Early gastric cancer: From basic knowledge to understanding how to find it by endoscopy: Review – Dao Truong Giang

Journal of military pharmaco-medicine n o 8-2018 210 EARLY GASTRIC CANCER: FROM BASIC KNOWLEDGE TO UNDERSTANDING HOW TO FIND IT BY ENDOSCOPY: REVIEW Dao Truong Giang1; Duong Xuan Nhuong1 SUMMARY Early gastric cancer is defined as invasive gastric cancer that invades no more deeply than the submucosa, irrespective of lymph node metastasis (T1, any N). The need for better approaches to the treatment of early gastric cancer has led to the development of advanced endoscopic techniques to diagnosis and resect early gastric cancer. This review aims: To guide gastrointestinal doctor to understand early gastric cancer from basic histologic knowledge and the usefulness of conventional endoscopy to advanced endoscopy to diagnose early gastric cancer. * Keywords: Gastric cancer; Endoscopy. DEFINITION The concept of early gastric cancer (EGC) was originated in Japan in 1962. At that time, an EGC was defined as a neoplasm that could be successfully treated with surgery. EGC is now defined more specifically as an adenocarcinoma that is restricted to mucosa or submucosa, irrespective of lymph node metastasis (T1, any N). These cancers have a significantly better prognosis (approximately 90% five-year survival rate) than do more advanced stages of gastric cancer. In Japan, gastric cancer screening began in the 1960s, and was continued to be the leading cause of cancer mortality. There has been a transition to magnification chromo-endoscopy with indigo-carmine spray in experienced centers in Eastern Asia. In addition, there is variation in screening practices by country and region. Methods used to screen for gastric cancer include endoscopy, H. pylori serology, and serum pepsinogen testing. HISTOLOGICAL CLASSIFICATION Gastric cancers can be classified in a number of ways, according to both histological and macroscopic findings. 1. Lauren classification. Histologically, gastric cancers are classified as intestinal (well-, moderately-, poorly- differentiated) or diffuse (undifferentiated) subtypes based on the Lauren classification [1]. These two types of gastric cancer have distinct morphologic appearances, epidemiology, pathogenesis, and genetic profiles. 1. 103 Military Hospital Corresponding author: Nguyen Truong Giang (giangle127@yahoo.com) Date received: 24/07/2018 Date accepted: 28/09/2018 Journal of military pharmaco-medicine n o 8-2018 211 2. Recently histologic classification. There are differences in gastric histologic interpretation between Japanese and Western pathologists to the higher proportion of EGCs among Japanese patients. The disagreement is centered in the characterization of high-grade dysplasia and intra-mucosal adenocarcinoma [2]. Western pathologists have typically required invasion of the lamina propria for diagnosis of cancer, whereas Japanese pathologists have based on the diagnosis of cytologic and architectural changes alone, without requiring invasion of the lamina propria. As a result, lesions classified as high-grade dysplasia by Western pathologists, may be classified as intramucosal carcinoma by Japanese pathologists. However, these differences in classification are usually not clinically meaningful because of the following reasons: - Patients with severe dysplasia or EGC are usually managed by endoscopic resection, since both diagnosis are associated with a low risk of lymph node metastasis. - Invasion of the lamina propria, which is the threshold for diagnosing cancer among Western pathologists, may be difficult to identify on histology. 3. The Vienna classification. In an attempt to close the gap between the Japanese and Western views and reporting schemes, consensus groups have formulated the Vienna classification of gastrointestinal epithelial neoplasia and the Padova international classification of dysplasia [2]. The Vienna classification recognizes the following categories: - Category 1: Negative for neoplasia/dysplasia. - Category 2: Indefinite for neoplasia/ dysplasia. - Category 3: Noninvasive low-grade neoplasia (low-grade adenoma/dysplasia). - Category 4: Noninvasive high-grade neoplasia. + High-grade adenoma/dysplasia. + Noninvasive carcinoma (carcinoma in situ). + Suspicion of invasive carcinoma. - Category 5: Invasive neoplasia: + Intramucosal carcinoma (invasion into the lamina propria or muscularis mucosae). + Submucosal carcinoma or beyond. 4. Macroscopic classification [3]. - Basic classification: Gross tumor morphology is categorized as either superficial or advanced type. Superficial type is typical of T1 tumors while T2 - 4 tumors usually manifest as advanced types. From the mucosal surface, gross tumor appearance is categorized into 6 types. Journal of military pharmaco-medicine n o 8-2018 212 Table 1: Type 0 (superficial) Typical of T1 tumors Type 1 (mass) Polypoid tumors, sharply demarcated from the surrounding mucosa Type 2 (ulcerative) Ulcerated tumors with raised margins surrounded by a thickened gastric wall with clear margins Type 3 (infiltrative ulcerative) Ulcerated tumors with raised margins, surrounded by a thickened gastric wall without clear margins Type 4 (diffuse infiltrative) Tumors without marked ulceration or raised margins, the gastric wall is thickened and indurated and the margin is unclear Type 5 (unclassifiable) Tumors that cannot be classified into any of the above types Type 0 is subdivided according to the macroscopic classification of EGC. Table below shows subclassification of type 0. Table 2: Type 0 - I (protruding)* Polypoid tumors Type 0 - II (superficial) Tumors with or without minimal elevation or depression relative to the surrounding mucosa Type 0 - Iia (superficial elevated)a Slightly elevated tumors Type 0 - Iib (superficial flat) Type 0 - Iic (superficial depressed) Tumors without elevation or depression. Slightly depressed tumors Type 0 - III (excavated) Tumors with deep depression (*: Tumors with ≤ 3 mm elevation are usually classified as 0 - IIa, with more elevated tumors being classified as 0 - I) Journal of military pharmaco-medicine n o 8-2018 213 BASIC PRINCIPLES FOR DETECTING EGC BY CONVENTIONAL ENDOSCOPY In order to detect suspicious lesions for EGC, doctor should familiarize themselves with the basic principles of technique and knowledge. 1. Preparation. - Ideal preparation: The aim of right preparation: To minimize time and remove mucus and froth from the mucosal surface. 30 minutes before the procedure, patients drink a mixture of water with mucolytic and defoaming agents: + 100 mL of water with 20,000 U pronase, 1 g of sodium bicarbonate, and 10 mL of dimethylpolysiloxane (20 mg/mL). + Or 100 mL of water mixed with 2 mL of acetylcysteine and 0.5 mL activated dimethicone. - Use of an antiperistaltic agent: In the physiological state, the gastric wall always moves due to peristalsis, for administering an anticholinergic agent such as: + 10 to 20 mg of scopolamine butylbromide (buscopan) intramuscularly or intravenously just before inserting the endoscopy. + Or 1 mg of glucagon if there are contraindications to the use of anticholinergic agents. 2. Avoiding blind spots [4]. The first step in diagnosing EGC endoscopically is to detect any suspicious lesions, to characterize them and make an accurate diagnosis [5]. First of all, use white light endoscopy (WLE). During the endoscopy, in order to avoid blind spots, doctor should employ a standardized procedure to map the entire stomach. - A basic technique for avoiding blind spots: + Extending the gastric wall by air insufflation. + Rinsing mucus and the froth from the gastric mucosa through irrigation with water and a defoaming agent. + Mapping the entire stomach. - Use SSS system protocol (Systematic Screening protocol for the Stomach): This is very useful, as shown in figure 1. In the SSS, pictures are arranged according to the order of the procedure, and take pictures of 4 or 3 quadrant views in either a clockwise or counter-clockwise manner. If you find lesions, additional pictures can be taken. Journal of military pharmaco-medicine n o 8-2018 214 Figure 1: Systematic screening protocol for the stomach. (Q: Quadrant; L: Lesser curvature; A: Anterior wall; G: Greater curvature; P: Posterior wall) 3. Knowledge of the endoscopist. - Determining the risk of development of EGC: As soon as inserting the scope into the stomach, defining whether risk factors for gastric cancer are present in the background mucosa, such as Helicobacter pylori-associated gastritis, gastric atrophy or intestinal metaplasia [6]. If the appearance of gastric mucosa is normal, with none of the abovementioned risk factors, suspicious lesions for gastric cancer are less likely. Magnified endoscopic observation, if available, is useful for determining whether the gastric mucosa is accompanied by such risk factors. - Awareness of signs of suspicious lesions: + With polypoid and ulcerative types (early gastric neoplasias) are easily detected if doctors follow the SSS with optimum preparation. + With superficial mucosal lesions that mimic gastritis (gastritis-like lesions) are very difficult to detect. Accordingly, the key signs for detecting superficial mucosal neoplasia are the two distinct markers for detection on surface and color change, other markers changes in light reflection and spontaneous bleeding (figure 2). Journal of military pharmaco-medicine n o 8-2018 215 Figure 2: Endoscopic findings of superficial depressed (0 IIc) type EGC in the gastric cardia. 4. Basic principles for characterization of detected lesions. - Characterization using conventional white light imaging (C-WLI) or chromoendoscopy (CE): After detecting a suspicious lesion through careful SSS using conventional endoscopy, doctor needs to differentiate between cancerous and non-cancerous lesions (characterization). For characterization, two distinct markers, namely color and surface morphology, should be applied to the interpretation of the C-WLI endoscopic findings. CE using indigo carmine is useful in enhancing the surface pattern [7]. Differential diagnosis using the following criteria: + Well-demarcated border. + Irregularity in color/surface pattern. If the C-WLI or CE findings fulfill both criteria, we make the endoscopic diagnosis of EGC. However, it is difficult to correctly diagnose minor gastric cancers (≤ 5 mm) or superficial flat (0 IIb) gastric cancers using C-WLI or CE, because these lesion types yield only non-specific findings using conventional endoscopy alone. In such cases, the following advanced imaging is useful in differentiating between small/flat cancers and focal gastritis. Figure 3: Endoscopic findings of superficial elevated (0 IIa) type EGC in the gastric antrum. (A: C-WLI shows a slightly elevated lesion. The light reflection suggests something different in surface morphology. B: Indigo carmine CE demonstrates a well-demarcated superficial elevated lesion with an irregular surface pattern) Journal of military pharmaco-medicine n o 8-2018 216 - Characterization using advanced endoscopy (magnifying endoscopy with narrow-band imaging (M-NBI)): According to Pasechnikov V et al, there are several advanced endoscopic techniques like magnifying endoscopy, CE, novel high resolution virtual CE techniques with narrow-band imaging (NBI) with or without magnification (NBI- ME), flexible spectral imaging color enhancement (FICE) endoscopy with or without magnification (FIME) and confocal laser endomicroscopy (CLE), have been tested for the diagnosis of EGC, with promising results. The most investigated endoscopic technique seems to be NBI, which has given promising results. Since M-NBI can help clearly visualize both the microvascular pattern and microsurface pattern [8]. They developed the M-NBI technique and proposed a comprehensive diagnostic system, the vessel plus surface (VS) classification system [9]. - Three categories of microvascular pattern are defined: + Regular microvascular pattern: The mucosal capillaries have a uniform shape that can be closed-looped (polygonal) or open-looped. They have a homogeneous morphology, have symmetrical distribution and regular arrangement. + Irregular microvascular pattern: The vessels differ in shape, being closed- looped (polygonal), open-looped, tortuous, branched, or bizarrely shaped, with or without a network. They have a heterogeneous morphology, asymmetrical distribution and irregular arrangement. + Absent microvascular pattern: The subepithelial microvascular pattern is obscured by the presence of a white opaque substance (WOS) within the superficial part of the mucosa. - Three categories of microsurface pattern are defined: + Regular microsurface pattern: The morphology of the marginal crypt epithelium shows a uniform linear/curved/oval/circular structure. It shows a homogeneous morphology, symmetrical distribution and regular arrangement. When WOS is present, regular WOS can be an additional marker of a regular microsurface pattern, defined as a well-organized and symmetrical distribution of WOS in a regular reticular/maze-like/speckled pattern. + Irregular microsurface pattern: The morphology of the marginal crypt epithelium shows an irregular linear/curved/oval/ circular/villous structure. It shows a heterogeneous morphology, asymmetrical distribution and irregular arrangement. When WOS is present, irregular WOS can be an additional marker of an irregular microsurface pattern, defined as a disorganized and asymmetrical distribution of WOS in an irregular reticular/speckled pattern. + Absent microsurface pattern: Neither the marginal crypt epithelial structure nor WOS are visible using M-NBI. According to the VS classification system, the characteristic M-NBI findings of EGC are a clear demarcation line between the background noncancerous mucosa and the cancerous mucosa, and an irregular microvascular pattern and/or irregular Journal of military pharmaco-medicine n o 8-2018 217 microsurface pattern within the demarcation line. Accordingly, we set the criteria for making a diagnosis of gastric cancer as follows: If the endoscopic findings fulfill either or both, make the diagnosis of cancer, and make the diagnosis of non- cancer if neither is fulfilled. And 97% of EGCs fit the above criteria [10]. Figure 4: VS classification. CONCLUSIONS In conclusion, to find EGC in endoscopy, we would like to stress that: - Should have knowledge about histologic classification of EGC. - Need to know how to have good preparation, avoid blind spots when doing endoscopy. - Need to familiarize ourselves with the basic principles, firstly for detection and secondly for characterization, using both conventional endoscopy and advanced endoscopic techniques (mostly as M-NBI endoscopy). REFERENCES 1. Lauren P. The two histological main types of gastric carcinoma: Diffuse and so- called intestinal-type carcinoma. An attempt at histo-clinical classification. Acta Pathologica et Microbiologica Scandinavica. 1965, 64, pp.31-49. 2. Eckardt V.F, Giessler W, Kanzler G, Remmele W, Bernhard G. Clinical and morphological characteristics of early gastric cancer: A case-control study. Gastroenterology. 1990, 98 (3), pp.708-714. 3. Japanese classification of gastric carcinoma: 3rd English edition. 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