The color of dysplasia in ulcerative colitis

Abstract

See article on page 880. There is much that is known regarding the risk of colorectal cancer (CRC) in ulcerative colitis (UC). It is widely accepted that outside of Denmark,1Langholz E Munkholm P Davidsen M Binder V. Colorectal cancer risk and mortality in patients with ulcerative colitis.Gastroenterology. 1992; 103: 1444-1451Abstract PubMed Google Scholar UC is associated with an increased risk of CRC.2Ekbom A Helmick C Zack M Adami H-O. Ulcerative colitis and colorectal cancer. A population-based study.N Engl J Med. 1990; 323: 1228-1233Crossref PubMed Scopus (1565) Google Scholar, 3Bernstein CN Kliewer E Wajda A Blanchard JF. The incidence of cancer among patients with IBD: a population-based study.Cancer. 2001; 91: 854-862Crossref PubMed Scopus (1015) Google Scholar Population-based studies from Sweden and Canada have estimated the relative risks of developing CRC in UC patients to be 5-6 fold and 2-3 fold, respectively (the Canadian study had a shorter duration of follow-up, potentially accounting for the lower relative risk).2Ekbom A Helmick C Zack M Adami H-O. Ulcerative colitis and colorectal cancer. A population-based study.N Engl J Med. 1990; 323: 1228-1233Crossref PubMed Scopus (1565) Google Scholar, 3Bernstein CN Kliewer E Wajda A Blanchard JF. The incidence of cancer among patients with IBD: a population-based study.Cancer. 2001; 91: 854-862Crossref PubMed Scopus (1015) Google Scholar A recent meta-analysis estimated the incidence rate at 7 of 1000 person-years duration and 12 of 1000 person-years duration in the second and third decades of disease, respectively.4Eaden JA Abrams KR Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis.Gut. 2001; 48: 526-535Crossref PubMed Scopus (2308) Google Scholar It was also estimated that the cumulative probability of CRC by 30 years was 18% (nearly 1 in 5).4Eaden JA Abrams KR Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis.Gut. 2001; 48: 526-535Crossref PubMed Scopus (2308) Google Scholar Furthermore, there is convincing evidence that CRC risk correlates with increased disease extent and increased disease duration.5Lennard-Jones JE Melville DM Morson BC Ritchie JK Williams CB. Precancer and cancer in extensive ulcerative colitis: findings among 401 patients over 22 years.Gut. 1990; 31: 800-806Crossref PubMed Scopus (410) Google Scholar, 6Lofberg R Brostrom O Karlen P Tribukait B Ost A. Colonoscopic surveillance in long-standing total ulcerative colitis—a 15 year follow-up study.Gastroenterology. 1990; 99: 1021-1031PubMed Google Scholar, 7Pinczowski D Ekbom A Baron J Yuen J Adami HO. Risk factors for colorectal cancer in patients with ulcerative colitis: a case-control study.Gastroenterology. 1994; 107: 117-120Abstract PubMed Google Scholar, 8Bansal P Sonnenberg A. Risk factors for colorectal cancer in inflammatory bowel disease.Am J Gastroenterol. 1996; 91: 44-48PubMed Google Scholar The evidence is strong that the risk is higher in those with a concurrent diagnosis of primary sclerosing cholangitis,9Shetty K Rybicki L Brzezinski A Carey WD Lashner BA. The risk for cancer or dysplasia in ulcerative colitis patients with primary sclerosing cholangitis.Am J Gastroenterol. 1999; 94: 1643-1649Crossref PubMed Scopus (244) Google Scholar and in those with a positive family history of sporadic colon cancer.10Nuako KW Ahlquist DA Mahoney DW Schaid DJ Siems DM Lindor NM. Familial predisposition for colorectal cancer in chronic ulcerative colitis: a case control study.Gastroenterology. 1998; 115: 1079-1083Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar, 11Eaden J Abrams K Ekbom A Jackson E Mayberry J. Colorectal cancer prevention in ulcerative colitis: a case-control study.Aliment Pharmacol Ther. 2000; 14: 145-153Crossref PubMed Scopus (518) Google Scholar CRC prevention in UC is based on the premise that dysplasia (a neoplastic change confined to the epithelium) antecedes cancer.12Riddell RH Goldman H Ransohoff DF Appelman HD Fenoglio CM Haggitt RC Ahren C Correa P Hamilton SR Morson BC Sommers SC Yardley JH. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications.Hum Pathol. 1983; 14: 931-968Abstract Full Text PDF PubMed Scopus (1620) Google Scholar Despite the widespread practice of dysplasia surveillance endoscopy as a means to reduce CRC morbidity and mortality, dysplasia surveillance endoscopy remains a poorly studied endeavor.13Bernstein CN. Challenges in designing a randomized trial of surveillance colonoscopy in IBD.Inflamm Bowel Dis. 1998; 4: 132-141PubMed Google Scholar A randomized controlled study proving its value has never been conducted.13Bernstein CN. Challenges in designing a randomized trial of surveillance colonoscopy in IBD.Inflamm Bowel Dis. 1998; 4: 132-141PubMed Google Scholar Nonetheless, colonoscopy is generally a low-risk procedure and both physicians and patients are keen to pursue avenues of cancer prevention. Two main questions recurrently arise in the pursuit of dysplasia surveillance endoscopy. The answer to this question may simply be as many as possible. One study from the University of Washington addressed this in a critical fashion where colons containing cancers were serially sectioned. To have a 95% confidence that the highest grade of neoplasm (dysplasia or cancer) is found, 64 biopsies were required. To have a 90% confidence of finding the highest degree of dysplasia, 33 biopsies were required. To have a 95% confidence of finding any degree of dysplasia in a patient with cancer, 18 biopsies were required.14Rubin CE Haggitt RC Burmer GC Brentnall TA Stevens AC Levine DS Dean PJ Kimmey M Perera OR Rabinovitch PS. DNA aneuploidy in colonic biopsies predicts future development of dysplasia in ulcerative colitis.Gastroenterology. 1992; 103: 1611-1620Abstract PubMed Google Scholar Hence, the safest approach would be to take at least 30-40 biopsies during a dysplasia surveillance endoscopy with increased biopsies in the lower left colon where cancers are more likely to arise, and to obtain a biopsy of any masses.13Bernstein CN. Challenges in designing a randomized trial of surveillance colonoscopy in IBD.Inflamm Bowel Dis. 1998; 4: 132-141PubMed Google Scholar Despite a similar rigorous approach to dysplasia surveillance, the group at St. Mark's Hospital reported patients presenting with colon cancer within 1-2 years of a prior dysplasia surveillance colonoscopy.15Connell WR Lennard-Jones JE Williams CB Talbot IC Price AB Wilkinson KH. Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis.Gastroenterology. 1994; 107: 934-944PubMed Google Scholar The search for masses that may harbor dysplasia in colons that may have scattered fields of pseudopolyps is a daunting challenge and a major pitfall of dysplasia surveillance. A dysplasia-associated lesion or mass (DALM) induces fear in gastroenterologists and finding such a lesion has typically mandated a colectomy.16Bernstein CN Weinstein WM Levine DS Shanahan F. Physicians' perceptions of dysplasia and approaches to surveillance colonoscopy in ulcerative colitis.Am J Gastroenterol. 1995; 90: 2106-2114PubMed Google Scholar, 17Eaden JA Ward BA Mayberry JF. How gastroenterologists screen for colonic cancer in ulcerative colitis: an analysis of performance.Gastrointest Endosc. 2000; 51: 123-128Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar However, all benign sporadic adenomas are also, by definition, dysplastic lesions or masses. Two groups have reported on outcomes from polypectomy of polyps and polyp-like lesions occurring in the setting of UC with subsequent dysplasia surveillance endoscopy.18Engelsgjerd M Farraye F Odze RD. Polypectomy may be adequate treatment for adenoma-like dysplastic lesions in chronic ulcerative colitis.Gastroenterology. 1999; 117: 1288-1294Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar, 19Rubin PH Friedman S Harpaz N Goldstein E Weiser J Schiller J Waye JD Present DH. Colonoscopic polypectomy in chronic colitis: conservative management after endoscopic resection of dysplastic polyps.Gastroenterology. 1999; 117: 1295-1300Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar Lesions that might be distinguished from DALMS, in that they appear as benign sporadic adenomas, include polyps on a distinct stalk, sporadic adenoma-like polyps proximal to the area of colitis, and adenoma-like masses (ALMs) (with characteristics of small benign lesions in noncolitis patients) within the colitis area. These 2 reports suggested that it is safe to pursue a polypectomy in all 3 of these lesions and pursue further surveillance as opposed to necessarily pursuing a colectomy simply because a dysplastic lesion has been found. The main critique of these studies was not of the methodologies or results but rather the implication that endoscopists can easily identify ALMs.20Bernstein CN. ALMs versus DALMs in ulcerative colitis: Polypectomy or colectomy?.Gastroenterology. 1999; 117: 1488-1491Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Few would argue with the suggestion that polyps on stalks within or proximal to the colitis area, or benign-appearing sessile sporadic-type adenomas proximal to the colitis, could be easily identified and safely endoscopically removed with a plan for future surveillance. However, the most difficult controversy is with regard to the sessile lesion that occurs within the colitis mucosa. It can be problematic for clinicians to discern within the colitis field a benign-type lesion that could be simply removed with polypectomy versus an inflammatory pseudopolyp that can be left alone. A fear harbored by endoscopists is that ignoring many lumps when some are obviously pseudopolyps may lead to missing a potentially dysplastic lesion. Another dilemma faced by endoscopists is in distinguishing a benign neoplastic lesion that could be simply removed with polypectomy (ALM) versus a DALM, a lesion associated with potentially more serious consequences. To date, no defining endoscopic characteristics have been reported to facilitate definite distinctions between inflammatory polyps, ALMs and DALMs (and particularly between these latter 2 lesions). It was reported by the 2 groups of investigators that they could clearly identify lesions that are like sporadic adenomas (ALMs). Although it is controversial as to whether ALM lesions in colitis zones should be treated with polypectomy and subsequent surveillance or mandate a colectomy, the critical issue arises earlier in the decision-making process. That is, whether endoscopists can easily identify which lumps are inflammatory and which are dysplastic, warranting biopsy or removal. Since dysplasia surveillance colonoscopy has been widely adopted16Bernstein CN Weinstein WM Levine DS Shanahan F. Physicians' perceptions of dysplasia and approaches to surveillance colonoscopy in ulcerative colitis.Am J Gastroenterol. 1995; 90: 2106-2114PubMed Google Scholar, 17Eaden JA Ward BA Mayberry JF. How gastroenterologists screen for colonic cancer in ulcerative colitis: an analysis of performance.Gastrointest Endosc. 2000; 51: 123-128Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar and yet obviously flawed, investigators have pursued novel adjunctive methods to enhance the finding of neoplasia.21Bernstein CN. The case against dysplasia surveillance in ulcerative colitis.in: Trends in inflammatory bowel disease therapy. Kluwer,, the Netherlands1996: 268-276Google Scholar Studying the tissue for the presence of aneuploidy has been proven to be a harbinger of dysplasia, but requires specialized flow cytometry and interest that has typically been available only in specialized centers. Others have used various special immunohistochemical stains for oncogenes such as p53, for altered mucins such as sialisyl-Tn, or for altered carbohydrates such as sucrase isomaltase (reviewed by Bernstein21Bernstein CN. The case against dysplasia surveillance in ulcerative colitis.in: Trends in inflammatory bowel disease therapy. Kluwer,, the Netherlands1996: 268-276Google Scholar). These additional staining approaches have been adopted by some investigators but only enhance recognition of changes in tissues that already have been extracted. These approaches do not enhance the endoscopist's ability to choose biopsy sites. They do not enhance the endoscopist's decisions regarding which lump should be biopsied and which flat area is most worthy of random biopsy. In this issue of Gastroenterology, Kiesslich et al.22Kiesslich R Fritsch J Holtmann M Koehler HH Stolte M Kanzler S Nafe B Jung M Galle PR Neurath MF. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis.Gastroenterology. 2003; 124: 880-888Abstract Full Text Full Text PDF PubMed Scopus (789) Google Scholar report an exciting development in the field of dysplasia surveillance colonoscopy. They have performed the first randomized controlled study involving dysplasia surveillance. This in and of itself is an important accomplishment and should encourage other investigators that the process can be improved upon with randomized studies without contravening any ethical concerns of not offering a patient a surveillance endoscopy. These investigators randomized 81 subjects with UC to undergo routine dysplasia surveillance colonoscopy with 5 biopsies taken every 10 cm randomly (and additional biopsies of suspicious lumps) and a well-matched group of 84 subjects with UC who underwent chromoendoscopy to facilitate targeted biopsies. Chromoendoscopy was performed by spraying methylene blue 0.1% on the colonic mucosa in 30-cm segments and observing the mucosa with a special magnifying endoscope. Biopsies were directed to the paler, less blue, or white areas because neoplastic epithelium is less likely to take up the dye. During the course of the chromoendoscopy the mucosa was scored for inflammation. The investigators found that chromoendoscopy better delineated the extent of inflammation by an average of 14 cm. More importantly, chromoendoscopy identified significantly more neoplastic lesions (35 in 13 cases, of which 32 were dysplasias and 3 were cancers, versus routine endoscopy plus biopsy where neoplasia was detected 11 times in 6 cases, of which 10 were dysplasias and 1 was cancer). Methylene blue was introduced as an agent to distinguish inflammation from normal colonic mucosa approximately 25 years ago.23Tada M Katoh S Kohli Y Kawai K. On the dye spraying method in colonofiberscopy.Endoscopy. 1977; 8: 70-74Crossref PubMed Scopus (59) Google Scholar, 24Baldi F di Febo G Biasco G Gizzi G Ferrarini F Milazzo G Barbara L. Methylene blue dye spraying method in patients with ulcerative proctitis: a comparative study with morphological findings and functional capacity of the rectal epithelium.Endoscopy. 1979; 11: 179-184Crossref PubMed Scopus (6) Google Scholar In the past decade, however, it has been studied as an adjunctive technique for identifying neoplastic from nonneoplastic mucosa. Missing some foci of inflammation in an otherwise obviously inflamed organ has much less clinical implication than missing neoplastic foci in either an inflamed or noninflamed organ. Methylene blue staining was reported to be highly accurate in identifying dysplasia in Barrett's esophagus25Canto MI Setrakian S Willis JE Chak A Petras RE Sivak MV. Methylene blue staining of dysplastic and nondysplastic Barrett's esophagus: an in vivo and ex vivo study.Endoscopy. 2001; 33: 391-400Crossref PubMed Scopus (136) Google Scholar and recently touted by a panel of experts as an important advance in Barrett's esophagus surveillance.26Canto MI Yoshida T Gossner L. Chromoscopy of intestinal metaplasia.Endoscopy. 2002; 34: 330-336Crossref PubMed Scopus (37) Google Scholar Kiesslich's group of investigators has also reported on the use of methylene blue as an adjunct to obtaining a biopsy in Barrett's esophagus.27Kiesslich R Hahn M Herrmann G Jung M. Screening for specialized columnar epithelium with methylene blue: chromoendoscopy in patients with Barrett's esophagus and a normal control group.Gastrointest Endosc. 2001; 53: 47-52Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar In that report, methylene blue enhanced the detection of specialized columnar epithelium (the extent of the Barrett's) but not necessarily of finding dysplastic lesions, most of which were visible endoscopically. Several other investigators have also found methylene blue staining to not be highly predictive of dysplastic mucosa in Barrett's. For instance, the positive predictive value for identifying dysplasia was 41% in one study,28Gangarosa L Balmain L Halter S Mertz H. Endoscopic ultrasound evaluation and methylene blue staining of Barrett's esophagus with low grade dysplasia.Dig Dis Sci. 2000; 45: 225-229Crossref PubMed Scopus (46) Google Scholar and in another prospective crossover design study comparing methylene blue-directed biopsy with a usual random biopsy there was no difference in pick up rates of dysplasia.29Wo JM Ray MB Mayfield-Stokes S Al-Sabbagh G Gebrail F Slone SP Wilson MA. Comparison of methylene blue-directed biopsies and conventional biopsies in the detection of intestinal metaplasia and dysplasia in Barrett's esophagus: a preliminary study.Gastrointest Endosc. 2001; 54: 294-301Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar In a recent Barrett's esophagus study, methylene blue staining was only 37% sensitive in picking up dysplastic lesions compared with routine histologic assessment of 4 quadrant biopsies. Although the specificity was good in this latter study (97%), to obviate the need for multiple biopsies, sensitivity would have to be excellent.30Egger K Werner M Meining A Ott R Allescher HD Hofler H Classen M Rosch T. Biopsy surveillance is still necessary in patients with Barrett's oesophagus despite new endoscopic imaging techniques.Gut. 2003; 52: 18-23Crossref PubMed Scopus (141) Google Scholar Therefore, high rates of predictive value of methylene blue for identifying dysplasia are either operator dependent or may require specialized magnifying endoscopes. There is also precedent for the use of methylene blue to identify microfoci of colonic dysplasia. For instance, it can enhance the detection of aberrant crypt foci in the normal colon.31Di Gregorio C Losi L Fante R Modica S Ghidoni M Pedroni M Tamassia MG Gafa L Ponz de Leon M Roncucci L. Histology of aberrant crypt foci in the human colon.Histopathology. 1997; 30: 328-334Crossref PubMed Scopus (79) Google Scholar These lesions, also termed microadenomas, are considered to be precursor lesions of adenomas.32Pretlow TP O'Riordan MA Pretlow TG Stellato TA. Aberrant crypts in human colonic mucosa: putative preneoplastic lesions.J Cell Biochem Suppl. 1992; 16G: 55-62Crossref PubMed Scopus (169) Google Scholar Methylene blue staining of resected colectomy specimens also identified flat adenomas,33Masaki T Sheffield JP Talbot IC Williams CB. Non-polypoid adenoma of the large intestine.Int J Colorectal Dis. 1994; 9: 180-183Crossref PubMed Scopus (7) Google Scholar although this technique for finding flat adenomas remains unproven in vivo via endoscopy. Magnifying endoscopy with a dye technique has previously been shown to have a high success rate at identifying colonic neoplasms.34Kudo S Tamura S Nakajima T Yamano H Kusaka H Watanabe H. Diagnosis of colorectal tumorous lesions by magnifying endoscopy.Gastrointest Endosc. 1996; 44: 8-14Abstract Full Text Full Text PDF PubMed Scopus (874) Google Scholar The success in the Kiesslich study in UC may relate simply to the use of methylene blue, which could be widely adopted by endoscopists with little extra cost. However, based on the experience with Barrett's esophagus, it may more likely reflect the use of the specialized magnifying endoscopes in combination with the dye. The availability of this technique may be dependent on the availability of these specialized endoscopes, and their widespread purchase will likely depend on further validation of this method. The authors do not discuss the use of a mucolytic agent because mucous can interfere with the uptake of the dye by colonic epithelium, and it is possible that the addition of such an agent may even further improve upon the technique.25Canto MI Setrakian S Willis JE Chak A Petras RE Sivak MV. Methylene blue staining of dysplastic and nondysplastic Barrett's esophagus: an in vivo and ex vivo study.Endoscopy. 2001; 33: 391-400Crossref PubMed Scopus (136) Google Scholar The ability of the dye technique to more accurately predict the extent of histological inflammation by approximately 15 cm will likely have little clinical impact. This alone will not likely change approaches to dysplasia surveillance (other than possibly ensuring that an appropriate number of biopsies are obtained randomly from the entire colitis field) and will not greatly impact on therapeutic decisions for colitis. The ability of the dye technique to identify neoplastic from nonneoplastic lesions to enhance pick up of more dysplastic lesions in flat mucosa is a potential major advance in dysplasia surveillance. In fact, this technique may help to provide answers for the 2 key questions posed previously. This technique may help target biopsies so that they are less random and ultimately some form of a proven dye technique may help the endoscopist who has little enthusiasm to persist through the tedium of 30-40 biopsies. Perhaps considerably fewer biopsies will be necessary. This technique may also help solve the problem of identifying at endoscopy those lumps that are neoplastic and not simply inflammatory. Although I would argue that using conventional endoscopy and random biopsy can not adequately provide dysplasia surveillance for those with multiple pseudopolyps (even the most enthusiastic endoscopist could not sample all raised areas in such a daunting colon), if chromoendoscopy can identify which are the neoplastic targets to be sampled and which are the nonneoplastic targets to be ignored this would be a major advance. However, in colons widely studded with pseudopolyps, the effects of the dye may be obscured. There were 2 false-negative results where nontargeted biopsies from colons studded with pseudopolyps proved to contain dysplasia that was not identified by chromoendoscopy.22Kiesslich R Fritsch J Holtmann M Koehler HH Stolte M Kanzler S Nafe B Jung M Galle PR Neurath MF. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis.Gastroenterology. 2003; 124: 880-888Abstract Full Text Full Text PDF PubMed Scopus (789) Google Scholar False-positives are also evident with chromoendoscopy as both highly inflamed areas and neoplastic areas do not take up the methylene blue dye.22Kiesslich R Fritsch J Holtmann M Koehler HH Stolte M Kanzler S Nafe B Jung M Galle PR Neurath MF. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis.Gastroenterology. 2003; 124: 880-888Abstract Full Text Full Text PDF PubMed Scopus (789) Google Scholar Thus, chromoendoscopy will not aid in the dilemma of distinguishing dysplasia histologically in the setting of severe inflammation. Although not studied in this article, it would be of interest to learn how well chromoendoscopy could identify which ALMs are really like sporadic adenomas and which are more like DALMs. A previous report described the potential value of chromoendoscopy in identifying neoplasms among protuberant and flat polypoid lesions in UC.35Jaramillo E Watanabe M Befrits R Ponce de Leon E Rubio C Slezak P. Small, flat colorectal neoplasias in long-standing ulcerative colitis detected by high-resolution electronic video endoscopy.Gastrointest Endosc. 1996; 44: 15-22Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar The 2 groups in this study were sufficiently comparable in their UC characteristics, and were sufficiently large to validate the results of finding more neoplastic lesions with chromoendoscopy. The study would have even had more impact had they followed up the routine endoscopy group with a chromoendoscopy and proved that lesions were in fact missed with routine endoscopy. It is plausible that some of the lesions missed at routine endoscopic surveillance (that chromoendoscopy would otherwise have identified for targeted biopsy) could account for those cases who have undergone thorough dysplasia surveillance endoscopies and return within 2 years with advanced CRC.14Rubin CE Haggitt RC Burmer GC Brentnall TA Stevens AC Levine DS Dean PJ Kimmey M Perera OR Rabinovitch PS. DNA aneuploidy in colonic biopsies predicts future development of dysplasia in ulcerative colitis.Gastroenterology. 1992; 103: 1611-1620Abstract PubMed Google Scholar It is reasonable that patients presenting to their local gastroenterologists tomorrow for cancer surveillance in UC should undergo a conventional colonoscopy with random biopsy and targeted biopsies of suspicious lesions. However, if the data by Kiesslich's group are reproduced by others, we may see the day where dysplasia surveillance without chromoendoscopy is second rate. Dysplasia surveillance endoscopy in UC has always engendered colorful debate. Soon it may simply be colorful.