- Email: [email protected]
The clinical meaning of a nonstructural pattern in early gastric cancer on magnifying endoscopy
ORIGINAL ARTICLE
The clinical meaning of a nonstructural pattern in early gastric cancer on magnifying endoscopy Tatsuya Yoshida, MD, Hiroshi Kawachi, MD, Keita Sasajima, MD, Akira Shiokawa, MD, Shin-ei Kudo, MD Yokohama, Japan
Background: In the field of colorectal cancer, the presence of a nonstructural pattern in magnifying colonoscopy means that cancer involves the submucosal layer. Since en bloc EMR was developed, differentiation between mucosal and submucosal cancer is a critical issue in the management of gastric cancer. In this study, we evaluated the clinical meaning of a nonstructural pattern in magnifying gastroscopy. Methods: Between April 2002 and July 2003, 59 patients with 50 cancers and 11 adenomas were enrolled in this study. A cancerous lesion was subclassified into a differentiated-type group or a undifferentiated-type group according to histologic type. Before treatment, magnifying endoscopic observation was performed. After EMR or surgical intervention, resected specimens were observed by using stereomicroscopy. In both in vivo magnifying endoscopic and in vitro stereomicroscopic observations, the presence of a nonstructural pattern on the lesion was investigated. Compared with histologic findings, the clinical meaning of the presence of a nonstructural pattern on the gastric neoplastic lesion was evaluated. Results: A nonstructural pattern could not be confirmed in any adenomas and in 29 of 31 mucosal differentiated cancers. However, in 9 of 11 submucosal cancers, a nonstructural pattern could be identified. Conclusions: The presence of a nonstructural pattern appeared to be a useful marker to not proceed with EMR of gastric cancer. (Gastrointest Endosc 2005;62:48-54.)
Now EMR is an established treatment option for an early gastric cancer. Endoscopic resection with submucosal injection of normal saline solution for the neoplastic lesion in the digestive tract was first reported in 1973 by Deyhle et al.1 In 1984, Tada et al2,3 reported endoscopic resection of early gastric cancer. In the 1990s, EMR became widely accepted as a curative treatment for mucosal cancer of the stomach, which rarely has lymph-node metastasis.4-6 At the end of the 1990s, en bloc EMR, which now is called ‘‘endoscopic submucosal dissection technique’’ in Japan, was developed.7-11 With the advent of this brand-new technique, EMR for gastric cancer now is being applied to larger lesions that have laterally spread further along the stomach wall. However, in regard to the depth of invasion, the Japanese Gastric Cancer Association treatment guidelines12,13 restrict the application of EMR to mucosal cancer, hence, the differentiation between mucosal and submucosal cancer is critical.
In the field of colorectal cancer, the application of EMR also is restricted to mucosal cancer. To make an accurate diagnosis of colorectal lesions before treatment, Kudo’s classification of pit pattern by using magnifying colonoscopy is now accepted.14-16 According to the Kudo’s classification, the appearance of the type VN shows a nonstructural pattern, in which a normal tubular pit pattern cannot be identified. This suggests that the cancer involves the submucosal layer and that the lesion must be surgically treated. However, the appearance of a nonstructural pattern in gastric lesion has rarely been reported. In this study, we evaluated the clinical meaning of magnifying endoscopic findings that show a nonstructural pattern on neoplastic lesions of the stomach.
PATIENTS AND METHODS Patients
Copyright ª 2005 by the American Society for Gastrointestinal Endoscopy 0016-5107/$30.00 PII: S0016-5107(05)00373-1
48 GASTROINTESTINAL ENDOSCOPY Volume 62, No. 1 : 2005
Between April 2002 and July 2003, 121 consecutive patients with a neoplastic lesion of the stomach who were treated in our hospital underwent upper-GI endoscopy. Of these 121 patients, 60 patients with an endoscopic www.mosby.com/gie
Yoshida et al
diagnosis of advanced gastric cancer and two with a neoplastic lesion of nonmucosal origin were excluded, and 59 patients (37 men, 22 women; age 65.3 G 10.3 years) with an endoscopic diagnosis of either early gastric cancer or adenoma were enrolled in this study (Table 1). We included 50 lesions with a clinical diagnosis of early gastric cancer and 11 with gastric adenoma, which were all confirmed with histologic assessment of biopsy specimens before the treatment. Furthermore, neoplastic lesions with a benign ulcer or an ulcer scar were excluded from this study by endoscopic findings. We treated all patients by either EMR or surgical intervention. Whether the cancer was managed by EMR or surgical intervention, the decision was made according to Japanese gastric cancer treatment guidelines,12 based upon both the depth of invasion and the histologic type of the cancer. Before examination, informed consents for both an endoscopic examination and participation in this study were obtained.
Nonstructural pattern on magnifying gastroscopy
Capsule Summary What is already known on this topic d
d
Endoscopic mucosal resection (EMR) is an increasingly utilized treatment option for early gastric cancer. Critical factors in the management of early gastric cancer are: - Depth of invasion - Tumor differentiation - Presence of an ulcer
d
Magnification chromoendoscopy is useful in defining endoscopic resectability by revealing mucosal detail and surface patterns.
What this study adds to our knowledge d
In a prospective observational study from Japan, the presence of a ‘‘non-structural’’ pattern on an early gastric cancer precludes EMR.
Methods In the endoscopic examination, we used a GIF-Q240Z videoendoscope (Olympus Optical Co, Ltd, Tokyo, Japan) with a magnifying power of 80 at maximum. With the patient under sedation with the administration of diazepam or midazolam, endoscopic observation was performed by the endoscopist, who was blinded to the previous results of the histologic assessment of the biopsy specimen. After regular observation, magnifying endoscopy was applied to the target lesion, to assess the in vivo fine gastric mucosal pattern. Then, the presence of a nonstructural pattern, which corresponds to type VN in Kudo’s classification of magnifying colonoscopy,14-16 was investigated (Fig. 1). To exclude the artificial change of the previous biopsy, a nonstructural pattern of more than approximately 3 to 4 mm dealt with the presence of a nonstructured pattern in this study. Even if a nonstructural pattern was verified in the lesion that occupied only a small area of the entire lesion, the lesion was considered to have a nonstructural pattern. First, regular magnifying endoscopic observation without dye spray was applied. Second, magnifying endoscopic observation with indigo carmine dye spray was performed. Third, after indigo carmine dye was thoroughly washed away with water, magnifying endoscopic observation with crystal violet (0.05 g/100 mL) dye spray was finally performed. All endoscopic images were stored in formats of both BMP and JPEG (640 480 pixels, 72 dpi). After EMR or surgical intervention, a resected specimen was fixed with formalin for 1 or 2 days, deprived of mucus, and then stained with Karachi hematoxylin. To assess the in vitro fine gastric mucosal pattern of the resected specimen, we used a SZX12 stereomicroscope (Olympus) and observed the specimen with the specimen under water immersion. Stereomicroscopic evaluation was performed by an endoscopist, who was blinded to the previous results of magnifying endoscopic evaluation. Stereowww.mosby.com/gie
TABLE 1. Patient characteristics Parameter
No.
Patients
59
Men
37
Women
22
Age (mean SD)
65.3 G 10.3
Men
64.9 G 9.6
Women
66.0 G 11.6
Clinical diagnosis Adenoma
9 patients, 12 lesions
Early cancer
50 patients, 50 lesions
Treatment EMR
38 patients, 40 lesions
Surgery
21 patients, 21 lesions
SD, Standard deviation.
microscopic images were captured with a HC-2500 digital camera with 1.4 megapixel charge-coupled device (Fuji Photo Film Co, Ltd, Tokyo, Japan), which was connected with the stereomicroscope. All stereomicroscopic images were stored in formats of both BMP and JPEG (1280 1000 pixels, 72 dpi). Finally, formal histologic assessment was performed with H&E staining as a criterion standard assessment. In all the specimens, we classified the depth of invasion of cancerous lesion according to the Japanese classification of gastric carcinoma17,18 into pM (the cancer is limited in the mucosal layer), pSM (the cancer invades into the submucosal layer), and pMP (the cancer involves proper Volume 62, No. 1 : 2005 GASTROINTESTINAL ENDOSCOPY 49
Nonstructural pattern on magnifying gastroscopy
Figure 1. Magnifying endoscopic images of gastric lesion with crystal violet dye spray. A, Tubular pattern can be clearly identified; nonstructural pattern cannot be identified. B, Tubular pattern is completely destroyed; nonstructural pattern can be identified.
muscle layer). And, pSM cancer subclassified into pSM1 (the cancer invades into the submucosal layer, and the submucosal invasion is limited to the upper 0.5 mm from the muscularis mucosae) and pSM2 (the cancer invades deeper into the submucosal layer). Furthermore, in regard to histologic types, we classified into two groups according to the Japanese classification of gastric carcinoma17,18 and gastric cancer treatment guidelines12,13 both issued by Japanese Gastric Cancer Association. One was classified as a differentiated-type cancer group (D group), including papillary adenocarcinoma, well-differentiated adenocarcinomas, and moderately differentiated adenocarcinomas. The other was classified as an undifferentiated-type cancer group (U group), which is called else-type cancer in an English abstract of the gastric cancer treatment guidelines,13 including poorly differentiated adenocarcinoma, signet-ring-cell carcinoma, and mucinous adenocarcinoma.
RESULTS Of all the adenomas, 4 lesions were located in the middle third of the stomach and 7 were in the lower third. 50 GASTROINTESTINAL ENDOSCOPY Volume 62, No. 1 : 2005
Yoshida et al
Of all the cancers, 9 were located in the upper third, 21 in the middle third, and 20 in the lower third. All adenomas and 29 cancers were managed by EMR, and 21 cancers were managed by surgical intervention. The results of the formal histologic assessment in regard to the depth of cancer invasion and histologic type were as follows. 38 lesions were pM (D group, 31; U group, 7), 7 were pSM1 (D group, 1; U group, 6), and 4 were pSM2 (D group, 2; U group, 2). Only one lesion was confirmed as pMP cancer (U group). In all patients, magnifying endoscopic visualization with and without dye spray was achieved. From the comparison of 3 magnifying endoscopic observations, without dye spray, with indigo carmine dye spray, and with crystal violet dye spray, it was our experience that crystal violet dye spray appeared to be the most superior in evaluating the microstructure of the gastric mucosa, because it was easy to identify the fine gastric mucosal pattern (Figs. 2 and 3). No complications attributable to this study were encountered in all cases. Results of in vivo magnifying endoscopic findings and of in vitro stereomicroscopic findings of resected specimens according to the depth of cancerous invasion and the histologic types are shown in Table 2. In magnifying endoscopic observation, all adenomas showed clearly focused microstructure. A nonstructural pattern, which could not be identified as a tubular pattern, did not appear on the surface of any adenomas. Stereomicroscopic findings of formalin-fixed specimens of adenoma completely agreed with in vivo magnifying endoscopic findings, and a nonstructural pattern could not be identified in any specimen of adenomas. In 29 of 31 D group pM cancers (93.5%), a nonstructural pattern could not be identified on the surface of the lesion (Fig. 2A to D). Only two (6.5%) lesions showed a nonstructural pattern in the tiny area of the lesions. On stereomicroscopic observation of resected specimens, 27 of 31 D group pM lesions (87.1%) did not show a nonstructural pattern; a tiny nonstructural pattern could be identified in 4 lesions (12.9%) (Fig. 2E). On the other hand, 5 of 7 U group pM lesions (71.4%) showed a nonstructural pattern on the surface of the lesion in magnifying endoscopy in vivo (Fig. 3A to D). However, tubular pattern also could be identified in some part of these lesions. Only two lesions (28.6%) did not show a nonstructural pattern. Stereomicroscopic findings of resected U group pM specimens completely agreed with in vivo magnifying observation; 5 of 7 lesions (71.4%) had a nonstructural pattern (Fig. 3E). Of 6 U group pSM1 lesions, 5 lesions (83.3%) showed a nonstructural pattern in the cancerous area in both in vivo magnifying endoscopic and in vitro stereomicroscopic observations. Only one U group pSM1 lesion could not be confirmed as a nonstructural pattern under in vivo magnifying endoscopic observation. Of all lesions, only one lesion was classified as D group pSM1, www.mosby.com/gie
Yoshida et al
Nonstructural pattern on magnifying gastroscopy
Figure 2. Endoscopic and stereomicroscopic images of a differentiated-type gastric cancer, which is limited in the mucosal layer. A nonstructural pattern cannot be identified. A, Regular endoscopic image without dye spray. B, Magnifying endoscopic image without dye spray. C, Magnifying endoscopic image with indigo carmine dye spray. D, Magnifying endoscopic image with crystal violet dye spray. E, Stereomicroscopic image of resected specimen (Karachi hematoxylin, orig. mag. 50).
and a nonstructural pattern could not be confirmed in that lesion under in vivo magnifying endoscopic observation. All the 5 lesions, including pSM2 and pMP cancers (100%), had a nonstructural pattern both on in vivo magnifying endoscopic findings and in vitro stereomicroscopic findings. www.mosby.com/gie
The result from the standpoint of the presence of nonstructural pattern in magnifying endoscopic findings in vivo is shown in Table 3. Of 30 cases of D group without nonstructural pattern, 29 cases (96.7%) were pM cancers, only one lesion was pSM cancer. Of 12 cases of U group with nonstructural pattern, 5 cases (41.7%) with pM cancer were included. Volume 62, No. 1 : 2005 GASTROINTESTINAL ENDOSCOPY 51
Nonstructural pattern on magnifying gastroscopy
Yoshida et al
Figure 3. Endoscopic and stereomicroscopic images of an undifferentiated-type gastric cancer, which is limited in the mucosal layer. Nonstructural pattern can be identified both on magnifying endoscopic and stereomicroscopic images. A, Regular endoscopic image without dye spray. B, Magnifying endoscopic image without dye spray. C, Magnifying endoscopic image with indigo carmine dye spray. D, Magnifying endoscopic image with crystal violet dye spray. E, Stereomicroscopic image of resected specimen (Karachi hematoxylin, orig. mag. 50).
DISCUSSION EMR for an early gastric cancer is now one of the most important therapeutic options. However, the procedure must be strictly limited to the lesion without lymph-node metastasis. In the management of early gastric cancer, the following factors are critical issues, depth of cancer in52 GASTROINTESTINAL ENDOSCOPY Volume 62, No. 1 : 2005
vasion, histologic type (differentiated or undifferentiated type), and presence of benign ulcer or ulcer scar. Before the treatment, these factors must be judged accurately. According to the gastric cancer treatment guidelines issued by Japanese Gastric Cancer Association,12 of 2273 D group pM cancer, 25 lesions (1.1%) had lymph node metastasis. On the other hand, of 1311 U group pM www.mosby.com/gie
Yoshida et al
Nonstructural pattern on magnifying gastroscopy
TABLE 2. The presence of nonstructural pattern according to depth of invasion and histologic types In vivo findings* D/U Adenoma Cancer
pM
pSM1
pSM2
pMP
Total
NS(C) (%)
In vitro findingsy
NS() (%)
NS(C) (%)
NS() (%)
11
0 (0)
11 (100)
0 (0)
11 (100)
D
31
2 (6.5)
29 (93.5)
4 (12.9)
27 (87.1)
U
7
5 (71.4)
2 (28.6)
5 (71.4)
2 (28.6)
D
1
0 (0)
1 (100)
0 (0)
1 (100)
U
6
5 (83.3)
1 (16.7)
5 (83.3)
1 (16.7)
D
2
2 (100)
0 (0)
2 (100)
0 (0)
U
2
2 (100)
0 (0)
2 (100)
0 (0)
U
1
1 (100)
0 (0)
1 (100)
0 (0)
D, Differentiated-type cancer; U, undifferentiated-type cancer; NS, nonstructural pattern. *In vivo magnifying endoscopic findings. yIn vitro stereomicroscopic findings of resected specimens.
cancer, 63 lesions (4.8%) had lymph-node metastasis. In regard to pSM cancer, 252 lesions (15.6%) of 1616 D group pSM cancers and 210 lesions (20.8%) of 1008 U group pSM cancers had lymph-node metastasis. Therefore, application of EMR generally is limited to the D group pM cancer, which rarely has lymph-node metastasis.12 Thus, differentiation between pM and pSM cancer is a critical issue in the clinical situation. Now, in the field of colorectal cancer, Kudo’s classification14-16 of magnifying colonoscopy is accepted. According to the classification of colorectal lesions, the cancer with a nonstructural pattern involves the submucosal layer at a high rate.16 Therefore, a colorectal cancer with a nonstructural pattern is recommended to be managed surgically. However, clinical meanings of a nonstructural pattern of gastric cancer have rarely been reported. Hence, we evaluated the presence of a nonstructural pattern of early gastric cancer in this study. Many investigators have reported on magnifying endoscopy of the stomach to date.19-23 Sakaki is one of the pioneers of magnifying endoscopy of the stomach. Sakaki et al19 reported on magnifying endoscopic observation of the stomach, which mainly focused on gastritis, and established an endoscopic classification of the fine gastric mucosal pattern. However, the instrument was a fiberscope, and it was not a fully developed one compared with a currently available high-resolution videoendoscope. In the 1990s, the magnifying videoendoscope was developed, and it now is clinically available. Furthermore, as mentioned above, differentiation between mucosal and submucosal cancer is an even more critical issue now than it was before, because we have begun using the en bloc EMR technique. Therefore, currently, the www.mosby.com/gie
TABLE 3. Depth of cancer invasion according to presence of nonstructural pattern (in vivo magnifying endoscopic findings)
D group
U group
NS
Total
pM (%)
pSM (%)
NS(C)
4
2 (50)
2 (50)
NS()
30
29 (96.7)
1 (3.3)
NS(C)
12
5 (41.7)
7 (58.3)
NS()
3
2 (66.7)
1 (33.3)
NS, Nonstructural pattern; D, differentiated-type cancer; U, undifferentiated-type cancer.
clinical meaning of magnifying endoscopy of the stomach is attracting considerable attention again. According to the Kudo’s classification of colonoscopy,14-16 fine mucosal pattern (pit pattern) of colorectal lesions vividly reflects the histologic finding of the lesion, i.e., normal mucosa, hyperplastic polyp, adenoma with mild to severe atypia, mucosal cancer, and invasive cancer. And Kudo et al14-16 demonstrated the relation between magnifying endoscopic and histologic findings. With regard to the stomach, there is no definitive classification of magnifying endoscopy, especially for gastric cancer. Some investigators assess the fine mucosal pattern of the lesion, and others assess the microvascular pattern of the lesion.22 The assessment of a microvascular pattern is a very attractive approach. Kudo’s classification of magnifying colonoscopy14-16 does not attempt to assess the microvascular pattern. In the magnifying endoscopy of the esophagus, in which magnifying endoscopy cannot demonstrate mucosal pattern, Inoue et al24,25 and Kumagi Volume 62, No. 1 : 2005 GASTROINTESTINAL ENDOSCOPY 53
Nonstructural pattern on magnifying gastroscopy
et al26 advocated their original magnifying endoscopic classification for the esophageal lesions, depending on the microvascular pattern. We reported that the classification agrees with histologic findings at a high rate.27 In this study, we evaluated the clinical meaning of nonstructural findings of gastric neoplasms when using magnifying videoendoscopy and stereoscopic microscopy. Both in vivo magnifying endoscopic findings and in vitro stereoscopic microscopic finding of resected specimen are closely correlated with each other. According to the results of this study, the appearance of a nonstructural pattern in the neoplastic lesion of the stomach means that the lesion is usually a U group cancer or a cancer with submucosal involvement, or both. This is a very important fact in the clinical situations before EMR for early gastric cancer. Based on the results of this study, when the nonstructural pattern appears on the neoplastic lesion of the stomach during magnifying endoscopy, the patient should not be treated endoscopically. In other words, if the histologic assessment of the biopsy confirmed D group cancer or adenoma, then the absence of a nonstructural pattern in the lesion during magnifying endoscopy suggested that the lesion could be managed endoscopically. Although this study includes only 59 patients, magnifying endoscopy before EMR of the gastric lesion appeared to be a very useful diagnostic modality, in addition to regular endoscopy, chromoendoscopy, and EUS.
ACKNOWLEDGMENT We thank Ms. Masako Kitatani of the Digestive Disease Center, Showa University Northern Yokohama Hospital, Yokohama, Japan, for providing assistance in the preparation of this manuscript. REFERENCES 1. Deyhle P, Largiader F, Jenny S, Fumagalli I. A method for endoscopic electroresection of sessile colonic polyps. Endoscopy 1973;5:38-40. 2. Tada M, Shimada M, Murakami F, Mizumachi M, Arima K, Yanai H, et al. Development of the strip-off biopsy [in Japanese with English abstract]. Gastroenterol Endosc 1984;26:833-9. 3. Tada M, Murakami A, Karita M, Yanai H, Okita K. Endoscopic resection of early gastric cancer. Endoscopy 1993;25:445-50. 4. Takekoshi T, Takagi K, Fujii A, Kato Y. Treatment of early gastric cancer by endoscopic double snare polypectomy (EDSP) [in Japanese]. Gan No Rinsho 1986;32:1185-90. 5. Hirao M, Masuda K, Asanuma T, Naka H, Noda K, Matsuura K, et al. Endoscopic resection of early gastric cancer and other tumors with local injection of hypertonic saline-epinephrine. Gastrointest Endosc 1988;34:264-9. 6. Tani M, Takeshita K, Inoue H, Iwai T. Adequate endoscopic mucosal resection for early gastric cancer obtained from the dissecting microscopic features of the resected specimens. Gastric Cancer 2001;4:122-31. 7. Gotoda T, Kondo H, Ono H, Saito Y, Yamaguchi H, Saito D, et al. A new endoscopic mucosal resection procedure using an insulation-tipped electrosurgical knife for rectal flat lesions: report of two cases. Gastrointest Endosc 1999;50:560-3.
54 GASTROINTESTINAL ENDOSCOPY Volume 62, No. 1 : 2005
Yoshida et al 8. Ono H, Kondo H, Gotoda T, Shirao K, Yamaguchi H, Saito D, et al. Endoscopic mucosal resection for treatment of early gastric cancer. Gut 2001;48:225-9. 9. Yamamoto H, Yube T, Isoda N, Sato Y, Sekine Y, Higashizawa T, et al. A novel method of endoscopic mucosal resection using sodium hyaluronate. Gastrointest Endosc 1999;50:251-6. 10. Oyama T, Kikuchi Y, Shimatani S, Tomori A, Hotta K, Miyata Y, et al. Aggressive endoscopic mucosal resection for early gastric cancer: hook knife EMR method [in Japanese with English abstract]. Endoscopia Digestiva 2002;14:1747-52. 11. Yahagi N, Fujishiro M, Kakushima N, Kobayashi K, Hashimoto T, Oka M, et al. Endoscopic submucosal dissection for early gastric cancer using the tip of an electrosurgical snare (thin type). Dig Endosc 2004;16:34-8. 12. Japanese Gastric Cancer Association. Gastric cancer treatment guidelines. 2nd ed. Tokyo: Kanehara; 2004. 13. Japanese Gastric Cancer Association. Gastric cancer treatment guidelines [in Japanese with English abstract] [cited 2004 Sept 20]. Available from: URL: http://www.jgca.jp/PDFfiles/E-gudeline.PDF. 14. Kudo S, Tamura S, Nakajima T, Yamano H, Kusaka H, Watanabe H. Diagnosis of colorectal tumorous lesions by magnifying endoscopy. Gastrointest Endosc 1996;44:8-14. 15. Kudo S, Hirota S, Nakajima T, Hosobe S, Kusaka H, Kobayashi T, et al. Colorectal tumours and pit pattern. J Clin Pathol 1994;47:880-5. 16. Kudo S, Rubio CA, Teixeira CR, Kashida H, Kogure E. Pit pattern in colorectal neoplasia: endoscopic magnifying view. Endoscopy 2001; 33:367-73. 17. Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma [in Japanese]. 13th ed. Tokyo: Kanehara; 1999. 18. Japanese Research Society for Gastric Cancer. Japanese classification of gastric carcinoma. 1st ed. Tokyo: Kanehara; 1999. 19. Sakaki N, Iida Y, Okazaki Y, Kawamura S, Takemoto T. Magnifying endoscopic observation of the gastric mucosa, particularly in patients with atrophic gastritis. Endoscopy 1978;10:269-74. 20. Tobita K. Study on minute surface structures of the depressed-type early gastric cancer with magnifying endoscopy. Dig Endosc 2001;13:121-6. 21. Miwa H, Sato N. Shed light again on magnifying endoscopy for diagnosis of early gastric cancer. Dig Endosc 2001;13:127-8. 22. Yao K, Oishi T, Matsui T, Yao T, Iwashita A. Novel magnified endoscopic findings of microvascular architecture in intramucosal gastric cancer. Gastrointest Endosc 2002;56:279-84. 23. Yagi K, Nakamura A, Sekine A. Comparison between magnifying endoscopy and histological, culture and urease test findings from the gastric mucosa of the corpus. Endoscopy 2002;34:376-81. 24. Inoue H, Honda T, Yoshida T, Nishikage T, Nagahama T, Yano K, et al. Ultra-high magnification endoscopy of the normal esophageal mucosa. Dig Endosc 1996;8:134-8. 25. Inoue H, Kumagai Y, Yoshida T, Kawano T, Endo M, Iwai T. High-magnification endoscopic diagnosis of the superficial esophageal cancer. Dig Endosc 2000;12:S32-5. 26. Kumagai Y, Inoue H, Nagai K, Kawano T, Iwai T. Magnifying endoscopy, stereoscopic microscopy, and the microvascular architecture of superficial esophageal carcinoma. Endoscopy 2002;34:369-75. 27. Yoshida T, Inoue H, Usui S, Satodate H, Fukami N, Kudo S. Narrow-band imaging system with magnifying endoscopy for superficial esophageal lesions. Gastrointest Endosc 2004;59:288-95.
Received October 2, 2004. Accepted February 16, 2005. Current affiliations: Department of Surgery, Kudanzaka Hospital, Tokyo, Japan; Department of Pathology, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan; Digestive Disease Center, Department of Pathology, Showa University Northern Yokohama Hospital, Yokohama, Japan. Reprint requests: Tatsuya Yoshida, MD, Department of Surgery, Kudanzaka Hospital, Kudan-minami 2-1-39, Chiyoda-ku, Tokyo 102-0074, Japan.
www.mosby.com/gie
The clinical meaning of a nonstructural pattern in early gastric cancer on magnifying endoscopy Tatsuya Yoshida, MD, Hiroshi Kawachi, MD, Keita Sasajima, MD, Akira Shiokawa, MD, Shin-ei Kudo, MD Yokohama, Japan
Background: In the field of colorectal cancer, the presence of a nonstructural pattern in magnifying colonoscopy means that cancer involves the submucosal layer. Since en bloc EMR was developed, differentiation between mucosal and submucosal cancer is a critical issue in the management of gastric cancer. In this study, we evaluated the clinical meaning of a nonstructural pattern in magnifying gastroscopy. Methods: Between April 2002 and July 2003, 59 patients with 50 cancers and 11 adenomas were enrolled in this study. A cancerous lesion was subclassified into a differentiated-type group or a undifferentiated-type group according to histologic type. Before treatment, magnifying endoscopic observation was performed. After EMR or surgical intervention, resected specimens were observed by using stereomicroscopy. In both in vivo magnifying endoscopic and in vitro stereomicroscopic observations, the presence of a nonstructural pattern on the lesion was investigated. Compared with histologic findings, the clinical meaning of the presence of a nonstructural pattern on the gastric neoplastic lesion was evaluated. Results: A nonstructural pattern could not be confirmed in any adenomas and in 29 of 31 mucosal differentiated cancers. However, in 9 of 11 submucosal cancers, a nonstructural pattern could be identified. Conclusions: The presence of a nonstructural pattern appeared to be a useful marker to not proceed with EMR of gastric cancer. (Gastrointest Endosc 2005;62:48-54.)
Now EMR is an established treatment option for an early gastric cancer. Endoscopic resection with submucosal injection of normal saline solution for the neoplastic lesion in the digestive tract was first reported in 1973 by Deyhle et al.1 In 1984, Tada et al2,3 reported endoscopic resection of early gastric cancer. In the 1990s, EMR became widely accepted as a curative treatment for mucosal cancer of the stomach, which rarely has lymph-node metastasis.4-6 At the end of the 1990s, en bloc EMR, which now is called ‘‘endoscopic submucosal dissection technique’’ in Japan, was developed.7-11 With the advent of this brand-new technique, EMR for gastric cancer now is being applied to larger lesions that have laterally spread further along the stomach wall. However, in regard to the depth of invasion, the Japanese Gastric Cancer Association treatment guidelines12,13 restrict the application of EMR to mucosal cancer, hence, the differentiation between mucosal and submucosal cancer is critical.
In the field of colorectal cancer, the application of EMR also is restricted to mucosal cancer. To make an accurate diagnosis of colorectal lesions before treatment, Kudo’s classification of pit pattern by using magnifying colonoscopy is now accepted.14-16 According to the Kudo’s classification, the appearance of the type VN shows a nonstructural pattern, in which a normal tubular pit pattern cannot be identified. This suggests that the cancer involves the submucosal layer and that the lesion must be surgically treated. However, the appearance of a nonstructural pattern in gastric lesion has rarely been reported. In this study, we evaluated the clinical meaning of magnifying endoscopic findings that show a nonstructural pattern on neoplastic lesions of the stomach.
PATIENTS AND METHODS Patients
Copyright ª 2005 by the American Society for Gastrointestinal Endoscopy 0016-5107/$30.00 PII: S0016-5107(05)00373-1
48 GASTROINTESTINAL ENDOSCOPY Volume 62, No. 1 : 2005
Between April 2002 and July 2003, 121 consecutive patients with a neoplastic lesion of the stomach who were treated in our hospital underwent upper-GI endoscopy. Of these 121 patients, 60 patients with an endoscopic www.mosby.com/gie
Yoshida et al
diagnosis of advanced gastric cancer and two with a neoplastic lesion of nonmucosal origin were excluded, and 59 patients (37 men, 22 women; age 65.3 G 10.3 years) with an endoscopic diagnosis of either early gastric cancer or adenoma were enrolled in this study (Table 1). We included 50 lesions with a clinical diagnosis of early gastric cancer and 11 with gastric adenoma, which were all confirmed with histologic assessment of biopsy specimens before the treatment. Furthermore, neoplastic lesions with a benign ulcer or an ulcer scar were excluded from this study by endoscopic findings. We treated all patients by either EMR or surgical intervention. Whether the cancer was managed by EMR or surgical intervention, the decision was made according to Japanese gastric cancer treatment guidelines,12 based upon both the depth of invasion and the histologic type of the cancer. Before examination, informed consents for both an endoscopic examination and participation in this study were obtained.
Nonstructural pattern on magnifying gastroscopy
Capsule Summary What is already known on this topic d
d
Endoscopic mucosal resection (EMR) is an increasingly utilized treatment option for early gastric cancer. Critical factors in the management of early gastric cancer are: - Depth of invasion - Tumor differentiation - Presence of an ulcer
d
Magnification chromoendoscopy is useful in defining endoscopic resectability by revealing mucosal detail and surface patterns.
What this study adds to our knowledge d
In a prospective observational study from Japan, the presence of a ‘‘non-structural’’ pattern on an early gastric cancer precludes EMR.
Methods In the endoscopic examination, we used a GIF-Q240Z videoendoscope (Olympus Optical Co, Ltd, Tokyo, Japan) with a magnifying power of 80 at maximum. With the patient under sedation with the administration of diazepam or midazolam, endoscopic observation was performed by the endoscopist, who was blinded to the previous results of the histologic assessment of the biopsy specimen. After regular observation, magnifying endoscopy was applied to the target lesion, to assess the in vivo fine gastric mucosal pattern. Then, the presence of a nonstructural pattern, which corresponds to type VN in Kudo’s classification of magnifying colonoscopy,14-16 was investigated (Fig. 1). To exclude the artificial change of the previous biopsy, a nonstructural pattern of more than approximately 3 to 4 mm dealt with the presence of a nonstructured pattern in this study. Even if a nonstructural pattern was verified in the lesion that occupied only a small area of the entire lesion, the lesion was considered to have a nonstructural pattern. First, regular magnifying endoscopic observation without dye spray was applied. Second, magnifying endoscopic observation with indigo carmine dye spray was performed. Third, after indigo carmine dye was thoroughly washed away with water, magnifying endoscopic observation with crystal violet (0.05 g/100 mL) dye spray was finally performed. All endoscopic images were stored in formats of both BMP and JPEG (640 480 pixels, 72 dpi). After EMR or surgical intervention, a resected specimen was fixed with formalin for 1 or 2 days, deprived of mucus, and then stained with Karachi hematoxylin. To assess the in vitro fine gastric mucosal pattern of the resected specimen, we used a SZX12 stereomicroscope (Olympus) and observed the specimen with the specimen under water immersion. Stereomicroscopic evaluation was performed by an endoscopist, who was blinded to the previous results of magnifying endoscopic evaluation. Stereowww.mosby.com/gie
TABLE 1. Patient characteristics Parameter
No.
Patients
59
Men
37
Women
22
Age (mean SD)
65.3 G 10.3
Men
64.9 G 9.6
Women
66.0 G 11.6
Clinical diagnosis Adenoma
9 patients, 12 lesions
Early cancer
50 patients, 50 lesions
Treatment EMR
38 patients, 40 lesions
Surgery
21 patients, 21 lesions
SD, Standard deviation.
microscopic images were captured with a HC-2500 digital camera with 1.4 megapixel charge-coupled device (Fuji Photo Film Co, Ltd, Tokyo, Japan), which was connected with the stereomicroscope. All stereomicroscopic images were stored in formats of both BMP and JPEG (1280 1000 pixels, 72 dpi). Finally, formal histologic assessment was performed with H&E staining as a criterion standard assessment. In all the specimens, we classified the depth of invasion of cancerous lesion according to the Japanese classification of gastric carcinoma17,18 into pM (the cancer is limited in the mucosal layer), pSM (the cancer invades into the submucosal layer), and pMP (the cancer involves proper Volume 62, No. 1 : 2005 GASTROINTESTINAL ENDOSCOPY 49
Nonstructural pattern on magnifying gastroscopy
Figure 1. Magnifying endoscopic images of gastric lesion with crystal violet dye spray. A, Tubular pattern can be clearly identified; nonstructural pattern cannot be identified. B, Tubular pattern is completely destroyed; nonstructural pattern can be identified.
muscle layer). And, pSM cancer subclassified into pSM1 (the cancer invades into the submucosal layer, and the submucosal invasion is limited to the upper 0.5 mm from the muscularis mucosae) and pSM2 (the cancer invades deeper into the submucosal layer). Furthermore, in regard to histologic types, we classified into two groups according to the Japanese classification of gastric carcinoma17,18 and gastric cancer treatment guidelines12,13 both issued by Japanese Gastric Cancer Association. One was classified as a differentiated-type cancer group (D group), including papillary adenocarcinoma, well-differentiated adenocarcinomas, and moderately differentiated adenocarcinomas. The other was classified as an undifferentiated-type cancer group (U group), which is called else-type cancer in an English abstract of the gastric cancer treatment guidelines,13 including poorly differentiated adenocarcinoma, signet-ring-cell carcinoma, and mucinous adenocarcinoma.
RESULTS Of all the adenomas, 4 lesions were located in the middle third of the stomach and 7 were in the lower third. 50 GASTROINTESTINAL ENDOSCOPY Volume 62, No. 1 : 2005
Yoshida et al
Of all the cancers, 9 were located in the upper third, 21 in the middle third, and 20 in the lower third. All adenomas and 29 cancers were managed by EMR, and 21 cancers were managed by surgical intervention. The results of the formal histologic assessment in regard to the depth of cancer invasion and histologic type were as follows. 38 lesions were pM (D group, 31; U group, 7), 7 were pSM1 (D group, 1; U group, 6), and 4 were pSM2 (D group, 2; U group, 2). Only one lesion was confirmed as pMP cancer (U group). In all patients, magnifying endoscopic visualization with and without dye spray was achieved. From the comparison of 3 magnifying endoscopic observations, without dye spray, with indigo carmine dye spray, and with crystal violet dye spray, it was our experience that crystal violet dye spray appeared to be the most superior in evaluating the microstructure of the gastric mucosa, because it was easy to identify the fine gastric mucosal pattern (Figs. 2 and 3). No complications attributable to this study were encountered in all cases. Results of in vivo magnifying endoscopic findings and of in vitro stereomicroscopic findings of resected specimens according to the depth of cancerous invasion and the histologic types are shown in Table 2. In magnifying endoscopic observation, all adenomas showed clearly focused microstructure. A nonstructural pattern, which could not be identified as a tubular pattern, did not appear on the surface of any adenomas. Stereomicroscopic findings of formalin-fixed specimens of adenoma completely agreed with in vivo magnifying endoscopic findings, and a nonstructural pattern could not be identified in any specimen of adenomas. In 29 of 31 D group pM cancers (93.5%), a nonstructural pattern could not be identified on the surface of the lesion (Fig. 2A to D). Only two (6.5%) lesions showed a nonstructural pattern in the tiny area of the lesions. On stereomicroscopic observation of resected specimens, 27 of 31 D group pM lesions (87.1%) did not show a nonstructural pattern; a tiny nonstructural pattern could be identified in 4 lesions (12.9%) (Fig. 2E). On the other hand, 5 of 7 U group pM lesions (71.4%) showed a nonstructural pattern on the surface of the lesion in magnifying endoscopy in vivo (Fig. 3A to D). However, tubular pattern also could be identified in some part of these lesions. Only two lesions (28.6%) did not show a nonstructural pattern. Stereomicroscopic findings of resected U group pM specimens completely agreed with in vivo magnifying observation; 5 of 7 lesions (71.4%) had a nonstructural pattern (Fig. 3E). Of 6 U group pSM1 lesions, 5 lesions (83.3%) showed a nonstructural pattern in the cancerous area in both in vivo magnifying endoscopic and in vitro stereomicroscopic observations. Only one U group pSM1 lesion could not be confirmed as a nonstructural pattern under in vivo magnifying endoscopic observation. Of all lesions, only one lesion was classified as D group pSM1, www.mosby.com/gie
Yoshida et al
Nonstructural pattern on magnifying gastroscopy
Figure 2. Endoscopic and stereomicroscopic images of a differentiated-type gastric cancer, which is limited in the mucosal layer. A nonstructural pattern cannot be identified. A, Regular endoscopic image without dye spray. B, Magnifying endoscopic image without dye spray. C, Magnifying endoscopic image with indigo carmine dye spray. D, Magnifying endoscopic image with crystal violet dye spray. E, Stereomicroscopic image of resected specimen (Karachi hematoxylin, orig. mag. 50).
and a nonstructural pattern could not be confirmed in that lesion under in vivo magnifying endoscopic observation. All the 5 lesions, including pSM2 and pMP cancers (100%), had a nonstructural pattern both on in vivo magnifying endoscopic findings and in vitro stereomicroscopic findings. www.mosby.com/gie
The result from the standpoint of the presence of nonstructural pattern in magnifying endoscopic findings in vivo is shown in Table 3. Of 30 cases of D group without nonstructural pattern, 29 cases (96.7%) were pM cancers, only one lesion was pSM cancer. Of 12 cases of U group with nonstructural pattern, 5 cases (41.7%) with pM cancer were included. Volume 62, No. 1 : 2005 GASTROINTESTINAL ENDOSCOPY 51
Nonstructural pattern on magnifying gastroscopy
Yoshida et al
Figure 3. Endoscopic and stereomicroscopic images of an undifferentiated-type gastric cancer, which is limited in the mucosal layer. Nonstructural pattern can be identified both on magnifying endoscopic and stereomicroscopic images. A, Regular endoscopic image without dye spray. B, Magnifying endoscopic image without dye spray. C, Magnifying endoscopic image with indigo carmine dye spray. D, Magnifying endoscopic image with crystal violet dye spray. E, Stereomicroscopic image of resected specimen (Karachi hematoxylin, orig. mag. 50).
DISCUSSION EMR for an early gastric cancer is now one of the most important therapeutic options. However, the procedure must be strictly limited to the lesion without lymph-node metastasis. In the management of early gastric cancer, the following factors are critical issues, depth of cancer in52 GASTROINTESTINAL ENDOSCOPY Volume 62, No. 1 : 2005
vasion, histologic type (differentiated or undifferentiated type), and presence of benign ulcer or ulcer scar. Before the treatment, these factors must be judged accurately. According to the gastric cancer treatment guidelines issued by Japanese Gastric Cancer Association,12 of 2273 D group pM cancer, 25 lesions (1.1%) had lymph node metastasis. On the other hand, of 1311 U group pM www.mosby.com/gie
Yoshida et al
Nonstructural pattern on magnifying gastroscopy
TABLE 2. The presence of nonstructural pattern according to depth of invasion and histologic types In vivo findings* D/U Adenoma Cancer
pM
pSM1
pSM2
pMP
Total
NS(C) (%)
In vitro findingsy
NS() (%)
NS(C) (%)
NS() (%)
11
0 (0)
11 (100)
0 (0)
11 (100)
D
31
2 (6.5)
29 (93.5)
4 (12.9)
27 (87.1)
U
7
5 (71.4)
2 (28.6)
5 (71.4)
2 (28.6)
D
1
0 (0)
1 (100)
0 (0)
1 (100)
U
6
5 (83.3)
1 (16.7)
5 (83.3)
1 (16.7)
D
2
2 (100)
0 (0)
2 (100)
0 (0)
U
2
2 (100)
0 (0)
2 (100)
0 (0)
U
1
1 (100)
0 (0)
1 (100)
0 (0)
D, Differentiated-type cancer; U, undifferentiated-type cancer; NS, nonstructural pattern. *In vivo magnifying endoscopic findings. yIn vitro stereomicroscopic findings of resected specimens.
cancer, 63 lesions (4.8%) had lymph-node metastasis. In regard to pSM cancer, 252 lesions (15.6%) of 1616 D group pSM cancers and 210 lesions (20.8%) of 1008 U group pSM cancers had lymph-node metastasis. Therefore, application of EMR generally is limited to the D group pM cancer, which rarely has lymph-node metastasis.12 Thus, differentiation between pM and pSM cancer is a critical issue in the clinical situation. Now, in the field of colorectal cancer, Kudo’s classification14-16 of magnifying colonoscopy is accepted. According to the classification of colorectal lesions, the cancer with a nonstructural pattern involves the submucosal layer at a high rate.16 Therefore, a colorectal cancer with a nonstructural pattern is recommended to be managed surgically. However, clinical meanings of a nonstructural pattern of gastric cancer have rarely been reported. Hence, we evaluated the presence of a nonstructural pattern of early gastric cancer in this study. Many investigators have reported on magnifying endoscopy of the stomach to date.19-23 Sakaki is one of the pioneers of magnifying endoscopy of the stomach. Sakaki et al19 reported on magnifying endoscopic observation of the stomach, which mainly focused on gastritis, and established an endoscopic classification of the fine gastric mucosal pattern. However, the instrument was a fiberscope, and it was not a fully developed one compared with a currently available high-resolution videoendoscope. In the 1990s, the magnifying videoendoscope was developed, and it now is clinically available. Furthermore, as mentioned above, differentiation between mucosal and submucosal cancer is an even more critical issue now than it was before, because we have begun using the en bloc EMR technique. Therefore, currently, the www.mosby.com/gie
TABLE 3. Depth of cancer invasion according to presence of nonstructural pattern (in vivo magnifying endoscopic findings)
D group
U group
NS
Total
pM (%)
pSM (%)
NS(C)
4
2 (50)
2 (50)
NS()
30
29 (96.7)
1 (3.3)
NS(C)
12
5 (41.7)
7 (58.3)
NS()
3
2 (66.7)
1 (33.3)
NS, Nonstructural pattern; D, differentiated-type cancer; U, undifferentiated-type cancer.
clinical meaning of magnifying endoscopy of the stomach is attracting considerable attention again. According to the Kudo’s classification of colonoscopy,14-16 fine mucosal pattern (pit pattern) of colorectal lesions vividly reflects the histologic finding of the lesion, i.e., normal mucosa, hyperplastic polyp, adenoma with mild to severe atypia, mucosal cancer, and invasive cancer. And Kudo et al14-16 demonstrated the relation between magnifying endoscopic and histologic findings. With regard to the stomach, there is no definitive classification of magnifying endoscopy, especially for gastric cancer. Some investigators assess the fine mucosal pattern of the lesion, and others assess the microvascular pattern of the lesion.22 The assessment of a microvascular pattern is a very attractive approach. Kudo’s classification of magnifying colonoscopy14-16 does not attempt to assess the microvascular pattern. In the magnifying endoscopy of the esophagus, in which magnifying endoscopy cannot demonstrate mucosal pattern, Inoue et al24,25 and Kumagi Volume 62, No. 1 : 2005 GASTROINTESTINAL ENDOSCOPY 53
Nonstructural pattern on magnifying gastroscopy
et al26 advocated their original magnifying endoscopic classification for the esophageal lesions, depending on the microvascular pattern. We reported that the classification agrees with histologic findings at a high rate.27 In this study, we evaluated the clinical meaning of nonstructural findings of gastric neoplasms when using magnifying videoendoscopy and stereoscopic microscopy. Both in vivo magnifying endoscopic findings and in vitro stereoscopic microscopic finding of resected specimen are closely correlated with each other. According to the results of this study, the appearance of a nonstructural pattern in the neoplastic lesion of the stomach means that the lesion is usually a U group cancer or a cancer with submucosal involvement, or both. This is a very important fact in the clinical situations before EMR for early gastric cancer. Based on the results of this study, when the nonstructural pattern appears on the neoplastic lesion of the stomach during magnifying endoscopy, the patient should not be treated endoscopically. In other words, if the histologic assessment of the biopsy confirmed D group cancer or adenoma, then the absence of a nonstructural pattern in the lesion during magnifying endoscopy suggested that the lesion could be managed endoscopically. Although this study includes only 59 patients, magnifying endoscopy before EMR of the gastric lesion appeared to be a very useful diagnostic modality, in addition to regular endoscopy, chromoendoscopy, and EUS.
ACKNOWLEDGMENT We thank Ms. Masako Kitatani of the Digestive Disease Center, Showa University Northern Yokohama Hospital, Yokohama, Japan, for providing assistance in the preparation of this manuscript. REFERENCES 1. Deyhle P, Largiader F, Jenny S, Fumagalli I. A method for endoscopic electroresection of sessile colonic polyps. Endoscopy 1973;5:38-40. 2. Tada M, Shimada M, Murakami F, Mizumachi M, Arima K, Yanai H, et al. Development of the strip-off biopsy [in Japanese with English abstract]. Gastroenterol Endosc 1984;26:833-9. 3. Tada M, Murakami A, Karita M, Yanai H, Okita K. Endoscopic resection of early gastric cancer. Endoscopy 1993;25:445-50. 4. Takekoshi T, Takagi K, Fujii A, Kato Y. Treatment of early gastric cancer by endoscopic double snare polypectomy (EDSP) [in Japanese]. Gan No Rinsho 1986;32:1185-90. 5. Hirao M, Masuda K, Asanuma T, Naka H, Noda K, Matsuura K, et al. Endoscopic resection of early gastric cancer and other tumors with local injection of hypertonic saline-epinephrine. Gastrointest Endosc 1988;34:264-9. 6. Tani M, Takeshita K, Inoue H, Iwai T. Adequate endoscopic mucosal resection for early gastric cancer obtained from the dissecting microscopic features of the resected specimens. Gastric Cancer 2001;4:122-31. 7. Gotoda T, Kondo H, Ono H, Saito Y, Yamaguchi H, Saito D, et al. A new endoscopic mucosal resection procedure using an insulation-tipped electrosurgical knife for rectal flat lesions: report of two cases. Gastrointest Endosc 1999;50:560-3.
54 GASTROINTESTINAL ENDOSCOPY Volume 62, No. 1 : 2005
Yoshida et al 8. Ono H, Kondo H, Gotoda T, Shirao K, Yamaguchi H, Saito D, et al. Endoscopic mucosal resection for treatment of early gastric cancer. Gut 2001;48:225-9. 9. Yamamoto H, Yube T, Isoda N, Sato Y, Sekine Y, Higashizawa T, et al. A novel method of endoscopic mucosal resection using sodium hyaluronate. Gastrointest Endosc 1999;50:251-6. 10. Oyama T, Kikuchi Y, Shimatani S, Tomori A, Hotta K, Miyata Y, et al. Aggressive endoscopic mucosal resection for early gastric cancer: hook knife EMR method [in Japanese with English abstract]. Endoscopia Digestiva 2002;14:1747-52. 11. Yahagi N, Fujishiro M, Kakushima N, Kobayashi K, Hashimoto T, Oka M, et al. Endoscopic submucosal dissection for early gastric cancer using the tip of an electrosurgical snare (thin type). Dig Endosc 2004;16:34-8. 12. Japanese Gastric Cancer Association. Gastric cancer treatment guidelines. 2nd ed. Tokyo: Kanehara; 2004. 13. Japanese Gastric Cancer Association. Gastric cancer treatment guidelines [in Japanese with English abstract] [cited 2004 Sept 20]. Available from: URL: http://www.jgca.jp/PDFfiles/E-gudeline.PDF. 14. Kudo S, Tamura S, Nakajima T, Yamano H, Kusaka H, Watanabe H. Diagnosis of colorectal tumorous lesions by magnifying endoscopy. Gastrointest Endosc 1996;44:8-14. 15. Kudo S, Hirota S, Nakajima T, Hosobe S, Kusaka H, Kobayashi T, et al. Colorectal tumours and pit pattern. J Clin Pathol 1994;47:880-5. 16. Kudo S, Rubio CA, Teixeira CR, Kashida H, Kogure E. Pit pattern in colorectal neoplasia: endoscopic magnifying view. Endoscopy 2001; 33:367-73. 17. Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma [in Japanese]. 13th ed. Tokyo: Kanehara; 1999. 18. Japanese Research Society for Gastric Cancer. Japanese classification of gastric carcinoma. 1st ed. Tokyo: Kanehara; 1999. 19. Sakaki N, Iida Y, Okazaki Y, Kawamura S, Takemoto T. Magnifying endoscopic observation of the gastric mucosa, particularly in patients with atrophic gastritis. Endoscopy 1978;10:269-74. 20. Tobita K. Study on minute surface structures of the depressed-type early gastric cancer with magnifying endoscopy. Dig Endosc 2001;13:121-6. 21. Miwa H, Sato N. Shed light again on magnifying endoscopy for diagnosis of early gastric cancer. Dig Endosc 2001;13:127-8. 22. Yao K, Oishi T, Matsui T, Yao T, Iwashita A. Novel magnified endoscopic findings of microvascular architecture in intramucosal gastric cancer. Gastrointest Endosc 2002;56:279-84. 23. Yagi K, Nakamura A, Sekine A. Comparison between magnifying endoscopy and histological, culture and urease test findings from the gastric mucosa of the corpus. Endoscopy 2002;34:376-81. 24. Inoue H, Honda T, Yoshida T, Nishikage T, Nagahama T, Yano K, et al. Ultra-high magnification endoscopy of the normal esophageal mucosa. Dig Endosc 1996;8:134-8. 25. Inoue H, Kumagai Y, Yoshida T, Kawano T, Endo M, Iwai T. High-magnification endoscopic diagnosis of the superficial esophageal cancer. Dig Endosc 2000;12:S32-5. 26. Kumagai Y, Inoue H, Nagai K, Kawano T, Iwai T. Magnifying endoscopy, stereoscopic microscopy, and the microvascular architecture of superficial esophageal carcinoma. Endoscopy 2002;34:369-75. 27. Yoshida T, Inoue H, Usui S, Satodate H, Fukami N, Kudo S. Narrow-band imaging system with magnifying endoscopy for superficial esophageal lesions. Gastrointest Endosc 2004;59:288-95.
Received October 2, 2004. Accepted February 16, 2005. Current affiliations: Department of Surgery, Kudanzaka Hospital, Tokyo, Japan; Department of Pathology, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan; Digestive Disease Center, Department of Pathology, Showa University Northern Yokohama Hospital, Yokohama, Japan. Reprint requests: Tatsuya Yoshida, MD, Department of Surgery, Kudanzaka Hospital, Kudan-minami 2-1-39, Chiyoda-ku, Tokyo 102-0074, Japan.
www.mosby.com/gie