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Narrow-band imaging in the prediction of submucosal invasive colon cancer: how “NICE” is it?
EDITORIAL
Narrow-band imaging in the prediction of submucosal invasive colon cancer: how “NICE” is it? Colorectal cancer continues to be one of the leading causes of cancer deaths in the Western world.1 Colonoscopy and polypectomy are central to the detection and prevention of colorectal cancer. Because the majority of the polyps detected during colonoscopies are diminutive (%5 mm) and rarely harbor advanced histology, there has been a recent interest in real-time in vivo characterization of polyp histology. Of all the novel imaging technologies for characterizing polyp histology, narrow-band imaging (NBI) has been studied the most extensively and is easy to use and practical. NBI accentuates the mucosal surface and vascular pattern by using predominantly blue light wavelength for illumination. The ultimate goal of real-time prediction of histology of diminutive colon polyps would be to implement the “diagnose, resect, and discard” strategy for diminutive polyps and the “do not resect” strategy for diminutive hyperplastic polyps in the rectosigmoid.2 The overarching goal of these endeavors is to improve the efficiency and cost-effectiveness of colonoscopy. In this issue of Gastrointestinal Endoscopy, Hayashi and colleagues3 have attempted to add another dimension to the use of NBI during colonoscopydthe prediction of deep submucosal colorectal carcinoma.
Given the overall low risk of lymph node metastasis and cancer dissemination and recurrence in T1 disease, risk stratification to identify patients at relatively higher risk of unfavorable outcomes after endoscopic removal is reasonable. T1 colorectal cancers are classified as lesions at low risk of lymph node metastasis if the following criteria are fulfilled9-18: complete endoscopic resection with negative lateral and deep margins, well-differentiated or moderately differentiated adenocarcinoma, the absence of lymphatic or vascular invasion, depth of submucosal invasion less than 1000 mm, and the absence of tumor budding.
The overall accuracy of predicting submucosal invasion and proportion of predictions made with high confidence, especially among experts, was less than ideal.
Copyright ª 2013 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2013.06.015
Although prospective long-term data on outcomes after endoscopic resection of submucosal invasive colorectal cancers are relatively sparse, it has been suggested that patients with these low-risk features can be managed with endoscopic resection alone, whereas patients with high-risk features (poorly differentiated adenocarcinoma, lymphovascular invasion, depth of submucosal invasion R1000 mm) should undergo additional curative surgical resection. In a retrospective study, Meining et al12 reported unfavorable outcomes (local recurrence, metastasis, or death from colorectal cancer) in 390 patients with T1 colorectal cancers treated with endoscopic resection. Significant predictors of unfavorable outcomes included lymphatic vessel infiltration (odds ratio [OR] 7.8), poor tumor grade (OR 3.3), and positive resection margins (OR 2.6). In a recent study, Ikematsu et al10 reported long-term outcomes for patients with T1 colorectal cancers from 6 centers in Japan. Patients were categorized as low risk when complete resection of the lesion was achieved, and there was the presence of well- or moderately differentiated adenocarcinoma, absence of vascular invasion, and depth of submucosal invasion less than 1000 mm, whereas others were categorized as high risk. In patients with low-risk lesions undergoing endoscopic resection, recurrence rates in submucosal colon and rectal cancer (median follow-up
www.giejournal.org
Volume 78, No. 4 : 2013 GASTROINTESTINAL ENDOSCOPY 633
SUBMUCOSAL INVASIVE COLORECTAL CANCER: DEFINITION, RISK STRATIFICATION, AND MANAGEMENT Determining the true depth of invasion of colorectal cancer is imperative in establishing an optimal treatment plan. Tis stage is defined by intraepithelial cancer or invasion into the lamina propria, whereas T1 stage is defined by infiltration of the tumor into the submucosa. Patients with Tis disease (high-grade dysplasia and intramucosal colorectal cancer) have no risk of lymphovascular spread and are deemed suitable candidates for curative endoscopic removal (EMR or endoscopic submucosal dissection).4-7 On the other hand, patients with T1 colorectal cancers have a risk of lymph node metastasis (w10%-12%). Given this risk, albeit low, referring these patients for surgical resection and removal of regional lymph nodes has been considered the standard of care.8-10
Editorial
54.4 months) were 0% (0/104) and 6.3% (1/16), respectively (P ! .05). There were no significant differences noted in disease-free (95.9% vs 90%) and overall (95.9% vs 88.9%) survival between patients with low-risk submucosal cancer in the colon and rectum. In the group of patients with high-risk lesions undergoing endoscopic resection alone, recurrence rates of submucosal colon and rectal cancer (median follow-up 56.1 months) were 1.4% (1/69) and 16.2% (6/37), respectively. Disease-free survival was better in patients with submucosal colon cancer compared with those with rectal cancer (96.5% vs 77.7%, P ! .01) with no differences in overall survival period (98.3% vs 96.2%). In the group of patients with high-risk lesions undergoing endoscopic resection followed by surgical resection or only surgical resection, recurrence rates of submucosal colon and rectal cancer (median follow-up 62.5 months) were 1.9% (7/376) and 4.5% (7/156), respectively. There were no significant differences noted in the disease-free (97.3% vs 95%) and overall (99.1% vs 97.3%) survival between patients with submucosal colon and rectal cancer. Tumor location (colon vs rectum) was the only significant predictor of disease recurrence and death (hazard ratio 6.73, 95% confidence interval [CI], 1.04-43.4; P Z .04). These results provide evidence to support complete endoscopic resection alone in patients with low-risk T1 colon cancers and the recommendations for additional curative surgery in patients with T1 rectal cancer. Moreover, these data also provide important estimates that can be used during discussion with the patient regarding treatment options, which, in our opinion, constitutes an integral part of the management of submucosal invasive colorectal cancer.
Wani & Rastogi
system have improved the ability to predict submucosal invasion.23 In a large prospective, multicenter study of 479 patients with sessile colorectal polyps referred for EMR, Moss et al19 showed that risk factors for submucosal cancer were Paris 0-IIaþc morphology, nongranular surface, or the presence of Kudo pit pattern V.
Role of NBI to assess depth of invasion
Several techniques have been evaluated for the assessment of submucosal invasion and thereby the resectability of early colorectal cancer. A nonlifting sign after injection of fluid is important to identify lesions with deeper invasion. However, the presence of a nonlifting sign is not definitive for submucosal invasive cancer because it may be a result of submucosal fibrosis from previous electrocautery injury from an earlier attempt at endoscopic resection. The likelihood of a nonlifting sign increases by sixfold with previous electrocautery injury.19 A prospective, multicenter study showed that the nonlifting sign had low sensitivity (61%), a moderate positive predictive value (80%), and a high negative predictive value (96%) for submucosal invasion.20 EUS by using high-frequency probes has been evaluated and may help to differentiate T1 colorectal cancers from more advanced lesions.21,22 However, this practice is not universal and depends on local expertise and availability. The use of standardized classifications for describing these lesions such as the Paris classification, granularity (nongranular vs granular), and pit patterns by using the Kudo classification
Previous classification systems have been proposed to help predict deep submucosal colorectal cancers by using NBI with optical magnification (Sano,24 Hiroshima,25 and Showa26 classification systems). However, these classification systems have not been put through the rigors of validation nor are they practiced clinically because they require magnification colonoscopy that is not routinely available in clinical practice, at least in the Western countries. In this issue of the Gastrointestinal Endoscopy, Hayashi et al3 have extended the NBI International Colorectal Endoscopic (NICE) classification that differentiates hyperplastic (type 1) from adenomatous polyps (type 2)27 to include deep submucosal invasive carcinoma (type 3) and should be commended for their efforts. The study involved the use of still NBI (without magnification) of 22 tubular adenomas, 23 adenomatous lesions with highgrade dysplasia or superficially invasive submucosal carcinoma (!1000 mm) (type 2) and 35 deeply invasive submucosal carcinoma (R1000 mm) (type 3). The validation steps described were similar to those reported in the earlier study describing the NICE classification.27 Phase 1 involved evaluation of accuracy and reliability of histological prediction of deep submucosal invasion by 5 expert colonoscopists. The overall accuracy was 75.6% (95% CI, 71%-80%) and accuracy in high confidence diagnosis was 84.1% (95% CI, 79%-88%). The overall proportion of high confidence diagnosis was 70% but ranged from 53% to 85% among these experts. The weighted multirater k coefficient for predicting deep submucosal invasion was 0.66 among experts (k Z 0.97 for high confidence diagnosis). Phase 2 involved the use of a modified Delphi process for expansion of the NICE classification and development of component criteria. Phase 3 involved validation of individual criteria among novice raters (5 medical students). Presence of any 1 of the 3 deep submucosal invasive carcinoma (color, vessels, or surface pattern) had the best diagnostic characteristics (94% accuracy, 96% negative predictive value) compared with any of the criteria alone or in combination. Finally, phase 4 involved assessments of performance characteristics and reliability among the same medical students after a training session. Significant improvement in accuracies was reported for individual criteria (color, vessels, and surface pattern) and overall accuracy. For a diagnosis made with high confidence (50%), the accuracy was 90% with a negative predictive value of 92%. Although we applaud the efforts of the authors, there are, however, several limitations of this study that need
634 GASTROINTESTINAL ENDOSCOPY Volume 78, No. 4 : 2013
www.giejournal.org
ENDOSCOPIC PREDICTION OF SUBMUCOSAL CANCER
Wani & Rastogi
Editorial
to be highlighted. As the authors acknowledge, it would have been ideal to use high-definition videos as opposed to still images. The methodology used to select the images was not provided, and the possibility of selection bias cannot be excluded. This is important because recent studies have shown that the accuracy demonstrated during training and ex vivo evaluation of still images does not translate into similar optimal results during real-time colonoscopy.28-30 In the group of images in patients with high-grade dysplasia and superficially invasive submucosal carcinoma, the number of images with the latter is unclear. This is crucial information before NBI patterns can be used reliably to assess depth of invasion. Is it possible that the classification system would have better performance in differentiating lesions with and without submucosal cancer (superficial and deep)? Although this makes intuitive sense, it needs to be explored further. Furthermore, the overall accuracy of predicting submucosal invasion and proportion of predictions made with high confidence, especially among experts, was less than ideal. This raises the question of whether refinement of criteria is required by using a larger database of images/videos. What are acceptable benchmarks for accurate diagnosis when using this classification system? The stakes are high when, as endoscopists, we are dealing with advanced lesions and assume the role of pathologists, and in that context, are accuracy and negative predictive values of 75% (84% with high confidence diagnosis) and 85% (87% with high confidence diagnosis) clinically acceptable?
WHERE DO WE GO FROM HERE? A simplistic approach for validation of new imaging technologies and classification systems for real-time histology prediction is highlighted in Figure 1. With the availability of newer commercially available colonoscopes with magnification capability (Exera III System, Olympus America, Center Valley, Pa), the ability of NBI to predict submucosal invasion as well as its depth may improve further and should be assessed in future trials. Similar to the benchmarks set by the American Society for Gastrointestinal Endoscopy that need to be achieved for real-time endoscopic assessment of histology of diminutive colorectal polyps,2 acceptable thresholds for real-time endoscopic assessment of submucosal invasive cancer in colorectal polyps will need to be defined. Finally, prospective multicenter studies are required to validate the classification system among other experts, nonexperts in the community and academic centers as well as trainees and most importantly assess the performance during real-time colonoscopy. Until this classification system is ready for prime time, the practical approach to these lesions should entail standardized assessment (size, location, Paris classification, granularity, pit pattern) with potential referral to an expert center if required. If endoscopic resection is www.giejournal.org
Figure 1. Simplistic approach to validation of classification systems for real-time histology prediction.
deemed feasible (based on submucosal injection, size) and necessary expertise is available, then one can proceed with endoscopic resection and let our pathologists determine the depth of invasion, which should then dictate future care after deliberation with the patient.
DISCLOSURE The following author disclosed a financial relationship relevant to this publication: Dr. Rastogi received a research grant from Olympus America Inc. The other author disclosed no financial relationship relevant to this publication. Volume 78, No. 4 : 2013 GASTROINTESTINAL ENDOSCOPY 635
Editorial
Wani & Rastogi
Sachin Wani, MD Division of Gastroenterology and Hepatology University of Colorado Anschutz Medical Center Aurora, Colorado, USA Division of Gastroenterology and Hepatology Department of Veterans Affairs Eastern Colorado Health Care System Denver, Colorado, USA Amit Rastogi, MD Division of Gastroenterology Veterans Affairs Medical Center Kansas City, Missouri Division of Gastroenterology and Hepatology University of Kansas Medical Center Kansas City, Kansas, USA Abbreviations: CI, confidence interval; NBI, narrow-band imaging; NICE, NBI International Colorectal Endoscopic classification.
REFERENCES 1. Edwards BK, Ward E, Kohler BA, et al. Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer 2010;116:544-73. 2. Rex DK, Kahi C, O'Brien M, et al. The American Society for Gastrointestinal Endoscopy PIVI (Preservation and Incorporation of Valuable Endoscopic Innovations) on real-time endoscopic assessment of the histology of diminutive colorectal polyps. Gastrointest Endosc 2011;73:419-22. 3. Hayashi N, Tanaka S, Hewett DG, et al. Endoscopic prediction of deep submucosal invasive carcinoma: validation of the Narrow-Band Imaging International Colorectal Endoscopic (NICE) classification. Gastrointest Endosc 2013;78:625-32. 4. Fujimori T, Kawamata H, Kashida H. Precancerous lesions of the colorectum. J Gastroenterol 2001;36:587-94. 5. Ueno H, Mochizuki H, Hashiguchi Y, et al. Risk factors for an adverse outcome in early invasive colorectal carcinoma. Gastroenterology 2004;127:385-94. 6. Okabe S, Shia J, Nash G, et al. Lymph node metastasis in T1 adenocarcinoma of the colon and rectum. J Gastrointest Surg 2004;8:1032-9; discussion 1039-40. 7. Cooper HS, Deppisch LM, Gourley WK, et al. Endoscopically removed malignant colorectal polyps: clinicopathologic correlations. Gastroenterology 1995;108:1657-65. 8. Kitajima K, Fujimori T, Fujii S, et al. Correlations between lymph node metastasis and depth of submucosal invasion in submucosal invasive colorectal carcinoma: a Japanese collaborative study. J Gastroenterol 2004;39:534-43. 9. Nascimbeni R, Burgart LJ, Nivatvongs S, et al. Risk of lymph node metastasis in T1 carcinoma of the colon and rectum. Dis Colon Rectum 2002;45:200-6. 10. Ikematsu H, Yoda Y, Matsuda T, et al. Long-term outcomes after resection for submucosal invasive colorectal cancers. Gastroenterology 2013;144:551-9; quiz e14. 11. Watanabe T, Itabashi M, Shimada Y, et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer. Int J Clin Oncol 2012;17:1-29.
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12. Meining A, von Delius S, Eames TM, et al. Risk factors for unfavorable outcomes after endoscopic removal of submucosal invasive colorectal tumors. Clin Gastroenterol Hepatol 2011;9:590-4. 13. Fujimori T, Fujii S, Saito N, et al. Pathological diagnosis of early colorectal carcinoma and its clinical implications. Digestion 2009;79(Suppl 1):40-51. 14. Shimomura T, Ishiguro S, Konishi H, et al. New indication for endoscopic treatment of colorectal carcinoma with submucosal invasion. J Gastroenterol Hepatol 2004;19:48-55. 15. Tateishi Y, Nakanishi Y, Taniguchi H, et al. Pathological prognostic factors predicting lymph node metastasis in submucosal invasive (T1) colorectal carcinoma. Mod Pathol 2010;23:1068-72. 16. Tominaga K, Nakanishi Y, Nimura S, et al. Predictive histopathologic factors for lymph node metastasis in patients with nonpedunculated submucosal invasive colorectal carcinoma. Dis Colon Rectum 2005;48:92-100. 17. Kazama S, Watanabe T, Ajioka Y, et al. Tumour budding at the deepest invasive margin correlates with lymph node metastasis in submucosal colorectal cancer detected by anticytokeratin antibody CAM5.2. Br J Cancer 2006;94:293-8. 18. Ogawa T, Yoshida T, Tsuruta T, et al. Tumor budding is predictive of lymphatic involvement and lymph node metastases in submucosal invasive colorectal adenocarcinomas and in non-polypoid compared with polypoid growths. Scand J Gastroenterol 2009;44:605-14. 19. Moss A, Bourke MJ, Williams SJ, et al. Endoscopic mucosal resection outcomes and prediction of submucosal cancer from advanced colonic mucosal neoplasia. Gastroenterology 2011;140:1909-18. 20. Kobayashi N, Saito Y, Sano Y, et al. Determining the treatment strategy for colorectal neoplastic lesions: endoscopic assessment or the nonlifting sign for diagnosing invasion depth? Endoscopy 2007;39: 701-5. 21. Waxman I, Saitoh Y. Clinical outcome of endoscopic mucosal resection for superficial GI lesions and the role of high-frequency US probe sonography in an American population. Gastrointest Endosc 2000;52: 322-7. 22. Hurlstone DP, Brown S, Cross SS, et al. Endoscopic ultrasound miniprobe staging of colorectal cancer: can management be modified? Endoscopy 2005;37:710-4. 23. Kudo S, Hirota S, Nakajima T, et al. Colorectal tumours and pit pattern. J Clin Pathol 1994;47:880-5. 24. Ikematsu H, Matsuda T, Emura F, et al. Efficacy of capillary pattern type IIIA/IIIB by magnifying narrow band imaging for estimating depth of invasion of early colorectal neoplasms. BMC Gastroenterol 2010;10:33. 25. Kanao H, Tanaka S, Oka S, et al. Narrow-band imaging magnification predicts the histology and invasion depth of colorectal tumors. Gastrointest Endosc 2009;69:631-6. 26. Wada Y, Kudo SE, Kashida H, et al. Diagnosis of colorectal lesions with the magnifying narrow-band imaging system. Gastrointest Endosc 2009;70:522-31. 27. Hewett DG, Kaltenbach T, Sano Y, et al. Validation of a simple classification system for endoscopic diagnosis of small colorectal polyps using narrow-band imaging. Gastroenterology 2012;143: 599-607.e1. 28. Ladabaum U, Fioritto A, Mitani A, et al. Real-time optical biopsy of colon polyps with narrow band imaging in community practice does not yet meet key thresholds for clinical decisions. Gastroenterology 2013;144:81-91. 29. Kuiper T, Marsman WA, Jansen JM, et al. Accuracy for optical diagnosis of small colorectal polyps in nonacademic settings. Clin Gastroenterol Hepatol 2012;10:1016-20; quiz e79. 30. Paggi S, Rondonotti E, Amato A, et al. Resect and discard strategy in clinical practice: a prospective cohort study. Endoscopy 2012;44: 899-904.
www.giejournal.org
Narrow-band imaging in the prediction of submucosal invasive colon cancer: how “NICE” is it? Colorectal cancer continues to be one of the leading causes of cancer deaths in the Western world.1 Colonoscopy and polypectomy are central to the detection and prevention of colorectal cancer. Because the majority of the polyps detected during colonoscopies are diminutive (%5 mm) and rarely harbor advanced histology, there has been a recent interest in real-time in vivo characterization of polyp histology. Of all the novel imaging technologies for characterizing polyp histology, narrow-band imaging (NBI) has been studied the most extensively and is easy to use and practical. NBI accentuates the mucosal surface and vascular pattern by using predominantly blue light wavelength for illumination. The ultimate goal of real-time prediction of histology of diminutive colon polyps would be to implement the “diagnose, resect, and discard” strategy for diminutive polyps and the “do not resect” strategy for diminutive hyperplastic polyps in the rectosigmoid.2 The overarching goal of these endeavors is to improve the efficiency and cost-effectiveness of colonoscopy. In this issue of Gastrointestinal Endoscopy, Hayashi and colleagues3 have attempted to add another dimension to the use of NBI during colonoscopydthe prediction of deep submucosal colorectal carcinoma.
Given the overall low risk of lymph node metastasis and cancer dissemination and recurrence in T1 disease, risk stratification to identify patients at relatively higher risk of unfavorable outcomes after endoscopic removal is reasonable. T1 colorectal cancers are classified as lesions at low risk of lymph node metastasis if the following criteria are fulfilled9-18: complete endoscopic resection with negative lateral and deep margins, well-differentiated or moderately differentiated adenocarcinoma, the absence of lymphatic or vascular invasion, depth of submucosal invasion less than 1000 mm, and the absence of tumor budding.
The overall accuracy of predicting submucosal invasion and proportion of predictions made with high confidence, especially among experts, was less than ideal.
Copyright ª 2013 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2013.06.015
Although prospective long-term data on outcomes after endoscopic resection of submucosal invasive colorectal cancers are relatively sparse, it has been suggested that patients with these low-risk features can be managed with endoscopic resection alone, whereas patients with high-risk features (poorly differentiated adenocarcinoma, lymphovascular invasion, depth of submucosal invasion R1000 mm) should undergo additional curative surgical resection. In a retrospective study, Meining et al12 reported unfavorable outcomes (local recurrence, metastasis, or death from colorectal cancer) in 390 patients with T1 colorectal cancers treated with endoscopic resection. Significant predictors of unfavorable outcomes included lymphatic vessel infiltration (odds ratio [OR] 7.8), poor tumor grade (OR 3.3), and positive resection margins (OR 2.6). In a recent study, Ikematsu et al10 reported long-term outcomes for patients with T1 colorectal cancers from 6 centers in Japan. Patients were categorized as low risk when complete resection of the lesion was achieved, and there was the presence of well- or moderately differentiated adenocarcinoma, absence of vascular invasion, and depth of submucosal invasion less than 1000 mm, whereas others were categorized as high risk. In patients with low-risk lesions undergoing endoscopic resection, recurrence rates in submucosal colon and rectal cancer (median follow-up
www.giejournal.org
Volume 78, No. 4 : 2013 GASTROINTESTINAL ENDOSCOPY 633
SUBMUCOSAL INVASIVE COLORECTAL CANCER: DEFINITION, RISK STRATIFICATION, AND MANAGEMENT Determining the true depth of invasion of colorectal cancer is imperative in establishing an optimal treatment plan. Tis stage is defined by intraepithelial cancer or invasion into the lamina propria, whereas T1 stage is defined by infiltration of the tumor into the submucosa. Patients with Tis disease (high-grade dysplasia and intramucosal colorectal cancer) have no risk of lymphovascular spread and are deemed suitable candidates for curative endoscopic removal (EMR or endoscopic submucosal dissection).4-7 On the other hand, patients with T1 colorectal cancers have a risk of lymph node metastasis (w10%-12%). Given this risk, albeit low, referring these patients for surgical resection and removal of regional lymph nodes has been considered the standard of care.8-10
Editorial
54.4 months) were 0% (0/104) and 6.3% (1/16), respectively (P ! .05). There were no significant differences noted in disease-free (95.9% vs 90%) and overall (95.9% vs 88.9%) survival between patients with low-risk submucosal cancer in the colon and rectum. In the group of patients with high-risk lesions undergoing endoscopic resection alone, recurrence rates of submucosal colon and rectal cancer (median follow-up 56.1 months) were 1.4% (1/69) and 16.2% (6/37), respectively. Disease-free survival was better in patients with submucosal colon cancer compared with those with rectal cancer (96.5% vs 77.7%, P ! .01) with no differences in overall survival period (98.3% vs 96.2%). In the group of patients with high-risk lesions undergoing endoscopic resection followed by surgical resection or only surgical resection, recurrence rates of submucosal colon and rectal cancer (median follow-up 62.5 months) were 1.9% (7/376) and 4.5% (7/156), respectively. There were no significant differences noted in the disease-free (97.3% vs 95%) and overall (99.1% vs 97.3%) survival between patients with submucosal colon and rectal cancer. Tumor location (colon vs rectum) was the only significant predictor of disease recurrence and death (hazard ratio 6.73, 95% confidence interval [CI], 1.04-43.4; P Z .04). These results provide evidence to support complete endoscopic resection alone in patients with low-risk T1 colon cancers and the recommendations for additional curative surgery in patients with T1 rectal cancer. Moreover, these data also provide important estimates that can be used during discussion with the patient regarding treatment options, which, in our opinion, constitutes an integral part of the management of submucosal invasive colorectal cancer.
Wani & Rastogi
system have improved the ability to predict submucosal invasion.23 In a large prospective, multicenter study of 479 patients with sessile colorectal polyps referred for EMR, Moss et al19 showed that risk factors for submucosal cancer were Paris 0-IIaþc morphology, nongranular surface, or the presence of Kudo pit pattern V.
Role of NBI to assess depth of invasion
Several techniques have been evaluated for the assessment of submucosal invasion and thereby the resectability of early colorectal cancer. A nonlifting sign after injection of fluid is important to identify lesions with deeper invasion. However, the presence of a nonlifting sign is not definitive for submucosal invasive cancer because it may be a result of submucosal fibrosis from previous electrocautery injury from an earlier attempt at endoscopic resection. The likelihood of a nonlifting sign increases by sixfold with previous electrocautery injury.19 A prospective, multicenter study showed that the nonlifting sign had low sensitivity (61%), a moderate positive predictive value (80%), and a high negative predictive value (96%) for submucosal invasion.20 EUS by using high-frequency probes has been evaluated and may help to differentiate T1 colorectal cancers from more advanced lesions.21,22 However, this practice is not universal and depends on local expertise and availability. The use of standardized classifications for describing these lesions such as the Paris classification, granularity (nongranular vs granular), and pit patterns by using the Kudo classification
Previous classification systems have been proposed to help predict deep submucosal colorectal cancers by using NBI with optical magnification (Sano,24 Hiroshima,25 and Showa26 classification systems). However, these classification systems have not been put through the rigors of validation nor are they practiced clinically because they require magnification colonoscopy that is not routinely available in clinical practice, at least in the Western countries. In this issue of the Gastrointestinal Endoscopy, Hayashi et al3 have extended the NBI International Colorectal Endoscopic (NICE) classification that differentiates hyperplastic (type 1) from adenomatous polyps (type 2)27 to include deep submucosal invasive carcinoma (type 3) and should be commended for their efforts. The study involved the use of still NBI (without magnification) of 22 tubular adenomas, 23 adenomatous lesions with highgrade dysplasia or superficially invasive submucosal carcinoma (!1000 mm) (type 2) and 35 deeply invasive submucosal carcinoma (R1000 mm) (type 3). The validation steps described were similar to those reported in the earlier study describing the NICE classification.27 Phase 1 involved evaluation of accuracy and reliability of histological prediction of deep submucosal invasion by 5 expert colonoscopists. The overall accuracy was 75.6% (95% CI, 71%-80%) and accuracy in high confidence diagnosis was 84.1% (95% CI, 79%-88%). The overall proportion of high confidence diagnosis was 70% but ranged from 53% to 85% among these experts. The weighted multirater k coefficient for predicting deep submucosal invasion was 0.66 among experts (k Z 0.97 for high confidence diagnosis). Phase 2 involved the use of a modified Delphi process for expansion of the NICE classification and development of component criteria. Phase 3 involved validation of individual criteria among novice raters (5 medical students). Presence of any 1 of the 3 deep submucosal invasive carcinoma (color, vessels, or surface pattern) had the best diagnostic characteristics (94% accuracy, 96% negative predictive value) compared with any of the criteria alone or in combination. Finally, phase 4 involved assessments of performance characteristics and reliability among the same medical students after a training session. Significant improvement in accuracies was reported for individual criteria (color, vessels, and surface pattern) and overall accuracy. For a diagnosis made with high confidence (50%), the accuracy was 90% with a negative predictive value of 92%. Although we applaud the efforts of the authors, there are, however, several limitations of this study that need
634 GASTROINTESTINAL ENDOSCOPY Volume 78, No. 4 : 2013
www.giejournal.org
ENDOSCOPIC PREDICTION OF SUBMUCOSAL CANCER
Wani & Rastogi
Editorial
to be highlighted. As the authors acknowledge, it would have been ideal to use high-definition videos as opposed to still images. The methodology used to select the images was not provided, and the possibility of selection bias cannot be excluded. This is important because recent studies have shown that the accuracy demonstrated during training and ex vivo evaluation of still images does not translate into similar optimal results during real-time colonoscopy.28-30 In the group of images in patients with high-grade dysplasia and superficially invasive submucosal carcinoma, the number of images with the latter is unclear. This is crucial information before NBI patterns can be used reliably to assess depth of invasion. Is it possible that the classification system would have better performance in differentiating lesions with and without submucosal cancer (superficial and deep)? Although this makes intuitive sense, it needs to be explored further. Furthermore, the overall accuracy of predicting submucosal invasion and proportion of predictions made with high confidence, especially among experts, was less than ideal. This raises the question of whether refinement of criteria is required by using a larger database of images/videos. What are acceptable benchmarks for accurate diagnosis when using this classification system? The stakes are high when, as endoscopists, we are dealing with advanced lesions and assume the role of pathologists, and in that context, are accuracy and negative predictive values of 75% (84% with high confidence diagnosis) and 85% (87% with high confidence diagnosis) clinically acceptable?
WHERE DO WE GO FROM HERE? A simplistic approach for validation of new imaging technologies and classification systems for real-time histology prediction is highlighted in Figure 1. With the availability of newer commercially available colonoscopes with magnification capability (Exera III System, Olympus America, Center Valley, Pa), the ability of NBI to predict submucosal invasion as well as its depth may improve further and should be assessed in future trials. Similar to the benchmarks set by the American Society for Gastrointestinal Endoscopy that need to be achieved for real-time endoscopic assessment of histology of diminutive colorectal polyps,2 acceptable thresholds for real-time endoscopic assessment of submucosal invasive cancer in colorectal polyps will need to be defined. Finally, prospective multicenter studies are required to validate the classification system among other experts, nonexperts in the community and academic centers as well as trainees and most importantly assess the performance during real-time colonoscopy. Until this classification system is ready for prime time, the practical approach to these lesions should entail standardized assessment (size, location, Paris classification, granularity, pit pattern) with potential referral to an expert center if required. If endoscopic resection is www.giejournal.org
Figure 1. Simplistic approach to validation of classification systems for real-time histology prediction.
deemed feasible (based on submucosal injection, size) and necessary expertise is available, then one can proceed with endoscopic resection and let our pathologists determine the depth of invasion, which should then dictate future care after deliberation with the patient.
DISCLOSURE The following author disclosed a financial relationship relevant to this publication: Dr. Rastogi received a research grant from Olympus America Inc. The other author disclosed no financial relationship relevant to this publication. Volume 78, No. 4 : 2013 GASTROINTESTINAL ENDOSCOPY 635
Editorial
Wani & Rastogi
Sachin Wani, MD Division of Gastroenterology and Hepatology University of Colorado Anschutz Medical Center Aurora, Colorado, USA Division of Gastroenterology and Hepatology Department of Veterans Affairs Eastern Colorado Health Care System Denver, Colorado, USA Amit Rastogi, MD Division of Gastroenterology Veterans Affairs Medical Center Kansas City, Missouri Division of Gastroenterology and Hepatology University of Kansas Medical Center Kansas City, Kansas, USA Abbreviations: CI, confidence interval; NBI, narrow-band imaging; NICE, NBI International Colorectal Endoscopic classification.
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