Current status of endoscopic submucosal dissection for the management of early gastric cancer: A Korean perspective

Abstract

The early diagnosis of gastric cancer allows patients and physicians to pursue the option of endoscopic resection, which is significantly less invasive than conventional surgical resection. In Korea, the use of endoscopic submucosal dissection (ESD) has been increasing, and many reports on ESD have been published. In addition, Korean gastroenterologists from several hospitals performing ESD have conducted formal meetings to discuss useful information regarding ESD. Here, we discuss the Korean experience with ESD, including outcomes and prospects of endoscopic treatments.

Key Words: Early gastric cancer; Endoscopic submucosal dissection; Endoscopic mucosal resection

INTRODUCTION

Early gastric cancer (EGC) is defined as gastric carcinoma confined to the mucosa or submucosa, regardless of the presence of regional lymph node metastases[1]. In the 1980s, surgery was typically used to treat early gastric cancer. However, the development of endoscopic devices and skills has resulted in a different approach to treatment. Endoscopic mucosal resection (EMR) is a procedure for the resection of gastrointestinal (GI) neoplasms that was first introduced in Japan. However, since it is difficult to achieve en bloc resection of specimens larger than 20 mm with EMR, this procedure has recently been replaced by endoscopic submucosal dissection (ESD)[2,3]. The improvement in ESD technique has led to extension of the indications for endoscopic treatment to that of early gastric cancer. In Korea, ESD has become an effective alternative treatment method to manage early gastric cancer. In this review, we provide an overview of ESD in Korea.

THE DEVELOPMENT OF ENDOSCOPIC RESECTION

Endoscopic therapy has been in continuous development since the injection of saline into submucosal tissue for cutting sessile rectal polyps by Dehyle in 1973[4] In 1984, strip-off biopsy (strip biopsy) was introduced for gastric cancer treatment in Japan[5]. Although successfully used to treat early gastric cancer, strip biopsies cannot be used to resect depressed ulcers or neoplasms. In the 1990s, EMR by cap-fitted panendoscope (EMR-C) and EMR with ligation (EMR-L) methods were developed in Japan for resection of early gastric cancer[6,7]. However, lesions larger than 2 cm cannot be removed en bloc with these techniques. Because piecemeal resection carries a high risk of recurrence and does not facilitate exact pathological staging, ESD was developed to remove early gastric neoplasm en bloc[8].

ESD was introduced in the late 1990s and allows direct dissection of the submucosa. ESD allows for certain histological diagnoses and reduces the rate of recurrence compared to EMR. The en bloc resection of large lesions is possible with insulation-tipped (IT) electrosurgical knives[9], as well as hook, flex, triangle and flush knives[8].

THE DEVELOPMENT AND OUTCOMES OF ENDOSCOPIC RESECTION IN KOREA

EMR for early gastric cancer was performed for the first time in Korea in 1996 by Hyun[10]. Several small-scale studies of ESD and EMR have been performed in Korea since then[11] (Table 1).

Table 1 Endoscopic mucosal resection/endoscopic submucosal dissection therapeutic outcomes.

Author	Yr	n	Method	Complete resection (%)	Local recurrence (%)	Bleeding (%)	Perforation (%)
Lee	1996	19	Strip biopsy	37.8	28.6
Hyun	1996	20	Strip biopsy
Cheon	2000	28	Strip biopsy	64.3	3.6
Seong	2002	35	Strip biopsy	94.3	6.1
Hyun	2003	45	Strip biopsy	55.6	0.0	24.4	0.0
Kim	2000	20	EMR-L	85.0	5.9	0.0	0.0
Kim	2005	109	Strip biopsy, EMR-C, EMR-P	67.9	1.4	8.3	2.8
Youn	2006	149	Strip biopsy, EMR-C, EMR-L, ESD	84.6	4.0	22.8	1.3
Kim	2007	514	Strip biopsy, EMR-C, EMR-L, EMR-P, ESD	77.6	6.0	13.8	0.6
Jung	2007	360	EMR-P	82.8		10.6	1.1
Min	2009	103	EMR-P	75.7	0.0	3.9	1.9
Jung	2007	264	ESD	87.9		9.8	3.8
Kang	2008	456	ESD	80.3	0.0
Park	2008	434	ESD	77.4	1.8	8.1	2.3
Min	2009	243	ESD	88.9	0.0	5.3	4.5
Chung	2009	534	ESD	87.7		15.6	1.2

EMR: Endoscopic mucosal resection; ESD: Endoscopic submucosal dissection; EMR-C: EMR by cap-fitted panendoscope; EMR-L: EMR with ligation; EMR-P: Precutting followed by snare resection.

A large-scale, multicenter, retrospective study of EMR treatment was reported in 2007[12]. From January 2000 to December 2002, 514 EGCs in 506 patients were treated by EMR at 13 institutions. The most commonly used procedure was circumferential precutting followed by snare resection (EMR-P, n = 269, 52.3%). Complete resection and incomplete resection after EMR were confirmed in 399 lesions (77.6%) and 103 lesions (20.0%), respectively. In the completely resected mucosal cancer group (n = 399), local recurrence was detected in 24 cases (6.0%) with a median interval between EMR and recurrence of 17.9 mo (range, 3.5-51.7 mo). There were 3 cases of perforation and 71 cases of bleeding. There were no deaths related to the recurrence of gastric cancer during the overall median follow-up period of 39 mo[12].

The use of ESD has increased in many Korean hospitals over the last 5 years, accompanied by a subsequent increase in published reports about ESD treatment. Park et al[13] initially reported 27 cases of ESD treatment using the IT knife in Korea in 2004, after which use of the ESD procedure increased rapidly in Korea. The Korean Society of Gastrointestinal Endoscopy (KSGE) organized an ESD research group in 2003 to exchange professional opinions and develop ESD techniques. The KSGE held hands-on courses to introduce ESD procedures and devices using animal models. Live international ESD demonstrations have been held over a telemedicine network since 2006[14].

In 2009, a large multicenter study of ESD treatment was published[2]. From January 2006 to June 2007, 1000 early gastric cancers in 952 patients (502 men, 450 women; mean age 62.1 years, range 43-90 years) were treated by using ESD at six Korean ESD study group (KESG)–related university hospitals in Korea. The rates of en bloc resection, complete en bloc resection, vertical incomplete resection, and piecemeal resection were 95.3%, 87.7%, 1.8% and 4.1%, respectively. The rates of delayed bleeding, significant bleeding, perforation, and surgery related to complications were 15.6%, 0.6%, 1.2% and 0.2%, respectively. The rates of en bloc resection differed significantly based on the location of the lesions (upper portion vs middle portion vs lower portion of the stomach, 88.6% vs 95.2% vs 96.0%, respectively; P = 0.002), presence of a scar (no vs yes, 96.0% vs 89.5%, respectively; P = 0.002), and histologic type (low-grade adenoma vs high-grade adenoma vs differentiated early gastric cancer vs undifferentiated early gastric cancer, 95.8% vs 94.6% vs 96.2% vs 83.8%, respectively; P = 0.007)[2]. The results of this study suggested that the ESD techniques used in Korea achieve high rates of complete resection (87.7%) with an acceptable rate of complications. In addition, ESD outcomes from several hospitals show that en bloc and complete resection rates are 87%-100%, which are superior to those of conventional EMR treatment[15] (Table 2).

Table 2 Endoscopic submucosal dissection outcomes.

Result of resection	n (%)
Complete resection	877 (87.7)
En bloc resection	953 (95.3)
Free margin of en bloc resection	901 (90.1)
Failure of en bloc resection	6 (0.6)
ESD time (min), mean ± SD	47.8 ± 38.3
Submucosal invasion of tumor	74 (7.4)
Lymphovascular invasion of tumor	30 (3.0)

ESD: Endoscopic submucosal dissection.

THE CHALLENGE OF ESD IN KOREA

Currently accepted classical indications for EMR according to the gastric cancer treatment guidelines published in 2001 by the Japanese Gastric Cancer Association are: (1) well-differentiated elevated cancers less than 2 cm in diameter; (2) small (< 1 cm) depressed lesions without ulceration; (3) moderately- or well-differentiated cancers confined to the mucosa; and (4) no lymphatic or vascular involvement[8,16]. However, the classical indications for EMR may be too strict and lead to unnecessary surgery[8].

Japanese studies have expanded the indications for endoscopic treatment of gastric cancer[8,17]. ESD has been developed to allow dissection directly along the submucosal layer using electronic knives. Gotoda et al[8,18] defined the risk of lymph node metastasis in patients with EGC using a large database of more than 5000 patients who underwent gastrectomy with meticulous R2 level lymph node dissection. This group of patients was characterized by having either no risk or a lower risk of lymph node metastasis compared to risk of mortality from surgery. Thus, expanded criteria for endoscopic resection were proposed: (1) mucosal cancer without ulcer findings, irrespective of tumor size; (2) mucosal cancer with an ulcer < 3 cm in diameter; and (3) min (< 500 μm from the muscularis mucosa) submucosal invasive cancer < 3 cm in size.

Ryu et al[19] investigated surgery as indicated for non-curative endoscopic resection in EGC in Korea. Neither residual cancer nor lymph node metastasis was found in patients with less than 500 μm submucosal invasion without margin involvement in ER specimens. An et al[20] studied predictive factors for lymph node metastasis in EGC with submucosal invasion. They concluded that lymphatic involvement and tumor size are independent risk factors for lymph node metastasis in EGC with submucosal invasion. Minimally invasive treatment such as EMR may be feasible for highly selective submucosal cancers with no lymphatic involvement, SM1 invasion, and tumor size < 1 cm. In addition, Park et al[21] reported that EGC with signet ring cell histology can be treated by endoscopic mucosal resection, if it is smaller than 25 mm, limited to the SM2 layer, and does not involve the lymphatic-vascular structure. Another Korean study showed that poorly differentiated EGC confined to the mucosa or with minimal submucosal infiltration (< or = 500 μm) could be considered for curative EMR due to the low risk of lymph node metastasis[22]. However, extending the indications for ESD remains controversial because the long-term outcomes of these procedures have not been fully documented.

Histopathologic diagnosis of EMR/ESD specimens is very important, but the diagnostic criteria, terminology and grading systems differ between the East and the West. Most Western pathologists focus on structural invasion to diagnose carcinoma, but Japanese pathologists emphasize severe dysplastic cytologic atypia irrespective of the presence of invasion[23,24]. In 2000, the Vienna classification was proposed to reduce diagnostic discrepancies between Japanese and Western pathologists[25]. However, there is still confusion about the pathological diagnosis of gastric epithelial lesions[26]. In Korea, gastroenterologists and pathologists did not have clear guidelines for diagnosis, and efforts were made to improve consensus. Korean ESD techniques have been influenced by Japan, but Korean doctors are also influenced by advances in Western medical science in general.

Pathologic diagnosis of gastric cancer tissue obtained by ESD was discussed among gastroenterologists and pathologists at a joint symposium of the Gastrointestinal Pathology Study Group of Korean Society of Pathologists (GIPS-KSP) and the ESD study group held in Korea in 2007. This collaboration continues, with the goal of establishing consensus for ESD indications in Korea, as well as internationally.

The following criteria have been suggested for the pathological diagnosis of gastric epithelial lesions: (1) standardization of the number of biopsy specimens (introduction of the number of biopsy specimens according to the size of the lesion); (2) introduction of criteria for determination of the adequacy of a biopsy specimen (marking of muscularis mucosa, submucosa); (3) establishing criteria for diagnosis of advanced adenomas (including nuclear findings and structural abnormalities); and (4) establishing criteria of lamina propria invasion and submucosal invasion[27].

THE PROSPECTS OF KOREAN ESD

Improvements in the ability to endoscopically identify and distinguish cancer and the development of diagnostic tools will enable the diagnosis of ultra-early lesions. The detection of these ultra-early lesions will eventually result in more active use of ESD for treatment.

The rapid evolution of ESD has allowed the procedure to be more widely indicated. In addition, new diagnostic and therapeutic techniques have become available. One example is natural orifice transluminal endoscopic surgery (NOTES), by which abdominal operations are performed with an endoscope passed through a natural orifice (e.g. mouth, urethra, anus) and then through an internal incision in the stomach, vagina or colon[28]. This procedure allows extension of a flexible endoscope to reach organs outside of the lumen of the bowel. NOTES is minimally invasive compared to open surgery and is associated with fewer risks. EMR and/or ESD can be combined with laparoscopic/thoracoscopic sentinel node mapping to allow successful endoscopic treatment of gastrointestinal cancers with a potential risk of lymph node metastasis using NOTES[29]. The KSGE organized a NOTES research group to discuss, investigate and spread information about the use of NOTES.

Since the KSGE organized the Korean ESD study group, there have been several meetings of gastroenterologists and gastroenteropathologists from hospitals where ESD is performed to discuss standardization of the pathology. The short- and long-term outcomes of ESD for the treatment of early gastric cancer have also been discussed at these regular meetings regarding the progress and outcomes of ESD in Korea[2,12]. However, these evaluations are limited by their retrospective methods, and the absence of an international focus on long-term outcomes. There is agreement that multicenter clinical studies are necessary to obtain prospective results. Therefore, the National Evidence-Based Health Care Collaborating Agency (NECA) and KSGE suggested the prospective study of short-term and long-term clinical outcomes of EGC treated by ESD. Many tertiary university hospitals have been involved in this study, which is expected to provide indications for endoscopic treatment of EGC in Korea and worldwide.

CONCLUSION

ESD is a useful method for complete resection of EGCs, but has many limitations. To improve the safety and efficacy of ESD, many Korean research groups are currently concentrating on the development of new techniques and devices.