Since the concept of early gastric cancer was first described in Japan in 1962, its treatment has evolved from curative surgical resection to endoscopic resection, initially with polypectomy to more recently with endoscopic submucosal dissection. As worldwide experience with these endoscopic techniques evolve and gain acceptance, studies have confirmed its comparable effectiveness with historical surgical outcomes in carefully selected patients. The criteria for endoscopic resection have expanded to offer more patients improved quality of life, avoiding the morbidity and mortality associated with surgery. This article summarizes the evolutional role of endoscopic and surgical therapy in early gastric cancer.
Key Points
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Gastric adenomas are a precursor for early gastric cancer (EGC) and patients should undergo endoscopic resection followed by appropriate surveillance.
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Endoscopic resection of EGC has become the preferred therapeutic procedure within the appropriate criteria, and it provides the most accurate tumor staging and risk assessment for lymph node metastasis.
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Endoscopic submucosal dissection allows resection in a wider range of patients, and the criteria have expanded for endoscopic treatment.
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A less invasive surgical approach has been investigated, yielding promising results for nonendoscopic resection candidates and noncurative endoscopic resections.
Introduction
Gastric adenocarcinoma is the second leading cause of global cancer mortality, with nearly 1 million cases annually. Gastric cancer has marked geographic and ethnic variability (with high-incidence areas in Eastern Asia, Latin America, parts of Europe, and the Middle East, and increased rates in certain ethnic groups such as Asians, Hispanics, and African Americans). In Western countries, early gastric cancer (EGC) accounts only for 15% to 21% of gastric cancer. Early detection is particularly important, because EGC has a much better prognosis than more advanced stages of gastric adenocarcinoma, with a 5-year survival rate of approximately 90%. EGC is defined as gastric cancer that invades the mucosa and submucosa, irrespective of lymph node metastases (T1, any N), and is of particular importance in Eastern Asia. In Japan, the incidence of EGC is higher than in the western population anywhere, from 15% to as high as 57%, because screening programs were implemented many decades ago.
Consideration for the Treatment of EGC
EGC was first described in Japan in 1962, and it was defined as a neoplasm that could be successfully treated with surgery. Later, it was internationally defined more specifically as gastric adenocarcinoma that is restricted to the mucosa and submucosa irrespective of lymph node metastases (T1, any N). The ongoing debate regarding whether nodal metastatic disease should still be considered “early” gastric cancer stems from the difficulty in selecting appropriate candidates for endoscopic resection versus gastrectomy, which removes regional lymph nodes. Some patients with EGC are at high risk for nodal metastases and are not appropriate for endoscopic resection. However, preremoval image-based assessment to determine the need for surgical therapy was proven to be less accurate than postendoscopic removal histologic assessment. Thus, endoscopic resection with intent to cure is often considered the final staging assessment to stratify patients who would benefit from more invasive surgical therapy. In summary, as worldwide experience in endoscopic resection continues to grow and provide further evidence (including comparative studies with surgical treatments), the criteria for endoscopic therapy is expected to expand.
Introduction
Gastric adenocarcinoma is the second leading cause of global cancer mortality, with nearly 1 million cases annually. Gastric cancer has marked geographic and ethnic variability (with high-incidence areas in Eastern Asia, Latin America, parts of Europe, and the Middle East, and increased rates in certain ethnic groups such as Asians, Hispanics, and African Americans). In Western countries, early gastric cancer (EGC) accounts only for 15% to 21% of gastric cancer. Early detection is particularly important, because EGC has a much better prognosis than more advanced stages of gastric adenocarcinoma, with a 5-year survival rate of approximately 90%. EGC is defined as gastric cancer that invades the mucosa and submucosa, irrespective of lymph node metastases (T1, any N), and is of particular importance in Eastern Asia. In Japan, the incidence of EGC is higher than in the western population anywhere, from 15% to as high as 57%, because screening programs were implemented many decades ago.
Consideration for the Treatment of EGC
EGC was first described in Japan in 1962, and it was defined as a neoplasm that could be successfully treated with surgery. Later, it was internationally defined more specifically as gastric adenocarcinoma that is restricted to the mucosa and submucosa irrespective of lymph node metastases (T1, any N). The ongoing debate regarding whether nodal metastatic disease should still be considered “early” gastric cancer stems from the difficulty in selecting appropriate candidates for endoscopic resection versus gastrectomy, which removes regional lymph nodes. Some patients with EGC are at high risk for nodal metastases and are not appropriate for endoscopic resection. However, preremoval image-based assessment to determine the need for surgical therapy was proven to be less accurate than postendoscopic removal histologic assessment. Thus, endoscopic resection with intent to cure is often considered the final staging assessment to stratify patients who would benefit from more invasive surgical therapy. In summary, as worldwide experience in endoscopic resection continues to grow and provide further evidence (including comparative studies with surgical treatments), the criteria for endoscopic therapy is expected to expand.
Pretreatment evaluation
Macroscopic description of early gastrointestinal neoplasia (EGN), including dysplasia and cancer, was summarized in the Vienna classification of gastrointestinal epithelial neoplasia and the Japanese macroscopic classification of superficial gastric carcinoma (Japan Gastroenterological Endoscopy Society [JGES] classification system), from which an international consensus system was proposed in 2002 called the Paris system , underscoring the importance of these classifications. Gastric adenoma, defined as intraepithelial or noninvasive gastric dysplasia, progresses in an unpredictable time frame from low-grade to high-grade dysplasia or carcinoma in situ, and to invasive neoplasia (adenocarcinoma). High-grade dysplasia is a direct precursor to invasive cancer, with a known risk for associated synchronous cancer, and therefore a treatment is indicated and the remainder of the stomach must be carefully examined. Endoscopic resection is recommended for all gastric adenomas because of the risk for transformation to adenocarcinoma.
Endoscopic detection of EGN requires meticulous evaluation and photodocumentation of lesions. Their appearance varies widely, and can include a subtle polypoid protrusion, a superficial plaque, ulcer, depression, or even a mucosal discoloration. Novel endoscopic imaging technologies have been investigated to improve detection, including chromoendoscopy, magnification endoscopy, special image acquisition or processing (eg, narrow band imaging [NBI]), and autofluorescence imaging. Endoscopic findings can predict tumor stage and depth of invasion of EGN. Mucosal disease is suggested by smooth surface protrusion or depression, slight marginal elevation, and smooth tapering of converging folds, whereas submucosal disease is indicated by an irregular surface, marked marginal elevation, clubbing, abrupt cutting, or fusion of converging folds. Tumor factors associated with lymph node metastasis derived from “ histological ” data are summarized in Box 1 .
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Large tumor size (>20, especially >30 mm)
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Diffuse (undifferentiated) or mixed (intestinal/undifferentiated) histology
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Ulceration
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Submucosal involvement (especially >0.5 mm)
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Lymphovascular invasion
Endoscopic ultrasound
Endoscopic ultrasound (EUS) is the most reliable nonhistopathologic method for evaluating the invasion depth of gastric cancer, allowing visualization of the gastric wall layers. T-stage determination with EUS is more accurate than computed tomography (CT) scanning for gastric cancer, and EUS-guided fine-needle aspiration of suspicious nodes has increased the accuracy of nodal staging. The limitations of EUS are that the staging accuracy is limited in separating among T1m and T1sm 1 through 3, and it varies with the size, location, and differentiation of the tumor (eg, overstaged with inflammation when >3 cm and located in the mid-stomach, and understaged with poorly differentiated tumors). EUS is used less for pretreatment evaluation of EGC, because endoscopic findings and the postendoscopic resection specimen can guide treatment.
Treatment options
Endoscopic Resection
Endoscopic mucosal resection
Polypectomy was first introduced in 1968, and endoscopic mucosal resection (EMR) has emerged and evolved since the 1980s. It is an alternative to gastrectomy for patients who meet the standard criteria for endoscopic resection of EGC. Historical standard criteria for EMR according to JGES was protruded lesions equal or less than 2 cm, flat or depressed lesions equal or less than 1cm and the cancers limited to mucosa ( Box 2 ). A review of the Japanese literature showed that an extremely high rate of disease-specific survival is achieved when the JGES criteria for EMR are satisfied (>99% among 1353 patients followed up for 4 months to 11 years). In addition, both Japanese and Western studies have shown high survival rates in patients with EGC treated with EMR, with a low complication rate, shorter median hospital stay, and lower cost of care. EMR is usually performed using 1 of 2 techniques—with suction (suck-and-cut) or without (lift-and-cut)—using a submucosal injection to separate the mucosa and muscularis propria to reduce the risk of perforation. Normal saline, hypertonic saline, 50% dextrose, 10% glycerol, 5% fructose, fibrinogen mixture, autologous blood, sodium hyaluronate, and hydroxypropyl methylcellulose have been used for injection. Nonlifting or puckering of the lesion during injection suggests invasion of the deep submucosa or muscularis propria.
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Protruded type lesions ≤2 cm
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Flat or depressed lesions ≤1 cm
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Cancers that are limited to the mucosa
Endoscopic submucosal dissection
Endoscopic submucosal dissection (ESD) was developed in late 1990 to completely remove the gastric dysplasia and cancer regardless of size and location. The size limitation and margin evaluation had been challenges with EMR for gastric cancer in achieving curative resection, especially when it required piecemeal resection. These limitations had caused high rates of residual disease and recurrence, resulting in inferiority to surgical therapy. ESD uses a specialized needle knife or equipment to dissect the lesions from the intestinal wall, assisted by a long-lasting submucosal fluid cushion ( Figs. 1–8 ). The major advantage of ESD is that it offers significantly larger en bloc resection of tumor than EMR. It was most extensively investigated for a treatment of EGC, and its use has expanded to lesions in the esophagus and colon. ESD uses various types of endoscopic electrosurgical needle knives, and many new devices have been developed with improved features for ease and safety. This technique requires advanced skill and training, and is not widely available in the United States except in specialized centers. Details of the ESD procedure are published elsewhere and are beyond the scope of this section.
Meta-analysis of comparative studies of ESD and EMR showed that patients with EGC who underwent ESD had lower rates of local recurrence and higher en bloc and curative resection rates compared with those who underwent EMR for malignant and premalignant lesions of the gastrointestinal tract. However, tumors smaller than 10 mm (especially <7 mm) may be managed with EMR with comparable outcome. The drawbacks of ESD are the longer procedure time and higher risk for intraoperative (but not delayed) bleeding and perforation, although these complications can be managed endoscopically without surgery. According to meta-analyses, the perforation rate for ESD was 4.5%, compared with 1.0% for EMR. The factors associated with perforations during ESD were suggested to be tumors of the upper stomach and tumor size greater than 20 mm.
Surgical Resection
Because of the lack of expertise in endoscopic resection techniques, gastrectomy remains the most widely used approach to treating EGC worldwide. Gastrectomy with regional lymph node dissection is recommended for patients who do not fulfill the criteria for endoscopic resection, for whom lymph node metastasis is highly suspected during preoperative staging, or who are at increased risk of lymph node metastases according to postendoscopic resection assessment. Surgical resection for EGC offers a 5-year survival rate of up to 98%. Recurrence rates and mortality after surgery are higher in Western countries than in Asia, which may reflect differences in follow-up protocol (endoscopic surveillance for synchronous and metachronous lesions); the extent and method of lymph node dissection (for example, one based on anatomical lymph node distribution for determining accurate stage-specific survival in Asia, and the other in the West based on an absolute number of lymph nodes investigated ; and the pathologic criteria used to determine malignancy.
Surveillance for Metachronous Gastric Cancer
Surveillance after treatment of gastric cancer requires special attention. Even though the overall 5-year survival rate for surgically or endoscopically treated EGC is more than 90%, the recurrence rate is reported from 2 to 15 %, with the higher range quoted in the Western literature. Regardless of surgical or endoscopic treatment, synchronous and metachronous gastric cancers are seen in patients with EGC. High-risk groups for metachronous cancers include patients with multifocal synchronous EGCs, older age, male sex, submucosal invasion, and proximal gastrectomy. Long-term follow-up studies have found that metachronous lesions occur in anywhere from 2% to 8% of patients, including in the gastric remnant, which is seen even after 10 years of surgery. While CT scanning, positron emission tomography scanning, and tumor markers are important to detect metastatic recurrence, they play no role in detecting gastric metachronous lesions. Therefore, endoscopic surveillance is advocated for early detection because the survival rate of patients treated for remnant gastric cancer had been low because of discovery at later stage. Endoscopic resection has been applied to metachronous cancer in the gastric remnant and after endoscopic resection and seems to be feasible and safe.
Treatment for Helicobacter pylori Infection
Helicobacter pylori infection is a well-defined risk factor for gastric adenocarcinoma, and chronic infection is associated with metachronous tumors. Treatment of H pylori infection has been shown to decrease the risk of developing gastric and metachronous cancer, although a longer follow-up period (>5 years) was reported to be associated with less difference in incidence once gastric mucosal atrophy had developed. Based on the available data from a randomized controlled trial, all patients with EGC should be treated for H pylori infection if present, and successful eradication should be confirmed with an appropriate test.
Investigations with endoluminal therapy
Standard and Expanding Criteria for Endoscopic Resection, and Risk Stratification
Criteria for selecting appropriate patients with EGC for endoscopic resection with either EMR or ESD are shown in Box 3 . ESD virtually eliminated the restriction on the size of lesion to be removed endoscopically and enabled comprehensive histologic assessment. Gotoda and colleagues proposed a lower-risk category, derived from an analysis of more than 5000 surgical specimens, which allowed the criteria for endoscopic resection to be expanded to larger tumors and an inclusion of certain submucosal tumors ( Box 4 ). Submucosal cancer, when it satisfies certain criteria, shows very small risk for lymph node metastasis, similar to mucosal cancer (eg, <30 mm, tumor confined to the upper 0.5 mm of submucosa, absence of lymphovascular invasion), and patients may be followed closely without surgery. As a result, the traditional consensus indications for gastrectomy with removal of perigastric lymph nodes ( Box 5 ) are no longer absolute, and treatment decisions are made based on the availability of endoscopic expertise, comorbidities, and patient preference, especially when presented with the option of minimally invasive surgery.
- 1.
High probability of en bloc resection
- 2.
Tumor histology
- a.
Intestinal-type adenocarcinoma
- b.
Tumor confined to the mucosa
- a.
- 3.
Tumor size and morphology
- a.
Less than 20 mm without ulceration
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Less than 10 mm if Paris classification IIb or IIc
- a.
- 1.
Mucosal tumors of any size without ulceration
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Mucosal tumors less than 30 mm with ulceration (1.2 are for differentiated adenocarcinoma)
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Poorly differentiated adenocarcinoma or signet-ring cell carcinoma: Mucosal tumors less than 20 mm without ulceration
- 1.
Low probability of en bloc resection with EMR or ESD, most likely piecemeal
- 2.
Diffuse-type (undifferentiated) adenocarcinoma
- 3.
Submucosal tumor size greater than 30 mm, or tumors with ulceration
- 4.
Evidence of lymphovascular invasion in the primary tumor, or known/suspected lymph node metastasis
Curative resection for EGC with ESD
Many retrospective studies in single and multiple centers evaluated curative resection after ESD. Noncurative resection is defined as the presence of positive lateral or vertical margins, submucosal and lymphovascular invasion, or undifferentiated histology, which implies a higher risk for adverse events (eg, lymph node and distant metastasis or recurrence), and additional surgical therapy is likely beneficial. However, when only positive or unclear lateral margins are seen, this indicates a lower risk for lymph node metastasis in the absence of other factors listed earlier. Invasion depth was also carefully evaluated. When the tumor is differentiated and has no lymphovascular invasion, less than 0.5 mm of submucosal involvement is considered a criterion for expanded curative resection. The likelihood of noncurative resection increases with large (>30 mm), piecemeal excised/non–en bloc resected, ulcerated, undifferentiated (especially >20 mm), and deep submucosal (>0.5 mm) tumors; with tumors located in the upper third of the stomach location (for ulcerative tumors in the upper and mid-stomach); and in elderly patients (>75 years of age). Complication rates of bleeding and perforation associated with ESD may increase based on the expanded criteria compared with the traditional criteria. In elderly patients, ESD remains a valid method for curative resection and should not be excluded, although increased rates of postprocedure pneumonia have been reported.
Management of Incomplete Resection: Piecemeal Versus En Bloc; Positive Margins; and Histologic Risk Factors
In patients with positive lateral margins without other risk factors found on histopathologic evaluation of lesions treated with EMR/ESD, either careful endoscopic follow-up and as-needed adjunct endoscopic therapy or minimally invasive surgery can be considered, because they have a lower risk for experiencing metastasis. However, gastrectomy is recommended for patients with positive vertical margins, submucosal involvement (with high-risk features), or lymphovascular invasion. Current research focuses on whether patients with incomplete resection after EMR/ESD can be managed with laparoscopic gastrectomy, or even laparoscopic lymph node dissection without gastrectomy when margins are negative.
Laparoscopic gastrectomy
Laparoscopic gastrectomy has been performed in specialized centers. Comparing the outcome with traditional open surgery, laparoscopic approach was shown to benefit patients with lower complications, faster recovery, and improved quality of life. Various laparoscopic surgical techniques are being implemented based on location (distal versus proximal), tumor characteristics, and the field of lymph node dissection.
Laparoscopic lymph node dissection without gastrectomy
Another area of active investigation is laparoscopic lymph node dissection without gastrectomy in patients treated with ESD who have negative margins but are considered to have had noncurative resections based on the presence of other criteria (ie, submucosal invasion, lymphovascular invasion, or undifferentiated adenocarcinoma). The area chosen for lymph node dissection in the small case series was based on the location of the tumor and/or the lymphatic drainage of the stomach visualized with standard laparoscopy or infrared-ray electronic laparoscopy after submucosal injection of indocyanine green (ICG) around post-ESD scars (sentinel lymph node). A retrospective study of 21 patients showed that 10% (n = 2) had lymph node metastases confirmed after lymph node dissection without gastrectomy, and none had local or distant recurrence at a median follow-up of 61 months. This approach may be acceptable for carefully selected patients. Further prospective comparison studies are needed to generalize this approach to clinical practice.
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