GASTRIC CANCER IS the third leading cause of cancer

Transcription

1 Digestive Endoscopy 2016; 28: doi: /den Guideline Magnifying endoscopy simple diagnostic algorithm for early gastric cancer (MESDA-G) Manabu Muto, 1,2,3 Kenshi Yao, 1,2,3 Mitsuru Kaise, 1,2,3 Mototsugu Kato, 1,2,3 Noriya Uedo, 1,2,3 Kazuyoshi Yagi 1,2,3 and Hisao Tajiri 1,2,3 1 The Japanese Gastroenterological Association, 2 Japan Gastroenterological Endoscopy Society, Tokyo, and 3 The Japanese Gastric Cancer Association, Kyoto, Japan Gastric cancer is the third leading cause of cancer death worldwide. Early detection and accurate diagnosis of mucosal cancer is desirable in order to achieve decreased mortality; cause-specific survival of patients with early gastric cancer is reported to exceed 95%. Endoscopy is the functional modality to detect early cancer; however, the procedure is not definitive when using conventional white-light imaging. In contrast, magnifying narrow-band imaging (M-NBI), a novel endoscopic technology, is a powerful tool for characterizing gastric mucosal lesions because it can visualize the microvascular architecture and microsurface structure. To date, many reports on the diagnosis of early gastric cancer by M-NBI, including multicenter prospective randomized studies conducted in Japan, have been published in peer-reviewed international journals. Based on these published data, we devised a proposal for a diagnostic strategy for gastric mucosal cancer using M-NBI to simplify the process of diagnosis and improve accuracy. Herein, we recommend a diagnostic algorithm for early gastric cancer using magnifying endoscopy. Key words: diagnosis, early cancer, gastric cancer, magnifying endoscopy, narrow-band imaging INTRODUCTION GASTRIC CANCER IS the third leading cause of cancer death worldwide. Effective endoscopic diagnosis of tumors in their early stages is essential for reducing gastric cancer death by curative treatment. As many previous studies demonstrated that magnifying endoscopy (ME) is a highly accurate technique for detecting early gastric cancer (EGC), this modality is currently the key to its effective diagnosis and curative treatment. However, because many different criteria or algorithms for the diagnosis and classification of EGC have been proposed, there is controversy about which criteria or algorithm should be used. Therefore, a unified algorithm for general use in the clinical setting is necessary for enhancing the efficacy of ME diagnosis of EGC. The Japanese Gastroenterological Association (JGA) established a working group and proposed Corresponding: Manabu Muto, Department of Therapeutic Oncology, Kyoto University Graduate School Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto , Japan. mmuto@kuhp.kyoto-u.ac.jp Received 3 November 2015; accepted 17 February that the Japan Gastroenterological Endoscopy Society (JGES), the Japanese Gastric Cancer Association (JGCA), and the World Endoscopy Organization (WEO) jointly devise a unified international algorithm for ME diagnosis of EGC (Magnifying Endoscopy Simple Diagnostic Algorithm for Gastric cancer [MESDA-G], Fig. 1) using an evidence-based approach. METHODS TO PROPOSE THIS algorithm, a PubMed search of the English language medical literature was conducted for the period between 1 January 1990 and 10 February We used the following key words for our search: gastric or stomach and cancer or carcinoma and magnifying or magnification or zoom. In addition, all relevant articles were manually inspected to identify publications that may have been missed using the preceding search terms. Reference lists of all identified studies were also reviewed, and full original articles were retrieved for any potentially relevant citations. After this peer-reviewed process, 169 articles were found by searching PubMed and 22 more articles were obtained by manual search. Among them, randomized controlled studies, observational studies, case series, and review articles were selected for bs_bs_banner 2016 The Author Digestive Endoscopy published by John Wiley & Sons Australia, Ltd 379 on behalf of Japan Gastroenterological Endoscopy Society This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

2 380 M. Muto et al. Digestive Endoscopy 2016; 28: Figure 1 Magnifying Endoscopy Simple Diagnostic Algorithm for Gastric cancer (MESDA-G). DL, demarcation line; IMVP, irregular microvascular pattern; IMSP, irregular microsurface pattern. Figure 2 Macroscopic types of early gastric carcinoma by Japanese Classification of Gastric Carcinoma provided by Japan Gastric Cancer Association. sup., superficial. this algorithm. Studies were excluded if they were not original reports on the diagnosis of EGC or if they were case reports. After this filtering, 66 articles were selected for use in this algorithm (57 from PubMed and nine from the manual search) Among the selected articles, the most commonly accepted diagnostic system was used for constructing the diagnostic algorithm for EGC by using ME. CANCER DEFINITION AND MACROSCOPIC CLASSIFICATION CANCER DEFINITIONS AND macroscopic classifications are shown in Figure 2). EGC is defined as carcinoma confined to the mucosa and submucosa, with or without regional lymph node metastasis. 67 The histological diagnosis of EGC corresponds to categories 4 (mucosal highgrade neoplasm) and 5 (submucosal invasion by carcinoma) according to the Vienna classification. 68,69 Endoscopic screening is useful to detect EGC. Macroscopic classification of the JGCA distinguishes a superficial-type tumor (Type 0) as a typical gross morphological type of EGC. Type 0 is further subdivided into protruding (Type 0-I), superficial elevated (Type 0-IIa), superficial flat (Type 0-IIb), superficial depressed (Type 0-IIc), and excavated (Type 0-III) types Tumors with <3 mm elevation are usually classified as Type 0-IIa, whereas more elevated tumors are classified as Type 0-I. In this review, we focused mainly on lesions of 0- IIa, 0-IIb and 0-IIc, because most of the evidence was from these lesions. MAGNIFYING ENDOSCOPY SIMPLE DIAGNOS- TIC ALGORITHM OF EGC: MESDA-G FIGURE 1 SHOWS THE MESDA-G algorithm. To diagnose EGC, one has to identify any suspicious lesion that is potentially a neoplasm. To recognize such a lesion, we carefully observe the color change (whitish or reddish) or morphological change (elevated, flat, or depressed) on the gastric mucosal surface. If we detect a suspicious lesion, identification of a demarcation line (DL) between the lesion and the background mucosa is the first step in distinguishing EGC from a non-cancerous lesion. If a DL is absent, the diagnosis of a benign lesion may be made. If a DL is present, the subsequent presence of an irregular microvascular (MV) pattern and an irregular microsurface (MS) pattern should be determined. If irregular MV and/or MS patterns are present within the demarcation line, the diagnosis of EGC can be made. ENDOSCOPIC IMAGING OF NON-NEOPLASTIC GASTRIC MUCOSA UNDERSTANDING THE ENDOSCOPIC finding of the non-neoplastic gastric mucosa is important for: (i)

3 Digestive Endoscopy 2016; 28: Diagnostic algorithms for EGC by ME 381 identification of high-risk individuals who develop gastric cancer; (ii) distinguishing neoplastic lesions from nonneoplastic lesions; and (iii) determination of the tumor boundary in order to make treatment decisions. Gastric cancer, especially the non-cardiac type, usually develops in patients with chronic Helicobacter pylori (H. pylori) infections; therefore, the surrounding mucosa is mostly affected by inflammatory cell infiltration, atrophy, or intestinal metaplasia. H. pylori-associated chronic gastritis alters the MVarchitecture and the MS structure of non-neoplastic gastric mucosa. NORMAL FUNDIC GLAND MUCOSA A NORMAL FUNDIC gland mucosa indicates a corpus mucosa without any pathological change such as inflammation or atrophy as a result of H. pylori infection. Arterioles that run through the muscularis mucosa lead to mucosal capillaries forming a network inside the mucosa, and these capillaries surround the fundic glands and the surface epithelium of the crypt. Capillaries proceed to the venous plexus under the covering epithelium and converge at collecting venules, which vertically descend into the tunica muscularis mucosae (Fig. 3a). 73 ME with narrow-band imaging (NBI) of the normal fundic gland mucosa is characterized as follows: the surface epithelium lining crypt opening is visualized as an oval white belt-like structure which is reported to be the marginal crypt epithelium (MCE) 74 or the white zone 8 (Fig. 3b). Capillaries surrounding each crypt opening form honeycomb-like subepithelial capillary networks These capillaries converge into collecting venules that vertically descend under the tunica muscularis mucosae and flow into a main vein. Collecting venules have a starfish-like appearance with a cyan color NORMAL PYLORIC GLAND MUCOSA ANORMAL PYLORIC gland mucosa refers to a pyloric mucosa without any pathological changes such as inflammation or intestinal metaplasia as a result of H. pylori infection. The crypts in the pyloric gland mucosa form grooves. The intervening parts between the grooves form ridges. Arterioles through the muscularis mucosa proceed to capillary networks inside the mucosa, and these capillaries exist below the surface epithelium of the ridge-like structure surrounded by crypts (Fig. 4a). The ME with NBI of the normal pyloric mucosa shows that the intervening part is lined with a white belt-like structure, which is referred to as the MCE 74 or the white zone. 8 Coil-shaped subepithelial capillary networks are observed through the surface epithelium of the Figure 3 Schematic diagram of the microvascular architecture and the microsurface structure of the normal gastric fundic gland mucosa corresponding to the surface morphology as visualized by magnifying endoscopy (ME) with narrow-band imaging (NBI). The microvascular architecture is formed by the capillaries and collecting venules. The morphology of each capillary is that of a polygonal closed loop. These loops anastomose repeatedly with each other, forming a regular honeycomb-like subepithelial capillary network pattern. The microsurface structure is made up of the marginal crypt epithelium/white zone (MCE/WZ), and the intervening part in between. The epithelial morphology is visualized as a semitransparent white belt-like structure (the MCE/WZ), showing a circular or oval shape at the center of which lies the crypt opening. ME with NBI of normal fundic gland mucosa.

4 382 M. Muto et al. Digestive Endoscopy 2016; 28: Figure 4 Schematic diagram of the microvascular architecture and the microsurface structure of the normal gastric pyloric gland mucosa corresponding to the surface morphology as visualized by magnifying endoscopy (ME) with narrow-band imaging (NBI). The microvascular architecture is formed by capillaries and collecting venules, but the latter are rarely observed from the mucosal surface. The morphology of each capillary is that of coil-shaped open loops. The mucosal surface structure is made up of the marginal crypt epithelium/white zone (MCE/WZ) and the intervening parts surrounded by MCE/WZ. The MCE/WZ morphology usually shows polygonal structures but may be curved or linear. ME with NBI of normal pyloric gland mucosa. intervening part (Fig. 4b) The ME finding of the pyloric gland mucosa is completely different from that of the fundic gland mucosa. MUCOSA IN H. PYLORI-ASSOCIATED CHRONIC GASTRITIS PERSISTENT H. PYLORI INFECTION causes inflammation, atrophy, and intestinal metaplasia in the gastric mucosa. 80 This pathological condition is called chronic gastritis. The present review will not cover other causes of chronic gastritis, such as autoimmune gastritis. The ME images of the fundic gland mucosa with inflammation show an anomalous form and arrangement of the crypt openings (Fig. 5a), as well as elliptical or groove-like shapes with white color (Fig. 5b). 76,81,82 Capillaries may or may not be observed along the crypt opening (Fig. 5a,b). 76,81 The ME finding of an atrophic mucosa shows ridged or villous-to-granular (c) Figure 5 Magnifying endoscopy (ME) with narrow-band imaging (NBI) of the fundic gland mucosa with inflammation shows an anomalous form and arrangement of the crypt openings. ME with NBI of the fundic gland mucosa with inflammation shows elliptical or groove-like shapes with white color. (c) ME with NBI of atrophic mucosa of the corpus. Yellow arrows indicate a light blue crest.

5 Digestive Endoscopy 2016; 28: Diagnostic algorithms for EGC by ME 383 intervening parts encasing dilated, coiled subepithelial capillaries (Fig. 5c). 83 An atrophic mucosa often involves intestinal metaplasia which shows a light blue crest (LBC) by ME with NBI (Fig. 5c, yellow arrows). 84 The pyloric gland mucosa is not discussed in the present review because the characteristic distinction between an inflammation-free normal mucosa and chronic gastritis by ME is not clearly elucidated. 79 METAPLASTIC MUCOSA CHRONIC INFECTION OF H. pylori induces biomolecular alteration of the gastric mucosa, causing it to resemble an intestinal phenotype (intestinal metaplasia). 85,86 Intestinal metaplasia signifies a high risk of gastric cancer On white-light endoscopy, intestinal metaplasia looks slightly elevated (Fig. 6a) or exhibits whitish flat areas. 90 It can also resemble a flat mucosa with the same color as the surrounding mucosa (Fig. 7a,b), or else have shallow, depressed reddish areas. 91 NBI can contrast the color difference between metaplastic and non-metaplastic mucosa (Fig. 6b). 84 Upon image magnification, the MS structure of the normal gastric mucosa has a foveolar-type appearance in the corpus and a groove-type structure in the antrum, whereas the MS structure of intestinal metaplasia usually shows the groovetype or villiform structures mimicking the normal antral or intestinal mucosa (Figs 6c,7c). Upon ME with NBI images, a fine blue-white line of light is observed on the crests of the epithelial surface or gyri (an LBC, yellow arrowheads in Figs 6d,7d). 90 The LBC is presumed to originate from the reflection of light upon the ciliated structure on the surface of the intestinal metaplasia (the brush border). Moreover, the epithelium of the intestinal metaplasia (single asterisk in Fig. 6d) looks cloudy compared to the non-metaplastic mucosa (double asterisk in Fig. 6d). 92 SUSPICIOUS LESION THE FIRST STEP in diagnosing EGC is to identify a suspicious lesion using conventional white-light endoscopy. In order to detect EGC using this method, it is important to pay attention to subtle changes of mucosal color and morphology. Clues of a suspicious lesion include mucosal discoloration (erythema or pallor), morphological changes of the mucosal surface (protruding, elevated or depressed), tapered or interrupted mucosal folds, spontaneous bleeding, Figure 6 Gastric intestinal metaplasia in the antrum looks like a whitish, slightly elevated area. Narrow-band imaging (NBI) enhances the whitish color of the intestinal metaplasia. (c) In magnifying endoscopy (ME) with NBI, the metaplastic mucosa shows a groove-type mucosa (also see white box in ). (d) Magnifying view of white box in (c). On the crests of the mucosal surface/gyri, a light blue crest (yellow arrowheads) is seen (also see white box in (c)). Note that the marginal crypt epithelium in the metaplastic mucosa (white arrow, single asterisk) is wider and cloudier than that of the non-metaplastic mucosa (white arrow, double asterisk). (c) (d)

6 384 M. Muto et al. Digestive Endoscopy 2016; 28: (c) (d) Figure 7 Gastric intestinal metaplasia in the corpus appears as a flat mucosa without any particular finding in white light imaging and narrowband imaging (NBI). (c) In magnifying endoscopy (ME) with NBI, the mucosa shows a villiform microsurface structure (also see white box in ). (d) A light blue crest (yellow arrowheads) is observed on the surface of the villiform epithelium (also see white box in (c)). localized opacity of the mucosa (abrupt change in background vascular/mucosal pattern), or loss of mucosal glossiness. 93 In the case with ulcer formation, a suspicious lesion could be detected as subtle changes of mucosa surrounding an ulcer. Adequate preparation and use of proper techniques are important for the detection of EGC. 94 Preparation with mucolytic and defoaming agents, aspiration of fluids, and washing off any adherent mucus or bubbles using water irrigation facilitate careful observation of the mucosal surface. Adequate air insufflation and standardized techniques are necessary to avoid overlooking a suspicious lesion. 95 Subsequent image-enhanced endoscopic observation such as indigocarmine dye spraying and/or ME with NBI of the suspicious lesion improves visualization of mucosal characteristics to facilitate differentiation of a cancerous lesion from background mucosa. 50 Detection of either a clear border between Figure 8 Demonstrable case of noncancerous lesion. Conventional endoscopic findings with white-light imaging. A slightly reddened, depressed lesion (arrow) is noted at the gastric antrum. As there are no irregularities in the color and shape of the lesion, this lesion does not appear to be cancerous.. Magnifying endoscopic findings with narrow-band imaging. When we observe the marginal part of the lesion, there is no demarcation line. According to the diagnostic algorithm, this lesion can be diagnosed as non-cancer.

7 Digestive Endoscopy 2016; 28: Diagnostic algorithms for EGC by ME 385 the suspicious lesion and the background mucosa, and/or irregularity of the color and surface structure of the suspicious lesion, increase the likelihood of the growth being cancerous. 95 Demonstrable lesions are shown in Figures Figure 9 Demonstrable case of non-cancerous lesion. Conventional endoscopic findings with white-light imaging. A slightly reddened, depressed lesion (arrow) is detected in the lower gastric body. As the distribution of the redness is irregular and the margin of the lesion shows irregularity, cancer cannot be ruled out by this observation alone. Magnifying endoscopic findings with narrow-band imaging. A clear demarcation line (arrows) between the background mucosa and the lesion is detected (arrows). Inside the demarcation line, there are regular microvascular and regular microsurface patterns. Because neither an irregular microvascular nor irregular microsurface pattern is present, this lesion can be diagnosed as non-cancer. Figure 10 Demonstrable case of cancerous lesion. Conventional endoscopic findings with white-light imaging. A slightly depressed lesion with discoloration (arrows) is noted at the anterior wall of the gastric angle. Conventional white-light endoscopic findings with the dye (indigocarmine)- spraying method. After the dye is sprayed, the subtle lesion can be clearly visualized. As the margin of the lesion (arrows) shows irregularity, this lesion can be diagnosed as cancer. (c) Magnifying endoscopic findings with narrow-band imaging. A clear demarcation line (arrows) is noted at the margin of the lesion. Because both irregular microvascular and irregular microsurface patterns are present within the demarcation line, this lesion can be diagnosed as cancer. (d) Histological findings of endoscopically resected specimen shows well- to poorly differentiated adenocarcinoma limited to the mucosa. Arrow shows the horizontal extent of the cancerous tissue. (c) (d)

8 386 M. Muto et al. Digestive Endoscopy 2016; 28: (c) (d) Figure 11 Demonstrable case of cancerous lesion. Conventional endoscopic findings with white light imaging. A slightly reddened lesion with erosion (arrow) is detected at the gastric antrum.. Conventional whitelight endoscopic findings with the dye (indigocarmine)-spraying method. After the dye is sprayed, this lesion (arrow) depicts no signs characteristic of cancer. (c) Magnifying endoscopic findings with narrow-band imaging. A clear demarcation line (arrows) is detected. Within the demarcation line, a microvascular pattern is absent because of the presence of a white opaque substance, but the microsurface pattern is irregular. Accordingly, this lesion can be diagnosed as cancer. (d) Histological findings of endoscopically resected specimen demonstrate well-differentiated adenocarcinoma confined to the mucosa. Arrow shows the horizontal extent of the cancerous tissue. (c) (d) Figure 12 Demonstrable case of cancerous lesion. Conventional endoscopic findings with white light imaging. A focal pale mucosal lesion (arrow) is noted at the gastric antrum. Conventional white-light endoscopic findings with the dye (indigocarmine)- spraying method. No finding characteristic of cancer is detected (arrow). (c) Arrow indicate pale lesion in. Magnifying endoscopic findings with narrow-band imaging. A demarcation line (arrows) is noted. A microsurface pattern is absent, but the microvascular pattern is irregular. Accordingly, this lesion can be diagnosed as cancer. On the right side of the figure, slight irregular microvessels are also seen. However, they are not located in the welldemarcated area. Thus, this lesion is negligible for different diagnosis. (d) Histological findings of endoscopically resected specimen depict well- to moderately differentiated adenocarcinoma restricted to the mucosa. Arrow shows the horizontal extent of the cancerous tissue.

9 Digestive Endoscopy 2016; 28: Diagnostic algorithms for EGC by ME 387 DIAGNOSTIC SYSTEM BEHIND THE DIAGNOS- TIC ALGORITHM THE VS (VESSELS plus surface) classification system for the analysis of ME findings was developed by Yao et al. 55,62 This diagnostic system has proven to be very useful for correctly diagnosing superficial (0-II) cancer 22,40,66,96 and delineating the margins of EGC. 21 Anatomical terms are used to define the MVand MS patterns as visualized by ME. The MV pattern comprises a subepithelial capillary, a collecting venule, and pathological microvessels, whereas the MS pattern is identified by a MCE (white zone), a crypt opening, and an intervening part between crypts. According to the VS classification system, the characteristic ME findings of EGC are the presence of a clear DL between non-cancerous and cancerous mucosa, and the presence of an irregular MV pattern and/or irregular MS pattern within the DL. On principle, the MV and MS patterns need to be determined separately. The definition of a DL is a border between the lesion and non-lesion areas, discernible through an abrupt change in MV and/or MS patterns (Figs 13 15). 97 Accordingly, two criteria were set for making a diagnosis of high-grade dysplasia/egc: 62 (i) an irregular MV pattern with a DL; and/or (ii) an irregular MS pattern with a DL. If either or both criteria are fulfilled, an endoscopic diagnosis of EGC can be made and, according to our research, 97% of EGC cases fit these criteria. 62 Regarding the algorithm proposed in the present article, we first need to determine whether a DL is present between the mucosal lesion and the background mucosa. If a DL is absent (Figs 13, 14), the lesion is diagnosed as non-cancerous. If a DL is present, we should Figure 13 Vessels plus surface (VS) classification: The microvascular pattern (V) is classified as regular, irregular, or absent; the microsurface pattern (S) is also classified as regular, irregular, or absent. Arrows indicate the demarcation line in each panel.

10 388 M. Muto et al. Digestive Endoscopy 2016; 28: Figure 14 Demonstrable case of an absent demarcation line. Conventional endoscopic findings with white-light imaging. A flat reddened lesion (arrow) is detected at the gastric antrum. Magnified endoscopic findings with narrow-band imaging. The microvasculature (subepithelial capillary network) of the lesion is gradually dilated from the background mucosa. The microsurface pattern (marginal crypt epithelium/white zone) shows no abrupt change between the lesion and the background mucosa. Accordingly, no demarcation line is detected between the lesion and the background mucosa. Therefore, this lesion is diagnosed as non-cancer. next evaluate whether an irregular MV pattern and/or an irregular MS pattern are present (Figs 13, 15 17). Three categories of the MV and MS patterns are defined: regular, irregular, and absent (Fig. 13). In the regular MV pattern (Figs 13, 15), mucosal capillaries have a uniform shape that can be closed-looped (polygonal) or open-looped with a homogeneous morphology, a symmetrical distribution, and a regular arrangement. In the irregular MV pattern (Figs 13, 16), the vessels are closed-looped (polygonal), open-looped, tortuous, branched, or bizarrely shaped, have asymmetrical distribution and irregular arrangements. Cancer-specific morphology of irregular microvessels has been described as dilation, heterogeneity in shape, abrupt caliber alteration, and tortuousness. 33,68 If a MV pattern is not fully visualized because of the presence of a white opaque substance (WOS) which obscures subepithelial microvessels, the MV pattern is described as absent. 10,36,62 In cases in which the WOS is observed, rather than assessing the MVP, morphological analysis of the WOS could be an alternative marker of MS pattern. 10,36,62 as demonstrated in Figures 11, 13, 17. In the regular MS pattern (Figs 13, 15), the MCE/WZ is a uniform linear, curved, oval, or circular structure with homogeneous morphology, symmetrical distribution, and regular arrangement. In the irregular MS pattern (Figs 13, 16), the MCE/WZ is an irregular linear, curved, oval, circular, or villous structure with heterogeneous morphology, asymmetrical distribution, and Figure 15 Demonstrable case of a visible demarcation line. Conventional endoscopic findings with white-light imaging. A depressed reddened lesion (arrow) is detected at the gastric antrum. Magnified endoscopic findings with narrow-band imaging. The microvascular pattern (subepithelial capillary network) and the microsurface pattern (marginal crypt epithelium/white zone) have abruptly disappeared at the margin of the lesion. Accordingly, a clear demarcation line (arrows) is identified. Inside the demarcation line, both the microvascular and microsurface patterns are regular. Therefore, this lesion is diagnosed as non-cancer. [Correction added on 15 June, after first online publication: The captions of Figures 15, 16 and 17 were interchanged and have now been corrected.]

11 Digestive Endoscopy 2016; 28: Diagnostic algorithms for EGC by ME 389 (c) Figure 16 Demonstrable case of an irregular microvascular pattern in early gastric cancer. Within the demarcation line (arrows), the individual shapes of the microvessels show irregular closed loops. Each microvessel exhibits a heterogeneous morphology, an asymmetrical distribution, and an irregular arrangement. Within the demarcation line (arrows), the individual shapes of the microvessels show closed, open, or irregularly branched loops. Each microvessel demonstrates a heterogeneous morphology, an asymmetrical distribution, and an irregular arrangement. (c) Within the demarcation line (arrows), the individual shapes of microvessels show tiny closed loops. Each microvessel depicts a heterogeneous morphology, asymmetrical distribution, and an irregular arrangement. Accordingly, this lesion is diagnosed as cancer. [Correction added on 15 June, after first online publication: The captions of Figures 15, 16 and 17 were interchanged and have now been corrected.] irregular arrangement. If neither the MCE/WZ is visible my ME, the MS pattern is classified as absent (Fig. 13). Subclassification of irregular MV patterns was proposed for predicting histological patterns of gastric cancer. 51 Fine network pattern (Fig. 18a), in which abundant microvessels are well connected to one another like a mesh, is characteristic of differentiated adenocarcinoma. Corkscrew pattern (Fig. 18b), in which tortuous microvessels are isolated like a corkscrew, is characteristic of poorly differentiated adenocarcinoma. LIMITATIONS OF THE ALGORITHM ALTHOUGH THIS ALGORITHM could be expected to provide high accuracy (95%~), high positive predictive (c) Figure 17 Demonstrable case of irregular microsurface patterns in early gastric cancer. Within the demarcation line (arrows), the individual shape of the marginal crypt epithelium/white zone (MCE/WZ) is curved. Each MCE/WZ demonstrates a heterogeneous morphology, an asymmetrical distribution, and an irregular arrangement. Within the demarcation line (arrows), the individual shape of the MCE/WZ is curved. Each MCE/WZ represents a heterogeneous morphology, an asymmetrical distribution, and an irregular arrangement. (c) Within the demarcation line (arrows), a white opaque substance which obscures the subepithelial microvascular pattern is present. Each white opaque substance exhibits a heterogeneous morphology, an asymmetrical distribution, and an irregular arrangement. Thus, this lesion is diagnosed as cancer. [Correction added on 15 June, after first online publication: The captions of Figures 15, 16 and 17 were interchanged and have now been corrected.]

12 390 M. Muto et al. Digestive Endoscopy 2016; 28: Figure 18 Representative endoscopic images of the subclassification of irregular microvascular patterns. Fine network pattern and corkscrew pattern. value (79%) and high negative predictive value (99%) for making diagnosis of EGC, 22 it has some limitations. The diagnostic yield for diffuse-type EGC was unclear, because most of the evidence was proposed by the results of intestinal type. The other was that if the lesion showed easy contact bleeding or was covered by mucus, clear images for accurate diagnosis were difficult to obtain. Thus, careful and patient observation to obtain clear images is required in clinical practice. CONCLUSION MAGNIFYING ENDOSCOPY HAS proven to be a key modality for effective diagnosis of EGC. However, it is not widely used because of the absence of unified diagnostic criteria. The proposal of a unified algorithm and classification scheme constructed using an evidence-based approach, and consensus of the relevant clinical societies, provide a simple and effective way to diagnose EGC using ME. The clinical societies hope this algorithm (MESDA-G) and terminology will be generally and widely used in clinical practice, and may enhance early diagnosis of gastric cancer, resulting in reduction of gastric cancer-related death worldwide. ACKNOWLEDGMENTS WE GREATLY APPRECIATE the agreement of this algorithm by Japan Gastroenterological Endoscopy Society, the Japanese Gastric Cancer Association, and the World Endoscopy Organization. We acknowledge the secretaries of Japanese Gastroenterological Association, Ms Tomomi Sasaki and Ms Yoko Higuchi, for conducting the literature search and for special assistance in preparing this manuscript. CONFLICTS OF INTEREST MANABU MUTO RECEIVED a collaboration research expense from Olympus Co. Mototsugu Kato has served in speaking and teaching commitments for Eisai Co., Ltd, Daiichi Sankyo Company, Ltd, Takeda Pharmaceutical Co. Ltd, Otsuka Pharmaceutical Co., Ltd and AstraZeneca and has received scholarship grants from Eisai Co., Ltd, Takeda Pharmaceutical Co. Ltd, Daiichi Sankyo Company, Ltd, AstraZeneca and Astellas Pharma Inc. Hisao Tajiri was supported donations from Olympus Co., Fujifilm Co., and Eisai Co. Ltd. These funding sources had no role in the design, practice or analysis of this review. Drs Yao, Kaise, Uedo and Yagi declare no conflicts of interest for this article. REFERENCES 1 Kanesaka T, Sekikawa A, Tsumura T et al. Dense-typecrypt opening seen on magnifying endoscopy with narrow-band imaging is a feature of gastric adenoma. Dig. Endosc. 2014; 26: Tao G, Xing-Hua L, Ai-Ming Y et al. Enhanced magnifying endoscopy for differential diagnosis of superficial gastric lesions identified with white-light endoscopy. Gastric Cancer 2014; 17: Horiuchi H, Kaise M, Inomata H et al. Magnifying endoscopy combined with narrow band imaging may help to predict neoplasia coexisting with gastric hyperplastic polyps. Scand. J. Gastroenterol. 2013; 48: Miyaki R, Yoshida S, Tanaka S et al. Quantitative identification of mucosal gastric cancer under magnifying endoscopy with flexible spectral imaging color enhancement. J. Gastroenterol. Hepatol. 2013; 28: Kobayashi M, Hashimoto S, Nishikura K et al. Magnifying narrow-band imaging of surface maturation in early

13 Digestive Endoscopy 2016; 28: Diagnostic algorithms for EGC by ME 391 differentiated-type gastric cancers after Helicobacter pylori eradication. J. Gastroenterol. 2013; 48: Kikuchi D, Iizuka T, Hoteya S et al. Usefulness of magnifying endoscopy with narrow-band imaging for determining tumor invasion depth in early gastric cancer. Gastroenterol. Res. Pract. 2013; 2013: Meng XM, Zhou Y, Dang T, Tian XY, Kong J. Magnifying chromoendoscopy combined with immunohistochemical staining for early diagnosis of gastric cancer. World J. Gastroenterol. 2013; 21(19): Yagi K, Nozawa Y, Endou S, Nakamura A. Diagnosis of Early Gastric Cancer by Magnifying Endoscopy with NBI from Viewpoint of Histological Imaging: Mucosal Patterning in terms of White Zone Visibility and its Relationship to Histology. Diagn. Ther. Endosc. 2012; 2012: Mochizuki Y, Saito Y, Kobori A et al. Magnifying endoscopy with narrow-band imaging in the differential diagnosis of gastric adenoma and carcinoma and identification of a simple indicator. J. Gastrointest. Liver Dis. 2012; 21: Yao K, Iwashita A, Nambu M et al. Nature of white opaque substance in gastric epithelial neoplasia as visualized by magnifying endoscopy with narrow-band imaging. Dig. Endosc. 2012; 24: Li HY, Dai J, Xue HB et al. Application of magnifying endoscopy with narrow-band imaging in diagnosing gastric lesions: a prospective study. Gastrointest. Endosc. 2012; 76: Nonaka K, Namoto M, Kitada H et al. Usefulness of the DL in ME with NBI for determining the expanded area of early-stage differentiated gastric carcinoma. World J. Gastrointest. Endosc. 2012; 4: Kobara H, Mori H, Fujihara S et al. Prediction of invasion depth for submucosal differentiated gastric cancer by magnifying endoscopy with narrow-band imaging. Oncol. Rep. 2012; 28: Maki S, Yao K, Nagahama T et al. Magnifying endoscopy with narrow-band imaging is useful in the differential diagnosis between low-grade adenoma and early cancer of superficial elevated gastric lesions. Gastric Cancer 2013; 16: Miwa K, Doyama H, Ito R et al. Can magnifying endoscopy with narrow band imaging be useful for low grade adenomas in preoperative biopsy specimens? Gastric Cancer 2012; 15: Omori T, Kamiya Y, Tahara T et al. Correlation between magnifying narrow band imaging and histopathology in gastric protruding/or polypoid lesions: a pilot feasibility trial. BMC Gastroenterol. 2012; 12: Kosaka R, Tanaka K, Tano S et al. Magnifying endoscopy for diagnosis of residual/local recurrent gastric neoplasms after previous endoscopic treatment. Surg. Endosc. 2012; 26: Tsuji Y, Ohata K, Sekiguchi M et al. Magnifying endoscopy with narrow-band imaging helps determine the management of gastric adenomas. Gastric Cancer 2012; 15: Ang TL, Fock KM, Teo EK et al. The diagnostic utility of narrow band imaging magnifying endoscopy in clinical practice in a population with intermediate gastric cancer risk. Eur. J. Gastroenterol. Hepatol. 2012; 24: Zhang J, Guo SB, Duan ZJ. Application of magnifying narrow-band imaging endoscopy for diagnosis of early gastric cancer and precancerous lesion. BMC Gastroenterol. 2011; 11: Nagahama T, Yao K, Maki S et al. Usefulness of magnifying endoscopy with narrow-band imaging for determining the horizontal extent of early gastric cancer when there is an unclear margin by chromoendoscopy (with video). Gastrointest. Endosc. 2011; 74: Ezoe Y, Muto M, Uedo N et al. Magnifying narrowband imaging is more accurate than conventional white-light imaging in diagnosis of gastric mucosal cancer. Gastroenterology 2011; 141: Araki Y, Sasaki Y, Hanabata N et al. Morphometry for microvessels in early gastric cancer by narrow band imagingequipped magnifying endoscopy. Dig. Endosc. 2011; 23: Kobayashi M, Takeuchi M, Ajioka Yet al. Mucin phenotype and narrow-band imaging with magnifying endoscopy for differentiated-type mucosal gastric cancer. J. Gastroenterol. 2011; 46: Okada K, Fujisaki J, Kasuga A et al. Diagnosis of undifferentiated type early gastric cancers by magnification endoscopy with narrow-band imaging. J. Gastroenterol. Hepatol. 2011; 26: Nonaka K, Arai S, Ban S et al. Prospective study of the evaluation of the usefulness of tumor typing by narrow band imaging for the differential diagnosis of gastric adenoma and well-differentiated adenocarcinoma. Dig. Endosc. 2011; 23: Kiyotoki S, Nishikawa J, Satake M et al. Usefulness of magnifying endoscopy with narrow-band imaging for determining gastric tumor margin. J. Gastroenterol. Hepatol. 2010; 25: Kato M, Kaise M, Yonezawa J et al. Magnifying endoscopy with narrow-band imaging achieves superior accuracy in the differential diagnosis of superficial gastric lesions identified with white-light endoscopy: a prospective study. Gastrointest. Endosc. 2010; 72: Yokoyama A, Inoue H, Minami H et al. Novel narrow-band imaging magnifying endoscopic classification for early gastric cancer. Dig. Liver Dis. 2010; 42: Nakamura M, Shibata T, Tahara T et al. The usefulness of magnifying endoscopy with narrow-band imaging to distinguish carcinoma in flat elevated lesions in the stomach diagnosed as adenoma by using biopsy samples. Gastrointest. Endosc. 2010; 71: Ezoe Y, Muto M, Horimatsu T et al. Magnifying narrowband imaging versus magnifying white-light imaging for the differential diagnosis of gastric small depressive lesions: a prospective study. Gastrointest. Endosc. 2010; 71: Kadowaki S, Tanaka K, Toyoda H et al. Ease of early gastric cancer demarcation recognition: a comparison of four magnifying endoscopy methods. J. Gastroenterol. Hepatol. 2009; 24:

14 392 M. Muto et al. Digestive Endoscopy 2016; 28: Kaise M, Kato M, Urashima M et al. Magnifying endoscopy combined with narrow-band imaging for differential diagnosis of superficial depressed gastric lesions. Endoscopy 2009; 41: Yoshizawa M, Osawa H, Yamamoto H et al. Diagnosis of elevated-type early gastric cancers by the optimal band imaging system. Gastrointest. Endosc. 2009; 69: Yao K, Takaki Y, Matsui T et al. Clinical application of magnification endoscopy and narrow-band imaging in the upper gastrointestinal tract: new imaging techniques for detecting and characterizing gastrointestinal neoplasia. Gastrointest. Endosc. Clin. N. Am. 2008; 18: Yao K, Iwashita A, Tanabe H et al. White opaque substance within superficial elevated gastric neoplasia as visualized by magnification endoscopy with narrow-band imaging: a new optical sign for differentiating between adenoma and carcinoma. Gastrointest. Endosc. 2008; 68: Tanaka K, Toyoda H, Kadowaki S et al. Surface pattern classification by enhanced-magnification endoscopy for identifying early gastric cancers. Gastrointest. Endosc. 2008; 67: Areia M, Amaro P, Dinis-Ribeiro M et al. External validation of a classification for methylene blue magnification chromoendoscopy in premalignant gastric lesions. Gastrointest. Endosc. 2008; 67: Osawa H, Yoshizawa M, Yamamoto H et al. Optimal band imaging system can facilitate detection of changes in depressedtype early gastric cancer. Gastrointest. Endosc. 2008; 67: Yao K, Iwashita A, Tanabe H et al. Novel zoom endoscopy technique for diagnosis of small flat gastric cancer: a prospective, blind study. Clin. Gastroenterol. Hepatol. 2007; 5: Dinis-Ribeiro M Chromoendoscopy for early diagnosis of gastric cancer. Eur. J. Gastroenterol. Hepatol. 2006; 18: Fukui H, Shirakawa K, Nakamura T et al. Magnifying pharmacoendoscopy: response of microvessels to epinephrine stimulation in differentiated early gastric cancers. Gastrointest. Endosc. 2006; 64: Tanaka K, Toyoda H, Kadowaki S et al. Features of early gastric cancer and gastric adenoma by enhanced-magnification endoscopy. J. Gastroenterol. 2006; 41: Tamai N, Kaise M, Nakayoshi T et al. Clinical and endoscopic characterization of depressed gastric adenoma. Endoscopy 2006; 38: Kuznetsov K, Lambert R, Rey JF. Narrow-band imaging: potential and limitations. Endoscopy 2006; 38: Ohashi A, Niwa Y, Ohmiya N et al. Quantitative analysis of the microvascular architecture observed on magnification endoscopy in cancerous and benign gastric lesions. Endoscopy 2005; 37: Yagi K, Aruga Y, Nakamura A, Sekine A, Umezu H. The study of dynamic chemical magnifying endoscopy in gastric neoplasia. Gastrointest. Endosc. 2005; 62: Yao K, Iwashita A, Kikuchi Y et al. Novel zoom endoscopy technique for visualizing the microvascular architecture in gastric mucosa. Clin. Gastroenterol. Hepatol. 2005; 3: S Yoshida T, Kawachi H, Sasajima K, Shiokawa A, Kudo SE. The clinical meaning of a nonstructural pattern in early gastric cancer on magnifying endoscopy. Gastrointest. Endosc. 2005; 62: Sugano K, Sato K, Yao K. New diagnostic approaches for early detection of gastric cancer. Dig. Dis. 2004; 22: Nakayoshi T, Tajiri H, Matsuda K, Kaise M, Ikegami M, Sasaki H. Magnifying endoscopy combined with narrow band imaging system for early gastric cancer: correlation of vascular pattern with histopathology (including video). Endoscopy 2004; 36: Sumiyama K, Kaise M, Nakayoshi T et al. Combined use of a magnifying endoscope with a narrow band imaging system and a multibending endoscope for en bloc EMR of early stage gastric cancer. Gastrointest. Endosc. 2004; 60: Otsuka Y, Niwa Y, Ohmiya N et al. Usefulness of magnifying endoscopy in the diagnosis of early gastric cancer. Endoscopy 2004; 36: Tajiri H, Doi T, Endo H et al. Routine endoscopy using a magnifying endoscope for gastric cancer diagnosis. Endoscopy 2002; 34: Yao K, Oishi T, Matsui T, Yao T, Iwashita A. Novel magnified endoscopic findings of microvascular architecture in intramucosal gastric cancer. Gastrointest. Endosc. 2002; 56: Yang HJ, Wang JT, Wang TH, Lin JT, Sun CT. Diagnosis of gastric polypoid lesions by magnifying endoscopy and dye endoscopy. J. Formos. Med. Assoc. 1991; 90: Ueo T, Yonemasu H, Yada N et al. White opaque substance represents an intracytoplasmic accumulation of lipid droplets: immunohistochemical and immunoelectron microscopic investigation of 26 cases. Dig. Endosc. 2013; 25: Yoshizawa M, Osawa H, Yamamoto H et al. Newly developed optimal band imaging system for the diagnosis of early gastric cancer. Gastrointenst. Endosc. 2008; 67: Niwa Y, Ohashi A, Miyahara R, Ohmiya N, Goto H. Differential diagnosis of gastric lesions by magnifying endoscopy. Dig. Endosc. 2005; 17: S Endo T, Nosho K, Arimura Yet al. Study of the tumor vessels in depressed-type early gastric cancers using narrow band imaging magnifying endoscopy and cdna array analysis. Dig. Endosc. 2005; 17: Tobita K. Study on minute surface structures of the depressedtype early gastric cancer with magnifying endoscopy. Dig. Endosc. 2001; 13: Yao K, Anagnostopoulos GK, Ragunath K. Magnifying endoscopy for diagnosing and delineating early gastric cancer. Endoscopy 2009; 41: Yao K, Iwashita A, Yao T. Early Gastric Cancer: Proposal for a new diagnostic system based on microvasular architecture as visualized by magnified endoscopy. Dig. Endosc. 2004; 16: S Yagi K, Nakamura A, Sekine A, Umezu H. Magnifying endoscopy with narrow band imaging for early differentiated gastric adenocarcinoma. Dig. Endosc. 2008; 20:

15 Digestive Endoscopy 2016; 28: Diagnostic algorithms for EGC by ME Yao K. How is the VS (vessel plus surface) classification system applicable to magnifying narrow-band imaging examinations of gastric neoplasias initially diagnosed as low-grade adenomas? Gastric Cancer 2012; 15: Yamada S, Doyama H, Yao K et al. An efficient diagnostic strategy for small, depressed early gastric cancer with magnifying narrow-band imaging: a post-hoc analysis of a prospective randomized controlled trial. Gastrointest. Endosc. 2014; 79: Murakami T. Early cancer of the stomach. World J. Surg. 1979; 3: Schlemper RJ, Riddell RH, Kato Yet al. The Vienna classification of gastrointestinal epithelial neoplasia. Gut 2000; 47: Dixon MF. Gastrointestinal epithelial neoplasia: Vienna revisited. Gut 2002; 51: Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer 2011; 14: The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon: November 30 to December 1, Gastrointest. Endosc. 2003; 58: S Endoscopic Classification Review Group. Update on the Paris classification of superficial neoplastic lesions in the digestive tract. Endoscopy 2005; 37: Gannon B, Browning J, O Brien P, Rogers P. Mucosal microvascular architecture of the fundus and body of human stomach. Gastroenterology 1984; 86: Yao K, Nagahama T, Matsui T, Iwashita A. Detection and characterization of early gastric cancer for curative endoscopic submucosal dissection. Dig. Endosc. 2013; 25: S Yagi K, Nakamura A, Sekine A. Comparison between magnifying endoscopy and histological, culture and urease test findings from the gastric mucosa of the corpus. Endoscopy 2002; 34: Yagi K, Aruga Y, Nakamura A, Sekine A. Regular arrangement of collecting venules (RAC): a characteristic endoscopic feature of Helicobacter pylori-negative normal stomach and its relationship with esophago-gastric adenocarcinoma. J. Gastroenterol. 2005; 40: Singh R, Lee SY, Vijay N, Sharma P, Uedo N. Update on narrow band imaging in disorders of the upper gastrointestinal tract. Dig. Endosc. 2014; 26: Yao K, Oishi T. Microgastroscopic findings of mucosal microvascular architecture as visualized by magnifying endoscopy. Dig. Endosc. 2001; 13: S Yagi K, Nakamura A, Sekine A. Characteristic endoscopic and magnified endoscopic findings in the normal stomach without Helicobacter pylori infection. J. Gastroenterol. Hepatol. 2002; 17: Kuipers EJ, Uyterlinde AM, Pena AS et al. Long-term sequelae of Helicobacter pylori gastritis. Lancet 1995; 345: Yagi K, Honda H, Yang JM, Nakagawa S. Magnifying endoscopy in gastritis of the corpus. Endoscopy 2005; 37: Yagi K, Saka A, Nozawa Y, Nakamura A. Prediction of Helicobacter pylori status by conventional endoscopy, narrowband imaging magnifying endoscopy in stomach after endoscopic resection of gastric cancer. Helicobacter 2014; 19: Kawamura M, Abe S, Oikawa K et al. Topographic differences in gastric micromucosal patterns observed by magnifying endoscopy with narrow band imaging. J. Gastroenterol. Hepatol. 2011; 26: Uedo N, Ishihara R, Iishi H et al. A new method of diagnosing gastric intestinal metaplasia: narrow-band imaging with magnifying endoscopy. Endoscopy 2006; 38: Mutoh H, Hakamata Y, Sato K et al. Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice. Biochem. Biophys. Res. Commun. 2002; 294: Busuttil RA, Boussioutas A. Intestinal metaplasia: A premalignant lesion involved in gastric carcinogenesis. J. Gastroenterol. Hepatol. 2009; 24: Mutoh H, Sakurai S, Satoh K et al. Development of gastric carcinoma from intestinal metaplasia in Cdx2-transgenic mice. Cancer Res. 2004; 64: Uemura N, Okamoto S, Yamamoto S et al. Helicobacter pylori infection and the development of gastric cancer. N. Engl. J. Med. 2001; 345: de Vries AC, van Grieken NC, Looman CW et al. Gastric cancer risk in patients with premalignant gastric lesions: a nationwide cohort study in the Netherlands. Gastroenterology 2008; 134: Kaminishi M, Yamaguchi H, Nomura S et al. Endoscopic classification of chronic gastritis based on a pilot study by the Research Society for Gastritis. Dig. Endosc. 2002; 14: Nagata N, Shimbo T, Akiyama J et al. Predictability of Gastric Intestinal Metaplasia by Mottled Patchy Erythema Seen on Endoscopy. Gastroenterol. Res. 2011; 4: An JK, Song GA, Kim GH et al. Marginal turbid band and light blue crest, signs observed in magnifying narrow-band imaging endoscopy, are indicative of gastric intestinal metaplasia. BMC Gastroenterol. 2012; 12: Yoshida S, Yamaguchi H, Saitoh D. Endoscopic diagnosis: latest trends. In: Nishi M (ed). Gastric Cancer. Tokyo: Springer Verlag, 1993; Ono H. Early gastric cancer: diagnosis, pathology, treatment techniques and treatment outcomes. Eur. J. Gastroenterol. Hepatol. 2006; 18: Yao K. The endoscopic diagnosis of early gastric cancer. Ann. Gastroenterol. 2013; 26: Yao K, Doyama H, Gotoda T et al. Diagnostic performance and limitations of magnifying narrow-band imaging in screening endoscopy of early gastric cancer: a prospective multicenter feasibility study. Gastric Cancer 2014; 17: Yao K. The vessel plus surface (VS) classification system in the diagnosis of early gastric cancer. In: Yao K (ed). Zoom Gastroscopy. Tokyo: Springer, 2014;