a novel technique for and advances in SNNS in patients with early gastric cancer.

ON SNNS
Many researchers have reported retrospective findings on SNNS for patients with gastric cancer. [8][9][10] However, limited information is available on the accuracy of the SN concept based on prospective multicenter trials. Table 1 summarizes three prospective multicenter studies reported since 2013 on SNNS for patients with gastric cancer. [13][14][15] A prospective multicenter trial by the Japan Society of Sentinel Node Navigation Surgery assessed the clinical safety and efficacy of SNNS using the endoscopic dual tracer method in 397 patients with previously untreated cT1 or cT2 gastric cancer measuring <4.0 cm in diameter. 13 In this prospective study, SN detection and accuracy rates were 97.5% (387/397) and 99.0% (383/387), respectively. 13 T A B L E 1 Prospective multicenter trials on sentinel node navigation surgery for patients with gastric cancer Although four patients had false-negative results in terms of SN detection, pathological examinations showed pT2 or tumors measuring >4.0 cm in three patients. 13 Accordingly, this study group concluded that SNNS is applicable to patients who are preoperatively diagnosed with cT1 and cN0 gastric cancer measuring <4.0 cm in diameter. 13 The Japan Clinical Oncology Group (JCOG) conducted a multicenter trial (JCOG0302) to assess the accuracy of SN biopsy in patients with cT1 gastric cancer measuring <4.0 cm at the maximum diameter. 14 In the JCOG0302 trial, SN were identified using an intraoperative serosal injection of indocyanine green (ICG) and lymph node metastasis was intraoperatively evaluated by hematoxylin-eosin (HE) staining using only a single section. 14 Although 440 patients were enrolled in the study, the multicenter trial was suspended because of the high false-negative rate (46%). 14 However, they reported that the false-negative rate decreased to 14% when using additional sections for pathological assessments. 14 The main reason for this change in the rate of false-negatives with additional analysis is likely the heterogeneous distribution of metastatic foci in lymph nodes. 12 These findings demonstrated the clinical importance of pathological examinations using multiple sections for the intraoperative diagnosis of lymph node metastasis. Consequently, they concluded that intraoperative HE assessments using only one section were inadequate to accurately diagnose the metastatic status of SN. 14 A Korean group conducted a prospective multicenter feasibility study as prerequisite quality control for the surgical standardization of laparoscopic sentinel node basin dissection (SBD) before starting a phase III trial (SENORITA trial). 15 This study included 108 patients who had cT1 or cT2 tumors measuring <4.0 cm in diameter for the final analysis. 15 In this quality control study, the SN detection rate, sensitivity, and false-negative rate were 92.6% (100/108), 100%, and 0%, respectively. 15 These findings indicated that SBD is a feasible tool for patients with early gastric cancer, and planned the SENOR-ITA trial to assess oncological outcomes, postoperative morbidity and mortality, and QOL between laparoscopic stomach-preserving surgery with SBD and laparoscopic standard gastrectomy. 15 The clinical validity of the SN concept in patients with cT1 and cN0 gastric cancer has, thus, been adequately confirmed by clinical studies on SNNS, including retrospective analyses. As patients with early gastric cancer have a better prognosis after standard treatments, SNNS based on individualized lymphadenectomy should be safely carried out to prevent lymph node recurrence. Further standardization of clinical procedures will contribute greatly to the development of SNNS for patients with early gastric cancer. imaging system. 21 We believe that the ICG fluorescence imaging system is essentially a safe procedure for future use in SNNS.

| INTRAOPERATIVE DIAGNOSTIC TECHNOLOGIES FOR ASSESSING SN METASTASIS
Lymph node metastasis is one of the most significant prognostic indicators in patients with gastric cancer. 22 approximately 40 minutes. [26][27][28] Our study demonstrated that the sensitivity and specificity of the SmartCycler system are high as a result of multiplex assays using the double markers of carcinoembryonic antigen (CAE) and cytokeratin-19. 26 At our institution, we use a rapid RT-PCR assay using SmartCycler as well as HE staining for the intraoperative diagnosis of SN metastatic status when carrying out SNNS.

| LAPAROSCOPIC AND ENDOSCOPIC COOPERATIVE SURGERY BASED ON THE SN CONCEPT
Laparoscopic and endoscopic cooperative surgery (LECS) has been developed as a novel surgical technique for patients with gastric submucosal tumors, such as gastrointestinal stromal tumors. [29][30][31] As the classical LECS procedure devised by Hiki et al. 31  | 183 sutures at four sites around the tumor. These stay sutures are also used for counter-traction. The seromuscular layer is then dissected along the outside of the four stay sutures using a spatula-shaped electrocautery knife under laparoscopy (Figure 2A). A full-thickness specimen including the tumor is dissected using a laparoscopic stapling device ( Figure 2B). The most important factor in surgical procedures involving full-thickness resection is the establishment of a suture line from the greater to the lesser curvature in order to prevent postoperative stenosis.
In future, the indications for modified LECS with a non-exposed approach, such as NEWS and CLEAN-NET, will be progressively extended to patients with early gastric cancer meeting the indications for SNNS. If this method will be further stylized from the standpoint of surgical procedures, it may come to be regarded as a standard surgical tool in SNNS.

| FUTURE PROSPE CTS FOR SNNS AS A MINIMALLY INVASIVE APPROACH
A prospective multicenter phase II trial of personalized surgery based on a diagnosis of metastasis to SN is ongoing in Japan. This clinical study will advance medical care and, hence, we await its findings expectantly. If SNNS is clinically developed as a safe surgical approach based on the findings obtained, the clinical application of SNNS will be extensively extended among patients with early gastric cancer. Furthermore, advances have been made in endoscopic treatments for patients with early malignancies, including gastric cancer. 35,36 Therefore, ESD with laparoscopic SBD may become the ultimate stomach-preserving surgery for avoiding lymph node recurrence in selected patients with extended indications for ESD; however, further studies are needed prior to its expansion as a surgical approach.
In conclusion, we need to assess the patients' post-surgical QOL in order to confirm the clinical benefits of function-preserving gastrectomy for patients undergoing SNNS. If the benefits of SNNS on QOL are substantiated by prospective multicenter trials, minimally invasive surgery with individualized lymphadenectomy may become the recommended procedure for early gastric cancer in consideration of the balance between QOL and curability. Moreover, future studies on the surgical techniques used will greatly facilitate the establishment of SNNS for patients with early gastric cancer.