Given its morbidity and mortality, the early detection and diagnosis of gastric cancer is an area of intense research focus. This article reviews the emerging use of enhanced endoscopic imaging technologies in the detection and management of gastric cancer. The combined use of white-light endoscopy with enhanced imaging technologies, such as magnification narrow-band imaging, chromoendoscopy, and autofluorescence endoscopy, demonstrates promise in the improved ability to detect and delineate gastric neoplasia. However, widespread clinical use is still limited, mainly because of the restricted availability of the technologies.
Key points
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The early detection and diagnosis of gastric cancer continues to be a focus of intense research.
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Magnification narrow-band imaging has shown increased sensitivity and specificity for the detection of gastric neoplasia, and has also demonstrated promising results when combined with chromoendoscopy.
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Further imaging enhancing techniques, such as flexible spectral imaging color enhancement and autofluorescence endoscopic imaging, have also yielded results superior to those obtained by white-light endoscopy in the detection of gastric neoplasia.
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The common clinical use of these imaging techniques is limited by a lack of widespread availability.
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A major challenge to be overcome in the screening for gastric cancer is the large surface area of the gastric lumen and the need to perform image-enhanced wide-field imaging that can highlight small abnormal mucosal areas, which can be further targeted with imaging-enhancing techniques such as endomicroscopy.
Introduction
Gastric cancer remains a leading cause of morbidity and mortality. Worldwide, gastric cancer is the fourth most commonly diagnosed cancer in males and the fifth in females, with the highest incidence rates in Eastern Asia, the Middle East, and Latin America. Five-year survival rates are a dismal 15% to 20% primarily because of diagnosis at a late, less curable stage. Gastric cancer is subdivided into 2 main histopathologic subtypes, intestinal type and diffuse type. The diffuse type is poorly differentiated, is associated with hereditary diffuse gastric cancer, and has been linked to a molecular abnormality in the cell adhesion protein E-cadherin (CDH1). The intestinal type, the major subtype, is well differentiated and common in high-risk populations, is more often sporadic, and its development is usually also related to environmental factors. Early detection with screening endoscopy has been used in countries with high-risk populations, such as Japan, Chile, and Korea. Given that the prognosis of gastric cancer depends on the stage of the cancer at the time of diagnosis, early detection and treatment is the only way to reduce mortality. The incidence of early gastric cancer, that is, gastric cancer that invades the mucosa and submucosa irrespective of lymph node metastasis, has an incidence in Japan from 15% to 57%, following the implementation of screening programs. However, despite these screening methods, the sensitivity of endoscopy in detecting gastric cancer has been reported to range from 77% to 84%. Therefore, recent research in gastric cancer screening has focused on improving endoscopic detection with magnification endoscopy, narrow-band imaging, autofluorescence imaging, and chromoendoscopy. This review focuses on these endoscopic imaging techniques and their potential usefulness in the detection and management of early gastric cancer.
Introduction
Gastric cancer remains a leading cause of morbidity and mortality. Worldwide, gastric cancer is the fourth most commonly diagnosed cancer in males and the fifth in females, with the highest incidence rates in Eastern Asia, the Middle East, and Latin America. Five-year survival rates are a dismal 15% to 20% primarily because of diagnosis at a late, less curable stage. Gastric cancer is subdivided into 2 main histopathologic subtypes, intestinal type and diffuse type. The diffuse type is poorly differentiated, is associated with hereditary diffuse gastric cancer, and has been linked to a molecular abnormality in the cell adhesion protein E-cadherin (CDH1). The intestinal type, the major subtype, is well differentiated and common in high-risk populations, is more often sporadic, and its development is usually also related to environmental factors. Early detection with screening endoscopy has been used in countries with high-risk populations, such as Japan, Chile, and Korea. Given that the prognosis of gastric cancer depends on the stage of the cancer at the time of diagnosis, early detection and treatment is the only way to reduce mortality. The incidence of early gastric cancer, that is, gastric cancer that invades the mucosa and submucosa irrespective of lymph node metastasis, has an incidence in Japan from 15% to 57%, following the implementation of screening programs. However, despite these screening methods, the sensitivity of endoscopy in detecting gastric cancer has been reported to range from 77% to 84%. Therefore, recent research in gastric cancer screening has focused on improving endoscopic detection with magnification endoscopy, narrow-band imaging, autofluorescence imaging, and chromoendoscopy. This review focuses on these endoscopic imaging techniques and their potential usefulness in the detection and management of early gastric cancer.
Who to screen
The major histopathologic subtype of gastric cancer, the intestinal type, progresses through various histologic stages before developing into adenocarcinoma. An accepted model for the development of gastric adenocarcinoma, the Correa cascade, consists of the development of nonatrophic gastritis into multifocal atrophic gastritis followed by intestinal metaplasia, and finally dysplasia and the development of carcinoma. Intestinal metaplasia is a frequently identified histologic finding in the gastric biopsies of high-risk populations for gastric cancer, such as Asians and Latin Americans. In the United States, endoscopic surveillance is not routinely recommended in patients with gastric intestinal metaplasia, and is reserved for patients at high risk because of family history or ethnic background. Recently, several European societies of experts convened to propose guidelines for the diagnosis and management of patients with precancerous conditions of the stomach. The panel concluded that because gastric atrophy and intestinal metaplasia are part of the pathway of the development of intestinal-type gastric cancer, these lesions should be considered precancerous, and that patients with extensive atrophy and/or extensive intestinal metaplasia should therefore be offered surveillance endoscopy every 3 years ( Fig. 1 ). Further studies will be needed to determine the cost-effectiveness of this surveillance strategy. In addition, surveillance has been recommended in other patients at high risk for developing gastric cancer, which includes patients with adenomatous gastric polyps, familial adenomatous polyposis, and hereditary nonpolyposis colorectal cancer.
Endoscopic detection
White-Light Endoscopy
With the advent of the flexible gastroscope and the flexible gastric-biopsy tube, researchers found that there was little correlation between the endoscopist’s impression of gastritis or atrophy and the histologic findings present on biopsy. In 1956, Atkins and Benedict attempted to correlate gross endoscopic findings with histologic findings on biopsy. In cases with presumed chronic gastritis at gastroscopy, 76.7% were normal microscopically, and in cases of suspected acute gastritis 61.5% were microscopically normal. Despite continued advancements in the instruments used for endoscopy since this study, there is little evidence that high-resolution endoscopes have improved the correlation between gastroscopic and microscopic findings. A recent study attempted to classify the mucosal patterns of Helicobacter pylori –related gastritis in the gastric body with standard endoscopy and evaluate its reproducibility. One hundred twelve patients with dyspepsia had examinations with upper endoscopy, and the observed mucosal morphology in the gastric body was categorized into 4 types ( Fig. 2 ). The investigators found that type 3 mucosal patterns (defined as a mosaic mucosal pattern) and type 4 mucosal patterns (defined as a mosaic pattern with a focal area of hyperemia) had a sensitivity, specificity, and positive and negative predictive values for predicting H pylori –positive gastric mucosa of 100%, 86%, 94%, and 100%, respectively. In addition, the mean κ values for interobserver and intraobserver agreement in assessing the various endoscopic patterns were 0.808 (95% confidence interval [CI] 0.678–0.938) and 0.826 (95% CI 0.727–0.925), respectively. However, a previous study that examined 52 healthy subjects had found poor interobserver agreement between endoscopists for endoscopic features suggestive of gastritis, and although antral nodularity was highly specific for H pylori gastritis, it lacked sensitivity. Endoscopic determination of gastric atrophy has also been found to correlate poorly with histologic diagnosis. In a study performed on more than 1300 subjects referred for endoscopy, the sensitivity and specificity of endoscopy for the diagnosis of atrophy based on histologic diagnosis of atrophy were 61.5% and 57.7% in the antrum and 46.8% and 76.4% in the body of the stomach. Several studies have also found that gastric cancer is missed on initial endoscopic examinations. Sensitivity of endoscopy in detecting gastric cancer has ranged from 77% to 93%, with researchers suggesting that a high threshold for performing biopsies of lesions that appear benign as a possible cause of missed early gastric cancer ( Fig. 3 ).
Narrow-Band Imaging and Magnification Endoscopy
Narrow-band imaging (NBI) enhances the imaging of mucosal and glandular changes and the visualization of abnormal vascular patterns without using dyes. NBI uses optical filters that can be enabled or disabled during endoscopy and allow limited wavelengths of light, specifically blue light at 390 to 445 bandwidth and green light at 530 to 550 nm bandwidth. These wavelengths can only penetrate superficially and therefore enhance the visualization of the superficial mucosa and vasculature, aiding in the detection of cancer and precancerous lesions. An advantage of NBI is its ease of use and wide availability. In a study of patients with known intestinal metaplasia or dysplasia undergoing surveillance endoscopy, NBI without magnification increased the diagnostic yield for the detection of advanced premalignant gastric lesions in comparison with routine white-light endoscopy (WLE). The sensitivity, specificity, and positive and negative predictive values for the detection of premalignant lesions were 71%, 58%, 65% and 65% for NBI and 51%, 67%, 62% and 55% for WLE, respectively. However, several researchers have noted that a limitation of NBI without magnification is that, owing to the large gastric lumen, it produces dark images that are not meaningful for investigation. Recently a consensus of experienced endoscopists in the Asia-Pacific region convened, and agreed that it is often difficult to survey the whole gastric lumen by NBI; therefore almost all participants thought that NBI alone was not useful for detection of early gastric cancer. By contrast, magnification endoscopy with NBI (M-NBI) was found to be useful in distinguishing gastric neoplasia from nonneoplasia, and in determining tumor margins but not tumor depth.
The use of M-NBI, which enhances color differences with magnified views, has shown increased accuracy for the detection of premalignant lesions. However, a major limitation of M-NBI is its limited availability. The LUCERA system (Olympus Medical Systems Co. Inc, Tokyo, Japan) is a red/green/blue (RGB) sequential system that uses a monochromatic charge-coupled device (CCD) and is available in Japan, Korea, China, Taiwan, and the United Kingdom. The EXERA system (Olympus Medical Systems) is a nonsequential system that uses a color CCD, and is available in the rest of the world. Nevertheless, multiple studies performed using both platforms have demonstrated an increased accuracy for the detection of cancerous and precancerous lesions. Bansal and colleagues used the EXERA system with M-NBI, and found that the endoscopic finding of a ridge/villous pattern when correlated with histology had sensitivity of 80% and specificity of 100% for the detection of gastric intestinal metaplasia. Similarly, Tahara and colleagues found that the endoscopic appearance of tubulovillous pits had very high sensitivity for intestinal metaplasia, and Uedo and colleagues found that the endoscopic appearance of light blue crests, defined as a fine, blue-white line on the crests of the epithelial surface/gyri, correlated with histologic evidence of intestinal metaplasia with a sensitivity of 89%. Although these studies found improved diagnostic accuracy with M-NBI, there was variability in the NBI classification systems. A recent, multicenter study was performed to describe and estimate the accuracy and reliability of a classification system for NBI in the diagnosis of gastric lesions ( Table 1 ). Consecutive patients undergoing NBI endoscopy at 2 reference centers (N = 85, 33% with dysplasia) were included. In total, 224 different areas were biopsied and recorded onto video. Pattern A, defined as regular vessels with circular mucosa, was associated with normal histology (accuracy 83%; 95% CI 75%–90%). Pattern B, tubulovillous mucosa, was associated with intestinal metaplasia (accuracy 84%; 95 CI 77%–91%). Pattern C, irregular vessels and mucosa, was associated with dysplasia (accuracy 95%; 95 CI 90%–99%). Furthermore, the reproducibility of these patterns was high (κ = 0.62).
| A | B | HP+ | C | ||
|---|---|---|---|---|---|
| Mucosal Pattern | Regular circular | Regular ridge/tubulovillous | Light blue crest | Regular | Irregular/absent White opaque substance |
| Vascular Pattern | Regular thin/peripheric or thick/central vessels | Regular | Regular with variable vascular density | Irregular | |
| Expected Outcome | Normal | Intestinal metaplasia | Helicobacter pylori infection | Dysplasia | |
| Accuracy (95% confidence interval) | 83% (75%–90%) | 84% (77%–91%) | 70% (59%–80%) | 95% (90%–99%) | |
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