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The study of dynamic chemical magnifying endoscopy in gastric neoplasia
NEW METHODS
The study of dynamic chemical magnifying endoscopy in gastric neoplasia Kazuyoshi Yagi, MD, Yukio Aruga, MD, Atsuo Nakamura, MD, Atsuo Sekine, MD, Hazime Umezu, MD Niigata, Japan
Background: We assessed the usefulness of acetic acid–enhanced magnifying endoscopy in the diagnosis of gastric neoplasia. Methods: Forty-five patients (27 men, 18 women; median age 61.6 years) with gastric carcinoma or adenoma were enrolled in a prospective trial of enhanced magnifying endoscopy after instillation of 1.5% acetic acid. Acetic acid–enhanced magnified views of carcinoma or adenoma and the surrounding non-neoplastic mucosa were observed, and the duration of whitening time of each lesion was recorded. Observations: Magnified views of carcinoma showed a minute, grain-like pattern that differed from the surrounding noncancerous mucosa. The histopathologic diagnostic criteria were based on the Vienna classification of GI epithelial neoplasia. The mean duration of whitening differed with each histologic type: low-grade adenoma, 94 seconds; high-grade adenoma, 24.3 seconds; noninvasive carcinoma, 20.1 seconds; invasive intramucosal carcinoma, 3.5 seconds; and submucosal carcinoma or beyond, 2.5 seconds. The duration in the non-neoplastic surrounding mucosa was 90 seconds. After the disappearance of whitening in the carcinoma, the irregular pattern of the carcinoma reappeared, and the contrast between carcinomatous microvessels and the whitened nonneoplastic tissue became very clear on magnifying endoscopy. In accordance with the duration of whitening, more than 1 minute was termed ‘‘continuous whitening,’’ from 31 to 60 seconds was ‘‘delayed disappearance of whitening,’’ from 30 to 6 seconds was ‘‘early disappearance of whitening,’’ and 0 to 5 seconds was ‘‘no response.’’ Conclusions: Acetic acid–enhanced magnifying endoscopy was useful for the diagnosis of gastric adenocarcinoma. The duration of whitening differed among grades of neoplasia, and it was possible to observe changes in the whitening with time. Acetic acid–enhanced magnifying endoscopy, therefore, can be termed ‘‘dynamic chemical magnifying endoscopy.’’
The use of magnifying endoscopy in the diagnosis of GI tumors is spreading. Observation of pits is popular in magnifying endoscopy for the diagnosis of colorectal adenomas and carcinomas.1 Observation of the microvascular architecture by magnifying endoscopy has been reported in the diagnosis of gastric cancer.2 Yao et al3 described 3 characteristic findings in differentiated gastric adenocarcinoma: (1) the disappearance of the regular subepithelial capillary network pattern, (2) the presence of an irregular microvascular pattern, and (3) the presence of a demarcation line. The use of acetic acid–enhanced magnifying endoscopy was first reported by Guelrud and Herrera,4 who used it in Barrett’s esophagus to better define the columnar epithelium. Instillation of acetic acid gives the columnar See CME Section; p. 949. Copyright ª 2005 by the American Society for Gastrointestinal Endoscopy 0016-5107/$30.00 doi:10.1016/j.gie.2005.08.050
mucosa a whitened appearance, and the structure of the mucosa can then be observed clearly by magnifying endoscopy. Guelrud et al5 called this ‘‘enhanced-magnification endoscopy’’ and reported that it was very useful for the diagnosis of intestinal metaplasia in Barrett’s esophagus. Toyoda et al6 reported that enhanced-magnification endoscopy was very accurate for diagnosing intestinal metaplasia in the distal esophagus and at the esophagogastric junction. We have been studying the use of acetic acid–enhanced magnifying endoscopy for the diagnosis of gastric cancer and adenoma.7 We initially tried to observe the pit pattern or surface structure of gastric carcinoma. However, we then realized that the duration of aceto-whitening differed between gastric carcinoma and noncancerous gastric mucosa: aceto-whitening disappeared earlier in carcinoma than in the noncancerous mucosa. Furthermore, a clear contrast between cancerous and noncancerous mucosa could be observed by magnifying endoscopy. Acetic acid–enhanced
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Volume 62, No. 6 : 2005 GASTROINTESTINAL ENDOSCOPY 963
Dynamic chemical magnifying endoscopy
magnifying endoscopy is thought to be different from chromoendoscopy because no dyes are used and the chemical response of the mucosa to acetic acid produces the whitening changes. Furthermore, the fact that the degree of whitening changes with time and that the duration of whitening is dependent on the histology suggests that this new technique should be termed dynamic chemical magnifying endoscopy. The aim of this prospective study was to establish whether or not dynamic chemical magnifying endoscopy was useful in the diagnosis of gastric carcinoma and adenoma.
Yagi et al
Capsule Summary What is already known on this topic d
d
What this study adds to our knowledge d
PATIENTS AND METHODS Forty-five consecutive patients with gastric carcinoma or adenoma who underwent magnifying endoscopy between July 2004 and March 2005 were included in this uncontrolled, prospective cohort study. In all patients, the gastric carcinoma or adenoma had been diagnosed previously by conventional endoscopy and biopsy with histopathologic confirmation. However, the margins of each carcinoma or adenoma were not known at the time of dynamic chemical magnifying endoscopy. The protocol was approved by the ethics committee of our institution. All enrolled patients gave their written informed consent for participation in the study.
Endoscopic procedure To dissolve the mucus layer of the stomach, each patient ingested a solution containing 20,000 U pronase (Pronase MS; Kaken Pharmaceutical Products Inc, Tokyo, Japan) and 1 g NaHCO2 in 50 mL water, 10 minutes before the endoscopy. The procedure was performed with a magnifying endoscope (GIF-Q240Z; Olympus Optical Co, Ltd, Tokyo, Japan) in accordance with the following protocol. Gastric carcinomas or adenomas were initially observed by conventional endoscopy, followed by magnifying endoscopy. The regular subepithelial capillary network pattern of noncancerous mucosa and the irregular microvascular pattern of cancerous mucosa were observed by magnifying endoscopy. After that, 10 mL of 1.5% (v/v) acetic acid was sprinkled at low pressure onto the gastric mucosa by means of a syringe attached to the accessory channel of the endoscope. The margin diagnosed by magnifying endoscopy was observed continuously after sprinkling, and the time taken for the aceto-whitening of the carcinoma or adenoma to disappear was measured. The magnified views were recorded every 5 or 10 seconds until the aceto-whitening had disappeared. The whitening patterns were classified by the time taken for the whitening to disappear: 0 to 5 seconds, a ‘‘no response’’ pattern; 6 to 30 seconds, ‘‘early disappearance of whitening’’; 31 to 60 seconds, ‘‘delayed disappearance’’; and 61 seconds or more, ‘‘continuous whitening.’’ 964 GASTROINTESTINAL ENDOSCOPY Volume 62, No. 6 : 2005
Observation of the microvascular architecture by magnifying endoscopy has been used in the diagnosis of gastric cancer. The acetic acid–enhanced magnifying endoscopy has been used in Barrett’s esophagus to define the columnar epithelium.
d
The duration of whitening differed among grades of neoplasia. After the disappearance of whitening in the carcinoma, the contrast between carcinomatous microvascular architecture and the whitened non-neoplastic tissue became very clear on magnifying endoscopy.
One endoscopist (K.Y.) performed all of the magnifying endoscopic examinations and recorded all of the endoscopic findings.
Histopathology All carcinomas and adenomas were resected either endoscopically or surgically. The resected specimens were extended on boards with pins and fixed in 20% formalin. The lesions, together with the surrounding nonadenomatous or carcinomatous mucosa, were cut into 2- to 5-mm-wide serial-step sections; these dimensions were determined by the endoscopist who performed the study (K.Y.) to correspond to the portion of the magnified endoscopic images. The histopathologic diagnosis was done by a pathologist (H.U.) blinded to the endoscopic findings. The histopathologic diagnostic criteria were based on the Vienna classification of GI epithelial neoplasia: 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 (4.1 high-grade adenoma/ dysplasia, 4.2 noninvasive carcinoma); category 5 invasive neoplasia (5.1 intramucosal carcinoma, 5.2 submucosal carcinoma or beyond).8
Statistical analysis The duration until acetic acid whitening disappeared in each histological group was compared by means of the Mann-Whitney test. A p value of less than 0.05 was considered to be statistically significant.
RESULTS Histologic features of the lesions There were 5 patterns in the neoplasms that were observed by dynamic chemical magnifying endoscopy and www.giejournal.org
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Dynamic chemical magnifying endoscopy
Figure 1. A, A depressed lesion is observed on the greater curvature of the antrum. This lesion was diagnosed to be an adenocarcinoma by examination of a biopsy specimen. B, Magnified view 5 seconds after acetic acid was sprinkled on the lesion. Under magnification, this adenocarcinoma had a minute grain-like pattern, and the noncancerous mucosa had a granular surface pattern. C, Magnified view 10 seconds after sprinkling acetic acid. The acetowhitening of the adenocarcinoma is fading. D, Magnified view after 20 seconds after sprinkling acetic acid. Aceto-whitening of the adenocarcinoma has disappeared and the irregular microvascular pattern reappeared, although aceto-whitening continues in the noncancerous mucosa. The adenocarcinoma was resected by endoscopic mucosal resection and was revealed to be a noninvasive cancer (category 4.2).
resected endoscopically or surgically: low-grade adenoma (category 3), high-grade adenoma (category 4.1), noninvasive carcinoma (category 4.2), intramucosal carcinoma (category 5.1), and submucosal carcinoma or beyond (category 5.2). The numbers of tumors in each group were the following: low-grade adenoma, 5 lesions; high-grade adenoma, 5 lesions; noninvasive carcinoma, 21 lesions; intramucosal carcinoma, 6 lesions; and submucosal carcinoma or beyond, 8 lesions. The endoscopic macroscopic features of these lesions were as follows. All of the lowgrade adenomas and the high-grade adenomas were flat, elevated lesions; 13 of the noninvasive carcinomas were depressed lesions; 6 were flat, elevated lesions; and two were elevated lesions. Five of the intramucosal carcinomas were depressed lesions, and one was a flat, elevated lesion. Six of the carcinoma invasive to the submucosa or beyond were depressed lesions, and two were depressed lesions with ulceration. The areas of carcinomas or adenoma on the resected specimens corresponded to the areas of endoscopic diagnosis.
Magnifying endoscopic view before and after acetic acid sprinkling
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Initially, we used conventional endoscopic observation of gastric adenocarcinoma (Fig. 1A). Magnifying endoscopy was used to observe the area of the border between the adenocarcinoma and the noncancerous mucosa. Under magnification, the adenocarcinoma had an irregular microvascular pattern, and the noncancerous mucosa had a subepithelial microvascular network pattern. Five seconds after the acetic acid was sprinkled onto the area, the magnified view of this adenocarcinoma showed a minute grain-like pattern, and that of the noncancerous mucosa showed a granular surface pattern (Fig. 1B). Ten seconds after acetic acid sprinkling, the aceto-whitening of the adenocarcinoma was fading (Fig. 1C). Twenty seconds after sprinkling, the aceto-whitening of the adenocarcinoma had disappeared, and the irregular microvascular pattern had reappeared on the magnified view, although aceto-whitening continued in the area of noncancerous mucosa (Figure 1D).
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TABLE 1. Histologic diagnosis (n Z 45) and duration of aceto-whitening Histologic diagnosis (n Z 45) (Category of Vienna classification)
Duration until acetic acid whitening disappeared, mean, s (range)
Non-neoplastic mucosa (n Z 45)
90 (60-180)
(a)
Low-grade adenoma (n Z 5) (category 3)
94 (40-180)
(b)
High-grade adenoma (n Z 5) (category 4.1)
24.3 (10-35)
(c)
Noninvasive carcinoma (n Z 21) (category 4.2)
20.1 (5-50)
(d)
Intramucosal carcinoma (n Z 6) (invasive) (category 5.1)
3.5 (0-10)
(e)
Submucosal carcinoma (n Z 8) or beyond (category 5.2)
2.5 (0-5)
(f)
(a) vs. (b), not significant; (a) vs. (c) (d) (e) (f), p ! 0.01; (b) vs. (c) (d) (e) (f), P ! 0.01; (c) vs. (d), not significant; (d) vs. (e), p ! 0.01; (e) vs. (f), not significant. Mann-Whitney test.
TABLE 2. Histologic diagnosis and pattern of response to acetic acid Response pattern by acetic acid (number of patients) Histologic diagnosis (Category of Vienna classification)
No response*
Early disappearancey
Delayed disappearancez
Continuousx
Low-grade adenoma (n Z 5) (category 3)
0
0
2
3
High-grade adenoma (n Z 5) (category 4-1)
0
3
2
0
Noninvasive carcinoma (n Z 21) (category 4.2)
2
17
2
0
Intramucosal carcinoma (invasive) (n Z 6) (category 5.1)
5
1
0
0
Submucosal carcinoma or beyond (n Z 8) (category 5.2)
8
0
0
0
*0-5 s until disappearance of whitening. y6-30 s until disappearance of whitening. z31-60 s until disappearance of whitening. xO60 s until disappearance of whitening.
Duration of aceto-whitening of each mucosa: adenomas and carcinomas The durations of aceto-whitening depended on the histology (Table 1). Low-grade adenoma had a long mean duration of whitening (94 seconds). The mean duration in high-grade adenoma was 24.3 seconds. The durations in noninvasive carcinoma, intramucosal carcinoma, and submucosal or beyond were 20.1 seconds, 3.5 seconds, and 2.5 seconds, respectively. The duration in the non-neoplastic surrounding mucosa was 90 seconds. The duration of aceto-whitening did not differ significantly between low-grade adenoma and non-neoplastic mucosa but did differ significantly between high-grade adenoma, noninvasive carcinoma, intramucosal carcinoma, submucosal carcinoma, and non-neoplastic mucosa. The durations did not differ significantly between high-grade adenoma and noninvasive carcinoma but did differ significantly between noninvasive carcinoma and intramucosal carcinoma (invasive). The durations in cases of intramucosal carcinoma (invasive) was not significantly different from that in the case of submucosal carcinoma or beyond (Table 1). 966 GASTROINTESTINAL ENDOSCOPY Volume 62, No. 6 : 2005
The response patterns of each adenomas or carcinomas to acetic acid are shown in Table 2. All the submucosal carcinomas or beyond showed no response. Five of the 6 intramucosal carcinomas (invasive) were nonresponsive (Fig. 2), and one that showed early disappearance of whitening was an elevated type of intramucosal carcinoma. Seventeen (81%) of 21 noninvasive carcinomas showed early disappearance of whitening, two showed no response, and two showed a delayed disappearance. Of 5 high-grade adenomas, 3 showed early disappearance and two showed delayed disappearance. Of 5 low-grade adenomas, two showed delayed disappearance (Fig. 3) and 3 showed continuous whitening.
DISCUSSION Acetic acid produces reversible intracellular protein degeneration.9 It has been used as an aid in the detection of small lesions in the uterine cervical mucosa during colposcopy.10 Guelrud and Herrera4 reported the use of acetic www.giejournal.org
Yagi et al
Dynamic chemical magnifying endoscopy
Figure 2. A, A flat, reddish lesion was observed on greater curvature of the lower body; this lesion was diagnosed to be an adenocarcinoma by examination of a biopsy specimen. B, Endoscopic observation (A) 5 seconds after sprinkling acetic acid. The red area, shaped like a bottle gourd, is clarified by its lack of aceto-whitening: the surrounding noncancerous mucosa shows aceto-whitening. C, Magnified view of the nonresponsive red area, showing an irregular microvascular pattern and the surrounding noncancerous mucosa, showing whitening of the surface, with a tubular appearance. This lesion was resected by surgical operation and was revealed to be an intramucosal carcinoma (invasive) (category 5.1).
acid to improve the detection of columnar epithelium in patients with Barrett’s esophagus being treated with multipolar electrocoagulation; they later reported that magnification endoscopy with acetic acid instillation, which they called ‘‘enhanced magnification,’’ was an accurate method of predicting intestinal metaplasia in Barrett’s esophagus.5 They reported that enhanced-magnification endoscopy could identify, with outstanding clarity and resolution, the characteristic endoscopic patterns that were correlated with the histologic identification of intestinal metaplasia.4 Furthermore, Yao et al2,3 reported that magnifying endoscopy was useful for the diagnosis of intramucosal gastric carcinoma. They referred to 3 characteristic findings in differentiated carcinoma: (1) the disappearance of the regular subepithelial capillary network pattern, (2) the presence of an irregular microvascular pattern, and (3) the presence of a demarcation line.2,3 In Japan and Korea, intramucosal gastric carcinomas, even if over 2 cm, are now being resected endoscopically by submucosal dissection. Unlike conventional EMR, endoscopic submucosal dissection can be used to resect large intramucosal gastric carcinomas in one piece.11-13
To perform a complete resection, however, it is necessary to accurately determine the area of gastric carcinoma. Chromoendoscopy with indigo carmine is generally used in Japan. However, accurate delineation of the area of gastric carcinoma is often difficult, because indigo carmine simply emphasizes the depressive, elevated, or rugged surface of the carcinoma. To overcome these limitations, Yao et al2,3 suggest the use of magnifying endoscopic examination of the microvascular architecture to pursue a more accurate diagnosis. We have also diagnosed carcinomas by their microvascular architecture under magnifying endoscopy. However, it is sometimes difficult to observe the microvascular architecture clearly, and we considered that there was a need for a method of clarifying the margin between the carcinoma and noncarcinomatous mucosa. We, therefore, began by using acetic acid– enhanced magnifying endoscopy for the diagnosis of the gastric cancer. After the acetic acid was sprinkled onto the area, the magnified view of adenocarcinoma showed a minute grain-like pattern and that of the noncancerous mucosa showed a granular surface pattern; however, the border
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between the carcinoma and the noncarcinoma mucosa was not so clear. We then realized that aceto-whitening disappeared earlier in gastric adenocarcinoma than in the noncarcinomatous mucosa, and a clear border between the carcinoma and the noncarcinomatous mucosa appeared. Invasive intramucosal carcinomas and submucosal, or beyond, carcinomas tended to show no response to acetic acid or a disappearance of whitening after a few seconds, and noninvasive carcinoma showed whitening and disappearance after several seconds, but adenoma and nonneoplastic mucosa showed whitening for 30 seconds to 3 minutes. The higher the grade of the neoplasia, the shorter the duration of the whitening. The duration of aceto-whitening differed among the grades of neoplasia and indicated a chemical response. Furthermore, because it was possible to observe changes in the whitening with time, this new technique offers a promise of epoch-making proportions. Because no
dyes were used and the chemical response of the mucosa to acetic acid was whitening that changed with time, the duration of whitening was dependent on the histologic characteristics of the tissue. Accordingly, this new technique should be termed ‘‘dynamic chemical endoscopy.’’ In some cases, the area of gastric carcinoma could be observed clearly by regular endoscopy without magnification. However, a magnified view of adenocarcinoma and the surrounding non-neoplastic mucosa with aceto-whitening allowed accurate delineation of the area of gastric carcinoma with confidence. At present, we think that dynamic chemical magnifying endoscopy is able to allow accurate diagnosis of the area of gastric carcinoma. Diagnosis of gastric neoplasia involves detection of the neoplasia, determination of its extent, estimation of the depth of invasion, and estimation of the histopathologic type. Although dynamic chemical magnifying endoscopy is not suitable for the detection of the neoplasia, it is useful for ascertaining the borderline between neoplasia and non-neoplasia after detection of neoplasia by conventional endoscopic examination. For determining the extent of neoplasia, dynamic chemical magnifying endoscopy is practical and is particularly useful during preparation for EMR. In cases of noninvasive intramucosal cancer and high-grade adenoma, the contrast between neoplasia and non-neoplasia is not immediately obvious after sprinkling and appears only after about 20 to 30 seconds. On the other hand, in cases of invasive intramucosal cancer or submucosal cancer or beyond, contrast appears immediately after sprinkling. This knowledge is necessary for determining the extent of neoplasia. However, because the duration of aceto-whitening did not differ significantly between low-grade adenoma and non-neoplastic mucosa, dynamic chemical magnifying endoscopy was not practical for the determination of the extent of the low-grade adenomas. Estimation of the depth of invasion is impossible by dynamic chemical magnification endoscopy, because there is not a significant difference between invasive intramucosal cancer and submucosal cancer or beyond. Determination of the depth of invasion, therefore, should be done by other methods; for example, EUS. Dynamic chemical magnifying endoscopy is able to give information that allows the histologic type to be determined. For example, rapid disappearance of whitening in a lesion suggests that the lesion might be an invasive intramucosal cancer or a submucosal cancer or beyond, whereas a slow disappearance of whitening suggests that the lesion might be a highgrade adenoma or a noninvasive intramucosal cancer. However, many more types of neoplasia should be studied to obtain basic data that will allow more accurate determination of histologic type. The aceto-whitening of these carcinomas disappeared in less than 30 seconds. Because of movement of the gastric wall from contact with the endoscope, accurate observation of the time at which whitening disappears might be
968 GASTROINTESTINAL ENDOSCOPY Volume 62, No. 6 : 2005
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Figure 3. A, Elevated lesion on the antrum; this lesion was diagnosed to be an adenoma by examination of a biopsy specimen. B, Magnified view of the elevated lesion 40 seconds after sprinkling acetic acid. Aceto-whitening of the surface of the adenoma, with a tubular appearance, is observed. The surrounding non-neoplastic mucosa shows surface whitening with small pits. The aceto-whitening of the adenoma disappeared 60 seconds after sprinkling. This indicated delayed disappearance of aceto-whitening. This lesion was resected by EMR and was revealed to be a low-grade adenoma (category 3).
Yagi et al
difficult if the area of neoplasia is large. Furthermore, if the area of neoplasia is large or if the neoplasia is located in a position that makes observation difficult, dynamic chemical magnifying endoscopy might not be accurate. The reasons for the whitening with acetic acid and the lack of response of carcinoma to acetic acid are not well known. Lambert et al14 reported that the proportion of unbuffered acetic acid in contact with the surface epithelial cells of the mucosa determines the alteration in the structure of cellular proteins. Slight changes in pH and in the ambient ionic strength are known to break the disulfide and hydrogen bonds and to provoke deacetylation.14 Therefore, the acid interferes with the tertiary (spatial) structure of proteins in the nucleus and in the cytoplasm, and changes their optical properties.14 In conclusion, dynamic chemical magnifying endoscopy was thought to be useful for the determination of the extent of the gastric neoplasia.
REFERENCES 1. Kudo S, Tamura S, Nakajima T, et al. Diagnosis of colorectal tumorous lesions by magnifying endoscopy. Gastrointest Endosc 1996;44:8-14. 2. Yao K, Oishi T, Matsui T, et al. Novel magnified endoscopic findings of microvascular architecture in intramucosal gastric cancer. Gastrointest Endosc 2002;56:279-84. 3. Yao K, Iwashita A, Yao T. Early gastric cancer: proposal for a new diagnostic system based on microvascular architecture as visualized by magnified endoscopy. Dig Endosc 2004;16(Suppl):S110-7. 4. Guelrud M, Herrera I. Acetic acid improves identification of remnant islands of Barrett’s epithelium after endoscopic therapy. Gastrointest Endosc 1998;47:512-5.
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Dynamic chemical magnifying endoscopy 5. Guelrud M, Herrera I, Esssenfeld H, et al. Enhanced magnification endoscopy: a new technique to identify specialized intestinal metaplasia in Barrett’s esophagus. Gastrointest Endosc 2001;53:559-65. 6. Toyoda H, Rubio C, Befrits R, et al. Detection of intestinal metaplasia in distal esophagus and esophagogastric junction by enhanced-magnification endoscopy. Gastrointest Endosc 2004;59:15-21. 7. Yagi K, Aruga Y, Nakamura A, et al. Magnifying endoscopy for diagnosis of gastric cancer. Stomach Intestine 2005;40:791-9. 8. Schlemper RJ, Riddle RH, Kato Y, et al. The Vienna classification of gastrointestinal epithelial neoplasia. Gut 2000;47:251-5. 9. Cartier R. Practical colposcopy. Basel: Karger; 1997. 10. Cartier R. Role de la colposcopie dans le diagnostic et le tritement des dysplasies et des carcinomas intra-epitheliaux du col uterin. Bull Cancer 1979;66:447-54. 11. Yahagi N, Fujishiro M, Iguchi M, et al. Theoretical and technical requirements to expand EMR indication. Dig Endosc 2003;15(Suppl): S19-21. 12. Yamamoto H, Sekine Y, Higashizawa T, et al. Successful en bloc resection of a large superficial gastric cancer by using sodium hyaluronate and electrocautery incision forceps. Gastrointest Endosc 2001;54: 629-33. 13. Ono H, Kondo H, Gotoda T, et al. Endoscopic mucosal resection for treatment of early gastric cancer. Gut 2001;48:225-9. 14. Lambert R, Rey JF, Sankaranarayanan R. Magnification and chromoscopy with the acetic acid test. Endoscopy 2003;35:437-45.
Received March 12, 2005. Accepted August 11, 2005. Current affiliations: Department of Internal Medicine, Niigata Prefectural Yoshida Hospital, Yoshida-machi, Niigata-ken, Japan; Division of Pathology, Niigata University Medical and Dental Hospital, Niigata, Japan. Reprint requests: Kazuyoshi Yagi, MD, Department of Internal Medicine, Niigata-Prefectural Yoshida Hospital, Yoshida-machi, Niigata-ken, 959-0242, Japan.
Volume 62, No. 6 : 2005 GASTROINTESTINAL ENDOSCOPY 969
The study of dynamic chemical magnifying endoscopy in gastric neoplasia Kazuyoshi Yagi, MD, Yukio Aruga, MD, Atsuo Nakamura, MD, Atsuo Sekine, MD, Hazime Umezu, MD Niigata, Japan
Background: We assessed the usefulness of acetic acid–enhanced magnifying endoscopy in the diagnosis of gastric neoplasia. Methods: Forty-five patients (27 men, 18 women; median age 61.6 years) with gastric carcinoma or adenoma were enrolled in a prospective trial of enhanced magnifying endoscopy after instillation of 1.5% acetic acid. Acetic acid–enhanced magnified views of carcinoma or adenoma and the surrounding non-neoplastic mucosa were observed, and the duration of whitening time of each lesion was recorded. Observations: Magnified views of carcinoma showed a minute, grain-like pattern that differed from the surrounding noncancerous mucosa. The histopathologic diagnostic criteria were based on the Vienna classification of GI epithelial neoplasia. The mean duration of whitening differed with each histologic type: low-grade adenoma, 94 seconds; high-grade adenoma, 24.3 seconds; noninvasive carcinoma, 20.1 seconds; invasive intramucosal carcinoma, 3.5 seconds; and submucosal carcinoma or beyond, 2.5 seconds. The duration in the non-neoplastic surrounding mucosa was 90 seconds. After the disappearance of whitening in the carcinoma, the irregular pattern of the carcinoma reappeared, and the contrast between carcinomatous microvessels and the whitened nonneoplastic tissue became very clear on magnifying endoscopy. In accordance with the duration of whitening, more than 1 minute was termed ‘‘continuous whitening,’’ from 31 to 60 seconds was ‘‘delayed disappearance of whitening,’’ from 30 to 6 seconds was ‘‘early disappearance of whitening,’’ and 0 to 5 seconds was ‘‘no response.’’ Conclusions: Acetic acid–enhanced magnifying endoscopy was useful for the diagnosis of gastric adenocarcinoma. The duration of whitening differed among grades of neoplasia, and it was possible to observe changes in the whitening with time. Acetic acid–enhanced magnifying endoscopy, therefore, can be termed ‘‘dynamic chemical magnifying endoscopy.’’
The use of magnifying endoscopy in the diagnosis of GI tumors is spreading. Observation of pits is popular in magnifying endoscopy for the diagnosis of colorectal adenomas and carcinomas.1 Observation of the microvascular architecture by magnifying endoscopy has been reported in the diagnosis of gastric cancer.2 Yao et al3 described 3 characteristic findings in differentiated gastric adenocarcinoma: (1) the disappearance of the regular subepithelial capillary network pattern, (2) the presence of an irregular microvascular pattern, and (3) the presence of a demarcation line. The use of acetic acid–enhanced magnifying endoscopy was first reported by Guelrud and Herrera,4 who used it in Barrett’s esophagus to better define the columnar epithelium. Instillation of acetic acid gives the columnar See CME Section; p. 949. Copyright ª 2005 by the American Society for Gastrointestinal Endoscopy 0016-5107/$30.00 doi:10.1016/j.gie.2005.08.050
mucosa a whitened appearance, and the structure of the mucosa can then be observed clearly by magnifying endoscopy. Guelrud et al5 called this ‘‘enhanced-magnification endoscopy’’ and reported that it was very useful for the diagnosis of intestinal metaplasia in Barrett’s esophagus. Toyoda et al6 reported that enhanced-magnification endoscopy was very accurate for diagnosing intestinal metaplasia in the distal esophagus and at the esophagogastric junction. We have been studying the use of acetic acid–enhanced magnifying endoscopy for the diagnosis of gastric cancer and adenoma.7 We initially tried to observe the pit pattern or surface structure of gastric carcinoma. However, we then realized that the duration of aceto-whitening differed between gastric carcinoma and noncancerous gastric mucosa: aceto-whitening disappeared earlier in carcinoma than in the noncancerous mucosa. Furthermore, a clear contrast between cancerous and noncancerous mucosa could be observed by magnifying endoscopy. Acetic acid–enhanced
www.giejournal.org
Volume 62, No. 6 : 2005 GASTROINTESTINAL ENDOSCOPY 963
Dynamic chemical magnifying endoscopy
magnifying endoscopy is thought to be different from chromoendoscopy because no dyes are used and the chemical response of the mucosa to acetic acid produces the whitening changes. Furthermore, the fact that the degree of whitening changes with time and that the duration of whitening is dependent on the histology suggests that this new technique should be termed dynamic chemical magnifying endoscopy. The aim of this prospective study was to establish whether or not dynamic chemical magnifying endoscopy was useful in the diagnosis of gastric carcinoma and adenoma.
Yagi et al
Capsule Summary What is already known on this topic d
d
What this study adds to our knowledge d
PATIENTS AND METHODS Forty-five consecutive patients with gastric carcinoma or adenoma who underwent magnifying endoscopy between July 2004 and March 2005 were included in this uncontrolled, prospective cohort study. In all patients, the gastric carcinoma or adenoma had been diagnosed previously by conventional endoscopy and biopsy with histopathologic confirmation. However, the margins of each carcinoma or adenoma were not known at the time of dynamic chemical magnifying endoscopy. The protocol was approved by the ethics committee of our institution. All enrolled patients gave their written informed consent for participation in the study.
Endoscopic procedure To dissolve the mucus layer of the stomach, each patient ingested a solution containing 20,000 U pronase (Pronase MS; Kaken Pharmaceutical Products Inc, Tokyo, Japan) and 1 g NaHCO2 in 50 mL water, 10 minutes before the endoscopy. The procedure was performed with a magnifying endoscope (GIF-Q240Z; Olympus Optical Co, Ltd, Tokyo, Japan) in accordance with the following protocol. Gastric carcinomas or adenomas were initially observed by conventional endoscopy, followed by magnifying endoscopy. The regular subepithelial capillary network pattern of noncancerous mucosa and the irregular microvascular pattern of cancerous mucosa were observed by magnifying endoscopy. After that, 10 mL of 1.5% (v/v) acetic acid was sprinkled at low pressure onto the gastric mucosa by means of a syringe attached to the accessory channel of the endoscope. The margin diagnosed by magnifying endoscopy was observed continuously after sprinkling, and the time taken for the aceto-whitening of the carcinoma or adenoma to disappear was measured. The magnified views were recorded every 5 or 10 seconds until the aceto-whitening had disappeared. The whitening patterns were classified by the time taken for the whitening to disappear: 0 to 5 seconds, a ‘‘no response’’ pattern; 6 to 30 seconds, ‘‘early disappearance of whitening’’; 31 to 60 seconds, ‘‘delayed disappearance’’; and 61 seconds or more, ‘‘continuous whitening.’’ 964 GASTROINTESTINAL ENDOSCOPY Volume 62, No. 6 : 2005
Observation of the microvascular architecture by magnifying endoscopy has been used in the diagnosis of gastric cancer. The acetic acid–enhanced magnifying endoscopy has been used in Barrett’s esophagus to define the columnar epithelium.
d
The duration of whitening differed among grades of neoplasia. After the disappearance of whitening in the carcinoma, the contrast between carcinomatous microvascular architecture and the whitened non-neoplastic tissue became very clear on magnifying endoscopy.
One endoscopist (K.Y.) performed all of the magnifying endoscopic examinations and recorded all of the endoscopic findings.
Histopathology All carcinomas and adenomas were resected either endoscopically or surgically. The resected specimens were extended on boards with pins and fixed in 20% formalin. The lesions, together with the surrounding nonadenomatous or carcinomatous mucosa, were cut into 2- to 5-mm-wide serial-step sections; these dimensions were determined by the endoscopist who performed the study (K.Y.) to correspond to the portion of the magnified endoscopic images. The histopathologic diagnosis was done by a pathologist (H.U.) blinded to the endoscopic findings. The histopathologic diagnostic criteria were based on the Vienna classification of GI epithelial neoplasia: 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 (4.1 high-grade adenoma/ dysplasia, 4.2 noninvasive carcinoma); category 5 invasive neoplasia (5.1 intramucosal carcinoma, 5.2 submucosal carcinoma or beyond).8
Statistical analysis The duration until acetic acid whitening disappeared in each histological group was compared by means of the Mann-Whitney test. A p value of less than 0.05 was considered to be statistically significant.
RESULTS Histologic features of the lesions There were 5 patterns in the neoplasms that were observed by dynamic chemical magnifying endoscopy and www.giejournal.org
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Dynamic chemical magnifying endoscopy
Figure 1. A, A depressed lesion is observed on the greater curvature of the antrum. This lesion was diagnosed to be an adenocarcinoma by examination of a biopsy specimen. B, Magnified view 5 seconds after acetic acid was sprinkled on the lesion. Under magnification, this adenocarcinoma had a minute grain-like pattern, and the noncancerous mucosa had a granular surface pattern. C, Magnified view 10 seconds after sprinkling acetic acid. The acetowhitening of the adenocarcinoma is fading. D, Magnified view after 20 seconds after sprinkling acetic acid. Aceto-whitening of the adenocarcinoma has disappeared and the irregular microvascular pattern reappeared, although aceto-whitening continues in the noncancerous mucosa. The adenocarcinoma was resected by endoscopic mucosal resection and was revealed to be a noninvasive cancer (category 4.2).
resected endoscopically or surgically: low-grade adenoma (category 3), high-grade adenoma (category 4.1), noninvasive carcinoma (category 4.2), intramucosal carcinoma (category 5.1), and submucosal carcinoma or beyond (category 5.2). The numbers of tumors in each group were the following: low-grade adenoma, 5 lesions; high-grade adenoma, 5 lesions; noninvasive carcinoma, 21 lesions; intramucosal carcinoma, 6 lesions; and submucosal carcinoma or beyond, 8 lesions. The endoscopic macroscopic features of these lesions were as follows. All of the lowgrade adenomas and the high-grade adenomas were flat, elevated lesions; 13 of the noninvasive carcinomas were depressed lesions; 6 were flat, elevated lesions; and two were elevated lesions. Five of the intramucosal carcinomas were depressed lesions, and one was a flat, elevated lesion. Six of the carcinoma invasive to the submucosa or beyond were depressed lesions, and two were depressed lesions with ulceration. The areas of carcinomas or adenoma on the resected specimens corresponded to the areas of endoscopic diagnosis.
Magnifying endoscopic view before and after acetic acid sprinkling
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Initially, we used conventional endoscopic observation of gastric adenocarcinoma (Fig. 1A). Magnifying endoscopy was used to observe the area of the border between the adenocarcinoma and the noncancerous mucosa. Under magnification, the adenocarcinoma had an irregular microvascular pattern, and the noncancerous mucosa had a subepithelial microvascular network pattern. Five seconds after the acetic acid was sprinkled onto the area, the magnified view of this adenocarcinoma showed a minute grain-like pattern, and that of the noncancerous mucosa showed a granular surface pattern (Fig. 1B). Ten seconds after acetic acid sprinkling, the aceto-whitening of the adenocarcinoma was fading (Fig. 1C). Twenty seconds after sprinkling, the aceto-whitening of the adenocarcinoma had disappeared, and the irregular microvascular pattern had reappeared on the magnified view, although aceto-whitening continued in the area of noncancerous mucosa (Figure 1D).
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TABLE 1. Histologic diagnosis (n Z 45) and duration of aceto-whitening Histologic diagnosis (n Z 45) (Category of Vienna classification)
Duration until acetic acid whitening disappeared, mean, s (range)
Non-neoplastic mucosa (n Z 45)
90 (60-180)
(a)
Low-grade adenoma (n Z 5) (category 3)
94 (40-180)
(b)
High-grade adenoma (n Z 5) (category 4.1)
24.3 (10-35)
(c)
Noninvasive carcinoma (n Z 21) (category 4.2)
20.1 (5-50)
(d)
Intramucosal carcinoma (n Z 6) (invasive) (category 5.1)
3.5 (0-10)
(e)
Submucosal carcinoma (n Z 8) or beyond (category 5.2)
2.5 (0-5)
(f)
(a) vs. (b), not significant; (a) vs. (c) (d) (e) (f), p ! 0.01; (b) vs. (c) (d) (e) (f), P ! 0.01; (c) vs. (d), not significant; (d) vs. (e), p ! 0.01; (e) vs. (f), not significant. Mann-Whitney test.
TABLE 2. Histologic diagnosis and pattern of response to acetic acid Response pattern by acetic acid (number of patients) Histologic diagnosis (Category of Vienna classification)
No response*
Early disappearancey
Delayed disappearancez
Continuousx
Low-grade adenoma (n Z 5) (category 3)
0
0
2
3
High-grade adenoma (n Z 5) (category 4-1)
0
3
2
0
Noninvasive carcinoma (n Z 21) (category 4.2)
2
17
2
0
Intramucosal carcinoma (invasive) (n Z 6) (category 5.1)
5
1
0
0
Submucosal carcinoma or beyond (n Z 8) (category 5.2)
8
0
0
0
*0-5 s until disappearance of whitening. y6-30 s until disappearance of whitening. z31-60 s until disappearance of whitening. xO60 s until disappearance of whitening.
Duration of aceto-whitening of each mucosa: adenomas and carcinomas The durations of aceto-whitening depended on the histology (Table 1). Low-grade adenoma had a long mean duration of whitening (94 seconds). The mean duration in high-grade adenoma was 24.3 seconds. The durations in noninvasive carcinoma, intramucosal carcinoma, and submucosal or beyond were 20.1 seconds, 3.5 seconds, and 2.5 seconds, respectively. The duration in the non-neoplastic surrounding mucosa was 90 seconds. The duration of aceto-whitening did not differ significantly between low-grade adenoma and non-neoplastic mucosa but did differ significantly between high-grade adenoma, noninvasive carcinoma, intramucosal carcinoma, submucosal carcinoma, and non-neoplastic mucosa. The durations did not differ significantly between high-grade adenoma and noninvasive carcinoma but did differ significantly between noninvasive carcinoma and intramucosal carcinoma (invasive). The durations in cases of intramucosal carcinoma (invasive) was not significantly different from that in the case of submucosal carcinoma or beyond (Table 1). 966 GASTROINTESTINAL ENDOSCOPY Volume 62, No. 6 : 2005
The response patterns of each adenomas or carcinomas to acetic acid are shown in Table 2. All the submucosal carcinomas or beyond showed no response. Five of the 6 intramucosal carcinomas (invasive) were nonresponsive (Fig. 2), and one that showed early disappearance of whitening was an elevated type of intramucosal carcinoma. Seventeen (81%) of 21 noninvasive carcinomas showed early disappearance of whitening, two showed no response, and two showed a delayed disappearance. Of 5 high-grade adenomas, 3 showed early disappearance and two showed delayed disappearance. Of 5 low-grade adenomas, two showed delayed disappearance (Fig. 3) and 3 showed continuous whitening.
DISCUSSION Acetic acid produces reversible intracellular protein degeneration.9 It has been used as an aid in the detection of small lesions in the uterine cervical mucosa during colposcopy.10 Guelrud and Herrera4 reported the use of acetic www.giejournal.org
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Dynamic chemical magnifying endoscopy
Figure 2. A, A flat, reddish lesion was observed on greater curvature of the lower body; this lesion was diagnosed to be an adenocarcinoma by examination of a biopsy specimen. B, Endoscopic observation (A) 5 seconds after sprinkling acetic acid. The red area, shaped like a bottle gourd, is clarified by its lack of aceto-whitening: the surrounding noncancerous mucosa shows aceto-whitening. C, Magnified view of the nonresponsive red area, showing an irregular microvascular pattern and the surrounding noncancerous mucosa, showing whitening of the surface, with a tubular appearance. This lesion was resected by surgical operation and was revealed to be an intramucosal carcinoma (invasive) (category 5.1).
acid to improve the detection of columnar epithelium in patients with Barrett’s esophagus being treated with multipolar electrocoagulation; they later reported that magnification endoscopy with acetic acid instillation, which they called ‘‘enhanced magnification,’’ was an accurate method of predicting intestinal metaplasia in Barrett’s esophagus.5 They reported that enhanced-magnification endoscopy could identify, with outstanding clarity and resolution, the characteristic endoscopic patterns that were correlated with the histologic identification of intestinal metaplasia.4 Furthermore, Yao et al2,3 reported that magnifying endoscopy was useful for the diagnosis of intramucosal gastric carcinoma. They referred to 3 characteristic findings in differentiated carcinoma: (1) the disappearance of the regular subepithelial capillary network pattern, (2) the presence of an irregular microvascular pattern, and (3) the presence of a demarcation line.2,3 In Japan and Korea, intramucosal gastric carcinomas, even if over 2 cm, are now being resected endoscopically by submucosal dissection. Unlike conventional EMR, endoscopic submucosal dissection can be used to resect large intramucosal gastric carcinomas in one piece.11-13
To perform a complete resection, however, it is necessary to accurately determine the area of gastric carcinoma. Chromoendoscopy with indigo carmine is generally used in Japan. However, accurate delineation of the area of gastric carcinoma is often difficult, because indigo carmine simply emphasizes the depressive, elevated, or rugged surface of the carcinoma. To overcome these limitations, Yao et al2,3 suggest the use of magnifying endoscopic examination of the microvascular architecture to pursue a more accurate diagnosis. We have also diagnosed carcinomas by their microvascular architecture under magnifying endoscopy. However, it is sometimes difficult to observe the microvascular architecture clearly, and we considered that there was a need for a method of clarifying the margin between the carcinoma and noncarcinomatous mucosa. We, therefore, began by using acetic acid– enhanced magnifying endoscopy for the diagnosis of the gastric cancer. After the acetic acid was sprinkled onto the area, the magnified view of adenocarcinoma showed a minute grain-like pattern and that of the noncancerous mucosa showed a granular surface pattern; however, the border
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Dynamic chemical magnifying endoscopy
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between the carcinoma and the noncarcinoma mucosa was not so clear. We then realized that aceto-whitening disappeared earlier in gastric adenocarcinoma than in the noncarcinomatous mucosa, and a clear border between the carcinoma and the noncarcinomatous mucosa appeared. Invasive intramucosal carcinomas and submucosal, or beyond, carcinomas tended to show no response to acetic acid or a disappearance of whitening after a few seconds, and noninvasive carcinoma showed whitening and disappearance after several seconds, but adenoma and nonneoplastic mucosa showed whitening for 30 seconds to 3 minutes. The higher the grade of the neoplasia, the shorter the duration of the whitening. The duration of aceto-whitening differed among the grades of neoplasia and indicated a chemical response. Furthermore, because it was possible to observe changes in the whitening with time, this new technique offers a promise of epoch-making proportions. Because no
dyes were used and the chemical response of the mucosa to acetic acid was whitening that changed with time, the duration of whitening was dependent on the histologic characteristics of the tissue. Accordingly, this new technique should be termed ‘‘dynamic chemical endoscopy.’’ In some cases, the area of gastric carcinoma could be observed clearly by regular endoscopy without magnification. However, a magnified view of adenocarcinoma and the surrounding non-neoplastic mucosa with aceto-whitening allowed accurate delineation of the area of gastric carcinoma with confidence. At present, we think that dynamic chemical magnifying endoscopy is able to allow accurate diagnosis of the area of gastric carcinoma. Diagnosis of gastric neoplasia involves detection of the neoplasia, determination of its extent, estimation of the depth of invasion, and estimation of the histopathologic type. Although dynamic chemical magnifying endoscopy is not suitable for the detection of the neoplasia, it is useful for ascertaining the borderline between neoplasia and non-neoplasia after detection of neoplasia by conventional endoscopic examination. For determining the extent of neoplasia, dynamic chemical magnifying endoscopy is practical and is particularly useful during preparation for EMR. In cases of noninvasive intramucosal cancer and high-grade adenoma, the contrast between neoplasia and non-neoplasia is not immediately obvious after sprinkling and appears only after about 20 to 30 seconds. On the other hand, in cases of invasive intramucosal cancer or submucosal cancer or beyond, contrast appears immediately after sprinkling. This knowledge is necessary for determining the extent of neoplasia. However, because the duration of aceto-whitening did not differ significantly between low-grade adenoma and non-neoplastic mucosa, dynamic chemical magnifying endoscopy was not practical for the determination of the extent of the low-grade adenomas. Estimation of the depth of invasion is impossible by dynamic chemical magnification endoscopy, because there is not a significant difference between invasive intramucosal cancer and submucosal cancer or beyond. Determination of the depth of invasion, therefore, should be done by other methods; for example, EUS. Dynamic chemical magnifying endoscopy is able to give information that allows the histologic type to be determined. For example, rapid disappearance of whitening in a lesion suggests that the lesion might be an invasive intramucosal cancer or a submucosal cancer or beyond, whereas a slow disappearance of whitening suggests that the lesion might be a highgrade adenoma or a noninvasive intramucosal cancer. However, many more types of neoplasia should be studied to obtain basic data that will allow more accurate determination of histologic type. The aceto-whitening of these carcinomas disappeared in less than 30 seconds. Because of movement of the gastric wall from contact with the endoscope, accurate observation of the time at which whitening disappears might be
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Figure 3. A, Elevated lesion on the antrum; this lesion was diagnosed to be an adenoma by examination of a biopsy specimen. B, Magnified view of the elevated lesion 40 seconds after sprinkling acetic acid. Aceto-whitening of the surface of the adenoma, with a tubular appearance, is observed. The surrounding non-neoplastic mucosa shows surface whitening with small pits. The aceto-whitening of the adenoma disappeared 60 seconds after sprinkling. This indicated delayed disappearance of aceto-whitening. This lesion was resected by EMR and was revealed to be a low-grade adenoma (category 3).
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difficult if the area of neoplasia is large. Furthermore, if the area of neoplasia is large or if the neoplasia is located in a position that makes observation difficult, dynamic chemical magnifying endoscopy might not be accurate. The reasons for the whitening with acetic acid and the lack of response of carcinoma to acetic acid are not well known. Lambert et al14 reported that the proportion of unbuffered acetic acid in contact with the surface epithelial cells of the mucosa determines the alteration in the structure of cellular proteins. Slight changes in pH and in the ambient ionic strength are known to break the disulfide and hydrogen bonds and to provoke deacetylation.14 Therefore, the acid interferes with the tertiary (spatial) structure of proteins in the nucleus and in the cytoplasm, and changes their optical properties.14 In conclusion, dynamic chemical magnifying endoscopy was thought to be useful for the determination of the extent of the gastric neoplasia.
REFERENCES 1. Kudo S, Tamura S, Nakajima T, et al. Diagnosis of colorectal tumorous lesions by magnifying endoscopy. Gastrointest Endosc 1996;44:8-14. 2. Yao K, Oishi T, Matsui T, et al. Novel magnified endoscopic findings of microvascular architecture in intramucosal gastric cancer. Gastrointest Endosc 2002;56:279-84. 3. Yao K, Iwashita A, Yao T. Early gastric cancer: proposal for a new diagnostic system based on microvascular architecture as visualized by magnified endoscopy. Dig Endosc 2004;16(Suppl):S110-7. 4. Guelrud M, Herrera I. Acetic acid improves identification of remnant islands of Barrett’s epithelium after endoscopic therapy. Gastrointest Endosc 1998;47:512-5.
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Dynamic chemical magnifying endoscopy 5. Guelrud M, Herrera I, Esssenfeld H, et al. Enhanced magnification endoscopy: a new technique to identify specialized intestinal metaplasia in Barrett’s esophagus. Gastrointest Endosc 2001;53:559-65. 6. Toyoda H, Rubio C, Befrits R, et al. Detection of intestinal metaplasia in distal esophagus and esophagogastric junction by enhanced-magnification endoscopy. Gastrointest Endosc 2004;59:15-21. 7. Yagi K, Aruga Y, Nakamura A, et al. Magnifying endoscopy for diagnosis of gastric cancer. Stomach Intestine 2005;40:791-9. 8. Schlemper RJ, Riddle RH, Kato Y, et al. The Vienna classification of gastrointestinal epithelial neoplasia. Gut 2000;47:251-5. 9. Cartier R. Practical colposcopy. Basel: Karger; 1997. 10. Cartier R. Role de la colposcopie dans le diagnostic et le tritement des dysplasies et des carcinomas intra-epitheliaux du col uterin. Bull Cancer 1979;66:447-54. 11. Yahagi N, Fujishiro M, Iguchi M, et al. Theoretical and technical requirements to expand EMR indication. Dig Endosc 2003;15(Suppl): S19-21. 12. Yamamoto H, Sekine Y, Higashizawa T, et al. Successful en bloc resection of a large superficial gastric cancer by using sodium hyaluronate and electrocautery incision forceps. Gastrointest Endosc 2001;54: 629-33. 13. Ono H, Kondo H, Gotoda T, et al. Endoscopic mucosal resection for treatment of early gastric cancer. Gut 2001;48:225-9. 14. Lambert R, Rey JF, Sankaranarayanan R. Magnification and chromoscopy with the acetic acid test. Endoscopy 2003;35:437-45.
Received March 12, 2005. Accepted August 11, 2005. Current affiliations: Department of Internal Medicine, Niigata Prefectural Yoshida Hospital, Yoshida-machi, Niigata-ken, Japan; Division of Pathology, Niigata University Medical and Dental Hospital, Niigata, Japan. Reprint requests: Kazuyoshi Yagi, MD, Department of Internal Medicine, Niigata-Prefectural Yoshida Hospital, Yoshida-machi, Niigata-ken, 959-0242, Japan.
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