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Keywords:

  • fluorescence-guided colonoscopy;
  • surveillance;
  • ulcerative colitis;
  • low-grade dysplasia;
  • colorectal cancer

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Background:

Patients with long-standing ulcerative colitis require repeated endoscopies for early detection of neoplasias, which, however, are frequently missed by standard colonoscopy. Fluorescence-guided colonoscopy is known to improve the detection rate but the long-term effects of fluorescence-guided colonoscopy are unknown.

Methods:

Colitis patients with negative findings at index fluorescence-guided colonoscopy entered a prospective long-term study with conventional colonoscopies at 2-year intervals. Risk and time to progression were evaluated. The positive predictive value was assessed in patients with neoplasias at index fluorescence-guided colonoscopy who underwent immediate total colectomy.

Results:

Thirty-one patients with negative fluorescence-guided colonoscopy were surveyed for a mean of 7.8 ± 0.9 years. Neoplasia was observed in only two of them (6%) after 7 and 8 years of follow-up, respectively. Neoplasia at index fluorescence-guided colonoscopy was observed in 10 patients. In all of them, multiple flat low-grade intraepithelial neoplasia was diagnosed. At immediate colectomy performed in eight of them, the diagnosis of flat low-grade intraepithelial neoplasia was confirmed, corresponding to a positive predictive value of 100%. However, synchronous more advanced neoplasia was detected in three of the eight patients (38%). All patients, those with and those without neoplasia, were alive at the end of the study.

Conclusions:

Fluorescence-guided colonoscopy misses, in contrast to standard colonoscopy, few, if any, patients with neoplasia. Most neoplasia-negative patients remain negative during prolonged follow-up. However, when low-grade dysplasia is diagnosed by fluorescence-guided colonoscopy, colectomy is recommended because more than a third of the patients harbor synchronous, more advanced neoplasia. (Inflamm Bowel Dis 2012;)

Patients with long-standing ulcerative colitis (UC) are at increased risk of developing colorectal cancer1 and thus require colonoscopy for the early detection of precursor lesions. When high-grade intraepithelial neoplasias or early cancers are detected, immediate colectomy is recommended. Other aspects of cancer prevention remain controversial.2 Conflicting observations on the natural history and on the management of low-grade intraepithelial neoplasia have been published.3, 4 Some of these discrepancies may be related to diagnostic problems; there is, as we have observed in a previous study,5 no general consensus on the histological characteristics of low-grade intraepithelial neoplasias.6, 7 Evidence is particularly poor with respect to patients with negative index endoscopy because it is difficult to detect neoplastic precursor lesions by standard colonoscopy. They are frequently missed despite target biopsies of all suspicious lesions and four-quadrant random biopsies.8, 9 When index colonoscopy is negative and a later colonoscopy shows lesions, it is not known whether these lesions have newly developed or had been missed by the index examination. According to current guidelines, colonoscopic surveillance every 1–2 years with random and targeted biopsies is the state of the art,10, 11 but it is conceivable that follow-up intervals could be prolonged with a better detection rate.

Novel endoscopic techniques, fluorescence-guided colonoscopy (FGC),5, 12 confocal laser endomicroscopy,13 chromoendoscopy,14 and narrow band imaging,15 have been claimed to improve the detection rate. However, it is unknown how many neoplastic lesions are still missed by these new techniques. The natural history of neoplastic precursor lesions detected by these novel methods and in particular the fate of patients with negative examinations has not yet been investigated.

After having shown that the detection rate of flat low-grade intraepithelial neoplasia in patients with long-standing extensive UC is improved by FGC,5 we speculated that, as a consequence of better detection, patients with normal FGC can confidently be considered true negatives. In order to test this hypothesis we conducted a prospective long-term study. In this study we also compared the findings in FGC and in the subsequently resected colon and of patients with neoplastic precursor lesions. This should allow assessing the reliability of FGC.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients

Consecutive patients with an extensive colitis of more than 10 years duration who were scheduled for surveillance colonoscopy at the Charité between January 1999 and May 2002 were invited to participate in a prospective study.5 All patients were in clinical remission at time of inclusion into the trial (Table 1). Informed consent for the study was obtained before conventional video colonoscopy was performed. First a conventional video colonoscopy (Pentax Europe, Hamburg, Germany) with biopsies of all macroscopically suspect lesions and random 4-quadrant biopsies every 10 cm was performed. Two-weeks later, FGC was performed after topical application of an aqueous solution of delta-aminolevulinic acid (δ-ALA, Medac, Hamburg, Germany). An optical fiber was inserted into the colonoscope and put in contact with the mucosa in a circumferential pattern. Fluorescence-guided biopsies were taken at locations exhibiting high fluorescence intensity of protoporphyrin IX. We used an experimental, tunable, pulsed, solid state laser system which allowed online recording of delayed fluorescence spectra, simultaneously with white light endoscopy.

Table 1. Patient Characteristics at Study Entry
CharacteristicsPositive at Fluorescence Colonoscopy N = 10Negative at Fluorescence Colonoscopy N = 32P-value
  • a

    Student's t-test.

  • b

    Fisher's exact test.

  • c

    Chi-square test.

  • d

    Mann-Whitney test.

Age: years, mean + SD51 + 14.148 + 14.70.08a
Duration of colitis: years, mean + SD16 + 1.913 + 1.70.0001a
Gender: number female/male4063918/231.0b
Histological Colitis Score17.18: number   
 Normal190.44c
 Remission16 
 Mildly active27 
 Moderately active611 
 Highly active00 
Endoscopic Colitis Score19:   
 mean + SD5.5 + 2.75.0 + 2.40.68d
Global Score (Mayo Score)20:   
 mean + SD3.5 + 0.93.1 + 1.60.37d
Medication:   
Aminosalicylates only7220.5c
Aminosalicylates + prednisolone18 
Aminosalicylates + 6-mercatopurine11 
Aminosalicylates + azathioprine11 
Smoking3121b

Exclusion criteria were pregnancy, breastfeeding, coagulopathy (prothrombin time <50%, thrombocytes <70 000), porphyria, age ≤18 and ≥70 years, tubular adenomas and/or pseudopolyps at initial colonoscopy, history of colonic neoplasia, and inability to give informed consent.

Of the 42 patients who underwent FGC, 10 were excluded from the long-term study because a neoplastic precursor lesion was found. These patients were advised to undergo “immediate” total colectomy, i.e., surgery within 3 months. The remaining 32 patients entered the surveillance program, which lasted until May 2008. Risk, incidence rate, and time to progression were assessed.

Surveillance

Surveillance standard colonoscopy in patients with negative findings at index FGC was performed at 2-year intervals. The data of the surveillance colonoscopy were prospectively collected by one person (V.F.) who reviewed electronic endoscopic reports and paper-based histological reports. Conventional white light video-colonoscopies (videocolonoscopes Pentax Europe) with random 4-quadrant biopsies and targeted biopsies of all macroscopically suspect lesions were performed at 2-year intervals.

Parameters Investigated

Progression was defined as findings of neoplasia (low/high grade intraepithelial grade neoplasia, cancer, and/or adenoma) at surveillance colonoscopies of patients without neoplasia in previous examinations.

Breakthrough cancer was defined as a malignancy manifesting itself clinically during the interval following a negative colonoscopy.

The reliability of FGC was assessed by comparing index FGC findings with findings in specimens obtained at colectomy performed within 3 months. We assumed that in the time period 0–3 months between index FGC and colectomy there was no progression.

With the positive predictive value we evaluated whether FGC correctly predicted the findings in the colectomy specimens, which served as gold standards.

The rate of synchronous more advanced lesions (intraepithelial high-grade neoplasia, carcinoma) was assessed in the cases with low-grade dysplasia.

Histological Diagnosis

All biopsy samples were stained with hematoxylin and eosin and periodic acid Schiff for histopathologic examination. Specimens were classified according to the criteria that two pathologists participating in this study had previously elaborated and published together with 30 other pathologists16: no dysplasia, indefinite for dysplasia, low-grade intraepithelial neoplasia (dysplasia), high-grade intraepithelial neoplasia, or cancer. This classification was also accepted by the third participating pathologist. Biopsy samples were first examined by two blinded pathologists. When they did not agree on the diagnosis, the samples were also examined by a third blinded pathologist. In this case, a “consensus diagnosis” was made, i.e., the diagnosis of the two agreeing pathologists was taken and the diagnosis of the third pathologist was discarded.

Histological activity was classified according to Truelove and Richards17, 18: Thus, we differentiated between normal mucosa, remission, mild activity, moderate activity, and severe activity.

Ethical Guidelines

The study protocol was reviewed and approved by the Ethics Committee of the Medical Faculty Charité of the Humboldt University Berlin, Germany. Written informed consent was obtained from each patient before inclusion in the study.

Statistical Analysis

Statistical analyses were performed using GraphPad Prism v. 5 (GraphPad Software, San Diego, CA) and SPSS software v. 13.0 (SPSS, Chicago, IL). Continuous data are reported as means and standard deviation (SD). For nominal data contingency tables are used. Risk of progression is given as proportion. Incidence rates along with its 95% confidence interval (CI) are calculated on the basis of the Poisson distribution. Time to event was analyzed using the Kaplan–Meier estimates. Patients who did not progress to advanced neoplasia were censored at the date of the last colonoscopy.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients

All 32 patients (19 female, 23 male; mean age 48 ± 14.7) without neoplastic lesions at index FGC5 agreed to enter the surveillance program. One patient, a woman without dysplastic lesions at index FGC who moved to another city, was lost to follow-up (Fig. 1). The remaining 31 patients were prospectively followed till May 2008 with conventional colonoscopies. Neoplastic precursor lesions were found in 10 patients at index FGC. Agreement for immediate colectomy was obtained in 8 of the 10 patients.

thumbnail image

Figure 1. Flowchart of outcomes of patients after initial fluorescence-guided colonoscopy. fLGIN, flat low-grade intraepithelial neoplasia; HGIN, high-grade intraepithelial neoplasia. Ovals describe findings at colectomy; plaques describe findings during surveillance.

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There was no difference in age, gender, active histological inflammation, endoscopic score (Rachmilewitz Score),19 clinical activity (Mayo Score),20 smoking habits, and medication between patients with negative or positive FGC. Mean time of disease duration was 3 years longer in patients with multiple flat low-grade intraepithelial neoplasia than in patients with normal index FGC (Table 1). Neither patients with negative nor with positive findings at FGC presented with primary sclerosing cholangitis or a family history of colon cancer.

Progression in Patients Without Neoplastic Lesions at Index FGC

The 31 patients with negative findings at index FGC were surveyed for a mean of 7.8 ± 0.9 years by conventional colonoscopies. A mean number of 3.5 ± 0.5 surveillance colonoscopies was performed per patient and a mean number of 25.3 ± 8.1 biopsy samples per surveillance colonoscopy was taken. In all 31 cases the two pathologists who examined the fluorescence-guided biopsy samples agreed on the diagnosis of “absence of neoplasia.”

Progression was only observed in 2 of the 31 patients (6%, Fig. 2). One patient developed a tubular adenoma with low-grade intraepithelial neoplasia, found during surveillance colonoscopy after 7 years of follow-up. In the second patient a stage II (T1N0M0) colon cancer was detected at surveillance colonoscopy at 8.1 years of follow-up. The cumulative incidence to advanced neoplasia over time was 0% at 5 years, 4% at 7 years, and 11% at 9 years (Fig. 2). On an actuarial basis, the incidence rate was 1 case per 100-person-years at risk. No breakthrough cancers were seen. At the end of the follow-up all patients were alive.

thumbnail image

Figure 2. Kaplan–Meier curve in patients without dysplasia (group C). ⟂95% confidence interval, vertical line, censored.

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Positive Predictive Value of FGC

In all 10 patients with neoplasia at index FGC, histological diagnosis in fluorescence-guided biopsy samples was “low-grade intraepithelial neoplasia,” and in all 10 cases multiple neoplastic areas were found. In three of the eight patients who agreed to undergo immediate colectomy, a consensus diagnosis was reached by the three pathologists, two describing low-grade dysplasia and one high-grade dysplasia or cancer (Table 2). There was no tendency for a particular pathologist to systematically describe more or less severe grades of neoplasia. The eight resected colon specimens showed multiple sites of flat low-grade intraepithelial neoplasia (Table 2). Thus, the positive predictive value of the endoscopic consensus diagnosis “neoplasia” or “multiple low-grade intraepithelial neoplasia” was 100%. However, additional synchronous more severe lesions were observed in three of the eight patients with multiple low-grade intraepithelial neoplasia at index FGC (38%): in two patients UICC (Union International Contre Le Cancer) or AJCC (American Joint Committee on Cancer) stage I (T1N0M0) cancers were found and high-grade intraepithelial neoplasia was detected in the third patient. The tumor was located in the right colon in one patient and in the sigmoid in the second patient. Both cancers were well-differentiated adenocarcinomas of the diffuse infiltrating type without venous or lymphatic invasion (Table 2).

Table 2. Comparison of Findings at Colectomy with Findings at Conventional Endoscopy and Fluorescence Guided Colonoscopy
PatientWhite Light Colonoscopy: NeoplasiaFCG: Number of Biopsies TakenFGC: Number of Biopsies With Neoplasia (“Consensus Diagnosis”)aFGC: Diagnosis by Pathologists 1/2/3 in Biopsies with NeoplasiaaColectomy: Neoplasia
  • a

    Described by ≥1 pathologist.

  • bOnly part of the colon was examined.

  • AC, active colitis; CA, cancer; CR, colitis in remission; HIGN, high-grade intraepithelial neoplasia; IN, indefinite for neoplasia; LGIN, low-grade intraepithelial neoplasia; N, normal mucosa.

1LGIN74 LGINLGIN/AC/LGINLGIN (n = 3)
(n = 4)LGIN/AC/LGIN
 LGIN/AC/LGIN
 LGIN/AC/LGIN
2None84 LGINLGIN/N/LGINLGIN (n = 3)
1 INLGIN/N/LGIN
 LGIN/N/LGIN
 LGIN/LGIN/CR
 LGIN/IN/IN
3None63 LGINLGIN/IN/LGINLGIN (n = 4)a
1 INLGIN/AC/LGIN
 LGIN/AC/LGIN
 LGIN/IN/IN
4None117 LGINLGIN/IN/LGINLGIN (n = 6)
LGIN/IN/LGINHGIN (n = 4)
LGIN/AC/LGIN 
LGIN/AC/LGIN 
LGIN/LGIN/IN 
HGIN/LGIN/LGIN 
HGIN/LGIN/LGIN 
5None2910 LGINLGIN/AC/LGINLGIN (n = 11)
3 INLGIN/AC/LGINHGIN (n = 4)
 LGIN/AC/LGINUICC stage I cancer
 LGIN/AC/LGIN 
 LGIN/AC/LGIN 
 LGIN/LGIN/LGIN 
 LGIN/LGIN/IN 
 LGIN/LGIN/IN 
 LGIN/LGIN/HGIN 
 LGIN/LGIN/HGIN 
 LGIN/IN/IN 
 LGIN/IN/IN 
 LGIN/IN/IN 
6None93 LGINLGIN/N/LGINLGIN (n = 2)
LGIN/AC/LGIN
LGIN/AC/LGIN
7LGIN164 LGINLGIN/LGIN/LGINLGIN (n = 6)
(n = 1)2 INLGIN/N/LGIN
  LGIN/N/LGIN
  LGIN/IN/LGIN
  LGIN/IN/IN
  LGIN/IN/IN
8None203 LGINLGIN/LGIN/LGINLGIN (n = 7)
5 INLGIN/IN/LGINUICC stage I cancer
 CA/LGIN/LGIN 
 LGIN/IN/IN 
 LGIN/IN/IN 
 LGIN/IN/IN 
 LGIN/IN/IN 
 LGIN/IN/IN 

Interestingly, two of the cases with additional synchronous more severe lesions were identical with those in whom one of the three pathologists had described high-grade dysplasia or cancer at index FGC (Table 2). If we had systematically taken the most severe diagnosis instead of the consensus diagnosis, index FGC would have predicted all colectomy findings correctly in seven of eight cases. On the basis of the consensus diagnosis, intraepithelial neoplasia detected by index FGC had a positive predictive value of 25% as a marker for synchronous cancer. In all three patients with advanced neoplasia, conventional colonoscopy conducted at the time of index FGC had been normal; not even low-grade intraepithelial neoplasia was detected by this method.

When “indefinite for neoplasia” was considered as “no dysplasia,” sensitivities of FCG for detecting any neoplastic lesion found at colectomy were: 67% for consensus histology, 88% for pathologist 1, 23%, for pathologist 2, and 61%, for pathologist 3. Corresponding specificities were 95%, 90%, 100%, and 95%, respectively.

When “indefinite for neoplasia” was considered as “neoplasia,” sensitivities were: 88%, 88%, 53%, and 88% for consensus diagnosis, pathologist 1, 2, and 3, respectively. Corresponding specificities were 93%, 93%, 100%, and 94%, respectively. Thus, consensus diagnosis was not superior to the accuracy of certain pathologists.

Fate of Patients with Neoplasia

A clinical follow-up was conducted in the eight patients with neoplasia and colectomy. At the end of this study, they were all alive and clinically tumor-free.

Risk of Progression in Patients with Low-grade Intraepithelial Neoplasia Undergoing Surveillance

Two patients with low-grade intraepithelial neoplasia at index FGC refused surgery and entered the surveillance program. They were followed for 2 and 9.3 years, respectively. Four and seven colonoscopies were performed, respectively. A mean number of 37.5 ± 9.0 biopsies per colonoscopy was taken. In one of these two patients a well-differentiated UICC and AJCC stage I (T2N0M0) cancer with venous and lymphatic invasion was found at surveillance colonoscopy 2 years after index FGC. The second patient with low-grade intraepithelial neoplasia at index FGC did not show progression during follow-up. Surveillance colonoscopies consistently showed flat low-grade intraepithelial dysplasia.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In this prospective long-term study, FGC turned out to be reliable for the detection of neoplasias in patients with long-standing colitis.

In the group of patients with an FGC diagnosis of neoplasia, colectomy confirmed the endoscopic diagnosis in all cases, and therefore the positive predictive value of the FGC diagnosis of “neoplasia” was 100%. This is better than previously reported with standard colonoscopy. In all our positive patients, low-grade dysplasia was found at index FGC, and this type of neoplasia is notoriously difficult to diagnose with standard colonoscopy.21, 22 However, despite its good results, FGC had shortcomings. More than one-third of the patients diagnosed with low-grade neoplasia at index FGC had synchronous more severe lesions—high-grade dysplasia or cancer—in their colectomy specimens. This may be due to several reasons: first, complete sampling of all neoplastic areas of the colon mucosa may not be feasible with FGC. Also, some neoplasias may exhibit weak fluorescence or no fluorescence at all. Other authors have hoped to improve the results by using endoscopic inspection of fluorescence instead of analyzing fluorescence curves.12, 23, 24 Their results in detection of neoplastic lesions in UC are controversial and follow-up data have not yet been published.

Theoretically, an optimal endoscopic method for diagnosing neoplasias would identify all neoplastic foci, and it would allow to endoscopically remove all neoplastic foci at minimal risk, leaving the rest of the colon tumor-free. FGC is far from being such an ideal method. However, even if an optimal method would be developed in the future, a considerable degree of diagnostic uncertainty would remain because the histological diagnosis of dysplasia, in particular of low-grade dysplasia, depends, among other things, on subjective impressions. In our study we tried to minimize this problem by blinding two—and in cases of disagreement, three—expert pathologists. In cases of disagreement, a consensus diagnosis was made, i.e., the diagnosis of the two agreeing pathologists was considered correct. Two of our pathologists had previously taken active part in the elaboration of multinational histological criteria for dysplasia but they still disagreed among themselves in some cases. Consensus diagnosis as defined in our study was not more accurate than were individual pathologists, but FGC would have more accurately predicted the findings at colectomy if we had taken the worst diagnosis in each case instead of the consensus diagnosis. This observation may have clinical consequences and should be further tested in future prospective studies.

The invasive growth pattern of the two cancers may have been an additional reason why the lesions were not detected at index FGC and histological diagnoses were conflicting. Although fluorescence was high, the depth of endoscopic biopsies may not have been sufficient to diagnose cancer. In colorectal polyps it has been shown that biopsies are not adequate for grading neoplasia. In 63% of advanced neoplasia only low-grade intraepithelial neoplasia was diagnosed by biopsies.25

The low false-negative rate of FGC is a consequence of the multifocal occurrence of neoplasias in patients with long-standing UC; when at least some out of a multitude of neoplastic areas show strong fluorescence and are thus biopsied, the presence of neoplasia is correctly diagnosed. Along the same line of reasoning, the absence of fluorescence is easily recognizable, and FGC is a good method to exclude neoplasia. Normal FGC findings most likely reflect the absence of neoplasia and are true-negative. This explains the low progression rate in our study: neoplasia developed in only 6% of our initially negative patients and only after more than 7 years of follow-up, 20 years after the onset of colitis. Correspondingly, our patients with neoplasia at index FGC had suffered from colitis for 16 years on average. The higher progression rate reported in studies with standard colonoscopy is most likely due to a high rate of neoplasias missed at index endoscopy and not to a selection of more severe cases.

The progression rate was low in our study despite the fact that surveillance was performed with conventional colonoscopy. We could of course have missed neoplastic lesions, but this seems rather unlikely because no interval cancers were detected. Therefore, one could speculate that an accurate index colonoscopy with whichever method is crucial for a low progression rate and negative findings at surveillance colonoscopy.

The overall result of our approach, index FGC and colectomy in patients with neoplasia, is excellent. All 31 initially neoplasia-free patients who entered the follow-up program and also the eight patients with neoplasia who underwent immediate colectomy survived during the long, on average, 8-year observation period.

It will be of interest to conduct further studies where an entire collective of patients with long-standing colitis, with and without neoplasia, will be randomized to different managing schedules and followed up for prolonged time periods. Long-term data, including comparisons of FGC with other detection methods, are required before changing present surveillance strategies. Finally, larger trial will be needed; the small sample size is a weak point of our study.

In conclusion, FGC is a new method for detection and exclusion of intraepithelial neoplasia in patients with inflammatory bowel disease with a high sensitivity and specificity. The overall outcome of our management approach is excellent. Patients with negative findings at FGC can feel safe, since progression is rare and occurs late. Surveillance intervals might be prolonged for up to 4 years. Patients with multiple low-grade detected neoplasia at FGC should be advised to undergo colectomy.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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