**2.2 Optical methods for minimizing the overlooking of colorectal neoplasms**

Image-enhanced endoscopy is expected to be better at detecting adenomas than conventional white light imaging (WLI). There are two types of IEE: dye-based and equipment-based (Kaltenbach, et al., 2008). In dye-based IEE, absorptive or contrast dye is used to enhance the features of the lesion. The typical absorptive dye for colonoscopy is crystal violet and the typical contrast dye indigo carmine. Indigo carmine, which can provide enhancement of the details of lesions by highlighting subtle changes in mucosal topography, is usually used to minimize the overlooking of colorectal neoplasms. On the other hand, there are a number of categories of equipment-based IEE. These include optical method such as NBI, electronic methods such as FICE, and optical-digital methods such as AFI.

Recent Advances in Diagnostic Endoscopy for Colorectal Neoplasm 215

the most suitable wavelengths for each examination. Although some randomized controlled trials have been conducted (Aminalai et al., 2010 Chung et al., 2010), no one has yet

Autofluorescence imaging is an endoscopic technique for visualizing with reflected autofluorescence, which is emitted from an endogeneous fluorophore by exposing it to short wavelength excitation light (Fig. 4). The latest model of AFI system can switch between observation modes in a few seconds. Because colonic adenomas are shown as distinct purple areas in the surrounding green mucosa using AFI, this technique is expected to improve the detection rate of colonic tumors during screening colonoscopy, especially in regard to flat lesions, which are difficult to detect using WLI (Fig. 5). Matsuda et al. reported that AFI is better than WLI at detecting polyps in the right-sided colon. The miss rate for all polyps with AFI (30%) was significantly less than that with WLI (49%, *P*=0.01) (Matsuda et al., 2008).

demonstrated improvement in adenoma miss or detection rates compared with WLI.

Fig. 4. The mechanism of autofluorescence imaging (AFI). AFI images are produced by illuminating the mucosa by light that has passed through a rotation filter. The image processor artificially colors the autofluorescence images green, and the green reflection

**2.3 Combination of mechanical and optical methods for minimizing the overlooking of** 

To determine whether a combination of the different complementary mechanisms of AFI and a TH would be better at detecting colorectal neoplasms than conventional WLI without

In this trial, both patients undergoing colonoscopy for investigation of a positive screening fecal occult blood testing (FOBT) and those who had been referred for surveillance colonoscopy after endoscopic resection of colorectal neoplasms were enrolled. A 2 × 2 factorial design was adopted to investigate the impact of simultaneous AFI and a TH. The

images red and blue, then composite images are displayed on the video screen

a TH, a prospective, randomized controlled trial was conducted.

**colorectal neoplasms** 

Brooker et al. reported that total colonic dye-spray increases the detection of diminutive adenomas (Brooker et al., 2002). In their trial, they detected 89 diminutive adenomas using total dye-spray colonoscopy and 37 using conventional colonoscopy. Certainly, total colonic dye-spray might improve the adenoma detection rate, but it has not become a standard method for screening because it is much too complicated and time consuming for clinical use. Only methods that are simple and quick are likely to become widely adopted for screening colonoscopy.

Narrow band imaging is a type of equipment-based IEE that uses short-wavelength light (Fig. 3). NBI provides a unique image which emphasizes the capillary pattern as well as the surface pattern. Colorectal adenomas are shown as brownish areas by NBI and are significantly better visualized by NBI than by WLI. NBI is expected to result in better detection of colorectal adenomas and better distinction between neoplasms and nonneoplastic lesions. Recently, although several investigators in western countries have been trying to demonstrate its ability to detect colorectal adenomas, most randomized trials have reported negative results (Adler et al., 2008, 2009). On the other hands, Japanese investigators have reported positive results in their articles (Inoue et al., 2008; Uraoka et al., 2008). Therefore, the efficacy of NBI for detection of colorectal adenoma is still contentious and further investigation is needed.

Fig. 3. The mechanism of narrow band imaging (NBI). The NBI system is based on modification of spectral features with each optical filter narrowing a bandwidth of spectral transmittance. (RGB; Red, Green, Blue)

Flexible spectral imaging color enhancement modifies spectral transmittance arithmetically by using a computing processor; therefore, it does not require optical filters. Furthermore, because of its variable setting functions (up to 10), the operator has flexibility in selection of

Brooker et al. reported that total colonic dye-spray increases the detection of diminutive adenomas (Brooker et al., 2002). In their trial, they detected 89 diminutive adenomas using total dye-spray colonoscopy and 37 using conventional colonoscopy. Certainly, total colonic dye-spray might improve the adenoma detection rate, but it has not become a standard method for screening because it is much too complicated and time consuming for clinical use. Only methods that are simple and quick are likely to become widely adopted for

Narrow band imaging is a type of equipment-based IEE that uses short-wavelength light (Fig. 3). NBI provides a unique image which emphasizes the capillary pattern as well as the surface pattern. Colorectal adenomas are shown as brownish areas by NBI and are significantly better visualized by NBI than by WLI. NBI is expected to result in better detection of colorectal adenomas and better distinction between neoplasms and nonneoplastic lesions. Recently, although several investigators in western countries have been trying to demonstrate its ability to detect colorectal adenomas, most randomized trials have reported negative results (Adler et al., 2008, 2009). On the other hands, Japanese investigators have reported positive results in their articles (Inoue et al., 2008; Uraoka et al., 2008). Therefore, the efficacy of NBI for detection of colorectal adenoma is still contentious

Fig. 3. The mechanism of narrow band imaging (NBI). The NBI system is based on

modification of spectral features with each optical filter narrowing a bandwidth of spectral

Flexible spectral imaging color enhancement modifies spectral transmittance arithmetically by using a computing processor; therefore, it does not require optical filters. Furthermore, because of its variable setting functions (up to 10), the operator has flexibility in selection of

screening colonoscopy.

and further investigation is needed.

transmittance. (RGB; Red, Green, Blue)

the most suitable wavelengths for each examination. Although some randomized controlled trials have been conducted (Aminalai et al., 2010 Chung et al., 2010), no one has yet demonstrated improvement in adenoma miss or detection rates compared with WLI.

Autofluorescence imaging is an endoscopic technique for visualizing with reflected autofluorescence, which is emitted from an endogeneous fluorophore by exposing it to short wavelength excitation light (Fig. 4). The latest model of AFI system can switch between observation modes in a few seconds. Because colonic adenomas are shown as distinct purple areas in the surrounding green mucosa using AFI, this technique is expected to improve the detection rate of colonic tumors during screening colonoscopy, especially in regard to flat lesions, which are difficult to detect using WLI (Fig. 5). Matsuda et al. reported that AFI is better than WLI at detecting polyps in the right-sided colon. The miss rate for all polyps with AFI (30%) was significantly less than that with WLI (49%, *P*=0.01) (Matsuda et al., 2008).

Fig. 4. The mechanism of autofluorescence imaging (AFI). AFI images are produced by illuminating the mucosa by light that has passed through a rotation filter. The image processor artificially colors the autofluorescence images green, and the green reflection images red and blue, then composite images are displayed on the video screen

#### **2.3 Combination of mechanical and optical methods for minimizing the overlooking of colorectal neoplasms**

To determine whether a combination of the different complementary mechanisms of AFI and a TH would be better at detecting colorectal neoplasms than conventional WLI without a TH, a prospective, randomized controlled trial was conducted.

In this trial, both patients undergoing colonoscopy for investigation of a positive screening fecal occult blood testing (FOBT) and those who had been referred for surveillance colonoscopy after endoscopic resection of colorectal neoplasms were enrolled. A 2 × 2 factorial design was adopted to investigate the impact of simultaneous AFI and a TH. The

Recent Advances in Diagnostic Endoscopy for Colorectal Neoplasm 217

surgery; (2) symptoms suspicious of colorectal stenosis or cancer; (3) inflammatory bowel disease, familial polyposis or known colorectal cancer; (4) severe organ failure, noncorrectable coagulopathy, or receiving anticoagulant therapy; or (5) when the colonoscopist judged that the patient was unable to comprehend and give true consent to the process of random allocation. This left 561 patients to be randomly assigned to the different groups. One thousand one hundred and five lesions were detected in 380 patients. Specimens were not obtained from 13 lesions, thus histological diagnosis was available for 1092 lesions. Eight hundred and seventy-five lesions were diagnosed as neoplasms and 217 as non-neoplastic. There were 383 (69%) patients in whom lesions were detected and 329 (59%) with

Fig. 6. Study design of a 2 × 2 factorial designed randomized controlled trial for investigation the impact of autofluorescence imaging and a transparent hood. (R; randomization.)

Fig. 7. Primary endpoint of the randomized controlled trial. Neoplastic lesion detection rate in the AFI + TH group was significantly higher than in the WLI group. (AFI; Autofluorescence

imaging, TH; transparent hood, WLI; white light imaging)

neoplasms.

Fig. 5. Images of colonic tumor using autofluorescence imaging (AFI). (A) Conventional endoscopic image of colon cancer in the transverse colon. The lesion is flat and similar in color to the surrounding mucosa. (B) AFI image of the lesion. The lesion shows as a distinct purple area surrounded by green mucosa. (C) Chromo-endoscopic image of the lesion. The features of the lesion are enhanced by indigo carmine

participants were assigned randomly to the following four groups: (1) WLI: colonoscopy using WLI without a TH; (2) WLI + TH: colonoscopy using WLI with a TH; (3) AFI: colonoscopy using AFI without a TH; and (4) AFI + TH: colonoscopy using AFI with a TH (Fig. 6). All patients gave written informed consent to participate in this study and the study protocol was approved by the Research Ethics Committee of our center.

Between 4 November, 2008, and 11 November, 2009, 923 patients who had a positive FOBT or who had been referred for surveillance colonoscopy were scheduled to undergo colonoscopy in our endoscopy unit. Three hundred and sixty-two patients were excluded from enrolment for the following reasons: (1) a history of colorectomy or major abdominal

Fig. 5. Images of colonic tumor using autofluorescence imaging (AFI). (A) Conventional endoscopic image of colon cancer in the transverse colon. The lesion is flat and similar in color to the surrounding mucosa. (B) AFI image of the lesion. The lesion shows as a distinct purple area surrounded by green mucosa. (C) Chromo-endoscopic image of the lesion. The

participants were assigned randomly to the following four groups: (1) WLI: colonoscopy using WLI without a TH; (2) WLI + TH: colonoscopy using WLI with a TH; (3) AFI: colonoscopy using AFI without a TH; and (4) AFI + TH: colonoscopy using AFI with a TH (Fig. 6). All patients gave written informed consent to participate in this study and the study

Between 4 November, 2008, and 11 November, 2009, 923 patients who had a positive FOBT or who had been referred for surveillance colonoscopy were scheduled to undergo colonoscopy in our endoscopy unit. Three hundred and sixty-two patients were excluded from enrolment for the following reasons: (1) a history of colorectomy or major abdominal

features of the lesion are enhanced by indigo carmine

protocol was approved by the Research Ethics Committee of our center.

surgery; (2) symptoms suspicious of colorectal stenosis or cancer; (3) inflammatory bowel disease, familial polyposis or known colorectal cancer; (4) severe organ failure, noncorrectable coagulopathy, or receiving anticoagulant therapy; or (5) when the colonoscopist judged that the patient was unable to comprehend and give true consent to the process of random allocation. This left 561 patients to be randomly assigned to the different groups. One thousand one hundred and five lesions were detected in 380 patients. Specimens were not obtained from 13 lesions, thus histological diagnosis was available for 1092 lesions. Eight hundred and seventy-five lesions were diagnosed as neoplasms and 217 as non-neoplastic. There were 383 (69%) patients in whom lesions were detected and 329 (59%) with neoplasms.

Fig. 6. Study design of a 2 × 2 factorial designed randomized controlled trial for investigation the impact of autofluorescence imaging and a transparent hood. (R; randomization.)

Fig. 7. Primary endpoint of the randomized controlled trial. Neoplastic lesion detection rate in the AFI + TH group was significantly higher than in the WLI group. (AFI; Autofluorescence imaging, TH; transparent hood, WLI; white light imaging)

Recent Advances in Diagnostic Endoscopy for Colorectal Neoplasm 219

Fig. 8. Small (8 mm) submucosally invasive, polypoid colon cancer. (A) Endoscopic image of a small polypoid (Paris classification, 0-Is) lesion in the sigmoid colon. (B) Microscopic image of endoscopically resected specimen (hematoxylin and eosin stain). The lesion has invaded the submucosal layer. (C) Microscopic image of endoscopically resected specimen (Desmin stain). The muscularis mucosa has been disrupted by the invading carcinoma

Magnifying endoscopy is one method for obtaining histopathological findings by endoscopy *in vivo*. It has been reported that the capillary patterns observed by using NBI with magnifying endoscopy (NBI-ME) can help in assessing the degree of dysplasia in early colorectal neoplasia (Katagiri et al., 2008). Therefore, the present authors believe that NBI-ME provides a more accurate strategy than the conventional 'DISCARD' policy in which NBI is used without ME. Here, a new policy for management of small polyps using NBI-ME;

The diagnostic criteria in the 'DISCARD-ME' policy are basically according to the capillary pattern (CP) classification (Fig. 9), which has been reported to be useful for assessing the degree of dysplasia in early colorectal neoplasia (Katagiri et al., 2008). Lesions with invisible

**4. 'DISCARD with magnifying endoscopy (DISCARD-ME)' policy** 

namely the 'DISCARD-ME' policy, is proposed.

**4.1 Diagnostic criteria for the 'DISCARD-ME' policy** 

The primary endpoint, neoplasm detection rate (number of detected neoplasms per patient [95% CI]) in the AFI + TH group was significantly higher than in the WLI alone group (1.96 [1.50–2.43] vs 1.19 [0.93–1.44], *P* = 0.023 [Tukey-Kramer multiple comparison method]). AFI with a TH detected more neoplasms than did conventional colonoscopy (Fig. 7). Subgroup analysis revealed that mounting a TH resulted in a higher detection rate for polypoid neoplasms than did not mounting a TH, and that AFI observation resulted in a higher detection rate for flat neoplasms than did WLI observation. It was concluded that a combination of the different complementary mechanisms of AFI and a TH would be efficacious in the detection of colorectal neoplasms.
