29 Gastric Cancer Including Early Neoplasia and Preneoplastic Conditions
Improvements in the recognition of premalignant lesions and the detection of early gastric cancers (EGC) will enable organ-preserving endoscopic therapy. Whereas several factors such as Helicobacter pylori eradication, smoking cessation, and low-salt diet might prevent gastric carcinogenesis, gastroscopy according to the proper procedure is crucial to recognize EGC. However, it is possible that even the presence of the lesion may be overlooked if the observer has no knowledge of what an EGC looks like and simply views the endoscopic images. In recent years, image-enhanced endoscopy (IEE), such as narrow-band imaging (NBI), has become more common, but high-quality white-light endoscopy should be the gold standard as a starting point for the detection of early gastric neoplasia.
With the advancement of endoscope technology in the 1980s, the number of patients diagnosed with EGC has increased. Nowadays endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), which avoids the morbidity and mortality associated with gastrectomy, offer less invasive options. Endoscopic resection allows complete pathologic staging of the cancer, which is critical for risk stratification of metastatic potential, and en bloc resection with R0 (negative vertical and horizontal margins) is to protect the patient from the risk of local recurrence.
This chapter outlines the knack of steady detection of EGC without oversight by endoscopic observation under white-light and endoscopic resection strategy for EGC.
29.2 Diagnostic Approach
Medical Interview Prior to Endoscopy
The most important purpose of medical interviews prior to endoscopy is to prevent morbidities associated with the examination. Obtaining a history of the use of nonsteroidal anti-inflammatory drugs (NSAIDs), anticoagulants, and antiplatelet drugs is important for deciding whether to perform a biopsy. 1 Recently, it is also necessary to interview patients about their history of examination for or eradication of H. pylori in countries with high rates of gastric cancer. 2 , 3 , 4
Gastroscopy is preceded by the routine administration of a mixture of mucolytic and defoaming agent to improve mucosal visualization. 5 , 6 Proper premedication before endoscopy is important to ensure satisfactory visualization of the gastric wall, especially before chromoendoscopy. Premedication with mucolytic agent significantly improved the visibility of the gastric mucosa during conventional endoscopy and after chromoendoscopy. Mucolytic premedication also significantly shortened the duration of endoscopy because it eliminates the need to awkwardly manipulate a wash tube during the procedure.
A standard regimen is 100 mL of water mixed with 20,000 units of mucolytic agent (Pronase MS, Kaken Pharmaceutical, Japan), 1 g of sodium bicarbonate, and 3 mL of dimethylpolysiloxane (20 mg/mL). In the West, 100 mL of water with 2 mL of acetylcysteine (200 mg/mL; Parvolex, Celltech, United Kingdom) and 0.5 mL of activated dimethicone (40 mg/mL; Infacol, Forest Laboratories, United Kingdom) can be used as an alternative.
Although it is common to use a topical pharyngeal anesthetic, its usefulness is controversial. 7 , 8 At least it seems clear that topical pharyngeal anesthesia does not affect patient tolerance or procedure performance in gastroscopy under sedation. 9 , 10
There has been no study that demonstrated the usefulness and efficacy of antispasmodics, in particular, intramuscular or intravenous butylscopolamine bromide (hyoscine-N-butylbromide) (Buscopan 20 mg). Peppermint oil has been used as a herbal medicine since ancient times. 11 Active components of this medicine were extracted to obtain the product L-menthol (Minclea). 12 , 13
Sedation for the purpose of endoscopy is categorized as moderate sedation (conscious sedation) according to the classification of sedation and anesthesia prescribed by the American Society of Anesthesiologists. 14 , 15 The Ramsay sedation score is a widely used method for judging the depth of sedation and anesthesia. 16 Accidental symptoms associated with the use of sedative drugs include respiratory depression, cardiovascular depression, bradycardia, arrhythmia, anterograde amnesia, disinhibition, and hiccups.
▶Table 29.1 shows an outline of the interview, pretreatment, and sedation procedures necessary for performing safe and effective gastroscopy.
29.2.2 Endoscopic Technique
The JAG program from United Kingdom is supported by an initial course on basic skills in upper gastrointestinal endoscopy and competence in the technique evaluated by direct observation of procedural skill (DOPS) assessments in formative and then summative appraisals. 17 DOPS descriptors basically focus on manipulative skills and disease pathology, as well as patient comfort and safety. The American Society of Gastrointestinal Endoscopy (ASGE) has a similarly outlined curriculum for gastroscopy. 18 However, in Japan, training in gastroscopy focuses on the detection of subtle mucosal changes that might indicate EGC.
In 2001, the guideline of the European Society of Gastrointestinal Endoscopy (ESGE) recommended that four images be recorded for observation of the stomach. 19 In Japan, the systematic screening protocol for the stomach (SSS) has been proposed as a minimum required standard for screening procedures. 20 , 21 The SSS protocol should be initiated as soon as the endoscope is inserted into the gastric antrum. In the antegrade view, endoscopic images of four quadrants of the gastric antrum, incisura, lower–middle–upper body are obtained. In the retroflex view, two images of the gastric fundus and cardia by distant and closed view are taken. Overall, the SSS comprises 22 endoscopic images. However, there has been no study that actually examined the detection rate and prognosis of gastric cancer using observational procedures and the number of images recorded as key performance indicator (KPI).
29.2.3 Knowledge for Diagnosis
Mucosal Condition of H. pylori Infection
EGC often has only minute morphologic changes that can be difficult to detect on a background of atrophic gastritis. The detection of mild elevations or shallow depressions in the surface mucosa and subtle changes in color requires careful observation. During endoscopic examination, risk stratification should be routinely kept in mind, using specific procedures to assess the severity of a lesion and the risk of progression. This means that attention is focused on areas associated with an increased cancer risk. The presence of H. pylori infection, atrophy of the gastric mucosa, and intestinal metaplasia are closely related to the risk of gastric carcinogenesis. 22 Therefore, evaluation of relevant endoscopic findings is important for efficient detection of gastric cancer. A study performed in the United Kingdom also reported the detection of EGC when patients with previously diagnosed atrophic gastritis or intestinal metaplasia were monitored in annual gastroscopy (67% of detected cancers were stage I and II in the annual follow-up group, compared with 23% in the group that was referred with symptoms; p < 0.05), resulting in major improvements in survival outcomes (5-year survival 50% compared with 10%; p = 0.006). 23
The first step to efficient diagnosis of gastric cancer is to estimate the presence/absence of H. pylori infection. 24 The presence of little adhesion of mucus, regular arrangement of collecting venules (RAC), and fundic gland polyps strongly suggests, “gastric mucosa uninfected with H. pylori” (▶Fig. 29.1a–d). Diagnostic odds ratio as uninfected H. pylori status is 11.5 in patients with RAC and 34.5 in those with fundic gland polyps, respectively. In the subjects with those findings, the possibility of H. pylori infection is extremely low.
Conversely, atrophy of the gastric mucosa (▶Fig. 29.2a), meandering and thickening of the folds of the greater curvature of the gastric corpus (▶Fig. 29.2b, c), xanthoma (▶Fig. 29.2d), or goose flesh–like mucosa (nodular gastritis) (▶Fig. 29.2e), in the absence of the above findings, indicate a gastric mucosa currently or previously infected with H. pylori. 25 Attention should be paid to this finding because it is now considered to be a mucosal change associated with a higher risk of juvenile gastric cancer, particularly undifferentiated adenocarcinoma. 26 , 27
Evaluation of High-Risk Mucosal Condition
The clinically most important finding in diagnosing gastric cancer is presence or absence of atrophic changes in the gastric mucosa resulting from prolonged H. pylori infection. 28 , 29 , 30 Atrophy of the gastric corpus and intestinal metaplasia occurs in a multifocal fashion in the fundus gland mucosa, and gradually extends to cover a greater area, eventually resulting in replacement of the entire fundus gland mucosa by atrophic and intestinal metaplastic mucosa. 31
The borderline of the mucosa devoid of atrophy and intestinal metaplasia produced by the continuous presence of the fundus gland mucosa is almost consistent with the endoscopic atrophic border proposed by Kimura and Takemoto and Kono et al. 32 , 33 The inside of the endoscopic atrophic border corresponds to the fundus gland mucosa devoid of atrophy and intestinal metaplasia. Outside the border, there is an intermediate zone consisting of a mixture of multifocal atrophic and intestinal metaplastic mucosa and normal fundus gland mucosa, in addition to areas of atrophic and intestinal metaplastic mucosa having no fundus glands (▶Fig. 29.3, ▶Fig. 29.4). Therefore, undifferentiated carcinoma often originates from the region inside the endoscopic atrophic border or the intermediate zone (vicinity of the atrophic border). On the other hand, well-differentiated carcinoma often arises from the external region of the endoscopic atrophic border.
Chronic infection with H. pylori causes molecular alterations in the gastric mucosa and transforms the mucosa into the intestinal phenotype. 34 On white-light images, some intestinal metaplasia appears slightly elevated with whitish patches (▶Fig. 29.5a). NBI further reveals intestinal metaplasia by its whitish color (▶Fig. 29.5b). In magnifying NBI, a fine blue–white line of light is observed on the crests of the epithelial surface/gyri (light blue crest) of intestinal metaplasia (▶Fig. 29.5c). 35 The “light blue crest” is thought to be caused by the reflection of short wavelength light at the brush border on the surface of the intestinal metaplasia. 36
Recommended steps for diagnosing gastric cancer on the basis of H. pylori infection and the atrophy of gastric mucosa are shown in ▶Fig. 29.6. Because the development of gastric cancer from H. pylori uninfected patients is extremely rare, the first step to access the risk of gastric cancer is to recognize patients with no history of H. pylori infection by endoscopy according to the previous description. However, we have to pay attention that one of the most typical EGC in the H. pylori uninfected patients is signet-ring cell carcinoma. This type of EGC, when it is discovered at very early stage, hardly shows any morphologic changes but pale faded color. Moreover, because signet-ring carcinoma sometimes exists only in the middle layer of the lamina propria that is covered with normal foveolar epithelium, it is important to attempt obtaining enough deep biopsy specimens that contain the muscular mucosae with large forceps. Histopathologic types of EGC in H. pylori infected patients are associated with the morphologic type and color of EGC on white-light images. Most elevated EGC are of the differentiated type and some gastric superficial elevated type EGCs and adenomas appear whitish. Among the flat or depressed type EGCs, differentiated type cancers look reddish, whereas undifferentiated types appear whitish because of a difference in hemoglobin content (i.e., variations in vascular density).