Key points

Introduction

Gastroscopes first appeared in clinical use in the mid 1950s. Since polypectomy of gastric polyps with an electrocautery snare was performed in the 1960s, a flexible endoscope has been used not only as a diagnostic tool but also for therapeutic purposes. After the development and establishment of endoscopic mucosal resection (EMR) in the 1980s, endoscopic submucosal dissection (ESD) was introduced around 2000. With the advent of ESD, possible node-negative gastrointestinal cancers can be cured simply via a peroral approach with the flexible endoscope, irrespective of tumor size or submucosal scarring formation under the lesion.

Less-invasive surgical approaches with the flexible endoscope have been continuously explored by enthusiastic endoscopists who are now increasingly interested in moving beyond the submucosal layer. In this article, the current situation of advanced endoscopic techniques beyond ESD is explained after a brief history of ESD, followed by future perspectives.

Introduction

Gastroscopes first appeared in clinical use in the mid 1950s. Since polypectomy of gastric polyps with an electrocautery snare was performed in the 1960s, a flexible endoscope has been used not only as a diagnostic tool but also for therapeutic purposes. After the development and establishment of endoscopic mucosal resection (EMR) in the 1980s, endoscopic submucosal dissection (ESD) was introduced around 2000. With the advent of ESD, possible node-negative gastrointestinal cancers can be cured simply via a peroral approach with the flexible endoscope, irrespective of tumor size or submucosal scarring formation under the lesion.

Less-invasive surgical approaches with the flexible endoscope have been continuously explored by enthusiastic endoscopists who are now increasingly interested in moving beyond the submucosal layer. In this article, the current situation of advanced endoscopic techniques beyond ESD is explained after a brief history of ESD, followed by future perspectives.

Endoscopic submucosal dissection: dawn of radical intraluminal endoscopic resection

The previously developed EMR technique had limitations in terms of tumor size and the existence of ulcerative change. Because a snare is used for the resection, the tumor size should always be smaller than that of the snare for en bloc resection. Furthermore, when the lesion is accompanied by ulcer formation, the submucosal fibrosis sometimes disturbs en bloc resection because of slipping of the snare. In order to overcome these disadvantages, ESD was developed, whereby a lesion is resected by circumferential mucosal incision and subsequent submucosal dissection under direct visualization. By this technique, endoscopists have become capable to cure early cancers very reliably without the help of surgeons if the lesion has an extremely low possibility of lymph node metastasis. Several endoscopic devices specifically designed for ESD (eg, IT-Knife [Olympus, Co., Ltd., Tokyo, Japan], Hook Knife [Olympus], Dual knife [Olympus] and so forth) have been invented, and these devices have made this technique more feasible. Although technical difficulty is one of the disadvantages of ESD, this fascinating technique always attracts many therapeutic endoscopists. Therefore, live demonstrations by invited ESD experts or hands-on training in ex vivo/in vivo animal models are frequently held in selected institutions around the world. Nowadays, establishment of systematic training methods using isolated animal organs or other modalities are expected to obtain a safe and reliable ESD technique.

Endoscopic muscular/full-thickness resection: over the submucosal layer

Since endoscopists realized that the entire gastrointestinal wall could be cut freely with ESD knives from the inside, they started to explore how far endoscopic resection can be taken. To begin with a challenge to the deeper layers, subepithelial tumors (SETs) became a target. Lee and colleagues tried to resect SETs arising from the muscular layer by dissecting the muscular layer just beneath the tumor, resulting in 75% of complete resection rate without perforation. Hoteya and colleagues selected only SETs arising from the muscularis mucosae and demonstrated favorable outcomes in terms of both complete resection rates and complication rates. Going further, endoscopic full-thickness resection (EFTR), local transmural resection only with a flexible endoscope, was proposed (recognized as one of the natural orifice transluminal endoscopic surgery [NOTES]–related techniques, also known as pure EFTR). After submucosal injection and circumferential mucosal incision around the lesion, seromuscular incision is performed with intentional perforation on the exposed muscular layer. A lesion resected in a full-thickness fashion is retrieved transorally, followed by endoscopic defect closure with hemoclips or other devices. Zhou and colleagues demonstrated the feasibility of this challenging technique; other brave endoscopists, mainly in China, reported acceptable outcomes.

However, this technique is associated with several serious problems. First, a secure closure method only by endoluminal endoscopy has not been established so far. The grasping force of commercially available endoclips is too weak to reliably maintain secure closure of the full-thickness wall defect. Over-the-scope clips or endoscopic suturing systems may solve the problem, but their clinical utility in EFTR is not satisfactorily demonstrated yet. Second, endoscopic manipulation becomes more difficult after the intentional perforation because of the loss of insufflation and partial collapse of the stomach. Third, a blind approach in the phase of intentional perforation and successive seromuscular incision is more difficult and dangerous. For example, in case of bleeding from the abdominal cavity, endoscopic hemostasis from inside the lumen might be impossible. This method is, therefore, questionable in terms of both the feasibility and the safety; it does not seem to have gained widespread acceptance yet. However, some aggressive endoscopists are still trying to overcome these shortcomings and establishing safe and secure EFTR as a pure NOTES technique. For example, Mori and colleagues invented a novel endoscopic device sustaining the collapsing stomach after intentional perforation from the inside as well as a new endoscopic suturing instrument attached to the tip of endoscope for secure closure of the full-thickness defect. Further developments and wider application to humans are expected.

Laparoscopic endoscopic cooperative surgery: a safe approach for local resection

To overcome the drawbacks in EFTR, laparoscopic endoscopic cooperative surgery (LECS) or laparoscopy-assisted EFTR (hybrid NOTES) was developed. In this procedure, EFTR is performed under laparoscopic assistance and finally the wall defect is closed laparoscopically using linear staplers or a hand-suturing technique. This technique can address all the potential disadvantages previously described for pure EFTR. Using laparoscopic closure, the wall defect can be tightly and securely fastened. Even after intentional perforation of the seromuscular layer, laparoscopic assistance can help to maintain the endoscopic view by exerting traction and suspending the organ from the outside. Surrounding organs or vessels can also be monitored by laparoscopy during EFTR in order not to damage them. Moreover, laparoscopic seromuscular incision using an electrocautery knife or ultrasonically activated coagulating shears after endoscopic seromuscular perforation may save operation time. Hiki and colleagues promoted LECS starting in 2008, and it became accepted as one of the surgical methods covered by the health insurance system in Japan.

However, this promising technique also has an inevitable disadvantage. During the procedure, intentional perforation is required, which may lead to bacterial contamination into the peritoneal cavity and iatrogenic tumor dissemination in case of cancer or an ulcerated SET (eg, ulcerated gastrointestinal stromal tumor). Indeed, free cancer cells are detected in gastric lavage fluid from patients with gastric cancer even at an early stage, although there is room for discussion about the ability of these floating cancer cells to form dissemination foci on the peritoneum. To avoid this theoretic risk, Nunobe and colleagues developed an improved technique of LECS, called inverted LECS. In this technique, the gastric hole is hung up with several strings at the phase of intentional perforation in order not to spill the contents of the stomach. Inverted LECS is, however, still insufficient to avoid iatrogenic tumor seeding or possible port site metastasis because the surface of the neoplasm exposed toward the abdominal cavity might touch the laparoscopic instruments, which could implant tumor cells to other abdominal organs or the abdominal wall during the manipulation. Therefore, local resection in which transluminal communication is unavoidable should be refrained from, especially for cancers or SETs with ulcer formation. Thus, LECS should be limited only to SETs without ulcer findings.

Nonexposed full-thickness resection: challenge to minimally invasive partial gastrectomy for cancers

How can we do minimally sized local resection without transluminal access? Inoue and colleagues invented a technique of laparoscopic local gastrectomy by pulling a full uninjured mucosal layer including the target lesion toward the outside of the stomach after laparoscopic circumferential seromuscular incision, followed by resection at the bottom of the pulled area with linear staplers, and named this technique the combination of laparoscopic and endoscopic approaches to neoplasia with a nonexposure technique (CLEAN-NET). Using the intact mucosal layer as a safe and clean net to avoid spillage of the gastric contents and contact of laparoscopic instruments with the cancer surface, this method can be applied to SETs regardless of ulcer formation and even cancerous lesions. CLEAN-NET is a relatively simple and time-saving technique. For successful resection in this technique, a critical phase would be setting the resection area by placing markings on the serosal side because the operator cannot resect the lesion under the direct visualization of the target lesion from the inside of the stomach. Especially in cancers, serosal markings must be precisely placed just on the opposite side of the mucosal markings, which are precisely placed endoscopically by close observation of the demarcation line of the tumor.

To resect a target lesion accurately and completely while preserving as much normal tissue as possible, an intraluminal approach would be desirable at the final step of resection because the operator can confirm the demarcation line of the target lesion. Goto and colleagues invented a laparoscopy-assisted, nonexposure technique of EFTR in order to overcome all of these drawbacks mentioned earlier and named it nonexposed endoscopic wall-inversion surgery (NEWS) ( Fig. 1 ). Under general anesthesia in a spine position, a flexible endoscope is inserted perorally and a laparoscopy port is placed as well as some trocars for laparoscopic devices. Mucosal markings are accurately made endoscopically by close endoscopic observation, followed by laparoscopic serosal markings just on the opposite side of mucosal markings. After circumferential submucosal injection of a hyaluronic acid solution with a small amount of indigo carmine endoscopically, circumferential seromuscular incision is performed laparoscopically until the colored submucosal layer is well exposed. After creating sufficient width of a groove around the lesion, seromuscular hand suturing is performed on the peritoneal side isolating the tumorous area, which is inverted toward the inside of the stomach. Finally, endoscopic circumferential mucosal and submucosal incision is performed with the ESD technique around the inverted lesion. A distinctive feature of this technique is inverting the lesion toward the inside of the stomach by means of laparoscopic seromuscular suturing. In this step, it would be better to insert a spacer (eg, a surgical sponge) between the serosal side of the inverted lesion and the suturing plane to facilitate the subsequent endoscopic mucosal incision. In the endoscopic resection, the inserted spacer works as a vertical end point at the phase of the submucosal incision, a counter-tractor by lifting the lesion, and a protector of the suture line. After introducing this spacer technique to NEWS, we achieved more successful results compared with previous procedures without spacer.

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