EDITORIAL
Confocal Laser Endomicroscopy for the Detection of Atrophic Gastritis A New Application for Confocal Endomicroscopy? Avlin Imaeda, MD, PhD*w
N
ew technologies in the world of endoscopy abound, but success and widespread use is not always assured. Technologies that fill an unmet need or improve upon current technology in widespread use are more likely to be successful. Confocal laser endomicroscopy (CLE) is a technology that allows the user to get microscopic views of the mucosa in real time during endoscopy. The technology can be used through a single endoscope-based system (CLE) (OptiScan, Notting Hill, Australia) or through a probe-based system known as probe-based confocal laser endomicroscopy (PCLE) (Cellvizio; Mauna Kea Technologies, Paris, France). These technologies differ somewhat in the depth of penetration, variable with the endoscopebased system, and fixed with the probe-based system, and the size of the field of view. Both rely on fluorescence. In tissues without autofluorescence, as is the case for most mucosal tissues, a dye must be administered either topically or intravenously (fluorescein). Confocal technology has been applied for several uses throughout the GI tract, typically to distinguish neoplastic from non-neoplastic tissue, but also to diagnose and stage inflammatory conditions. Some applications are relatively well established in terms of evidence and clinical use; some applications have supportive data but are rarely used clinically, and new applications that may fit unmet clinical needs are being studied. Perhaps the most promoted use of endoscopic confocal technology has been in Barrett’s esophagus surveillance. A randomized controlled trial showed a higher diagnostic yield for patients randomized to highdefinition white light endoscopy and CLE with targeted biopsies than for standard highdefinition white light endoscopy and random biopsies.1 Narrow band imaging (NBI) was not compared in this study. The detection of neoplasia was comparable; the CLE group simply required fewer biopsies for diagnosis. This study, as in many studies using this advanced technology, was performed by expert endoscopists limiting the generalizability of the results. In addition, surveillance of large areas of involved mucosa is limited by the ability to visualize only tiny areas at a time, such that screening a long segment would be unwieldy and still require operator selection of areas to evaluate. This is likely more time consuming than targeted biopsy using high-definition white light and NBI. PCLE has been used to evaluate biliary strictures and suspected cholangiocarcinomas. Because cholangiocarcinoma can be otherwise difficult to diagnose, this is an area ripe for effective technology.2 CLE and PCLE have been used to distinguish neoplastic from non-neoplastic polyps in the colon. Some studies show sensitivity and specificity >90%, suggesting that a strategy to diagnose and discard could be reasonable.3,4 However, 1 study showed only moderate interobserver agreement for distinguishing neoplastic from non-neoplastic lesions.5 The technology has been used to detect flat dysplasia and disease activity in patients with inflammatory bowel disease and to diagnose microscopic colitis and celiac disease.6–8 These uses of confocal technology are less commonly applied in clinical use. CLE has been reported to have some amount of success in diagnosing gastric neoplasia and early gastric cancer, but lesions along the incisura may be difficult to examine because of limited flexibility of the endoscope.9–11 More recently it was used to detect mucosal responses to food antigens in patients with irritable bowel syndrome and food intolerances.12,13 PCLE is being used to evaluate pancreatic cysts, and a probe through which a biopsy needle may be passed is being evaluated. These new uses of the technology may gain broader acceptance as they fill unmet clinical needs. In any case, endoscopic confocal technology has not yet gained widespread use. Cost, reimbursement, and required additional time are limiting. As noted above, PCLE and the endoscopic confocal have limited fields of
From the *Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven; and wVACT Health Care System, West Haven, CT. The author declares that there is nothing to disclose. Reprints: Avlin Imaeda, MD, PhD, Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, 310 Cedar St, New Haven, CT 06510 (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Clin Gastroenterol
Volume 49, Number 5, May/June 2015
www.jcge.com |
355
J Clin Gastroenterol
Editorial
view. In addition, they require significant operator expertise, both for manipulating the probe to obtain stable images and in interpreting those images in real time.14 In this issue of the journal, Liu et al15 demonstrate a new application of endoscopic confocal technology. The authors prospectively compared the ability of CLE, NBI, and chromoendoscopy (CE) to diagnose atrophic gastritis with and without intestinal metaplasia in 89 consecutive patients (2 advanced gastric cancer excluded). The patients were high-risk, symptomatic patients evaluated at a medical center in China. The authors used magnifying endoscopes (up to 80-fold) for NBI and CE. Biopsy and histologic diagnosis was the gold standard. CLE criteria for atrophy were previously published.16–18 The authors found that CLE had a higher sensitivity, specificity, and accuracy compared with NBI and CE, which were equivalent for diagnosis of atrophic gastritis. The sensitivity and specificity of CLE for nonmetaplastic atrophy were 86.8% and 91.9%, and the sensitivity and specificity for metaplastic atrophy were 91.9% and 96.9%. This compared with 83.8% sensitivity and 78.9% specificity of CE for atrophy. The study was performed by 2 experienced endoscopists. Both were blinded to prior history of atrophy, and the endoscopist performing CLE was blinded to the findings on CE and NBI. The interobserver and intraobserver agreements when images were later reviewed by both endoscopists were good at 0.938 and 0.895, respectively. The caveat of this is that the authors only biopsied sites that they observed with CE, NBI, and CLE. They observed 2 sites in every patient, 2 cm from the pylorus, in both the lesser and the greater curvature. In their discussion, they noted that sites with lesions were also examined. However, they were limited in their ability to observe sites in the lesser curvature at the incisura angularis because of scope flexibility with CLE, and this is a common site for atrophic gastritis. Therefore, their per-patient sensitivity for detecting atrophic gastritis may be less than the reported sensitivity in that they may not have detected all cases of atrophic gastritis due to reduced sampling. A strength of their study is that they compared CLE with NBI and CE. Further evaluation to determine a per-patient negative predictive value for CLE in atrophic gastritis could be useful. The clinical utility of using CLE to detect atrophic gastritis is unclear, and the authors do not discuss clinical applications. However, atrophic gastritis is a precursor to gastric cancer. Gastric cancer is a frequent cause of cancerrelated death worldwide, and several countries (Japan, Venezuela, and Chile) with high prevalence have gastric cancer–screening programs. The optimal screening method is unknown. A systematic review of screening methods commissioned by the Japanese government and published in 2008 recommended radiography in individuals over 40 based largely on a lack of high-quality evidence to support the benefit of other modalities, including endoscopy.19 In any case, frequent, even annual, screening endoscopy is performed in some populations in Japan. A cost-effectiveness study of endoscopy every 2 years in high-risk 50- to 70year-old Chinese men argued for the cost-effectiveness of endoscopy in high-risk populations ($28,836 per qualityadjusted life years saved).20 Ideally, low-risk members of the population could be excluded on initial screening so that endoscopic evaluation with careful mapping and biopsy at appropriate intervals could be focused on highrisk individuals. Endoscopy with CLE but no biopsy might be a potential technique for this. If CLE is demonstrated in
356 | www.jcge.com
Volume 49, Number 5, May/June 2015
further studies to easily identify metaplastic and nonmetaplastic atrophic gastritis and dysplasia better than CE and NBI, it may well find a place in routine use. Further studies would be needed to compare its clinical utility and costeffectiveness with other modalities that have been used for gastric cancer screening, such as Helicobacter pylori and/or serum pepsinogen testing; which may also be beneficial to exclude low-risk individuals who do not require frequent endoscopic surveillance. In any case, the authors of this study identify a potentially new application of endoscopic confocal technology worthy of further study. The technology may find broader application in countries with high gastric cancer prevalence if it is shown to be useful in screening. In this case, identification of patients with and without atrophic gastritis is likely simpler than identifying tiny islands of dysplastic Barrett’s, as missed tiny islands of atrophic gastritis are less likely of clinical importance than a missed tiny island of dysplasia. New applications of endoscopic confocal technology may lead to more widespread use.
REFERENCES 1. Canto MI, Anandasabapathy S, Brugge W, et al. Confocal endomicroscopy for Barrett’s esophagus or confocal endomicroscopy for Barrett’s esophagus (CEBE) trial group. Gastrointest Endosc. 2014;79:211–221. 2. Meining A, Chen YK, Pleskow D, et al. Direct visualization of indeterminate pancreaticobiliary strictures with probe-based confocal laser endomicroscopy: a multicenter experience. Gastrointest Endosc. 2011;74:961–968. 3. Hurlstone DP, Baraz W, Brown S, et al. In vivo real-time confocal laser scanning endomicroscopic colonoscopy for the detection and characterization of colorectal neoplasia. Br J Surg. 2008;95:636–645. 4. Buchner AM, Shahid MW, Heckman MG, et al. Comparison of probe-based confocal laser endomicroscopy with virtual chromoendoscopy for classification of colon polyps. Gastroenterology. 2010;138:834–842. 5. Kuiper T, van den Broek FJ, van Eeden S, et al. New classification for probe-based confocal laser endomicroscopy in the colon. Endoscopy. 2011;43:1076–1081. 6. Tontinu GE, Vecchi M, Naurath MF, et al. Advanced endoscopic imaging techniques in Crohn’s disease. J Crohns Colitis. 2014;8:261–269. 7. Kiesslich R, Duckworth CA, Moussata D, et al. Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel disease. Gut. 2012;61:1146–1153. 8. Gunther U, Daum S, Heller F, et al. Diagnostic value of confocal endomicroscopy in celiac disease. Endoscopy. 2010;42:197–202. 9. Kitabatake S, Niwa Y, Miyahara R, et al. Confocal endomicroscopy for the diagnosis of gastric cancer in vivo. Endoscopy. 2006;38:1110–1114. 10. Zhang JN, Li YQ, Zhao YA, et al. Classification of gastric pit patterns by confocal endomicroscopy. Gastrointest Endosc. 2008;67:843–853. 11. Li WB, Zuo XL, Li CQ, et al. Diagnostic value of confocal laser endomicoscopy for gastric superficial cancerous lesions. Gut. 2011;60:299–306. 12. Fritscher-Ravens A, Schuppan D, Ellrichmann M, et al. Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology. 2014;147:1012–1020. 13. Turcotte JF, Kao D, Mah SJ, et al. Breaks in the wall: increased gaps in the intestinal epithelium of irritable bowel syndrome patients identified by confocal laser endomicroscopy. Gastrointest Endosc. 2013;77:624–630.
Copyright
r
2015 Wolters Kluwer Health, Inc. All rights reserved.
J Clin Gastroenterol
Volume 49, Number 5, May/June 2015
14. Lim LG, Yeoh KG, Salto-Tellez M, et al. Experienced versus inexperienced confocal endoscopists in the diagnosis of gastric adenocarcinoma and intestinal metaplasia on confocal images. Gastrointest Endosc. 2011;73:1141–1147. 15. Liu T, Zhen H, Gong W, et al. The accuracy of confocal laser endomicroscopy, narrow band imaging and chromoendoscopy for the detection of atrophic gastritis. J Clin Gastroenterol. 2015;49:379–386. 16. Sakaki N, Iida Y, Okazaki Y, et al. Magnifying endoscopic observation of the gastric mucosa, particularly in patients with atrophic gastritis. Endoscopy. 1978;10:269–274.
Copyright
r
Editorial
17. Tanaka K, Toyoda H, Kadowaki S, et al. Features of early gastric cancer and gastric adenoma by enhanced-magnification endoscopy. J Gastroenterol. 2006;41:332–338. 18. Tanaka K, Toyoda H, Kadowaki S, et al. Surface pattern classification by enhanced-magnification endoscopy for identifying early gastric cancers. Gastrointest Endosc. 2008;67:430–437. 19. Jamashima C, Shibuya D, Yamazaki H, et al. The Japanese guidelines for gastric cancer screening. Jpn J Clin Oncol. 2008;38:259–267. 20. Dan YY, So JB, Yeoh KG. Endoscopic screening for gastric cancer. Clin Gastroenterol Hepatol. 2006;4:709–716.
2015 Wolters Kluwer Health, Inc. All rights reserved.
www.jcge.com |
357
Confocal Laser Endomicroscopy for the Detection of Atrophic Gastritis A New Application for Confocal Endomicroscopy? Avlin Imaeda, MD, PhD*w
N
ew technologies in the world of endoscopy abound, but success and widespread use is not always assured. Technologies that fill an unmet need or improve upon current technology in widespread use are more likely to be successful. Confocal laser endomicroscopy (CLE) is a technology that allows the user to get microscopic views of the mucosa in real time during endoscopy. The technology can be used through a single endoscope-based system (CLE) (OptiScan, Notting Hill, Australia) or through a probe-based system known as probe-based confocal laser endomicroscopy (PCLE) (Cellvizio; Mauna Kea Technologies, Paris, France). These technologies differ somewhat in the depth of penetration, variable with the endoscopebased system, and fixed with the probe-based system, and the size of the field of view. Both rely on fluorescence. In tissues without autofluorescence, as is the case for most mucosal tissues, a dye must be administered either topically or intravenously (fluorescein). Confocal technology has been applied for several uses throughout the GI tract, typically to distinguish neoplastic from non-neoplastic tissue, but also to diagnose and stage inflammatory conditions. Some applications are relatively well established in terms of evidence and clinical use; some applications have supportive data but are rarely used clinically, and new applications that may fit unmet clinical needs are being studied. Perhaps the most promoted use of endoscopic confocal technology has been in Barrett’s esophagus surveillance. A randomized controlled trial showed a higher diagnostic yield for patients randomized to highdefinition white light endoscopy and CLE with targeted biopsies than for standard highdefinition white light endoscopy and random biopsies.1 Narrow band imaging (NBI) was not compared in this study. The detection of neoplasia was comparable; the CLE group simply required fewer biopsies for diagnosis. This study, as in many studies using this advanced technology, was performed by expert endoscopists limiting the generalizability of the results. In addition, surveillance of large areas of involved mucosa is limited by the ability to visualize only tiny areas at a time, such that screening a long segment would be unwieldy and still require operator selection of areas to evaluate. This is likely more time consuming than targeted biopsy using high-definition white light and NBI. PCLE has been used to evaluate biliary strictures and suspected cholangiocarcinomas. Because cholangiocarcinoma can be otherwise difficult to diagnose, this is an area ripe for effective technology.2 CLE and PCLE have been used to distinguish neoplastic from non-neoplastic polyps in the colon. Some studies show sensitivity and specificity >90%, suggesting that a strategy to diagnose and discard could be reasonable.3,4 However, 1 study showed only moderate interobserver agreement for distinguishing neoplastic from non-neoplastic lesions.5 The technology has been used to detect flat dysplasia and disease activity in patients with inflammatory bowel disease and to diagnose microscopic colitis and celiac disease.6–8 These uses of confocal technology are less commonly applied in clinical use. CLE has been reported to have some amount of success in diagnosing gastric neoplasia and early gastric cancer, but lesions along the incisura may be difficult to examine because of limited flexibility of the endoscope.9–11 More recently it was used to detect mucosal responses to food antigens in patients with irritable bowel syndrome and food intolerances.12,13 PCLE is being used to evaluate pancreatic cysts, and a probe through which a biopsy needle may be passed is being evaluated. These new uses of the technology may gain broader acceptance as they fill unmet clinical needs. In any case, endoscopic confocal technology has not yet gained widespread use. Cost, reimbursement, and required additional time are limiting. As noted above, PCLE and the endoscopic confocal have limited fields of
From the *Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven; and wVACT Health Care System, West Haven, CT. The author declares that there is nothing to disclose. Reprints: Avlin Imaeda, MD, PhD, Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, 310 Cedar St, New Haven, CT 06510 (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Clin Gastroenterol
Volume 49, Number 5, May/June 2015
www.jcge.com |
355
J Clin Gastroenterol
Editorial
view. In addition, they require significant operator expertise, both for manipulating the probe to obtain stable images and in interpreting those images in real time.14 In this issue of the journal, Liu et al15 demonstrate a new application of endoscopic confocal technology. The authors prospectively compared the ability of CLE, NBI, and chromoendoscopy (CE) to diagnose atrophic gastritis with and without intestinal metaplasia in 89 consecutive patients (2 advanced gastric cancer excluded). The patients were high-risk, symptomatic patients evaluated at a medical center in China. The authors used magnifying endoscopes (up to 80-fold) for NBI and CE. Biopsy and histologic diagnosis was the gold standard. CLE criteria for atrophy were previously published.16–18 The authors found that CLE had a higher sensitivity, specificity, and accuracy compared with NBI and CE, which were equivalent for diagnosis of atrophic gastritis. The sensitivity and specificity of CLE for nonmetaplastic atrophy were 86.8% and 91.9%, and the sensitivity and specificity for metaplastic atrophy were 91.9% and 96.9%. This compared with 83.8% sensitivity and 78.9% specificity of CE for atrophy. The study was performed by 2 experienced endoscopists. Both were blinded to prior history of atrophy, and the endoscopist performing CLE was blinded to the findings on CE and NBI. The interobserver and intraobserver agreements when images were later reviewed by both endoscopists were good at 0.938 and 0.895, respectively. The caveat of this is that the authors only biopsied sites that they observed with CE, NBI, and CLE. They observed 2 sites in every patient, 2 cm from the pylorus, in both the lesser and the greater curvature. In their discussion, they noted that sites with lesions were also examined. However, they were limited in their ability to observe sites in the lesser curvature at the incisura angularis because of scope flexibility with CLE, and this is a common site for atrophic gastritis. Therefore, their per-patient sensitivity for detecting atrophic gastritis may be less than the reported sensitivity in that they may not have detected all cases of atrophic gastritis due to reduced sampling. A strength of their study is that they compared CLE with NBI and CE. Further evaluation to determine a per-patient negative predictive value for CLE in atrophic gastritis could be useful. The clinical utility of using CLE to detect atrophic gastritis is unclear, and the authors do not discuss clinical applications. However, atrophic gastritis is a precursor to gastric cancer. Gastric cancer is a frequent cause of cancerrelated death worldwide, and several countries (Japan, Venezuela, and Chile) with high prevalence have gastric cancer–screening programs. The optimal screening method is unknown. A systematic review of screening methods commissioned by the Japanese government and published in 2008 recommended radiography in individuals over 40 based largely on a lack of high-quality evidence to support the benefit of other modalities, including endoscopy.19 In any case, frequent, even annual, screening endoscopy is performed in some populations in Japan. A cost-effectiveness study of endoscopy every 2 years in high-risk 50- to 70year-old Chinese men argued for the cost-effectiveness of endoscopy in high-risk populations ($28,836 per qualityadjusted life years saved).20 Ideally, low-risk members of the population could be excluded on initial screening so that endoscopic evaluation with careful mapping and biopsy at appropriate intervals could be focused on highrisk individuals. Endoscopy with CLE but no biopsy might be a potential technique for this. If CLE is demonstrated in
356 | www.jcge.com
Volume 49, Number 5, May/June 2015
further studies to easily identify metaplastic and nonmetaplastic atrophic gastritis and dysplasia better than CE and NBI, it may well find a place in routine use. Further studies would be needed to compare its clinical utility and costeffectiveness with other modalities that have been used for gastric cancer screening, such as Helicobacter pylori and/or serum pepsinogen testing; which may also be beneficial to exclude low-risk individuals who do not require frequent endoscopic surveillance. In any case, the authors of this study identify a potentially new application of endoscopic confocal technology worthy of further study. The technology may find broader application in countries with high gastric cancer prevalence if it is shown to be useful in screening. In this case, identification of patients with and without atrophic gastritis is likely simpler than identifying tiny islands of dysplastic Barrett’s, as missed tiny islands of atrophic gastritis are less likely of clinical importance than a missed tiny island of dysplasia. New applications of endoscopic confocal technology may lead to more widespread use.
REFERENCES 1. Canto MI, Anandasabapathy S, Brugge W, et al. Confocal endomicroscopy for Barrett’s esophagus or confocal endomicroscopy for Barrett’s esophagus (CEBE) trial group. Gastrointest Endosc. 2014;79:211–221. 2. Meining A, Chen YK, Pleskow D, et al. Direct visualization of indeterminate pancreaticobiliary strictures with probe-based confocal laser endomicroscopy: a multicenter experience. Gastrointest Endosc. 2011;74:961–968. 3. Hurlstone DP, Baraz W, Brown S, et al. In vivo real-time confocal laser scanning endomicroscopic colonoscopy for the detection and characterization of colorectal neoplasia. Br J Surg. 2008;95:636–645. 4. Buchner AM, Shahid MW, Heckman MG, et al. Comparison of probe-based confocal laser endomicroscopy with virtual chromoendoscopy for classification of colon polyps. Gastroenterology. 2010;138:834–842. 5. Kuiper T, van den Broek FJ, van Eeden S, et al. New classification for probe-based confocal laser endomicroscopy in the colon. Endoscopy. 2011;43:1076–1081. 6. Tontinu GE, Vecchi M, Naurath MF, et al. Advanced endoscopic imaging techniques in Crohn’s disease. J Crohns Colitis. 2014;8:261–269. 7. Kiesslich R, Duckworth CA, Moussata D, et al. Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel disease. Gut. 2012;61:1146–1153. 8. Gunther U, Daum S, Heller F, et al. Diagnostic value of confocal endomicroscopy in celiac disease. Endoscopy. 2010;42:197–202. 9. Kitabatake S, Niwa Y, Miyahara R, et al. Confocal endomicroscopy for the diagnosis of gastric cancer in vivo. Endoscopy. 2006;38:1110–1114. 10. Zhang JN, Li YQ, Zhao YA, et al. Classification of gastric pit patterns by confocal endomicroscopy. Gastrointest Endosc. 2008;67:843–853. 11. Li WB, Zuo XL, Li CQ, et al. Diagnostic value of confocal laser endomicoscopy for gastric superficial cancerous lesions. Gut. 2011;60:299–306. 12. Fritscher-Ravens A, Schuppan D, Ellrichmann M, et al. Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology. 2014;147:1012–1020. 13. Turcotte JF, Kao D, Mah SJ, et al. Breaks in the wall: increased gaps in the intestinal epithelium of irritable bowel syndrome patients identified by confocal laser endomicroscopy. Gastrointest Endosc. 2013;77:624–630.
Copyright
r
2015 Wolters Kluwer Health, Inc. All rights reserved.
J Clin Gastroenterol
Volume 49, Number 5, May/June 2015
14. Lim LG, Yeoh KG, Salto-Tellez M, et al. Experienced versus inexperienced confocal endoscopists in the diagnosis of gastric adenocarcinoma and intestinal metaplasia on confocal images. Gastrointest Endosc. 2011;73:1141–1147. 15. Liu T, Zhen H, Gong W, et al. The accuracy of confocal laser endomicroscopy, narrow band imaging and chromoendoscopy for the detection of atrophic gastritis. J Clin Gastroenterol. 2015;49:379–386. 16. Sakaki N, Iida Y, Okazaki Y, et al. Magnifying endoscopic observation of the gastric mucosa, particularly in patients with atrophic gastritis. Endoscopy. 1978;10:269–274.
Copyright
r
Editorial
17. Tanaka K, Toyoda H, Kadowaki S, et al. Features of early gastric cancer and gastric adenoma by enhanced-magnification endoscopy. J Gastroenterol. 2006;41:332–338. 18. Tanaka K, Toyoda H, Kadowaki S, et al. Surface pattern classification by enhanced-magnification endoscopy for identifying early gastric cancers. Gastrointest Endosc. 2008;67:430–437. 19. Jamashima C, Shibuya D, Yamazaki H, et al. The Japanese guidelines for gastric cancer screening. Jpn J Clin Oncol. 2008;38:259–267. 20. Dan YY, So JB, Yeoh KG. Endoscopic screening for gastric cancer. Clin Gastroenterol Hepatol. 2006;4:709–716.
2015 Wolters Kluwer Health, Inc. All rights reserved.
www.jcge.com |
357
