Development of a new contrast endoscopic method With Techno Color blue P

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1 Bulletin of the Osaka Medical College , Original Article Development of a new contrast endoscopic method With Toshihisa TAKEUCHI, Eiji UMEGAKI, Satoshi TOKIOKA, Nozomi TAKEUCHI, Minekazu OZAWA, Shingo YASUMOTO, Nanako SHIRAISHI, Yukiko YODA and Ken-ichi KATSU Department of Internal Medicine II, Osaka Medical Collage, Takatsuki-city, Osaka , Japan Key Words, contrast endoscopy, dye-enhanced endoscopy, magnification endoscopy, pit pattern ABSTRACT Natural gardenia pigment has been known from old times as a dye and colorant and is presently used widely in that area as a food colorant and its safety has already been established. We have comparatively investigated the application of, which is the natural gardenia pigment, against normal pigments in contrast endoscopy. coagulated thereby decreasing its solubility as the ph of the solvent became acidic. For the upper gastrointestinal tract, 10% and the lower gastrointestinal tract 20% of the Techno Color blue P solution is appropriate. In upper gastrointestinal endoscopy, coagulates in the acid secreting areas, and is therefore unsuitable as a contrast method. However, in the pyloric gland, atrophied areas of the gastric mucosa, and duodenal villi, it was superior to as a contrast method. In colonoscopy, intestinal fluids is alkaline and so showed a stable dyeing property with clearer contrasting compared to. Contrast endoscopy with, is useful as a contrast method for accentuated surface morphology of the gastric mucosa, duodenal mucosa, and colonic mucosa. Introduction Dye-enhanced endoscopy is a method whereby various types of dyes are dispersed or sprayed onto the gastrointestinal mucosa or gastrointestinal surfaces. The minute irregularities, changes in color tone, and function of the mucosa or organ are observed endoscopically using the properties of dyes. Presently, it is becoming an indispensable method for clear and detailed diagnosis of the pathophysiology of gastrointestinal diseases. Dye-enhanced endoscopy is classified into the contrast type, dye-enhanced type, dye-reaction type, and fluorescent endoscopy. Of these, the contrast type with (IC) (Daiichi Pharmaceuticals, Tokyo) is a test that can be performed comparatively easily, and then it is Address correspondence to: Eiji Umegaki, M.D., Department of Internal Medicine II, Osaka Medical Collage, 2-7 Daigaku-machi, Takatuki-city, Osaka , Japan Phone: Fax: in2038@poh.osaka-med.ac.jp

2 46 Toshihisa TAKEUCHI et al. generally popular. Recently, the development and popularization of endoscopic submucosal dissection (ESD) 1)-2) and less invasive surgery such as laparoscopic surgery 3) in treatment of malignant gastrointestinal tumors, is gradually increasing the attention paid to the importance of diagnosing the existence and range of minute lesions. In addition, endoscopy by specialty optics such as magnified 4)-6) and narrow band imaging (NBI) 7)-8) are being performed. However, they are not common. Of these, the importance of diagnosis by the contrast method 9) is again being emphasized. We have investigated the application of Techno Color blue P (TB) (Mitsubishi Kagaku Foods Corp., Tokyo), a natural gardenia pigment 10)-11) that has already been approved as a natural food additive, and there is ample information on its safety in contrast endoscopy. The aim was to further improve lesion diagnostic performance compared to the contrast method using IC. Materials and methods I. Fundamental investigation TB is a pre-dried powderized substance that was obtained by reacting a mixture of iridoid glycoside that is in the liquid extracted from the rubiaceous gardenia fruit and protein decomposed residue, with β-glucosidase and then adding dextran, a food raw material. In addition, it is hydrosoluble and is a food additive, and that makes a substance with superior protein dying properties. To 10 ml each of distilled water prepared to a ph of 1, 2, 3, 5, 7, and 9 was added TB 0.5 g, and this was used as the 5% solution to investigate the solubility. II. Clinical investigation Dyes used Upper gastrointestinal tract (stomach, duodenum) 0.1 % IC solution 10 % TB solution (ph 7) Lower gastrointestinal tract (colon, rectum) 0.1 % IC solution 20 % TB solution (ph 7) 1. Upper gastrointestinal endoscopy In upper gastrointestinal endoscopy, after performing a pre-treatment with the mucous solubilizer, pronase, the gastric contents were thoroughly aspirated. Next, a conventional was performed using an videoendoscope and 0.1% IC solution and 10% TB solution were dispersed under direct vision using a dispersion tube. Dye-enhanced endoscopy was then performed. In addition, images obtained by magnified endoscopy and specialty endoscopy by NBI were comparatively investigated when appropriate. In this study, gastric ulcer was classified by endoscopically classification of Sakita-Miwa 11), and gastric tumor by Japanese Classification of Gastric Carcinoma 13). 2. Colonoscopy Intestinal tract lavage fluid (polyethylene glycol solution) was administered based on the pre-treatment in the ordinary way of colonoscopy. was then performed using a videoendoscope. Next, 0.1% IC solution and 10% TB solution were dispersed under direct vision using a dispersion tube. Dye-enhanced endoscopy was then performed. In addition, like the upper gastrointestinal tract, a comparison was made with images obtained by specialty endoscopy. In this syudy, colorectal tumor was classified by Japanese classification of Colorectal Carcinoma 14), and by Kudo-Tsuruta classification in point of colonic pit pattern 15). 3. Stereo microscopic image of gastric resection specimen Fresh specimens of gastric tumor that were resected by ESD were observed by stereo microscopy ) 0.1% IC solution and 10% TB solution were dispersed and the structures of the glandular ducts in the tumor area were comparatively investigated. All of these patients gave informed consent prior to participation in this study. Bulletin of the Osaka Medical College , 2007

In addition, the mean size of the coagulated particles in the 5%TB solution at ph 1 was 87.6 µm and 5.6 µm at ph3.

With regard to the application of TB in contrast endoscopy, TB coagulates at lower ph, and may also be diluted by the

Therefore, 10% of TB solution were used for upper gastrointestinal endoscopy and 20% of TB solution for colonoscopy.

3 endoscopy with Results I. Fundamental investigation (solubility of TB) TB clearly coagulated at ph 1 and 2 and dissolved at ph 3, 5, 7, and 9. In addition, the mean size of the coagulated particles in the 5%TB solution at ph 1 was 87.6 µm and 5.6 µm at ph3. ph1 Fig.1 ph2 ph3 47 There was no significant difference between the values at ph 3, 5, 7 and 9 (Figure 1,2,3). With regard to the application of TB in contrast endoscopy, TB coagulates at lower ph, and may also be diluted by the gastrointestinal contents. Therefore, 10% of TB solution were used for upper gastrointestinal endoscopy and 20% of TB solution for colonoscopy. ph5 ph7 ph9 Solubility of at various ph values TB clearly coagulated at ph 1 and 2 and dissolved at ph 3, 5, 7, and 9. Fig.2 Observation of solution at a ph 1 (x 500) TB coagulated at ph 1 and the mean size of the coagulated particles in the 5%TB solution was 87.6 µm. Bulletin of the Osaka Medical College , 2007

48 Toshihisa TAKEUCHI et al. Fig.3 Sizes of the coagulated particles in the 5 % solution at various ph values The mean size of the coagulated particles at ph 1 was 87.6 µm and 5.6 µm at ph3.

Upper gastrointestinal endoscopy Case 1 (Figure 4) Upper gastrointestinal endoscopy showed a gastric adenoma 18) of 10 mm in diameter in the posterior wall of the gastric antrum.

4 48 Toshihisa TAKEUCHI et al. Fig.3 Sizes of the coagulated particles in the 5 % solution at various ph values The mean size of the coagulated particles at ph 1 was 87.6 µm and 5.6 µm at ph3. There was no significant difference between the values at ph 3, 5, 7 and 9. II. Clinical investigations 1. Upper gastrointestinal endoscopy Case 1 (Figure 4) Upper gastrointestinal endoscopy showed a gastric adenoma 18) of 10 mm in diameter in the posterior wall of the gastric antrum. In the conventional, it was recognized as an indistinct boundary of discoloration. The gastric foveola in the periphery of the lesion was enhanced by TB, enabling a clear imaging of the lesion boundary. Fig.4 Gastric adenoma The gastric foveola in the periphery of the lesion was enhanced by TB, enabling a clear imaging of the lesion boundary. Bulletin of the Osaka Medical College , 2007

endoscopy with Case 2 (Figure 5) Upper gastrointestinal endoscopy showed a malignant lymphoma19) in the

In the conventional, the enlarged folds of the greater curvature were observed.

There was consistent coagulation in the fundic gland area and acid secreting areas.

property and the lesion could be more clearly observed. Fig.5 49 Malignant lymphoma of the stomach Fig.

5 endoscopy with Case 2 (Figure 5) Upper gastrointestinal endoscopy showed a malignant lymphoma19) in the greater curvature of the upper part of the stomach. In the conventional, the enlarged folds of the greater curvature were observed. When TB was dispersed, it coagulated significantly. There was consistent coagulation in the fundic gland area and acid secreting areas. Case 3 (Figure 6) Upper gastrointestinal endoscopy showed an artificial ulcer scar after ESD in the lesser curvature of the gastric angle. Compared to the image obtained by IC dispersion, that obtained by TB dispersion showed superior dyeing property and the lesion could be more clearly observed. Fig.5 49 Malignant lymphoma of the stomach When TB was dispersed, it coagulated significantly. There was consistent coagulation in the fundic gland area and acid secreting areas. Fig.6 Gastric artificial ulcer scar after treatment of ESD Compared to the image obtained by IC dispersion, TB showed superior dyeing property and the lesion could be more clearly observed. Bulletin of the Osaka Medical College , 2007

cancer20)-21) of 20 mm in diameter in the lesser curvature of the gastric angle.

In the image obtained by IC dispersion, a granular tumor was captured but in that obtained by

formation of polypoid lesion due to the intertubular staining of the granular tumors.

regeneration of the epithelium in the ulcer margin.

8 Early gastric cancer (type 0 IIa) The boundary of the tumor was clear and it became clear

6 Toshihisa TAKEUCHI et al. 50 Case 4 (Figure 7) Upper gastrointestinal endoscopy showed a type 0 IIa early gastric cancer20)-21) of 20 mm in diameter in the lesser curvature of the gastric angle. In the conventional, the lesion was recognized as the discolored polypoid mucosa. In the image obtained by IC dispersion, a granular tumor was captured but in that obtained by TB dispersion, the boundary of the tumor was more clear and it became clear that there was formation of polypoid lesion due to the intertubular staining of the granular tumors. Case 5 (Figure 8) Upper gastrointestinal endoscopy showed a so called H2 stage gastric ulcer in the posterior wall of the antrum. Compared to the image obtained by IC dispersion, that obtained by TB dispersion showed clear regeneration of the epithelium in the ulcer margin. Even with NBI, minute patterns of epithelial regeneration in the mucosa were clear. Fig.7 Fig.8 Early gastric cancer (type 0 IIa) The boundary of the tumor was clear and it became clear that there was formation of polypoid lesion due to the intertubular staining of the granular tumors by TB. NBI view Gastric ulcer (H2 stage) The image obtained by TB dispersion showed clear regeneration of the epithelium in the ulcer margin. Bulletin of the Osaka Medical College , 2007

endoscopy with Case 6 (Figure 9) Upper gastrointestinal endoscopy showed a normal

In the image obtained by TB dispersion in the duodenum which is an alkaline area,

dispersion, could be clearly observed. 51 2.

good dyeing properties and so the pit pattern in the conventional was also superior.

9 Duodenal mucosa individual regular villus formation could be clearly observed. Fig.

7 endoscopy with Case 6 (Figure 9) Upper gastrointestinal endoscopy showed a normal mucosa of duodenum. In the image obtained by TB dispersion in the duodenum which is an alkaline area, individual regular villus formation, which was unclear in the image obtained by IC dispersion, could be clearly observed Colonoscopy Case 7 (Figure 10) Colonoscopy showed a type 0 IIa early rectal cancer with a diameter of 10 mm in the rectum. Compared to the image obtained by IC dispersion, that obtained by TB dispersion showed good dyeing properties and so the pit pattern in the conventional was also superior. The lesion was suggested to be the type IIIL pit pattern. Fig.9 Duodenal mucosa In the image obtained by TB dispersion in the duodenum which is an alkaline area, individual regular villus formation could be clearly observed. Fig.10 Colonic cancer (type 0 IIa) The image obtained by TB dispersion showed good dyeing properties and so the pit pattern in the conventional was also superior. Bulletin of the Osaka Medical College , 2007

periphery of the lumen of the sigmoid colon.

showed more contrast enhancement and so even the intermediate mucosa between the

Case 9 (Figure 12) Colonoscopy showed a magnified of type 0 IIa rectal cancer with

showed superior dyeing properties on the intertubular surface.

Fig.11 Granular lesion of colon (type 0 IIa) The image obtained by TB dispersion

Therefore, the contrast was better enhanced and a clear pit could be observed.

8 Toshihisa TAKEUCHI et al. 52 Case 8 (Figure 11) Colonoscopy showed a type 0 IIa granular lesion in 1/3 of the periphery of the lumen of the sigmoid colon. Compared to the image obtained by IC dispersion, that obtained by TB dispersion showed more contrast enhancement and so even the intermediate mucosa between the nodular tumors was clearly captured. Case 9 (Figure 12) Colonoscopy showed a magnified of type 0 IIa rectal cancer with an Rb diameter of 20 mm in the rectum. Compared to the image obtained by IC dispersion, that obtained by TB dispersion showed superior dyeing properties on the intertubular surface. Therefore, the contrast was better enhanced and a clear pit22) could be observed. Fig.11 Granular lesion of colon (type 0 IIa) The image obtained by TB dispersion showed more contrast enhancement and so even the intermediate mucosa between the nodular tumors was clearly captured. Fig.12 Magnified of colon cancer (type 0 IIa) The image obtained by TB dispersion showed superior dyeing properties on the intertubular surface. Therefore, the contrast was better enhanced and a clear pit could be observed. Bulletin of the Osaka Medical College , 2007

microscopy. Compared to the image obtained by IC dispersion, that obtained by TB dispersion showed high dyeing properties of the intertubular surface.

9 endoscopy with Stereo microscopic image of gastric adenoma from resected specimen(figure 13) IC and TC were dispersed onto fresh specimens of gastric adenoma and observed at a 200 x magnification by stereo microscopy. Compared to the image obtained by IC dispersion, that obtained by TB dispersion showed high dyeing properties of the intertubular surface. It became clear that it had a glandular convolution pattern. Fig.13 Observation of stereo microscopic images of gastric adenoma (x 200) TB showed high dyeing properties of the intertubular surface. It became clear that it had a glandular convolution pattern. Discussion If Lugol s solution is considered to be a pigment solution, then the history started when Schiller 23) applied Lugol s solution for diagnosing cervical uterine cancer in 1933, and it has presently reached the diagnosis of superficial cancer of the esophagus. Furthermore, in 1963, Richart 24) used Toluidine blue to diagnose cervical uterine cancer, and in 1968, Strong 25) et al. reported diagnosing oral cancer using Toluidine blue. All these were aimed at the early diagnosis of cancers that are located close to the body surface, and were not applications of dyes in endoscopy. However, these studies had a significant impact on the development of dye-enhanced endoscopy. The use of dyes in endoscopy was first reported by Niwa in 1965 when he reported using Toluidine blue in colonoscopy. For the upper gastrointestinal tract, in 1966, Chida and Okuda reported using Congo red 26) to observe the gastric acid secretory areas, and in that same year, Tsuda and Aoki reported using blue dye to diagnose gastric lesions. These studies have formed the base for the further development of dye-enhanced endoscopy. In Japan, classification of dye-enhanced endoscopy was proposed by the dye-enhanced endoscopy research committee in This classification consists of five classes: a) the contrast method, b) the dye-enhanced method, c) the pigment reaction method, d) fluorescence endoscopy, and e) other methods. Of these, the contrast method where the dye accumulation phenomenon is applied, is a simple method aimed at enhancing and observing the morphology of the folds of the gastrointestinal surface. The contrast method is very useful for capturing minute lesions and diagnosing the range of lesions with unclear margins, it is an essential method when biopsies, endoscopic mucosal resections and surgical operations, are being performed. However, the basic dyes used in the contrast method are shades that are often comparable with the color tone of the mucosa. And, they must be colors that do not change or get absorbed by the mucosal surface. IC, which is a reagent for testing gastric function, is the most commonly used dye. The TB used in this study was obtained when iridoid glycoside in solution extracted from the gardenia fruit was made to react with food enzymes. There are several types of gardenia Bulletin of the Osaka Medical College , 2007

10 54 Toshihisa TAKEUCHI et al. enzyme pigments gardenia blue, gardenia green, and gardenia red pigments. For this study, TB, which is gardenia blue pigment that is contrasts the color tone of the mucosa, was selected. The natural gardenia pigment has been used as a food additive from old times and its safety has been already established. IC has been reported to cause adverse reactions such as extreme shock when used as a reagent for testing renal function, however no such case has been reported when used in endoscopy. In fundamental investigations on TB, it was found not to dissolve but rather coagulate in strongly acidic solvents at ph 1 or 2 in vitro. In order to apply TB clinically, we considered that the solubility of TB increases with increase in alkalinity in vitro, it readily coagulates in the upper gastrointestinal tract which is highly acidic, and it may be diluted by the gastrointestinal substances in the upper and lower gastrointestinal tracts. Therefore, we used 10 and 20% of the TB solution for the upper and lower gastrointestinal tracts, respectively. Even in actual endoscopy, it coagulated in the gastric fundal gland area where there is no atrophy. Therefore, it cannot be indicated as a contrast method for acid secreting areas. In other gastric parts that are not strongly acidic, TB did not coagulate as in the in vitro results. In the comparison with IC, it showed superior dyeing properties towards the crypt and intertubular surface, and the lesions could be easily identified. As the duodenum is a more alkaline area than the stomach, clearer structures of the duodenal villi could be identified compared to IC. As the coloreutum is also an alkaline area, superior dyeing properties of the intertubular space that is also useful in the pit diagnosis of tumors was shown. Even in the stereo microscopic of isolated specimens, good dyeing property towards the intertubular surface was shown. Although there has been marked advancement in magnified endoscopy and endoscopic equipments such as NBI, the diagnostic process is complicated and has not yet been generally established. Attention is being paid to the contrast method, which is simple to perform, and contrast with TB, which has higher lesion diagnostic performance compared to IC, which is commonly used in general at present, has been reported. Conclusions Dye-enhanced endoscopy with TB was superior to IC as a contrast method that enhances the surface morphology of the gastric mucosa which is non-acid secreting areas, duodenal mucosa, and colon mucosa. This method would be thoroughly applied clinically as an adjuvant procedure for accurately diagnosing tumor margins. References 1. Masaki. Strategies for gastric cancer treatment in the twenty-first century: minimally invasive and tailored approaches integrating basic science and clinical medicine. Gastric Cancer. 2005;8: Oda I, Gotouda T, et al. Endoscopic submucosa dissection for early gastric cancer : technical feasibiliy, operation time and complications from a large consecutive series. Digestive Endoscopy. 2005;17: Tanigawa N. Gastric cancer: laparoscopic surgery and adjuvant chemotherapy. Nippon Geka Gakkai Zasshi. 2004;105: (in 4. Ida K, Okuda J, et al. Recent advances and problems in the endoscopic treatment of early gastric cancer. Digestive Endoscopy. 1996;8: Yao K, Iwashita A, Tao T. Early gastric cancer: proposal for a new diagnostic system based on microvascular architecture as visualized by magnified endoscopy. Digestive Endoscopy. 2004;16: Ohta A, Tominaga K, Sakai Y. Efficacy of magnifying colonoscopy for the diagnosis of colorectal neoplasia: comparison with histopathological findings. Digestive Endoscopy. 2004;16: Saito N, Tajiri H, et al. The usefulness of magnifying endoscopy using a narrow-band imaging system for detecting Barrett s mucosa. Jikeikai Medical Journal. 2004;51: (in 8. Sano Y, Kobayashi M, et al. New diagnostic method based on color imaging using narrow band imaging system for gastrointestinal tract. Gastrointestinal Endoscopy. 2001;53:AB Sugiura J, Ida K, et al. Multiple early gastric carcinoma in cases treated endoscopically. Digestive Endoscopy. 1992;4: Yougel T, Katsu K, et al. Application of dye from Gardenia to chromoendoscopy. Progress Bulletin of the Osaka Medical College , 2007

11 endoscopy with 55 of digestive endoscopy. 1989;34:96-8. (in 11. Yougel T, Katsu K, et al. Study of correlation between the crystal violet endoscopic dyeing method and ph on gastric mucosa using the electric endoscopy. Progress of digestive endoscopy. 1988;32: (in 12. Japan Gastroenterological Endoscopy Society. Guideline of Gastroenterology, 3rd ed. Tokyo, Igakushoin, 2006 (in 13. Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma, 13th ed. Tokyo, Kanehara, (in 14. Japanese Society for Cancer of the Colon and Rectum. Japanese classification of colorectal carcinoma, 7th ed. Tokyo, Kanehara, (in 15. Kudou S. Diagnosis of colonic pit pattern. Tokyo, Igakushoin, (in 16. Tani M, Takeshita K, et al. Adequate endoscopic mucosal resection for early gastric cancer obtained from the dissecting microscopic features of the resected specimens. Gastric Cancer. 2001;4: Umegaki E. Stereoscopic microscopy for gastrointestinal mucosal resection specimens. Gastroenterological Endoscopy. 2006;48:70-8. (in 18. Fujii T, Yoshida S, et al. Very well differentiated tubular adenocarcinoma of the stomach: its endoscopic and histopathological characteristics. Japanese Journal of Clinical Oncology. 1994;24: (in 19. Ishido T, Nishizawa M, et al. Assessment of new macroscopical classification of gastric malignant lymphoma. Japanese Journal of Cancer Research. 1991;82: (in 20. Tajiri H, Doi T, et al. Routine endoscopy using a magnifying endoscope for gastric cancer diagnosis. Endoscopy. 2002;34: (in 21. Yao K, Oishi T, et al. Novel magnified endoscopic findings of microvascular architecture in intramucosal gastric cancer. Gastrointestinal Endoscopy. 2002;56: (in 22. Tamura S, Yokoyama Y, et al. Evaluation of the type V pit pattern in the lesions of colonic Tis and T1 cancer. Digestive Endoscopy. 2003;15: Strong M.S, Vaughan C.W, INCZE J.S. Toluidine blue in the management of carcinoma of the oral cavity. Arch.Otolaryngo. 1968;l87: Richart R.M. A clinical staining test for the in vivo delineation of dysplasia and carcinoma in situ. J.Obstent.Gyneco. 1963;l86: Strong M.S, Vaughan C.W, Incze J.S. Toluidine blue in the management of carcinoma of the oral cavity. Arch.Otolaryngo. 1968;l87: Kimura K, Takemoto T. An endoscopic recognition of the atrophic border and its significance in chronic gastritis. Endoscopy. 1969;1: (in Received November 1, 2006 Accepted December 15, 2006 Bulletin of the Osaka Medical College , 2007

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