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Introduction
Colorectal cancer complicating ulcerative colitis (UC) was first recognized in 1925 by Crohn and Rosenberg. Colorectal cancer in UC accounts for only 1% of all cases of colorectal cancer seen in the general population1, but it accounts for 3-17% of all UC deaths.2,3 In a meta-analysis by Eaden et al.4, the overall prevalence of colorectal cancer in UC was 3.7%, and increased to 5.4% in cases of pancolitis. This study also determined that the cumulative risk of colorectal cancer in UC increased with longer duration of disease, resulting in a 2% risk after 10 years, an 8% risk after 20 years, and an 18% risk after 30 years of disease. It is important to note, however, that more recent studies have found a much lower risk of colorectal cancer in UC, with crude annual incidence rates ranging from 0.06% to 0.2%5.
The colorectal cancer risk in Crohn's disease approximates the risk in UC patients when matched for a similar anatomic extent and duration of disease6. Among patients with longstanding, unresected extensive Crohn's colitis, the relative risk for developing colorectal cancer ranges from 5.6 to 23.8.6 Even without adjustments for disease location or duration, the largest population-based study of cancer risk in inflammatory bowel disease (IBD) showed a relative risk of developing colorectal cancer of 2.64 for Crohn's disease patients, as compared to a relative risk of 2.75 for UC patients.7
Although there have not been any randomized clinical studies to determine whether current surveillance colonoscopy techniques prolong survival in IBD, the bulk of evidence seems to suggest a benefit.8,9 In this article, current guidelines for colon cancer surveillance in IBD will be reviewed, including pitfalls of current recommendations. In addition, the evolving role of new techniques for cancer surveillance in IBD will be addressed, including chromoendoscopy, narrow band imaging (NBI) and auto-fluorescence imaging (AFI).
Current Guidelines for Colon Cancer Surveillance in IBD
Current guidelines recommend annual or biannual surveillance colonoscopy after 8 to 10 years of colitis (including left-sided colitis), or at time of diagnosis of concurrent primary sclerosing cholangitis (PSC). Multiple biopsies at regular distances should be performed, usually in four quadrant fashion every 10 cm and, in addition, any abnormal lesions or strictures should be biopsied as well.10-13 A prior study has shown that 33 biopsies throughout the colon are required for 90% confidence of detection of dysplasia and 56 biopsies are required for 95% confidence of detection of dysplasia.14
There are, however, significant potential limitations and pitfalls with conventional colonoscopy for dysplasia surveillance in IBD. Although recent improvements in colonoscopic technology and more careful withdrawal can lead to increased detection of dysplastic lesions with conventional techniques15, a significant proportion of dysplastic lesions occur in flat, normal appearing mucosa that cannot be visually detected by conventional light colonoscopy.16 It is also important to realize that 10 random surveillance biopsies only cover an estimated 0.05% of the total colonic mucosal surface area.17 This fact is especially concerning when results of a survey of gastroenterologists revealed that 57% took 10 or fewer biopsies when performing IBD dysplasia surveillance, and only 2% took more than 20 biopsies.18 Given that most IBD dysplasia is flat and that there have been problems with physician adherence to the rigorous biopsy protocols required to maximize accurate dysplasia detection, new techniques that would better detect flat lesions and possibly minimize or abolish the need for numerous random mucosal biopsies of normal appearing mucosa could be of great benefit.
Chromoendoscopy
Chromoendoscopy has experienced a resurgence of interest as a potential superior technique for dysplasia surveillance in IBD. Chromoendoscopy was first described in 197619, and involves the topical application of stains or pigments to improve tissue localization, characterization, and diagnosis during endoscopy (Figures 1-4). There are three main types of stains that are used: absorptive stains such as methylene blue and Lugol's solution, reactive stains such as congo red or phenol red, and contrast stains such as indigo carmine.20 The two main types of dye that have been used in the colon are methylene blue and indigo carmine.
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Figure 1 |
Figure 2 |
Figure 3 |
Figure 4 |
| Lesions detected with 0.1% indigo carmine chromoendoscopy (white arrows) that were not seen with conventional white light colonoscopy. Lesions in Figures 1 and 2 are dysplastic, lesion in Figure 3 is hyperplastic, and lesion in Figure 4 is normal mucosa. Biopsy and pathologic evaluation were needed to determine which lesions were dysplastic. |
Methylene blue is taken up by actively absorbing tissues in the colon, and is not absorbed by abnormal colonic tissue that is inflamed or dysplastic. A mucolytic such as N-acetylcysteine is first sprayed, followed by a 0.1 to 2% methylene blue spray. The mucosa is then washed until the staining pattern is stable. It is important to note that some safety concerns have been raised regarding the use of methylene blue. Photosensitization of DNA with methylene blue, visible light, and oxygen results in oxidative damage and single strand breaks in plasmid DNA.21 When methylene blue was combined with white light, it also led to DNA damage in Barrett's mucosa as well as in colonic epithelium.22,23 The clinical relevance of this DNA damage remains unclear, but it is somewhat reassuring that a recent pilot study revealed that UC patients who had been exposed to methylene blue chromoendoscopy did not have a higher rate of colonic dysplasia during follow-up.24 Of note is the fact that these patients were only followed for 20 months, so it is unclear whether there will be additional risk for these patients in the future.
Indigo carmine is a combination of a blue plant dye and a red coloring agent. In contrast to methylene blue, it is not absorbed by the colon, and simply pools in the crevices between epithelial cells, thus highlighting small or flat lesions as well as mucosal irregularities. It can be administered via an oral capsule or oral lavage solution, but is usually applied as a 0.1 to 0.4% spray - no preceding mucolytic is required. There have been no reported safety issues with indigo carmine, and in contrast to methylene blue, there is no DNA damage to colonic epithelium when it is exposed to indigo carmine in combination with white light.23
There have been five major published studies from Europe and Japan evaluating the use of chromoendoscopy in UC (Table 1). Four of the five studies used indigo carmine, and four of the five studies used magnification or high resolution colonoscopes. Two additional studies from the United States have recently been presented in abstract form, evaluating the utility of chromoendoscopy for dysplasia detection in IBD.25,26
Study |
Dye |
Scope |
N |
Total #
Patients
with
Dysplasia |
# Patients
w/Visible
Dysplasia
w/White
Light
|
# Patients
w/Visible
Dysplasia
w/Chromo |
Relative
Rate of
Dysplasia
Detection
w/Chromo
|
P-
Value |
# Patients
w/Dysplasia
Only
w/Random
Biopsy
|
Matsumoto
et al. 2003 |
0.2%
Indigo
Carmen |
High
Res |
57 |
12 |
7 |
11* |
1.6 |
NS |
1 |
Kiesslich
et al. 2003 |
0.1%
Methylene
Blue |
Mag |
165 |
19 |
6 |
13 |
2.2 |
NS |
NR |
Rutter
et al. 2004 |
0.1%
Indigo
Carmen |
Stand |
100 |
7 |
2 |
7* |
3.5 |
NS |
0 |
Hurlstone
et al. 2004 |
0.5%
Indigo
Carmen |
Mag |
324 |
35 |
NR |
NR |
-- |
-- |
NR |
Hurlstone
et al. 2005 |
0.5%
Indigo
Carmen |
Mag |
700 |
81 |
19 |
62 |
3.3 |
NR |
NR |
* Since both conventional examination and chromendoscopy were performed on the same patient in this study, this number includes total visible lesions seen with both procedures.
** NS: not significant; NR: not reported; High Res: high resolution colonoscope; Mag: magnification colonoscope; Stand: standard colonoscope.
All of these studies showed that chromoendoscopy increases the number of detected dysplastic lesions in UC patients as well as the number of patients with detected dysplasia. Although these studies showed a statistically significant increase in the number of dysplastic lesions detected, the increase in the number of patients with dysplasia was not always statistically significant in these studies, though statistical significance likely would have been reached with larger sample sizes. This is an important point as finding more patients with dysplasia, who would not have otherwise been identified, is a more relevant clinical outcome that simply finding more dysplastic lesions in a single patient who already had a visible dysplastic area that was detected with conventional white light colonoscopy.
Indigo carmine chromoendoscopy can be carried out with a conventional colonoscope, a spray catheter, and commercially available indigo carmine dye. A 5 ml ampule of 0.8% indigo carmine is added to 35 ml of water in a 60 cc luer lock syringe and attached to the spray catheter. Once cecal intubation is achieved, the spray catheter can be inserted and segmental spraying of the colon can be performed during colonoscope withdrawal with careful examination of the mucosa for any highlighted lesions. Approximately 120 to 160 ml of the diluted dye is used per procedure (3 to 4 ampules of 0.8% indigo carmine).
Narrow Band Imaging (NBI)
NBI highlights the colonic mucosal surface and microvasculature by using special filters that narrow the respective red, green, and blue bands while simultaneously increasing the relative intensity of the blue band.27 Dysplastic areas with increased hemoglobin concentrations due to hypervascularity may appear brownish or dark with NBI28, 29, and an irregular, disrupted mucosa with an abnormal mucosal capillary configuration, such as a tortuous capillary pattern, may be apparent.29 Results from an initial case report30 as well as a pilot study29 evaluating the efficacy of NBI for neoplasia detection in UC were promising, but a recent prospective randomized study comparing NBI to white light colonoscopy for dysplasia surveillance revealed that the first generation NBI system was not superior to white light colonoscopy for dysplasia detection.28 A new NBI system was recently released, however, and the efficacy of this newer system needs to be evaluated.
NBI is now available on many new high resolution colonoscopes. The colonoscopic view can be toggled between the NBI mode and the conventional white light mode by simply pressing a button adjacent to the control wheel on the instrument shaft.
Auto-fluorescence Imaging (AFI)
When tissue is exposed to light of short wavelength, such as blue light, certain tissue components called fluorophores, such as mitochondria, lysosomes, and submucosal collagen, will autofluoresce, and other tissue molecules called chromophores, predominantly hemoglobin in the gastrointestinal tract, will absorb both the excitation and the autofluorescent light.27, 31 Since neoplastic tissue will contain more fluorophores and chromophores than the surrounding normal mucosa, the neoplastic tissue will appear red or purple on AFI, while normal tissue will appear green.31,32 There have been no published studies on the use of AFI for neoplasia surveillance in IBD, but studies evaluating this technology in Barrett's esophagus have shown increased detection rates of high grade dysplasia when compared to conventional white light endoscopy.31 Trials are needed to evaluate the efficacy of AFI for colon cancer surveillance in IBD. Some colonoscopes now come equipped with both NBI and AFI modes.
Conclusions
In summary, a significant proportion of dysplastic lesions in IBD are flat or very small and can be missed with conventional white light colonoscopy, though the advent of more advanced high resolution instruments is likely decreasing the number of these missed lesions. The number of random biopsies needed to detect this flat dysplasia can be cumbersome and there have been problems with adherence to recommended surveillance protocols.
Chromoendoscopy has been proposed as a better alternative, resulting in the detection of small, subtle, and flat dysplastic lesions with a decreased number of biopsies. Chromoendoscopy studies have revealed a 1.6 to 3.5 fold increase in the number of patients with detected dysplasia with chromoendoscopy as compared to conventional colonoscopy, but this technique can also be cumbersome and time consuming and has not yet been adopted on a wide scale. NBI and AFI are very promising techniques that seem to have the advantages of chromoendoscopy without the disadvantages of exogenous dye administration and the repeated insertion and withdrawal of a spray catheter, but more data is needed on the efficacy of these technologies in colon cancer surveillance in IBD.
Some have advocated doing away with random non-targeted biopsies and performing only dye or NBI targeted biopsies, as well as biopsies of any lesions visible with conventional white light. Although the yield is usually greater with targeted biopsies, dysplasia has still been found on random, non-targeted biopsies in most studies evaluating this issue. Several studies have found cases where patients were found to have dysplasia detected only by random biopsies without any other visible
lesions.25, 26, 28, 33 It would be prudent to continue the random biopsy protocol until more effective techniques are developed and verified for colon cancer surveillance in IBD.
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