Early gastric cancer: From basic knowledge to understanding how to find it by endoscopy: Review

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.

Journal of military pharmaco-medicine no8-2018 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 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 Lauren classification Histologically, gastric cancers are classified as intestinal (well-, moderately-, poorlydifferentiated) 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 103 Military Hospital Corresponding author: Nguyen Truong Giang (giangle127@yahoo.com) Date received: 24/07/2018 Date accepted: 28/09/2018 210 Journal of military pharmaco-medicine no8-2018 Recently histologic classification reporting schemes, consensus groups There are differences in gastric histologic have formulated the Vienna classification interpretation between Japanese and of gastrointestinal epithelial neoplasia and Western higher the Padova international classification of proportion of EGCs among Japanese dysplasia [2] The Vienna classification patients The disagreement is centered in recognizes the following categories: pathologists to the 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 - 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 classified as high-grade dysplasia by + High-grade adenoma/dysplasia Western pathologists, may be classified + Noninvasive carcinoma (carcinoma 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 in situ) + Suspicion of invasive carcinoma - Category 5: Invasive neoplasia: + Intramucosal carcinoma (invasion into the lamina propria or muscularis mucosae) are usually managed by endoscopic resection, + Submucosal carcinoma or beyond since both diagnosis are associated with Macroscopic classification [3] 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 - Basic classification: Gross tumor morphology is categorized as either superficial or advanced type Superficial type is typical of T1 tumors while T2 - tumors usually manifest as advanced The Vienna classification types From the mucosal surface, gross In an attempt to close the gap between tumor appearance is categorized into the Japanese and Western views and types 211 Journal of military pharmaco-medicine no8-2018 Table 1: Type (superficial) Typical of T1 tumors Type (mass) Polypoid tumors, sharply demarcated from the surrounding mucosa Type (ulcerative) Ulcerated tumors with raised margins surrounded by a thickened gastric wall with clear margins Type (infiltrative ulcerative) Ulcerated tumors with raised margins, surrounded by a thickened gastric wall without clear margins Type (diffuse infiltrative) Tumors without marked ulceration or raised margins, the gastric wall is thickened and indurated and the margin is unclear Type (unclassifiable) Tumors that cannot be classified into any of the above types Type is subdivided according to the macroscopic classification of EGC Table below shows subclassification of type Table 2: Type - I (protruding) * Polypoid tumors Type - II (superficial) Tumors with or without minimal elevation or depression relative to the surrounding mucosa Type - Iia (superficial a elevated) Slightly elevated tumors Type - Iib (superficial flat) Tumors without depression Type - Iic (superficial depressed) Slightly depressed tumors Type - III (excavated) Tumors with deep depression elevation or (*: Tumors with ≤ mm elevation are usually classified as - IIa, with more elevated tumors being classified as - I) 212 Journal of military pharmaco-medicine no8-2018 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 + Or mg of glucagon if there are contraindications to the use of anticholinergic agents Avoiding blind spots [4] The first step in diagnosing EGC endoscopically is to detect any suspicious Preparation lesions, to characterize them and make - Ideal preparation: an accurate diagnosis [5] First of all, use 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, g of sodium bicarbonate, and 10 mL of dimethylpolysiloxane (20 mg/mL) + Or 100 mL of water mixed with mL of acetylcysteine and 0.5 mL activated dimethicone - Use of an antiperistaltic agent: 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 In the physiological state, the gastric Screening protocol for the Stomach): This wall always moves due to peristalsis, for is very useful, as shown in figure In the administering an anticholinergic agent SSS, pictures are arranged according to such as: the order of the procedure, and take + 10 to 20 mg of scopolamine pictures of or quadrant views in either butylbromide (buscopan) intramuscularly a clockwise or counter-clockwise manner or intravenously just before inserting the If you find lesions, additional pictures can endoscopy be taken 213 Journal of military pharmaco-medicine no8-2018 Figure 1: Systematic screening protocol for the stomach (Q: Quadrant; L: Lesser curvature; A: Anterior wall; G: Greater curvature; P: Posterior wall) 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 214 - 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 no8-2018 criteria, we make the endoscopic diagnosis of EGC However, it is difficult to correctly diagnose minor gastric cancers (≤ 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 2: Endoscopic findings of superficial depressed (0 IIc) type EGC in the gastric cardia 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 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) 215 Journal of military pharmaco-medicine no8-2018 - 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 (NBIME), 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 closedlooped (polygonal), open-looped, tortuous, branched, or bizarrely shaped, with or without a network They have a heterogeneous morphology, asymmetrical distribution and irregular arrangement 216 + 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 no8-2018 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 noncancer 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 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 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 Japanese classification of gastric carcinoma: rd English edition Gastric cancer: Official Journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 2011,14 (2), pp.101-112 Hamashima C, Shibuya D, Yamazaki H, Inoue K, Fukao A, Saito H et al The Japanese guidelines for gastric cancer screening Japanese Journal of Clinical Oncology 2008, 38 (4), pp.259-267 217 Journal of military pharmaco-medicine no8-2018 Pasechnikov V, Chukov S, Fedorov E, Kikuste I, Leja M Gastric cancer: Prevention, screening and early diagnosis World Journal of Gastroenterology 2014, 20 (38), pp.13842-13862 for detecting and characterizing gastrointestinal neoplasia Gastrointestinal Endoscopy Clinics of North America 2008, 18 (3), pp.415-433, vii-viii Uedo N, Ishihara R, Iishi H, Yamamoto S, Yamamoto S, Yamada T et al A new method of diagnosing gastric intestinal metaplasia: Narrow-band imaging with magnifying endoscopy Endoscopy 2006, 38 (8), pp.819-824 Yao K The endoscopic diagnosis of early gastric cancer Annals of Gastroenterology: Quarterly Publication of the Hellenic Society of Gastroenterology 2013, 26 (1), pp.11-22 Kaltenbach T, Sano Y, Friedland S, Soetikno R American gastroenterological association (AGA) institute technology assessment on image-enhanced endoscopy Gastroenterology 2008, 134 (1), pp.327-340 Yao K, Takaki Y, Matsui T, Iwashita A, Anagnostopoulos G.K, Kaye P et al Clinical application of magnification endoscopy and narrow-band imaging in the upper gastrointestinal tract: New imaging techniques 218 10 Yao K, Anagnostopoulos G.K, Ragunath K Magnifying endoscopy for diagnosing and delineating early gastric cancer Endoscopy 2009, 41 (5), pp.462-467 11 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: Official Journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 2012, 15 (2), pp.118-120  ... 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... 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... the gastric mucosa is accompanied by such risk factors 214 - Awareness of signs of suspicious lesions: + With polypoid and ulcerative types (early gastric neoplasias) are easily detected if doctors