Endoscopic treatment for early gastric cancer

Abstract

Gastric cancer remains one of the most common causes of cancer death. However the proportion of early gastric cancer (EGC) at diagnosis is increasing. Endoscopic treatment for EGC is actively performed worldwide in cases meeting specific criteria. Endoscopic mucosal resection can treat EGC with comparable results to surgery for selected cases. Endoscopic submucosal dissection (ESD) increases the en bloc and complete resection rates and reduces the local recurrence rate. ESD has been performed with expanded indication and is expected to be more widely used in the treatment of EGC through the technological advances in the near future. This review will describe the techniques, indications and outcomes of endoscopic treatment for EGC.

Core tip: Gastric cancer remains one of the most common causes of cancer death. However the proportion of early gastric cancer (EGC) at diagnosis is increasing. Endoscopic mucosal resection is an effective treatment modality with comparable results to surgery for selected cases of EGC. Endoscopic submucosal dissection (ESD) increases en bloc and complete resection rates and reduces the local recurrence rate. Recently, favorable outcomes of ESD have been reported in patients meeting expanded criteria of endoscopic treatment for EGC. This review will describe the techniques, indications and outcomes of endoscopic treatment for EGC.

INTRODUCTION

Gastric cancer remains one of the most common causes of cancer death worldwide, although its incidence and mortality rate are decreasing[1,2]. Gastric cancer has become a relatively rare cancer in North America and in most Northern and Western Europe, but not in Eastern Europe, Russia and selected areas of Central and South America or East Asia[2]. Given that the high incidence of gastric cancer, the National Cancer Screening Program recommends that men and women aged 40 years and over undergo upper endoscopy or upper gastrointestinal series every other year in Korea[3] and similarly, gastric cancer screening has been conducted nationwide for all residents aged 40 years and over in Japan[4]. As a result, the proportion of early gastric cancer (EGC) at diagnosis is increasing. The prognosis of EGC is excellent with a 5-year survival rate of over 90%[5,6]. Furthermore, with the improved detection rate of EGC, the endoscopic treatment has become widespread due to advances in the instruments available and endoscopist’s experience[7-9]. This review will describe the techniques, indications and outcomes of endoscopic treatment for EGC.

TECHNIQUES OF ENDOSCOPIC TREATMENT FOR EGC

Endoscopic mucosal resection

The technique and instruments of endoscopic polypectomy were developed in Japan[10]. Since then, the strip biopsy was described as an extension of endoscopic snare polypectomy in 1984[11]. This technique uses a double channel endoscope. After submucosal injection under the lesion, a snare is inserted through one channel and is used to remove the lesion, while a grasper, inserted through the other channel, is used to lift the lesion. In 1988, Endoscopic mucosal resection(EMR) after circumferential pre-cutting was described[12]. In this technique, cutting around the lesion with a needle knife is done after submucosal injection using hypertonic saline mixed with diluted epinephrine, and then the lesion is removed by a snare. In 1992, EMR using transparent cap (EMR-C) was developed[13]. This technique uses a transparent plastic cap that is connected to the tip of an endoscope. After submucosal injection, the lesion is sucked into the cap while a specialized crescent shaped snare, which is deployed at the tip of the cap, is closed. With this technique intramucosal cancers 2 cm or less in diameter can be safely removed[14]. After that, EMR with ligation (EMR-L) was described[15]. In this technique, a standard variceal ligation device is used to capture the lesion. After sucking the lesion into the cap, lodged band is deployed underneath the lesion. The banded lesion is then resected by a snare. EMR-L is also safe and effective treatment modality for selected EGCs[16]. As described above, EMR-C and EMR-L are relatively simple and effective treatment modality for EGC. However, it is apt to fragment tumors that are larger than 1.5-2.0 cm in diameter, which results in incomplete histological diagnosis and possibly in an increased risk of local recurrence[17-19]. To overcome this drawback ESD, which is particularly effective for en bloc resection of tumors regardless of their size, was developed in late 1990s.

Endoscopic submucosal dissection

Endoscopic submucosal dissection (ESD) permits en bloc resection of larger lesions than that can be treated with EMR[20-26]. This technique consists of several steps (Figure 1)[27,28]. The marking around the lesion is done and circumferential mucosal pre-cutting is performed after submucosal injection. To distinguish clearly between the muscle layer and the submucosal layer and allow better hemostasis, normal saline mixed with diluted epinephrine and indigo-carmine is often used as submucosal injection solution. The injection is repeated a few times until the target mucosa is sufficiently raised. After lifting of the lesion, submucosal layer under the lesion is dissected with lateral movement using various knives. Several knives have been developed and used for ESD, which include needle knife, insulation-tipped diathermic knife (IT knife), hook knife, flex knife, triangle tip knife, flush knife, splash knife, IT-2 knife and dual knife[6,28-30]. After resection of the lesion, visible vessels in the artificial ulcer is treated with hemostatic devices to prevent delayed bleeding.

Figure 1.

Endoscopic submucosal dissection procedure. A: On the lesser curvature side of the antrum, a 1.2-cm type IIa + IIc early gastric cancer is observed; B: Indigo-carmine is sprayed along the extent of tumor to aid visualization. C: Marking outside the lesion; D: After injection of saline mixed with diluted epinephrine (1:100000) and indigo-carmine into the submucosal layer, circumferential mucosal pre-cutting is performed using a knife; E: After dissection of the submucosal layer, an artificial ulcer is observed; F: Fixation of the tissue specimen.

INDICATIONS

Determining an indication for endoscopic treatment appears to be the most important step in managing patients with EGC. To select appropriate patients with EGC and to achieve a complete resection, the exact margin and depth of tumor could be determined through endoscopic evaluations. The horizontal extent of tumor can be determined with standard endoscopy and chromoendoscopy (CE). In some cases with unclear margins even with CE, magnifying endoscopy with narrow-band imaging could be useful to identify the precise margin[31]. The depth of tumor invasion can also be assessed with standard endoscopy and CE. In addition, endoscopic ultrasonography could be used to further ascertain the depth. However, the accuracy of endoscopic ultrasonography in assessing the depth of invasion in EGC was reported to range from 71% to 78%[32,33].

Conventional indication

The standard criteria[8] for selection of patients with EGC who are appropriate for the endoscopic treatment are below: (1) well or moderately differentiated adenocarcinoma and/or papillary carcinoma; (2) confined to the mucosa; (3) smaller than 2 cm for superficially elevated type lesions; (4) smaller than 1 cm for the flat and depressed type lesions; (5) without ulcer or ulcer scar; and (6) without venous or lymphatic involvement[34]. The rationale for this guideline is based on the knowledge that patients meeting the criteria are expected free from lymph node (LN) metastasis[35].

Expanded indication

Expansion of the criteria for selection of patients with EGC who are appropriate for the endoscopic treatment has been proposed in Japan from clinical observations that the too strict absolute indication leads to unnecessary surgery[36]. From the surgical data involving 5265 patients who underwent gastrectomy for EGC, Gotoda et al[7] were able to further define the risk of LN metastasis in certain groups of patients with EGC and showed four groups with a low risk of LN metastasis: (1) differentiated intramucosal adenocarcinoma without lymphovascular invasion less than 3 cm in diameter, irrespective of ulcer findings; (2) differentiated intramucosal adenocarcinoma without lymphovascular invasion and ulcer findings, irrespective of tumor size; (3) undifferentiated intramucosal cancer without lymphovascular invasion and ulcer findings smaller than 2 cm in diameter; and (4) differentiated adenocarcinoma with minute submucosal penetration (SM1, cancer invasion into the upper third of the submucosa) but without lymphovascular invasion smaller than 3 cm in diameter. These results have allowed the development of expanded criteria for endoscopic treatment for EGC[8] (Table 1). In the study by An et al[37], predictive factors for LN metastasis in EGC with submucosal invasion were identified and possibility of EMR was addressed in highly selected submucosal cancers with no lymphatic involvement, SM1 invasion, and tumor size < 1 cm. In a recent study be Lee et al[38] to compare the therapeutic outcomes of conventional and expanded indications of ESD for differentiated EGC, the conventional indication group and expanded indication group did not differ with regard to the rates of local recurrence (0.7% vs 0%), metachronous recurrence (3.6% vs 3.3%) or cumulative disease-free survival. Survival outcome was similar in the subgroups classified by tumor depth and size.

Table 1.

Criteria for endoscopic treatment in patients with early gastric cancer

	Mucosal cancer				Submucosal cancer
	No ulceration		Ulceration		SM1	SM2
Size (mm)	≤ 20	> 20	≤ 30	> 30	≤ 30	Any size
Histology
Intestinal type	A	B	B	D	B	D
Diffuse type	C	D	D	D	D	D

SM1: Cancer invasion into the upper third of the submucosa; SM2: Cancer invasion into the middle third of the submucosa. A: Conventional indications; B: Expanded indications; C: Surgery, but need for further consideration; D: Surgery (gastrectomy + lymph node dissection); Data from Soetikno et al[8].

The risk of LN metastasis is known to increase in undifferentiated cancer due to lymphovascular invasion[39]. In the analysis of 3843 patients who underwent gastrectomy with LN dissection for solitary undifferentiated EGC, none of the 310 intramucosal cancers 20 mm or less in size without lymphovascular invasion and ulcerative findings was associated with LN metastases[40]. Recently, favorable outcomes of endoscopic resection have been reported in selected patients with undifferentiated mucosal cancer or minimal submucosal invasion cancer (SM1)[41-43]. However, these are all single center retrospective studies. Therefore, large scale, prospective studies are warranted to confirm the feasibility of ESD for undifferentiated gastric cancer.

To expand the indication of endoscopic treatment to submucosal invasion (SM1) differentiated EGC, the histological heterogeneity of gastric cancer is the important issue to be addressed. Based on morphological features and histological background, gastric carcinoma is divided into differentiated and undifferentiated type or intestinal and diffuse type[44,45]. Gastric cancer shows remarkable heterogeneity in histological pattern, cellular phenotype, and genotype[46]. In a retrospective study to compare the clinicopathologic features of node-positive and node-negative differentiated submucosal invasion differentiated gastric cancers, histological heterogeneity was the independent risk factor for LN metastasis[47]. Thus, it is recommended to apply the endoscopic treatment to the differentiated EGC without histological heterogeneity when it is considered in submucosal invasion cancer.

COMPLICATIONS

Bleeding

Bleeding is the most common major complication of endoscopic treatment for EGC. Most bleeding occurs during the procedure or within 24 h[48]. Bleeding is divided into immediate (intraoperative) bleeding during procedure and delayed bleeding after procedure. Significant immediate bleeding occurs more often in the upper and middle thirds of the stomach than in the lower third of the stomach because of the larger diameter of the submucosal arteries in the upper and middle thirds of the stomach[49]. However, bleeding can be successfully treated in most cases through coagulation of the bleeding vessels, or placement of metallic clips for severe bleeding. In terms of delayed bleeding, the incidence rates were reported to range from 0%-15.6% in the recent review involving 28 studies with at least 300 ESD cases for EGC[50]. Delayed bleeding is associated to tumor location, larger tumor, recurrent lesion, macroscopic type (flat or depressed), old age (≥ 80 years) and longer procedure time[51-55]. At first, delayed bleeding was reported to occur more frequently after ESD for lesions in the lower and middle thirds of the stomach compared to the upper third of the stomach[55]. However, the reason remains unclear. In the recent study involving 1000 cases of ESD for early gastric neoplasms, delayed bleeding occurs more often in upper portion of the stomach than in lower portion (28.6% vs 13.8%, P = 0.003)[51]. In relation to antiplatelet drugs, there is a controversy in the risk of bleeding after ES. Two Korean retrospective studies have reported conflicting results on the risk of bleeding after ESD for gastric neoplasms[56,57].

Perforation

Perforation is less common major complication of endoscopic resection for EGC than bleeding and has been reported to range from 1.2% to 5.2%[50]. Perforation is diagnosed when mesenteric fat or intra-abdominal space is directly observed during the procedure (frank perforation) or free air is found on a plain chest X-ray after the procedure without a visible stomach wall defect during the procedure (micro-perforation). Immediately recognized small perforations can be successfully treated without surgery with a combination of endoscopic clipping and broad spectrum antibiotics[58-60]. However, large perforations would require immediate surgery. In cases of micro-perforation, management is not well established. In a retrospective study by Jeong et al[61], 13 cases (3.18%) of micro-perforation after EMR for gastric neoplasms were reported. Among them, 11 cases were successfully treated only with fasting, nasogastric tube drainage and broad spectrum antibiotics. In severe pneumoperitoneum, respiratory deterioration and/or shock could occur. Decompression of the pneumoperitoneum must be performed with a puncture needle in such cases[60]. Instead of air insufflations, CO₂ insufflation during procedure could minimize such pneumoperitoneum caused by a perforation[62,63].

Other complications

Stenosis after gastric ESD has been reported to range from 0.7% to 1.9%[50]. In a retrospective study, stenosis occurred with 17% of cardiac resections and 7% of pyloric resections[64]. Circumferential extent of the mucosal defect of > 3/4 and longitudinal extent > 5 cm were related to stenosis with both cardiac and pyloric resections. However, all affected patients (n = 15) were successfully treated by endoscopic balloon dilation.

Aspiration pneumonia after gastric ESD has been reported to range from 0.8% to 1.6%[50]. However, the risk of aspiration pneumonia appears to increase in sedation with continuous propofol infusion with intermittent or continuous administration of an opiod[65,66]. In addition, longer procedure time (> 2 h), male gender and old age (> 75 years) are associated with occurrence of aspiration pneumonia after ESD.

Pain after endoscopic resection is usually mild and dull in nature and can be controlled by proton pump inhibitor and opioids[36].

OUTCOMES

EMR is often the procedure of choice for patients who meet the standard criteria for endoscopic resection of EGC. Studies have shown high survival and cure rates in patients with EGC who undergo EMR. In the analysis of 308 EGCs resected endoscopically, 89% of type IIa lesions less than 2 cm were resected curatively, while only 50% of those larger than 2 cm were resected completely. In type IIc, 83% of lesions less than 1 cm and 57% of those greater than 1 cm were excised completely by endoscopic resection. In type IIc, curative endoscopic resection was possible in 85% of differentiated carcinomas and 43% of undifferentiated carcinomas[67]. These successful outcomes have allowed EMR to become the standard treatment for EGC in Japan[36]. In a Japanese report of 131 patients with differentiated mucosal EGC less than 2 cm (without ulcerative change) that had been completely removed by EMR, two patients (1.5%) died of gastric cancer during the mean observation period of 58 mo. The disease-specific 5- and 10-year survival rates were 99% and 99%[68]. However, EMR is associated with risks of local recurrence, especially when resections are not performed en bloc, or when the resection margins are involved by tumor. The risk of local recurrence after EMR ranged from 2% to 35% in Japanese series[69]. In a recent cross-sectional, retrospective cohort study, maximum diameters exceeding 2 cm was the independent risk factor for piecemeal EMR and no recurrence was observed in the en bloc group[70]. In a Korean multicenter, retrospective study, complete resection rate after EMR was (77.6%) and local recurrence rate 6.0% with a median interval between EMR and recurrence of 17.9 mo (range 3.5-51.7 mo). No deaths were related to recurrence of gastric cancer during the overall median follow-up period of 39 mo[71]. ESD increases en bloc and complete resection rates and reduces the local recurrence rate. In a retrospective study, EMR and ESD were compared with each other[20]. En bloc and histologically complete resection rates were higher with ESD than with EMR, regardless of tumor size. Local recurrences were treated by incomplete EMR (en bloc, 2.9%; piecemeal, 4.4%) but no patient experienced recurrence after ESD. The outcomes of ESD show 94.9%-97.7% rates and 83.1%-97.1% 5-year survival rates[30,51,72-75]. In a retrospective study of EGC that fulfilled the expanded criteria, en bloc resection was achieved in 94.9% (559/589) and 550 of 581 lesions (94.7%) were deemed to have undergone curative resection[72]. En bloc resection was the only significant contributor to curative ESD. Patients with non-curative resection developed local recurrence more frequently. The 5-year overall and disease-specific survival rates were 97.1% and 100%, respectively[72]. In the long-term outcomes of ESD for EGC, en bloc resection rate was 97.7% for all lesions treated by ESD. The incidence of positive horizontal and vertical margins was 3.7% and 3.4%, respectively. There were no deaths related to ESD. Local recurrence was observed in five patients (1.1%), and metachronous recurrences in 7.8% of the patients. The post-treatment 5-year survival was 83.1%. There were no deaths as a result of gastric cancer associated with sites treated by ESD[75]. In a Korean multicenter, retrospective study, 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[51]. The rates of delayed bleeding, significant bleeding, perforation and surgery related to complication were 15.6%, 0.6%, 1.2% and 0.2%, respectively. In other Korean single center, retrospective study, en bloc and curative resection rates were 96.7% and 88.3%, respectively[74]. The curative resection rate was significantly lower in the expanded group than in the standard group (82.1% vs 91.5%, P = 0.001). During a median follow-up of 24 mo, the local tumor recurrence rate was also higher in the expanded group than in the standard group (7.0% vs 1.8%, P = 0.025). Local recurrence was more frequent in lesions with non-curative resection than in those with curative resection (20.0% vs 1.3%, P < 0.001). The 5-year overall and disease-specific survival rates were 88% and 100%, respectively; the difference between the standard and expanded groups was not significant (P = 0.834).

CONCLUSION

EMR is an effective treatment modality with comparable results to surgery for selected cases of EGC. However, there is a risk of piecemeal resection with EMR in cases of large EGC, which is associated with higher recurrence rates. ESD increases en bloc and complete resection rates and reduces the local recurrence rate. Recently, favorable outcomes of ESD have been reported in patients meeting expanded criteria of endoscopic treatment for EGC. However, its technical difficulty requires a long learning period and technical invasiveness increases the risk of complications. Thus, further efforts are needed to make ESD easier and safer, which could be achieved through the technological advances. In addition, standardization of the pathologic diagnosis is necessary for the more reliable ESD. Finally, confirmation of more long-term outcomes under the expanded indication is warranted for establishing an appropriate indication of ESD for EGC.