Dra. Maria Pellisé Urquiza
Hospital Universitari Clínic. Barcelona
Is already mentioned in previous sections, patients with longstanding inflammatory bowel disease (IBD) have a higher risk of developing colorectal cancer (CRC) than the general population. Although there are no randomised controlled trials showing that screening strategies are effective in reducing mortality from CRC in IBD patients, a large number of studies have suggested a clear benefit. Colonoscopy is considered the gold standard for following up on patients with IBD. The interest lies in the early detection and treatment of precancerous changes in the colorectal mucosa, disruption of the adenoma-carcinoma sequence and prevention of progression to CRC. Histologically, precursor lesions are classified as: indefinite for dysplasia (when it is not possible to decide whether or not dysplasia is present), low-grade dysplasia and high-grade dysplasia. Treatment is based on the appearance of dysplastic lesions and the possibility of endoscopic resection. However, the detection of dysplasia and cancer associated with colitis during follow-up endoscopy is difficult because the distribution of these lesions of often patchy and they frequently occur on macroscopically normal mucosa. Therefore, it is recommended that random biopsies be taken every 10 cm, which means that a minimum of 40–50 biopsies in total are needed to rule out dysplasia with an adequate safety margin.
With the development of video and camera control units, endoscopic technology has progressed to the extent that gastroenterologists are able to view and store high-resolution images of the gastrointestinal tract. This has unequivocally changed the management of precancerous and cancerous lesions of the gastrointestinal tract and biliary tree. However, significant difficulties still remain, especially in relation to diagnostic capacity. There are three major problems that arise in the diagnosis of dysplasia: first of all, endoscopists cannot identify dysplasia with the naked eye; to be detected, it needs to be linked to gross morphological changes such as polyps. Secondly, it is impossible to determine the borders between dysplastic and normal areas; therefore, once the histological diagnosis becomes available after the standard waiting time (24–48 h), it is not possible to verify where the biopsy was taken from; as a result, local treatment cannot be administered. Finally, there is significant disagreement among pathologists in the interpretation of dysplasia. This implies that many lesions are either invisible or difficult to visualise with standard white light endoscopy, and that histological mapping and multiple biopsies remain necessary in order to follow-up on various conditions, including the present one. Moreover, even when lesions are visible, it is still necessary to take biopsies to allow pathologists to establish a definitive diagnosis, which is sometimes disputed.
It therefore seems logical to think that the next advance in endoscopy consists of the successful identification of these invisible lesions, and the ability to obtain an immediate microscopic diagnosis without the need for biopsies, or to at least maximise their yield. Indeed, several approaches have been developed in recent years that seek to go further and perform “optical biopsies,” thus obtaining more accurate information, whether from a morphological or functional standpoint. These innovative endoscopic techniques are particularly useful in the context of CRC screening and monitoring in patients with longstanding IBD due to their inherent characteristics, which are extensively discussed above.
The two techniques we will now describe have current clinical applications and are backed by scientific evidence.
Staining or chromoendoscopy (CE) techniques are based on the topical application of stains or dyes on the gastrointestinal mucosa during endoscopy in order to improve the diagnostic yield of conventional endoscopy by increasing the ability to identify details in tissues (Video 1).
In recent years, several studies have shown that pancolonic dye spraying (PDS) is more efficient than conventional endoscopy for the detection of dysplastic areas in patients with longstanding ulcerative colitis (UC). In the first prospective randomised controlled study, Kiesslich et al.1 compared the diagnostic yield of PDS with methylene blue (n = 84 patients) against conventional endoscopy (n = 81 patients) for the detection of intraepithelial neoplasia and predicting the extension of inflammation in patients with longstanding UC. In this study, the authors demonstrated that dysplastic lesions were three times more likely to be detected via targeted biopsies using PDS than via conventional endoscopy (32 vs 10 p <0.005). The same group subsequently corroborated these results in another randomised controlled study, which aimed to evaluate the usefulness of confocal endomicroscopy for the diagnosis of dysplasia in patients with UC2. Hursltone et al.3 compared endoscopy with the selective staining of abnormal areas with indigo carmine (n = 162 patients) against conventional colonoscopy (n = 162 patients). The results showed that four times more dysplastic lesions were detected with CE than with conventional endoscopy. These same authors subsequently published a prospective comparative study4 of 700 patients, which once again demonstrated the superiority of CE. Furthermore, targeted biopsies had a higher diagnostic yield, so that in the normal colonoscopy group, intraepithelial neoplasia was detected in 0.14% of random biopsies (18 of 12,482) compared with 1.6% of targeted biopsies (6/369). This difference was even more striking in the group of patients who underwent CE, since random biopsies in these patients had a yield of 1.6% versus 8% for targeted biopsies (49 lesions detected in 644 biopsies). In a study with a different design in which each patient underwent two colonoscopies, Rutter et al.5 compared the yield of random biopsies with that of biopsies targeted via conventional endoscopy and biopsies targeted via PDS with carmine dye in a group of 100 patients. The 2,904 random biopsies did not detect any dysplastic areas; in contrast, targeted biopsies using PDS (n = 114) allowed for the detection of nine dysplastic areas in seven patients. A prospective North American study6 with 102 patients supported these results. Finally, a recent meta-analysis on the utility of CE in this context, which included a total of 1,277 patients with longstanding UC (>8 years), showed a difference of 7% between the detection of dysplasia via conventional white light and PDS. Taking into account only targeted biopsies, the difference increased to 44%7.
These results are summarised in Table I. These studies suggest that PDS is the method of choice for the detection of dysplasia in patients with longstanding UC, although targeted biopsy remains the most fruitful strategy.
As has been the case with other scientific evidence, the transfer of these results to clinical practice has been neither immediate nor widespread. However, at present there are already two clinical guidelines (a British one8 and a recent European one from the European Crohn’s and Colitis Organisation9) which consider PDS with targeted biopsies the method of choice for screening patients with longstanding IBD, provided that it is performed by expert endoscopists. Alternatively, if the treating physician is not experienced in CD, it is recommended that a conventional endoscopy be performed with a combination of random (40–50 biopsies) and targeted biopsies of any visible lesion.
To perform a screening colonoscopy under good conditions, it is important that the patient be in clinical remission, as it is difficult to discriminate between inflammation and dysplasia. In addition, excellent or at least good colon preparation is required, as well as adequate time for the examination. Within this principle, PDS does not entail longer examination times than the random biopsy strategy. However, one must take into account that such examinations inherently take longer than conventional diagnostic colonoscopy.
In certain cases, prior to administration of the dye, the use of a mucolytic agent may be required to remove excess mucus on the mucosal surface of the colon (N-acetylcysteine 10%, e.g. Flumil®) which should be allowed to take effect for about two minutes before applying the dye. When there are a lot of bubbles on the colon surface, prior use of an anti-foaming agent (e.g. Aero Red®) is helpful. High-power water pumps are especially useful, as they eliminate the layer of mucus or faeces that often lines the mucosa, preventing proper staining and evaluation of the mucosal pattern10.
Staining agents are typically inexpensive and easy-to-obtain master formulas. In the present case, it is advisable to stain the entire colon (PDS), to which end the use of a spray catheter is recommended for even application of the stain over large areas. The most common catheters are the single-use ones made by Wilson-Cook (Glo-Tip), and the reusable ones made by Olympus (PW-5V-1) (Fig. 1). The dye can also be added to the enema water, thus staining the colon as it is rinsed.
Types of dyes:
• Indigo carmine dye is the primary contrast stain used in the colon as it helps to increase the detection of neoplastic lesions, characterise their morphology, and define their borders with a view to possible endoscopic resection. Weak dilutions (0.1%) are normally used when staining large areas using a catheter. Starting from the caecum, the colon is examined during withdrawal in segments of 20–30 cm, initially without the use of dye spray so as not to interfere with the detection of other possible types of lesions (e.g. angiodysplasia), and then immediately after instillation of the indigo carmine dye.
• Methylene blue: a 0.1% dilution of the stain is used as above, allowing one minute for the dye to settle before suctioning off any excess. Methylene blue stains the normal absorptive colonic mucosa, so that unstained areas may reveal inflammatory or neoplastic changes. A study11 conducted in patients with Barrett’s oesophagus showed methylene blue to have a carcinogenic potential, although this has never been subsequently corroborated, least of all in patients with IBD. It should be noted that methylene blue is contraindicated in patients with a glucose-6-phosphate dehydrogenase deficit.
A group of experts published a guide for the proper use of CE in screening patients with longstanding CU called SURFACE12.
Possible examples of endoscopic findings after the instillation of indigo carmine in patients with longstanding CU are shown in Figure 2, Figure 3 and Figure 4.
NARROW BAND IMAGING
Narrow band imaging (NBI) is an endoscopic tool that relies on a filter that only allows light in the blue-green range to shine through. Blue only superficially penetrates the mucosa and also happens to be the colour most strongly absorbed by haemoglobin. As a result, NBI emphasises the capillary network in endoscopic images, thus allowing high-resolution and -contrast visualisation of the mucosal pattern without the need for staining agents. The application of this new technology in gastrointestinal endoscopy was only recently described in the literature, having proved useful in Barrett’s study of the oesophagus and in the detection and characterisation of colonic polyps based on their crypt pattern and degree of vascularisation12. Its potential advantages over PDS are that it is more convenient to handle and that the conventional white light image can be instantly and reversibly swapped with NBI via a switch.
Despite the potential usefulness of this “electronic chromoendoscopy” technology in screening patients with longstanding UC, scientific evidence to date does not allow a clear stance to be taken on the matter. Three randomised controlled trials have now been published that compare NBI to conventional white light endoscopy. In none did NBI prove superior in terms of the number of patients with dysplasia or the number of dysplastic lesions identified13-15. However, it should be borne in mind that in all cases NBI required shorter examination times and fewer biopsies (Video 2).
Spanish study was the first to compare the performance of NBI against CE in the detection of dysplasia in patients with IBD16. A total of 80 patients with IBD were included who underwent two colonoscopies over an eight-week period: one with PDS using a 4% indigo carmine dye and another using NBI, in random order. The time required for exploration was significantly lower with NBI than with PDS. Overall, NBI detected the same number of lesions with dysplasia using fewer biopsies. However, in the analysis by patient, NBI was found to have a higher rate of unidentified lesions, thus failing to identify a larger number of at-risk patients. This study is limited by a lack of statistical power, making it difficult to draw definitive conclusions. The preliminary results of a multi-centre randomised controlled study comparing NBI against PDS with methylene blue 0.1% recently showed the two methods to have a similar rate of detection of neoplasia. Once again, examination times were significantly shorter with NBI17.
Thus, in view of these results, NBI has proven useful and less awkward than conventional endoscopy with random biopsies and PDS. Consequently, it could constitute an alternative in sites with experience in NBI18. However, it is currently too soon to recommend NBI as a substitute for PDS in the detection of dysplasia in patients with IBD.
Some examples of possible endoscopic findings visualised using NBI in patients with longstanding UC are shown in Figure 5.
1. Kiesslich R, Fritsch J, Holtmann M, Koehler HH, Stolte M, Kanzler S, et al. Methylene Blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2003; 124: 880-8.
2. Kiesslich R, Burg J, Vieth M, Gnaendiger J, Enders M, Delaney P, et al. Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo. Gastroenterology. 2004; 127(3): 706-13.
3. Hurlstone DP, Mcalindon ME, Sanders DS, Keogh R, Lobo AJ, Cross SS. Further validation of high magnification chromoscopic colonoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology. 2004; 126: 376-7.
4. Hurlstone DP, Sanders DS, Lobo AJ, McAlindon ME, Cross SS. Indigo carmine-assisted high-magnification chromoscopic colonoscopy for the detection and characterisation of intraepithelial neoplasia in ulcerative colitis: a prospective evaluation. Endoscopy. 2005; 37(12): 1186-92.
5. Rutter MD, Saunders BP, Schofield G, Forbes A, Price AB, Talbot IC. Pancolonic indigocarmin dye spraying for the detection of dysplasia in ulcerative colitis. Gut. 2004; 53: 256-60.
6. Marion JF, Waye JD, Present DH, Israel Y, Bodian C, Harpaz N, et al. Chromoendoscopy-targeted biopsies are superior to standard colonoscopic surveillance for detecting dysplasia in inflammatory bowel disease patients: a prospective endoscopic trial. Am. J of Gastroenterol. 2008; 103: 2342-9.
7. Subramanian V, Mannath J, Ragunath K, Hawkey CJ. Meta-analysis: the diagnostic yield of chromoendoscopy for detecting dysplasia in patients with colonic inflammatory bowel disease. Aliment Pharmacol Ther. 2011; 33: 304-12.
8. Cairns S, Scholefield JH, Steele RJ, Dunlop MG, Thomas HJW, Evans GD, et al. Developed on behalf of The British Society of Gastroenterology and the Coloproctology for Great Britain and Ireland. Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut. 2010; 59: 666-90.
9. Van Assche G, Dugnass A, Bokemeyer B, Danese S, Gionchetti P, Moser G, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis: Special situations. J Crohn Colitis. 2013; 7: 1-33.
10. Pellisé M, Díaz Tasende J, Balaguer F, Bustamante-Balén M, Herráiz M, Herreros de Tejada A, et al. Technical review of advanced diagnostic endoscopy in patients at high risk of colorectal cancer. Gastroenterol Hepatol. 2012; 35(4): 278-92.
11. Olliver JR, Wild CP, Sahay P, Dexter S, Hardie LJ. Chromoendoscopy with methylene blue and associated DNA damage in Barrett’s oesophagus. Lancet. 2003; 362(9381): 373-4.
12. Rutter M, Bernstein C, Matsumoto T, Kiesslich R, Neurath MF. Endoscopic appearance of dysplasia in ulcerative colitis and the role of staining. Endoscopy. 2004; 36: 1109-14.
13. Pellisé M, Fernández-Esparrach G, Ginés A, Llach J. La endoscopia en el siglo XXI. En Abreu L, Garrido A, Albillos A, Barrios C, Calleja JL, Vera M, editores. Gastroenterología. Endoscopia diagnóstica y terapéutica. 2.ª ed. Madrid: Editorial Panamericana; 2007. p. 419-24.
14. Dekker E, van den Broek FJ, Reitsma JB, Hardwick JC, Offerhaus GJ, van Deventer SJ, et al. Narrow-band imaging compared with conventional colonoscopy for the detection of dysplasia in patients with longstanding ulcerative colitis. Endoscopy. 2007; 39(3): 216-21.
15. Van den Broek FJ, Fockens P, van Eeden S, Stokkers PC, Ponsioen CY, Reitsma JB, et al. Narrow-band imaging versus high-definition endoscopy for the diagnosis of neoplasia in ulcerative colitis. Endoscopy. 2011; 43(2): 108-15.
16. Ignjatovic A, East JE, Subramanian V, Suzuki N, Guenther T, Palmer N, et al. Narrow band imaging for detection of dysplasia in colitis: a randomized controlled trial. Am J Gastroenterol. 2012; 107(6): 885-90.
17. Pellisé M, López-Cerón M, Rodríguez de Miguel C, Jimeno M, Zabalza M, Ricart E, et al. Narrow-Band Imaging As An Alternative To Chromoendoscopy For The Detection Of Dysplasia In Long Standing Inflammatory Bowel Disease: A Prospective Randomized Crossover Study. Gastrointest Endosc. 2011; 74(4): 840-8.
18. Bisschops R, Bessissow T, Baert FJ, Ferrante M, Ballet V, Willekens H, et al. Chromoendoscopy versus narrow band imaging in ulcerative colitis: a prospective randomized controlled trial. Gastrointest Endosc. 2012; 75: AB148.