It is well established that patients with long-standing. Screening and Surveillance Colonoscopy in Chronic Crohn s Colitis. Materials and Methods

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1 GASTROENTEROLOGY 2001;120: Screening and Surveillance Colonoscopy in Chronic Crohn s Colitis SONIA FRIEDMAN,* PETER H. RUBIN, CAROL BODIAN, ERIC GOLDSTEIN, NOAM HARPAZ, and DANIEL H. PRESENT *Division of Gastroenterology, Brigham and Women s Hospital, Boston, Massachusetts; and Departments of Medicine, Biomathematical Science, and Pathology, Mount Sinai Medical Center, New York, New York Background & Aims: Unlike ulcerative colitis, there are few reports on the efficacy of surveillance colonoscopy in patients with chronic Crohn s colitis and therefore little agreement as to whether routine surveillance is indicated. We report on 259 patients with chronic Crohn s colitis who underwent screening and subsequent surveillance colonoscopy and biopsy since Methods: Biopsies were performed at 10-cm intervals and from strictures and polypoid masses. Pathology was classified as normal, dysplasia (indefinite, low-grade, high-grade), or carcinoma. Results: A total of 663 examinations were performed on 259 patients. The median interval between examinations was 24 months; examinations were performed more frequently (1 6 months) in patients with dysplasia on biopsy. A thinner-caliber colonoscope was required to complete 12% of screening examinations and 23% of surveillance examinations. The pediatric colonoscope helped increase our yield of neoplasia by 19%. The screening and surveillance program detected dysplasia or cancer in 16% (10 indefinite, 23 low-grade, and 4 high-grade dysplasias and 5 cancers). A finding of definite dysplasia or cancer was associated with age >45 years and increased symptoms. By life table analysis, the probability of detecting dysplasia or cancer after a negative screening colonoscopy was 22% by the fourth surveillance examination. Conclusions: Colonoscopic surveillance should be strongly considered in chronic extensive Crohn s colitis. It is well established that patients with long-standing chronic ulcerative colitis are at increased risk for developing colonic epithelial dysplasia and carcinoma. 1 8 Despite methodologic and geographic differences among studies, the observed increase in cancer rates has led to the endorsement of surveillance colonoscopies with biopsies as the standard of care for patients with chronic ulcerative colitis Much less is known about the risk of colonic dysplasia and cancer in chronic Crohn s colitis. The first description of a colon cancer complicating regional enteritis was more than 50 years ago, 18 and since then there have been many reports of colorectal cancers in series of patients with Crohn s disease, with accumulating evidence for similarity in the incidence of colorectal cancer in ulcerative and Crohn s colitis of similar duration and extent. 29,30 Unlike the case in ulcerative colitis, screening and surveillance colonoscopy with biopsy have not been reported in populations of outpatients with chronic Crohn s colitis. Therefore, we report our experience in a group of 259 patients who were screened and surveyed by periodic colonoscopy and biopsy. Materials and Methods Screening Colonoscopy Following a diagnosis of metastatic colon cancer in a patient with Crohn s colitis, the authors embarked on a systematic practice of calling back patients with Crohn s colitis to examine for neoplasia. Since January 1980, all of one author s (D.H.P.) patients with Crohn s colitis diagnosed for 8 years or longer and at least one third of the colon involved were offered the opportunity to undergo colonoscopic screening and surveillance. Crohn s disease was diagnosed by standard radiographic, endoscopic, and/or pathologic criteria. Colonic involvement was quantified by gross approximation using barium enema or colonoscopy. Patients without colonic involvement or with inflammation limited to the cecal tip or rectum were excluded. This corresponds to the lack of increased cancer risk in patients with proctitis and the minimally increased risk in patients with proctosigmoiditis. 31 Left-sided disease was defined as that distal to the splenic flexure. We now report on the 259 patients who participated. All patients underwent colonoscopy performed by the same endoscopist (P.H.R.). The colonoscopic technique was the same as that used for patients with chronic ulcerative colitis, namely, 4 circumferential biopsies performed at approximately 10-cm intervals and additional biopsies if strictures or suspi- Abbreviations used in this paper: CA, carcinoma; HGD, high-grade dysplasia; IND, indefinite for dysplasia; LGD, low-grade dysplasia by the American Gastroenterological Association /01/$35.00 doi: /gast

2 March 2001 SURVEILLANCE IN CHRONIC CROHN S COLITIS 821 cious polypoid lesions were observed. If complete colonoscopy was precluded by stricturing, a pediatric colonoscope (0.9-cm diameter) was used. No colonoscopic balloon dilation was attempted. All biopsy specimens accessed after 1983, when the UC guidelines for histologic interpretation of dysplasia were written, were classified as normal, indefinite for dysplasia (IND), low-grade dysplasia (LGD), high-grade dysplasia (HGD), or carcinoma (CA), and were read predominantly by one pathologist (N.H.). 32 Biopsy specimens read in 1983 or earlier were classified as mild, moderate, or severe dysplasia or CA. All biopsy specimens that were positive for LGD, HGD, or CA were reviewed by a second pathologist before the patient was sent for surgery. We use the term neoplasia to include LGD, HGD, and CA. Surveillance Colonoscopy If results of screening colonoscopy were negative for dysplasia or CA, the patient was contacted for a repeat examination in 2 years. Initially, a handwritten call-back list was maintained, but after 1992 the list was computerized. Some patients waited longer than 2 years to report for surveillance colonoscopy despite notification by phone and mail. Patients with IND on any colonoscopy were contacted for extensive repeat biopsies within 1 year. Patients with 1 area of LGD were contacted for repeat endoscopy within 1 6 months. Patients with recurrent or multifocal LGD, HGD, or CA were referred for surgery. Data were gathered by retrospective chart review during the fall of The cutoff date for the end of the study was August Statistical Methods Screening examination. Continuous variables such as age and disease duration were grouped, and the Fisher exact test was used to test for an association between each demographic variable and the chance of finding dysplasia or CA. Surveillance examinations. Analysis of a first positive finding on the surveillance examinations was conducted as for time-to-event data, with the consecutive surveillance examinations representing the time variable. Thus, for each of the demographic variables, separate contingency tables were constructed for each surveillance examination to compare the rates of dysplasia or CA between groups of persons in categories of the designated variable with no prior positive findings, and the results of each set of tables were tested using a Mantel Haenszel test. The probability of discovering new dysplasia or CA on a surveillance examination was estimated by life table analysis on all patients who had a negative screening examination result and at least 1 surveillance examination, with follow-up duration terminated at the earliest evidence of a positive finding or, in the case of patients without dysplasia, at the last surveillance examination. All analyses were performed using the SAS program (SAS User s Guide; SAS Institute, Inc., Cary, NC) on a VAX computer. Results A total of 663 examinations (screening and surveillance) were performed, with a mean of 2.6 examinations per patient (range, 1 10). Screening Examination Demographics of the study population are reported in Table 1. This was a unique group of patients in that 90% had extensive colitis. Thirty-four percent had previously undergone segmental colon resection. Only 1 dysplasia was found between 1980 and It was initially classified as mild and then reread after 1983 as indefinite. At the initial screening examination, definite dysplasia was found in 16 patients (6.2%) (Table 2). Eleven patients had LGD, 2 had HGD, and 3 had CA. Three had IND. One of these CAs and 1 LGD were found by use of a pediatric colonoscope. There were no colonoscopic complications. IND is a controversial finding and is not included as a neoplasia in most ulcerative colitis surveillance studies. 2,6 To be certain that disregarding IND in our statistical analyses made no difference, we recalculated all of our statistical tables to include IND and found the same associations (data not shown). The prevalence of neoplasia on screening examinations was higher in patients who were older than 45 years (P 0.065) and those who had a change in symptoms as the indication for colonoscopy (P 0.003; Table 3), whereas disease duration (using 20 years as a cutoff) did not Table 1. Demographics of Study Population Screening Examinations Female % Median age at diagnosis (yr) (range) 22 (2 61) Median disease duration (yr) (range) 19 (8 49) Median age at colonoscopy (yr) (range) 42 (16 80) Anatomic extent Ileocolitis % Colitis % Location Right-sided only 13 5% Left-sided only 13 5% Extensive colitis % Rectal sparing 93 40% First-degree relative with IBD 47 18% First-degree relative with colon cancer 10 4% Prior partial colonic resection 88 34% Clinical status at screening colonoscopy No change in symptoms % Increased symptoms 36 14% Complete colonoscopies % Regular colonoscope 196 Pediatric colonoscope 32 NOTE. N 259 patients. IBD, inflammatory bowel disease.

3 822 FRIEDMAN ET AL. GASTROENTEROLOGY Vol. 120, No. 4 Table 2. New Cancer/Dysplasia Found at Colonoscopy IND LGD HGD CA Total examinations Screening 3 11 (1) a 2 3 (1) a 259 Surveillance (1) a 1 1 (1) a (1) a b a Found with pediatric colonoscope. b No neoplasia was found at the 6th surveillance examination or thereafter. correlate with prevalence of neoplasia (data not shown). Among patients with shorter duration of colitis, however, the prevalence of neoplasia was higher in patients older than 45 years (P 0.055; Table 4). No significant difference in neoplasia prevalence was observed with respect to age in patients with disease duration more than 20 years. Forty-seven of our patients were younger than 14 years when they had Crohn s disease diagnosed. The mean time from diagnosis to screening colonoscopy in this particular group of patients was 22.3 years. Two LGDs were found on screening colonoscopies (4.3%). Surveillance Examinations Demographics of the patients who underwent surveillance colonoscopy are reported in Table 5. On surveillance examinations, a first positive finding of neoplasia was found in 16 patients (9.4%; 12 LGD, 2 HGD, 2 CA; Table 2). LGD, HGD, or CA was detected as late as the fourth surveillance examination. Seven patients with IND were detected during surveillance. Two of these LGDs and 1 CA were found only by use of a pediatric instrument. There were no colonoscopic complications. As with screening examinations, patients with neoplasia on surveillance examinations were more likely to be older than 45 years (P 0.048; Table 6). When disease Table 3. Demographic Features Associated With a Finding of Neoplasia on Screening Examination Factor No. positive for neoplasia (%) Significance Age 45 yr 5/146 (3.4) P yr 11/113 (9.7) Indication Routine 9/223 (4) P Change in symptoms 7/36 (19) Table 4. Test of Influence of Age on Yield (LGD, HGD, CA) by Duration of Disease Screening Examinations 8 20 yr 20 yr Age 45 yr 2.8% 5% (3/106) (2/40) Age 45 yr 12.1% 8.8% (4/33) (7/80) Significance P P duration was taken into account, the association between age and yield remained statistically significant (P 0.031; Table 7). Unlike the case in screening, there was no correlation of neoplasia with increased symptoms on surveillance examinations. Thirty-four patients whose conditions were diagnosed when they were younger than 14 years underwent at least 1 surveillance colonoscopic examination. One LGD was found on the first surveillance examination (2.9%). Three INDs were found; 2 on the first and 1 on the second surveillance examination. We used life table methods to estimate the cumulative yield achieved in succeeding examinations by instituting routine surveillance colonoscopy after a negative screening result in this referral practice. The probability of finding neoplasia by the fourth surveillance examination in this group of patients was 22% (95% confidence interval, 10% 34%; Figure 1). Patient Outcomes After a Finding of Dysplasia or Cancer Indefinite dysplasia. IND was found during screening or surveillance examinations in 10 patients. Because the significance of IND is controversial, we did not include it in any of our statistical analyses. Patient follow-up is indicated in Table 8. We found 1 CA on follow-up surveillance examination, a Dukes A lesion. It Table 5. Demographics of Study Population Surveillance Examinations Surveillance examinations not preceded by a positive finding (n 404) Median interval between examinations (mo) (range) 24 (6 77) Any prior partial colonic resection 109 patients (42%) Clinical status at surveillance colonoscopy No change in symptoms 384 examinations (95%) Increased IBD symptoms 20 examinations (5%) Complete colonoscopies 375 examinations (93%) Regular colonoscope 282 examinations Pediatric colonoscope 93 examinations NOTE. N 404 examinations in 171 patients. IBD, inflammatory bowel disease.

4 March 2001 SURVEILLANCE IN CHRONIC CROHN S COLITIS 823 Table 6. Demographic Features Associated With an Initial Finding of Neoplasia on Surveillance Examination Examination Age 45 yr a Age 45 yr a 1 2/82 (2.4%) 6/89 (6.7%) 2 0/43 (0%) 3/64 (4.7%) 3 0/18 (0%) 0/42 (0%) 4 1/11 (9%) 4/21 (19%) NOTE. Data represent number (%) positive for neoplasia. Overall significance, P a Age at the time of each surveillance examination. was found in a polyp in an area of surrounding colitis and was removed by snare cautery (follow-up, 43 months). Low-grade dysplasia. LGD was found during screening or surveillance examinations in 23 patients (Table 8). Surgical resection. Six patients underwent surgical resections for recurrent or multifocal LGD. Patient follow-up is detailed in Table 8. One CA was found at surgery. It was a Dukes B2 lesion, and the patient is now receiving chemotherapy. No surgical resection. Seventeen patients with unifocal LGD did not undergo surgical resection. Follow-up is indicated in Table 8. One HGD was found on follow-up surveillance colonoscopy. It was located in a polyp in an area of colitis in a 62-year-old man (followup, 10 months) and was removed by snare cautery. High-grade dysplasia. We found HGD in 4 patients on colonoscopy: 2 on screening and 2 on surveillance examinations. All had surgical resections (Table 8). One Dukes B2 CA was found at surgery. The patient has had no recurrence after chemotherapy (follow-up, 15 months colonoscopy to surgery, 8 months after chemotherapy). Table 7. Chance of an Initial Finding of Neoplasia (LGD, HGD, CA) on Surveillance Examination: Influence of Age on Yield by Duration of Disease 8 20 yr 20 yr 1st Surveillance Age 45 yr 3.8% (2/52) 0% (0/30) Age 45 yr 8.7% (2/23) 6% (4/66) 2nd Surveillance Age 45 yr 0% (0/24) 0% (0/19) Age 45 yr 7.7% (1/13) 4% (2/51) 3rd Surveillance Age 45 yr 0% (0/11) 0% (0/7) Age 45 yr 0% (0/8) 0% (0/34) 4th Surveillance Age 45 yr 0% (0/5) 17% (1/6) Age 45 yr 33% (1/3) 17% (3/18) NOTE. Controlling for duration and stratifying on examinations, overall P for influence of age on incidence of neoplasia. Age and duration are reported at the time of each surveillance examination. Figure 1. Probability of finding definite dysplasia or CA on surveillance examinations. Carcinoma. We found CAs on colonoscopy in 5 patients (Table 8). Three were found on screening and 1 each on the first and fourth surveillance examinations. Three had surgical resections immediately after diagnosis. Two were Dukes B2 lesions, and the patients received chemotherapy. In the third patient, no cancer was found Table 8. Follow-Up for Patients With Positive Examination Results: Worst Lesion Found on Colonic Resection or on Subsequent Examination if no Resection Initial finding (n) IND (10) (all underwent surveillance) Mean time interval (mo) (range) Worst lesion found (n) 24.2 (3 68) NEG (6) 4 (0 12) IND (3) 43 CA (1) LGD (23) Surgery (6) 23 IND (1) 19 (14 24) LGD (2) 7.5 (0 15) HGD (2) 20 CA (1) Surveillance (17) 35.3 (11 92) NEG (10) 12 IND (1) 26.8 (0 91) 10 LGD (5) HDG (1) HGD (4) (all had surgery) 7 NEG (1) 6 (0 12) HGD (2) 15 CA (1) CA (5) Surgery (3) 0 NEG (1) 0 CA (2) Polypectomy (2) 32 (2 62) NEG (2) NOTE. Arrows indicate time from initial finding to worst lesion found at surgery or subsequent colonoscopy. NEG, negative.

5 824 FRIEDMAN ET AL. GASTROENTEROLOGY Vol. 120, No. 4 at colonic resection despite extensive review of the gross and microscopic specimens, probably because all cancer was removed during endoscopic polypectomy. All 3 patients are disease free at a mean follow-up of 27 months (range, months). Two patients had Dukes A CA in polyps removed endoscopically by snare cautery in areas of surrounding colitis. Both had subsequent negative colonoscopies, with the last negative follow-up results at 2 and 62 months, respectively. Discussion This report describes a highly selected group of patients who were followed up based on clinical practice, not via a rigid protocol. We used pathology reports that were appropriate for each time period. In our longitudinal series of 259 patients, we found new dysplasia (LGD, HGD) or cancer in 32 (12%). Of the cases positive for neoplasia, 50% were found on screening examinations and 50% on surveillance examinations. After a negative screening result, the probability of finding neoplasia by the fourth surveillance examination was 22%. These rates are higher than those reported in earlier studies of Crohn s colitis 30 (8% at 22 years) but are comparable to those reported for chronic ulcerative colitis from a tertiary referral center 33,34 (13% at 20 years, 34% at 30 years). Although all of our study patients are in a private practice setting, our office is a tertiary referral center for inflammatory bowel disease. In contrast to the several population studies of the risk of CA in chronic Crohn s colitis in which only a small subset of patients had long-standing, extensive colonic disease, almost all of our patients (90%) had longduration, extensive colitis. Because the extent of disease in our patients parallels that in most ulcerative colitis studies 7,10,11 this may explain why the prevalence and incidence of neoplasia is similar. It is possible that if we had studied more patients with short-segment disease, there might have been a lower probability or later onset of developing neoplasia, just as patients with left-sided ulcerative colitis have been observed to develop neoplasia later in the course of the disease. 33 Unlike previous reports, 39,40 we did not find an increased incidence of anal or rectal dysplasia in this group of patients, possibly because we excluded patients with limited colonic involvement. Both the screening and surveillance phases of our study found that age 45 years at the time of colonoscopy was associated with an increased risk of neoplasia. Although we did not find an association of neoplasia with duration of disease per se, we found that on screening examinations, for patients with short-duration disease (8 20 years), age 45 years was especially important. On surveillance examination, in disease of both short (8 20 years) and long ( 20 years) duration, older age was also significant. Another group of patients of extra concern are those with a change in symptoms as the indication for screening colonoscopy. In our study, the prevalence of neoplasia was significantly greater if the indication was increased symptoms, although only 14% of our patients screened were in this category. On surveillance examination, an increase in symptoms as the indication for colonoscopy was not associated with an increased incidence of neoplasia. Although colonoscopy done for increased symptoms is usually not part of a routine surveillance program, we considered it important to include these patients in our analysis because they reflect the patients seen in an everyday outpatient gastroenterology practice, where colonoscopy is performed for increased symptoms. Patients with ulcerative colitis diagnosed before age 14 years have a high incidence of CA. 31 However, this was not the case in our series. In fact, patients younger than 14 years at diagnosis had a lower incidence and prevalence of neoplasia than all of the patients combined. However, this subset of patients is not a representative cohort of cases because they survived a long time without known dysplasia. Colonoscopy is often technically difficult in Crohn s disease because of stricturing. 41 A thinner-caliber pediatric colonoscope enabled us to improve our percentage of complete screening examinations by 16% and surveillance examinations by 33%, bringing total colonic visualization to 88% (screening) and 93% (surveillance). In fact, in 5 patients the first positive finding of neoplasia was achieved only by use of a pediatric colonoscope. Following the earlier view of Lindner et al., 42 we perform single-contrast barium enema examinations on patients in whom colonoscopy is incomplete. Many strictures can be shown to have a benign appearance, and thus far, no neoplasia has been detected in patients with incomplete examinations. Other limitations to surveillance in Crohn s colitis include bypassed or excluded segments of colon. There were no complications during or after the 663 colonoscopic examinations reported here. This is similar to the reported experience of safety in screening and surveillance programs for chronic ulcerative colitis. 12,17 Although the median time between examinations not preceded by a positive finding was 24 months, our longest time to follow-up was 77 months. This occurred despite our efforts to notify all of our patients. This is a

6 March 2001 SURVEILLANCE IN CHRONIC CROHN S COLITIS 825 common problem with all surveillance programs and gives us a realistic picture of the limitations of any surveillance program. We conclude that screening and surveillance colonoscopies in patients with 8 or more years of Crohn s colitis can detect neoplasia in a sizable portion of such patients. In our rather selected population of 259 patients with predominantly extensive colitis, the cumulative incidence of neoplasia parallels that reported in extensive ulcerative colitis. The data indicate that patients older than 45 years and/or those with a recent change in symptoms may be at particular risk. Because only 1 patient progressed from LGD to CA, longer-term surveillance programs are needed to determine whether surgical resection is necessary after a single finding of LGD. We believe recurrent or multifocal LGD, HGD, and CA are indications for surgical resection. Despite the high incidence and prevalence of neoplasia found in our study, all patients who have complied with surveillance are alive with no evidence of cancer. However, we recognize that this may be related to a short follow-up period for many patients, and continued surveillance is warranted. We recommend that all patients with extensive Crohn s and ulcerative colitis be kept in a registry and that the same surveillance programs already used in ulcerative colitis be strongly considered in patients with extensive Crohn s colitis. Only future prospective studies will determine the appropriate time intervals for surveillance. References 1. Dawson IM, Pryse-Davies J. The development of carcinoma of the large intestine in ulcerative colitis. Br J Surg 1959;47: Lindberg B, Persson B, Veress B, Ingelman-Sundberg H, Granqvist S. Twenty years colonoscopic surveillance of patients with ulcerative colitis: detection of dysplastic and malignant transformation. 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7 826 FRIEDMAN ET AL. GASTROENTEROLOGY Vol. 120, No. 4 Sommers SC, Yardley JH. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol 1983;14: Greenstein AJ, Sachar DB, Smith H, Pucillo A, Papatestas AE, Kreel I, Geller SA, Janowitz HD, Aufses AH Jr. Cancer in universal and left-sided ulcerative colitis: factors determining risk. Gastroenterology 1979;76: Desaint B, Legendre CI, Florent CH. Dysplasia and cancer in ulcerative colitis. Hepatogastroenterology 1989;26: Kvist N, Jacobsen O, Norgaard P, Ockelmann HH, Kuist HK, Schou G, Jarnum S. Malignancy in Crohn s disease. Scand J Gastroenterol 1986;21: Gollop JH, Phillips SH, Melton LJ, Zinzmeister AR. Epidemiologic aspects of Crohn s disease: a population based study in Olmstead County, Minnesota, Gut 1988;29: Fireman Z, Grossman A, Lilos P, Hacohen D, Bar Meir S, Rozen P, Gilat T. Intestinal cancer risk and mortality in patients with Crohn s disease. A population study in central Israel. Scand J Gastroenterol 1989;24: Sachar DB. Cancer in Crohn s disease: dispelling the myths. Gut 1994;35: Connell WR, Sheffield JP, Kamm MA, Ritchie JK, Hawley PR, Lennard-Jones JE. Lower gastrointestinal malignancy in Crohn s disease. Gut 1994;35: Nikias G, Eisner T, Katz S, Levin L, Eskries D, Urmacher C, McKinley M. Crohn s disease and colorectal cancer: rectal and perineal disease. Gastroenterology 1995;90: Yamazaki Y, Ribeiro MB, Sachar DB, Aufses AH, Greenstein AJ. Malignant colorectal strictures in Crohn s disease. Am J Gastroenterol 1991;86: Lindner AE, Marshak RH, Wolf BS, Janowitz HD. Granulomatous colitis: a clinical study. N Engl J Med 1963;269: Received February 8, Accepted November 8, Address requests for reprints to: Daniel H. Present, M.D., 12 East 86th Street, New York, New York Fax: (212) The authors thank Dr. Steven Itzkowitz for his time and expertise in helping to write and revise the manuscript.