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Jumbo forceps are superior to standard large-capacity forceps in obtaining diagnostically adequate inflammatory bowel disease surveillance biopsy specimens
ORIGINAL ARTICLE: Clinical Endoscopy
Jumbo forceps are superior to standard large-capacity forceps in obtaining diagnostically adequate inflammatory bowel disease surveillance biopsy specimens B. Joseph Elmunzer, MD, Peter D. R. Higgins, MD, PhD, MSc, Yong M. Kwon, MD, Christopher Golembeski, MD, Joel K. Greenson, MD, Sheryl J. Korsnes, MA, Grace H. Elta, MD Ann Arbor, Michigan, USA
Background: In inflammatory bowel disease (IBD) surveillance colonoscopy, an increased number of biopsy specimens correlates with a higher dysplasia detection rate. Larger biopsy specimens may also increase the diagnostic yield. Objective: To compare a new jumbo forceps with a standard large-capacity forceps in obtaining diagnostically adequate IBD surveillance biopsy specimens. Design: Prospective single-center study. Patients and Methods: Twenty-four patients who were undergoing an IBD surveillance colonoscopy were enrolled. As part of standard IBD surveillance, 8 paired biopsy specimens were obtained from the rectosigmoid by using the jumbo forceps and a standard large-capacity forceps. Outcome Measurements: Biopsy specimens were deemed adequate if they met all 3 of the following criteria: (1) length R3 mm, (2) penetration into the muscularis mucosa, and (3) !20% crush artifact. Results: The proportion of adequate biopsy specimens obtained with the jumbo forceps was significantly higher than that obtained with the large-capacity control forceps (67% vs 48%, P!.0001). The average length of the biopsy specimen obtained with the jumbo forceps was 4.00 mm (95% CI, 3.81-4.20 mm) compared with 3.19 mm (95% CI, 2.99-3.38 mm) with the large-capacity (control) forceps. Limitations: (1) No validated outcome measurement for the quality of GI biopsy specimens exists and (2) in this study, interobserver variability between pathologists was high. Conclusions: The jumbo forceps was superior to a standard large-capacity forceps in obtaining diagnostically adequate IBD surveillance biopsy specimens. Because biopsy specimens obtained with the jumbo forceps were larger, the use of this forceps for IBD surveillance will allow the endoscopist to sample a larger colonic mucosal surface area, potentially resulting in an increased dysplasia detection rate. (Gastrointest Endosc 2008;68:273-8.)
Histopathologic evaluation is critical in the diagnosis of GI disease. The overall quality of a specimen has a major impact on diagnostic accuracy, and it is widely accepted that specimen size is the most important factor contributing to the quality. This may be especially true in an inflammatory bowel disease (IBD) surveillance colonoscopy,
See CME section; p. 334. Copyright ª 2008 by the American Society for Gastrointestinal Endoscopy 0016-5107/$32.00 doi:10.1016/j.gie.2007.11.023
where it has been shown that an increased number of biopsy specimens (increased total surface area) correlates with higher sensitivity for detecting dysplasia.1 Several different endoscopic biopsy forceps are commercially available. Although these forceps differ in design and mechanics, they have been shown to produce generally equivalent biopsy specimens.2 The Radial Jaw 4-jumbo forceps (Boston Scientific Corp, Natick, Mass) is a disposable, Food and Drug Administration–approved, enlarged forceps that was engineered to pass through the accessory channel of a standard nontherapeutic colonoscope. Because of the enlarged size of the forceps cup, it is theoretically able to produce larger specimens with minimal artifact.
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Abbreviations: IBD, inflammatory bowel disease; ICC, intraclass correlation.
Biopsy specimens in inflammatory bowel disease
Because the total number of biopsy specimens has been shown to correlate with the sensitivity of detecting dysplasia in patients with IBD who are undergoing surveillance, larger, more interpretable specimens may also increase the diagnostic yield. This premise was demonstrated in Barrett’s esophagus, where a jumbo forceps has been recommended for obtaining surveillance biopsy specimens.3,4 Furthermore, because of chronic inflammation and fibrosis, some patients with IBD of long duration develop burned out, tubular colons with ‘‘stiff ’’ colonic mucosa, from which adequate biopsy specimens are difficult to obtain. Jumbo forceps may be particularly effective in acquiring diagnostically adequate biopsy specimens in this patient population. We compared the jumbo forceps with a standard large-capacity forceps in obtaining diagnostically adequate IBD surveillance biopsy specimens.
PATIENTS AND METHODS A total of 24 consecutive patients referred for an IBD surveillance colonoscopy consented to participate and were enrolled in the study. Inclusion criteria were R18 years of age and successful performance of a full colonoscopy with surveillance biopsies. Exclusion criteria were an inability or unwillingness to consent to the study and coagulopathy (defined as an international normalized ratio O1.4, partial thromboplastin time O1.5 times the upper limit of normal, or platelets !50,000/mm3). Because these patients were undergoing a colonoscopy for IBD surveillance, they all had quiescent or mildly active colitis. This study was approved by the University of Michigan Investigational Review Board. As part of standard surveillance, each enrolled patient had 8 control biopsy specimens and 8 additional jumbo (experimental) biopsy specimens obtained from the rectosigmoid segment, where the highest incidence of dysplasia and colorectal cancer is thought to occur. Each biopsy specimen obtained with the control forceps was immediately followed by an experimental biopsy obtained within 1.5 cm of the first biopsy, targeted at the same tissue. This strategy ensured that any particular set of biopsy specimens (control and experimental) was obtained from the same anatomical location in the same patient, thereby resulting in an internal control. Polypoid lesions or suspected dysplasia-associated lesions or masses were not included in the study biopsy specimens because of a possible inability to acquire comparable tissue (if small polyps were removed with the first biopsy). All biopsy specimens were handled, stored, and processed in a similar fashion. Specimen jars were labeled with a study code number, which ensured that the pathologist who was examining the specimens was blinded to which forceps was used in the acquisition of any particular set of biopsy specimens. The biopsy specimens were 274 GASTROINTESTINAL ENDOSCOPY Volume 68, No. 2 : 2008
Elmunzer et al
Capsule Summary What is already known on this topic d
An increased number of biopsy specimens taken during surveillance colonoscopy for inflammatory bowel disease (IBD) correlates with a higher dysplasia detection rate and may enhance the overall diagnostic yield.
What this study adds to our knowledge d
d
In a prospective comparison in 24 patients with IBD, the proportion of adequate biopsy specimens obtained with a jumbo forceps was significantly higher than that with a standard large-capacity forceps. The average specimen length obtained with the jumbo forceps was 4.00 mm compared with 3.19 mm with the large-capacity forceps.
evaluated by 1 pathologist for the following characteristics: (1) length in millimeters, (2) penetration into the muscularis mucosa, and (3) percentage of crush artifact. In the case of a fracture of a biopsy specimen, the 8 largest pieces from each jar were evaluated. In addition, clinical and procedure characteristics, including the patient’s age and sex; the type, extent, severity, and duration of colitis; the current use of corticosteroids; and the endoscopist performing the procedure were recorded. Based on published data2,5,6 and the expertise of the University of Michigan’s nationally renowned group of GI pathologists, a biopsy specimen adequacy outcome measure was defined before the initiation of the study. A specimen was deemed diagnostically adequate if it met all 3 of the following criteria: (1) length R3 mm, (2) penetration into the muscularis mucosa, and (3) !20% crush artifact. These criteria were determined a priori, without knowledge of the expected characteristics of jumbo forceps–obtained tissue. The control forceps was the Radial Jaw 3 large-capacity (with needle) forceps (Boston Scientific Corp). This product was chosen based on its high frequency of use nationally for the indication of IBD surveillance biopsies and its similarity to most commercially available large-capacity forceps. Interobserver variation between interpreters was assessed by having a second expert pathologist evaluate a subset of 80 biopsy specimens (40 control and 40 experimental specimens) for length and adequacy. These results were compared with the primary pathologist’s interpretation.
Statistical design The primary end point was the fraction of diagnostically adequate biopsy specimens obtained with the jumbo forceps compared with the fraction of diagnostically adequate biopsy specimens obtained with the standard large-capacity (control) forceps, when controlled for the www.giejournal.org
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effects of the individual patient, disease characteristics, and the endoscopist. The sample size was calculated with the goal of detecting a 15% difference in the fraction of adequate biopsy specimens between the jumbo and the control forceps. By assuming a 2-sided P value of .05 and a power of 80%, 113 biopsy specimens per group would be needed to detect this intended difference. Because the biopsy specimens are clustered by patient and not independent of one another within a given patient, multilevel modeling analysis and adjustment of the sample size was required. The sample-size adjustment was based on our estimate of the correlations between biopsy specimens within a patient (intraclass correlations [ICC]). Based on an estimated ICC of 0.7, the adjusted sample size was 194 biopsy specimens per group (24 patients). The ICC was estimated based on the standard premise that the range of reasonable outcomes divided by 4 is roughly equivalent to the standard deviation. To analyze the results, we used a mixed model (PROC GLIMMIX in SAS 9.1.3; SAS Inc, Cary, NC), with random intercept and a fixed effect of the biopsy forceps. We also included random effects of the subject and the subjectforceps interaction in the model. This allowed us to control for variation between patients and clustering of similar results by patient. We chose to use a fixed effect for the biopsy forceps, because we wanted to precisely estimate the effect of the forceps used. We chose to use random effects for the subject and subject-forceps interaction, because we wanted to control for these effects but did not want to precisely estimate the effect for an individual subject. Rather, our goal was to control for this effect to make our results generalizable to all patients with chronic colitis. As a secondary outcome, we evaluated the difference between the forceps in biopsy size (length) and fraction of biopsy specimens that penetrated the muscularis mucosa, controlling for patient, subject, and subjectforceps interaction. A similar statistical approach was used, with a mixed model, for this continuous outcome (PROC MIXED, SAS 9.1.3). This end point, because it uses a continuous outcome, has more power to detect a difference between the two forceps than the primary outcome; the sample size was more than sufficient for this end point. Point estimates and CIs for the adjusted mean biopsy length and adjusted probability of adequate biopsy specimens were generated after modeling with an LSMEANS statement in SAS 9.1.3.
Biopsy specimens in inflammatory bowel disease
biopsy specimen. The 95% upper CI for incremental cost was calculated by finding the difference between the lower CI for the number of adequate jumbo biopsy specimens and the upper CI for the number of adequate control biopsy specimens, and then dividing this value by the difference in cost between the forceps. The 95% lower CI for cost per additional adequate biopsy specimen was calculated by performing the same calculation with the upper CI for the number of adequate jumbo biopsy specimens and the lower CI for the number of adequate control biopsy specimens.
RESULTS Enrolled patient and disease characteristics are listed in Table 1. By design, no patients enrolled in this study had active colitis.
Biopsy specimens
A cost analysis of using the jumbo forceps instead of the control forceps was performed. This analysis evaluated the incremental cost of using the jumbo forceps as it relates to the number of additional adequate biopsy specimens that can be expected from using this forceps. The results are reported as the cost per additional adequate
The crude characteristics of biopsy specimens obtained with the control forceps and the jumbo forceps are listed in Table 2. Neither forceps resulted in crush artifact, presumably because of the large cup size of both devices. The probability of acquiring an adequate biopsy specimen with the jumbo forceps, controlling for variation between patients, was 0.67, 95% CI, 0.61-0.74. In comparison, the probability of acquiring an adequate biopsy specimen with the control forceps, controlling for variation between patients, was 0.48, 95% CI, 0.42-0.55. The difference was statistically significant (P ! .0001). The average length of biopsy specimen obtained with the jumbo forceps, controlling for variation between patients, was 4.00 mm, 95% CI, 3.81-4.20 mm. By comparison, the average length of biopsy specimen obtained with the control forceps, controlling for variation between patients, was 3.19 mm, 95% CI, 2.99-3.38 mm. The difference was statistically significant (P Z .0001). The probability of acquiring a biopsy specimen that penetrates into the muscularis mucosa with the jumbo forceps, controlling for variation between patients, was 77.8% (95% CI, 71.3%-83.6%), compared with 62.1% (95% CI, 54.6%-69.2%) with the control forceps. This difference was statistically significant (P Z .001). In multivariate analysis, the patient effect was significant. In other words, the variation between individual patients had a significant impact on the length and adequacy of their biopsy specimens. This was expected, because some patients have burned-out, tubular colons with ‘‘stiff ’’ mucosa, from which adequate biopsy specimens are difficult to obtain, whereas other patients have a softer mucosa that is more permissive of large biopsy specimens. We tested whether the jumbo forceps made a particular difference in the patients with the ‘‘more difficult’’ colon. The average jumbo forceps biopsy specimen length, sorted by whether the control forceps biopsy
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TABLE 1. Demographics and disease characteristics of patients Characteristics Crohn’s/ulcerative colitis Women (no./total)
10/13 (1 indeterminate colitis) 18/24 6/24
White (no./total)
23/24 (95.8%)
Median current age (y)
TABLE 2. Crude data on biopsy specimen characteristics by forceps
Characteristic
Control forceps
Jumbo forceps
Mean length, mm (SD)
3.2 (1.3)
4.0 (1.7)
61.7
77.9
None reported
None reported
Participants (n Z 24)
Men (no./total)
Mean age (y)
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Biopsy specimens penetrating MM (%) Crush artifact (%)
50.7 53 (range 29-76, IQR 40.0-59.5)
MM, Muscularis mucosa.
Location/type of disease (no./total) Left-sided ulcerative colitis
5/24
Ulcerative pancolitis
6/24
Crohn’s colitis
TABLE 3. Average jumbo forceps biopsy specimen length (sorted by tertile) Average biopsy specimen length, mm
10/24
Tertile
Control forceps
Jumbo forceps
Ulcerative colitis, unknown
2/24
Lowest
2.55
3.48
Indeterminate pancolitis
1/24
Middle
3.07
4.02
Highest
3.82
4.41
Mean duration of disease (y)
19.9
Median duration of disease (y)
17.5 (IQR 12-27)
Current steroid use (no./total)
2/24
IQR, Interquartile range.
specimen length was in the lowest, middle, or highest tertile, is listed in Table 3. Jumbo biopsy specimens are significantly larger in all 3 tertiles, indicating that the jumbo forceps obtain larger biopsy specimens even in patients with the ‘‘stiff ’’ mucosa phenomenon.
Patient characteristics and endoscopist effects We considered the effects of patient age, diagnosis of ulcerative colitis versus Crohn’s disease, duration, extent, and severity of colitis in the variation of biopsy length and adequacy. When tested in the multivariate model, none of these factors were significant predictors of biopsy specimen adequacy or length. A total of 13 endoscopists participated in this study. Endoscopist identity was not significant in the multivariate model, which suggested that endoscopist training and technique did not greatly influence the adequacy or length of biopsy specimen.
Cost analysis Based on the above results, 40 surveillance biopsy specimens obtained per colon with the jumbo forceps would yield an average of 26.9 adequate biopsy specimens. Forty surveillance biopsy specimens obtained with the control forceps would yield only 19.3 adequate biopsy specimens, resulting in an additional 7.6 adequate biopsy specimens per colonoscopy if the jumbo forceps is used. The average difference in cost between the jumbo forceps and the control forceps at our institution was $12. Therefore, the incremental cost for each additional adequate biopsy by using the jumbo forceps was $1.57. The 95% lower confidence bound for cost per additional adequate biopsy was $0.92 and the 95% upper confidence bound was $5.51. These results are illustrated in Table 4. Of note is that forceps pricing may vary significantly, depending on factors such as institution contract and purchase volume. Nevertheless, in 2006, the average price difference between a regular and a jumbo forceps in the United States was approximately $27. At this price difference, the incremental cost per additional adequate biopsy when using the jumbo forceps was $3.55, 95% CI, $2.11-$11.25.
Interobserver variation
No complications attributable to the jumbo forceps occurred in this study.
A subset of 80 biopsy specimens was also evaluated by a second pathologist. The Pearson correlation for length between pathologists was 0.256. The kappa values for muscularis mucosa penetration and adequacy could not be calculated because of scattered fixing of specimens per slide; we were unable to confidently ensure that the
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Safety
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TABLE 4. Incremental cost analysis of jumbo versus control forceps
Forceps
Incremental cost per patient, US$
Probability of a diagnostically adequate biopsy specimen (95% CI)
Control
–
0.48 (0.42-0.55)
19.3 (16.8-22)
Jumbo
12
0.67 (0.61-0.74)
26.9 (24.4-29.6)
pathologists were comparing the same exact specimen. Pathologist no. 1 deemed 60% of biopsy specimens in the jumbo forceps subset adequate and 30% of biopsy specimens in the control subset adequate. Pathologist no. 2 deemed 42.5% of biopsy specimens in the jumbo forceps subset adequate and 12.5% of biopsy specimens in the control subset adequate. Therefore, as demonstrated in Table 5, both pathologists were 30% more likely to consider a jumbo forceps specimen adequate compared with a control specimen.
No. diagnostically adequate biopsy specimens per 40 (95% CI)
Incremental cost per diagnostically adequate biopsy specimens (95% CI), US$ – 1.57 (0.92-5.51)
TABLE 5. Comparison of difference in adequacy of biopsy specimens between forceps, by pathologist Adequate biopsy specimens, no./total (%) Pathologist no. 1 2
Control forceps
Jumbo forceps
Difference
5/40 (12.5)
17/40 (42.5)
þ30%
24/40 (60)
þ30%
12/40 (30)
DISCUSSION This prospective clinical trial demonstrated, with a high level of statistical significance, that the jumbo forceps was superior to a standard large-capacity forceps in obtaining diagnostically adequate IBD surveillance biopsy specimens, as defined in this study. On average, the jumbo forceps produced an additional 8 diagnostically adequate biopsy specimens per surveillance colonoscopy. Furthermore, jumbo biopsy specimens were longer, more likely to penetrate into the muscularis mucosa, and came at a modest increase in cost. These findings are clinically relevant because biopsy specimens obtained with the jumbo forceps are approximately 25% larger, which enabled the endoscopist to sample 25% additional mucosa during an IBD surveillance colonoscopy. Moreover, the jumbo forceps were particularly effective in obtaining adequate biopsy specimens from patients with chronic inflammation and fibrosis who develop ‘‘stiff ’’ colonic mucosa, a group that has traditionally been difficult to surveil. Therefore, although this study does not prove an increased dysplasia detection rate with the jumbo forceps, it does suggest a potential clinical benefit in using this forceps for IBD surveillance. Some patients with IBD will still develop colorectal cancer, despite enrollment in a surveillance program.7 This occurs because dysplasia may arise from endoscopically normal mucosa that cannot be uniformly and completely sampled during an individual procedure. Alternative surveillance strategies, such as using biologic markers8,9 or advanced imaging–targeted biopsies10-13 are being actively studied as a means of reducing the dysplasia-carcinoma miss rate. Until one of these strategies is proven superior and gains widespread support, however, random colonic
biopsies remain the standard of care. Use of the jumbo forceps to obtain these biopsy specimens may be a means of improving the diagnostic yield. In addition, if a targeted biopsy strategy becomes the standard of care, then highquality specimens will remain important to maximize diagnostic accuracy. There were no complications attributable to use of the jumbo forceps in this study. The RJ4-jumbo is a Food and Drug Administration–approved device in widespread clinical use in the United States, where adverse events related to the forceps have not been described. Nevertheless, given the relatively limited clinical experience with this forceps, we recommend that clinicians remain wary of potential complications, such as bleeding and perforation. Further studies and broader clinical experience will be necessary to establish the long-term safety profile of this forceps. This study had 2 important limitations. First, a validated outcome measure for the quality of GI biopsy specimens does not exist. The primary end point in this study is a combination of critical histopathologic criteria devised by our group of nationally recognized GI pathologists on the basis of substantial personal experience and published precedent. Validation of this outcome measure would be important in future GI tissue acquisition research. Second, the interobserver correlation between pathologists in this study was low. This finding was congruent with both GI and non-GI pathology studies that demonstrate a high level of interobserver variation.14-16 This suggests that interobserver variation is a general limitation of the field rather than a limitation that is unique to this study per se. Nevertheless, both pathologists deemed 30% more jumbo forceps specimens to be adequate compared with the
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control specimens, which suggests that the results of this study are reproducible and clinically applicable. In summary, the jumbo forceps is superior to a standard large-capacity forceps in obtaining diagnostically adequate IBD surveillance biopsy specimens. Because biopsy specimens obtained with the jumbo forceps are larger, an increased surface area of colonic mucosa can be sampled during a surveillance colonoscopy, potentially increasing the dysplasia detection rate. This projected increase in diagnostic yield with the jumbo forceps comes at a reasonable increase in cost. DISCLOSURE The following authors report that they have no disclosures relevant to this publication: B. J. Elmunzer, P. D. R. Higgins, Y. M. Kwon, C. Golembeski, J. K. Greenson, S. J. Korsnes. The following author has disclosed actual or potential conflicts: G. Elta consults for Ethicon, Avantis, Olympus, and MGI Pharma. This study was funded by an American Society for Gastrointestinal Endoscopy endoscopic research award. The experimental and control forceps were provided free of charge by Boston Scientific Corp.
REFERENCES 1. Fireman Z, Grossman A, Lilos P, et al. Intestinal cancer in patients with Crohn’s disease. A population study in central Israel. Scand J Gastroenterol 1989;24:346-50. 2. Woods K, Anand D, Cole R, et al. Influence of endoscopic biopsy forceps characteristics on tissue specimens: results of a prospective randomized trial. Gastrointest Endosc 1999;49:177-83. 3. Reid B, Weinstein W, Lewin K, et al. Endoscopic biopsy can detect high grade dysplasia or early adenocarcinoma in Barrett’s esophagus. Gastroenterology 1988;94:81-90. 4. Levine D, Haggitt R, Blount P, et al. An endoscopic biopsy protocol can differentiate high grade dysplasia from early adenocarcinoma in Barrett’s esophagus. Gastroenterology 1993;105:40-50. 5. Fantin A, Neuweiler J, Binek J, et al. Diagnostic quality of biopsy specimens: comparison between a conventional forceps and Multibite forceps. Gastrointest Endosc 2001;54:600-4.
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Elmunzer et al 6. Dolwani S, Saleem H, Thompson IW, et al. A comparison of three types of biopsy forceps in the endoscopic surveillance of Barrett’s oesophagus. Endoscopy 2002;34:946-9. 7. Rutter MD, Saunders BP, Wilkinson KH, et al. Thirty year analysis of a surveillance program for neoplasia in ulcerative colitis. Gastroenterology 2006;130:1030-8. 8. Burmer GC, Rabinovitch PS, Haggitt RC, et al. Neoplastic progression in ulcerative colitis: histology, DNA content, and loss of a p53 allele. Gastroenterology 1992;103:1602-10. 9. Lo¨fberg R, Brostro¨m O, Karle´n P, et al. DNA aneuploidy in ulcerative colitis: reproducibility, topographic distribution, and relation to dysplasia. Gastroenterology 1992;102:1149-54. 10. Klesslich R, Fritsch J, Holtmann M, et al. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2003;124:880-8. 11. Marion JF, Waye JD, Present DH, et al. Methylene blue dye-spray targeted biopsies are superior to standard colonoscopic surveillance biopsies for detecting dysplasia in patients with ulcerative and Crohn’s colitis: a prospective endoscopic trial [abstract]. Gastroenterology 2007;132:A-67. 12. Dekker E, van den Broek FJ, Reitsma JB, et al. Narrow-band imaging compared with conventional colonoscopy for the detection of dysplasia in patients with longstanding ulcerative colitis. Endoscopy 2007;39: 216-21. 13. Watanabe K, Machida H, Kamata N, et al. The efficacy of surveillance colonoscopy for patients with ulcerative colitis associated cancer or dysplasia by using NBI (narrow band imaging) as handy optical pancolonic chromoendoscopy [abstract]. Gastrointest Endosc 2007;65:AB333. 14. Kerkhof M, van Dekken H, Steyerberg EW, et al. Grading of dysplasia in Barrett’s oesophagus: substantial interobserver variation between general and gastrointestinal pathologists. Histopathology 2007;50: 920-7. 15. de Vet HC, Knipshild PG, Schouten HJA, et al. Interobserver variation in histopathologic grading of cervical dysplasia. J Clin Epidemiol 1990;43: 1395-8. 16. el-Zimaity HM, Graham DY, al-Assi MT, et al. Interobserver variation in the histopathological assessment of Helicobacter pylori gastritis. Hum Pathol 1996;27:35-41.
Received July 25, 2007. Accepted November 14, 2007. Current affiliations: Division of Gastroenterology (B.J.E., P.D.H., S.J.K., G.H.E.), Department of Medicine (Y.M.K.), Department of Pathology (C.G., J.K.G.), University of Michigan School of Medicine, Ann Arbor, Michigan, USA. Reprint requests: B. Joseph Elmunzer, MD, University of Michigan Medical Center, Department of Internal Medicine, Division of Gastroenterology, 3912 Taubman Center, Ann Arbor, MI 48109.
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Jumbo forceps are superior to standard large-capacity forceps in obtaining diagnostically adequate inflammatory bowel disease surveillance biopsy specimens B. Joseph Elmunzer, MD, Peter D. R. Higgins, MD, PhD, MSc, Yong M. Kwon, MD, Christopher Golembeski, MD, Joel K. Greenson, MD, Sheryl J. Korsnes, MA, Grace H. Elta, MD Ann Arbor, Michigan, USA
Background: In inflammatory bowel disease (IBD) surveillance colonoscopy, an increased number of biopsy specimens correlates with a higher dysplasia detection rate. Larger biopsy specimens may also increase the diagnostic yield. Objective: To compare a new jumbo forceps with a standard large-capacity forceps in obtaining diagnostically adequate IBD surveillance biopsy specimens. Design: Prospective single-center study. Patients and Methods: Twenty-four patients who were undergoing an IBD surveillance colonoscopy were enrolled. As part of standard IBD surveillance, 8 paired biopsy specimens were obtained from the rectosigmoid by using the jumbo forceps and a standard large-capacity forceps. Outcome Measurements: Biopsy specimens were deemed adequate if they met all 3 of the following criteria: (1) length R3 mm, (2) penetration into the muscularis mucosa, and (3) !20% crush artifact. Results: The proportion of adequate biopsy specimens obtained with the jumbo forceps was significantly higher than that obtained with the large-capacity control forceps (67% vs 48%, P!.0001). The average length of the biopsy specimen obtained with the jumbo forceps was 4.00 mm (95% CI, 3.81-4.20 mm) compared with 3.19 mm (95% CI, 2.99-3.38 mm) with the large-capacity (control) forceps. Limitations: (1) No validated outcome measurement for the quality of GI biopsy specimens exists and (2) in this study, interobserver variability between pathologists was high. Conclusions: The jumbo forceps was superior to a standard large-capacity forceps in obtaining diagnostically adequate IBD surveillance biopsy specimens. Because biopsy specimens obtained with the jumbo forceps were larger, the use of this forceps for IBD surveillance will allow the endoscopist to sample a larger colonic mucosal surface area, potentially resulting in an increased dysplasia detection rate. (Gastrointest Endosc 2008;68:273-8.)
Histopathologic evaluation is critical in the diagnosis of GI disease. The overall quality of a specimen has a major impact on diagnostic accuracy, and it is widely accepted that specimen size is the most important factor contributing to the quality. This may be especially true in an inflammatory bowel disease (IBD) surveillance colonoscopy,
See CME section; p. 334. Copyright ª 2008 by the American Society for Gastrointestinal Endoscopy 0016-5107/$32.00 doi:10.1016/j.gie.2007.11.023
where it has been shown that an increased number of biopsy specimens (increased total surface area) correlates with higher sensitivity for detecting dysplasia.1 Several different endoscopic biopsy forceps are commercially available. Although these forceps differ in design and mechanics, they have been shown to produce generally equivalent biopsy specimens.2 The Radial Jaw 4-jumbo forceps (Boston Scientific Corp, Natick, Mass) is a disposable, Food and Drug Administration–approved, enlarged forceps that was engineered to pass through the accessory channel of a standard nontherapeutic colonoscope. Because of the enlarged size of the forceps cup, it is theoretically able to produce larger specimens with minimal artifact.
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Volume 68, No. 2 : 2008 GASTROINTESTINAL ENDOSCOPY 273
Abbreviations: IBD, inflammatory bowel disease; ICC, intraclass correlation.
Biopsy specimens in inflammatory bowel disease
Because the total number of biopsy specimens has been shown to correlate with the sensitivity of detecting dysplasia in patients with IBD who are undergoing surveillance, larger, more interpretable specimens may also increase the diagnostic yield. This premise was demonstrated in Barrett’s esophagus, where a jumbo forceps has been recommended for obtaining surveillance biopsy specimens.3,4 Furthermore, because of chronic inflammation and fibrosis, some patients with IBD of long duration develop burned out, tubular colons with ‘‘stiff ’’ colonic mucosa, from which adequate biopsy specimens are difficult to obtain. Jumbo forceps may be particularly effective in acquiring diagnostically adequate biopsy specimens in this patient population. We compared the jumbo forceps with a standard large-capacity forceps in obtaining diagnostically adequate IBD surveillance biopsy specimens.
PATIENTS AND METHODS A total of 24 consecutive patients referred for an IBD surveillance colonoscopy consented to participate and were enrolled in the study. Inclusion criteria were R18 years of age and successful performance of a full colonoscopy with surveillance biopsies. Exclusion criteria were an inability or unwillingness to consent to the study and coagulopathy (defined as an international normalized ratio O1.4, partial thromboplastin time O1.5 times the upper limit of normal, or platelets !50,000/mm3). Because these patients were undergoing a colonoscopy for IBD surveillance, they all had quiescent or mildly active colitis. This study was approved by the University of Michigan Investigational Review Board. As part of standard surveillance, each enrolled patient had 8 control biopsy specimens and 8 additional jumbo (experimental) biopsy specimens obtained from the rectosigmoid segment, where the highest incidence of dysplasia and colorectal cancer is thought to occur. Each biopsy specimen obtained with the control forceps was immediately followed by an experimental biopsy obtained within 1.5 cm of the first biopsy, targeted at the same tissue. This strategy ensured that any particular set of biopsy specimens (control and experimental) was obtained from the same anatomical location in the same patient, thereby resulting in an internal control. Polypoid lesions or suspected dysplasia-associated lesions or masses were not included in the study biopsy specimens because of a possible inability to acquire comparable tissue (if small polyps were removed with the first biopsy). All biopsy specimens were handled, stored, and processed in a similar fashion. Specimen jars were labeled with a study code number, which ensured that the pathologist who was examining the specimens was blinded to which forceps was used in the acquisition of any particular set of biopsy specimens. The biopsy specimens were 274 GASTROINTESTINAL ENDOSCOPY Volume 68, No. 2 : 2008
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Capsule Summary What is already known on this topic d
An increased number of biopsy specimens taken during surveillance colonoscopy for inflammatory bowel disease (IBD) correlates with a higher dysplasia detection rate and may enhance the overall diagnostic yield.
What this study adds to our knowledge d
d
In a prospective comparison in 24 patients with IBD, the proportion of adequate biopsy specimens obtained with a jumbo forceps was significantly higher than that with a standard large-capacity forceps. The average specimen length obtained with the jumbo forceps was 4.00 mm compared with 3.19 mm with the large-capacity forceps.
evaluated by 1 pathologist for the following characteristics: (1) length in millimeters, (2) penetration into the muscularis mucosa, and (3) percentage of crush artifact. In the case of a fracture of a biopsy specimen, the 8 largest pieces from each jar were evaluated. In addition, clinical and procedure characteristics, including the patient’s age and sex; the type, extent, severity, and duration of colitis; the current use of corticosteroids; and the endoscopist performing the procedure were recorded. Based on published data2,5,6 and the expertise of the University of Michigan’s nationally renowned group of GI pathologists, a biopsy specimen adequacy outcome measure was defined before the initiation of the study. A specimen was deemed diagnostically adequate if it met all 3 of the following criteria: (1) length R3 mm, (2) penetration into the muscularis mucosa, and (3) !20% crush artifact. These criteria were determined a priori, without knowledge of the expected characteristics of jumbo forceps–obtained tissue. The control forceps was the Radial Jaw 3 large-capacity (with needle) forceps (Boston Scientific Corp). This product was chosen based on its high frequency of use nationally for the indication of IBD surveillance biopsies and its similarity to most commercially available large-capacity forceps. Interobserver variation between interpreters was assessed by having a second expert pathologist evaluate a subset of 80 biopsy specimens (40 control and 40 experimental specimens) for length and adequacy. These results were compared with the primary pathologist’s interpretation.
Statistical design The primary end point was the fraction of diagnostically adequate biopsy specimens obtained with the jumbo forceps compared with the fraction of diagnostically adequate biopsy specimens obtained with the standard large-capacity (control) forceps, when controlled for the www.giejournal.org
Elmunzer et al
effects of the individual patient, disease characteristics, and the endoscopist. The sample size was calculated with the goal of detecting a 15% difference in the fraction of adequate biopsy specimens between the jumbo and the control forceps. By assuming a 2-sided P value of .05 and a power of 80%, 113 biopsy specimens per group would be needed to detect this intended difference. Because the biopsy specimens are clustered by patient and not independent of one another within a given patient, multilevel modeling analysis and adjustment of the sample size was required. The sample-size adjustment was based on our estimate of the correlations between biopsy specimens within a patient (intraclass correlations [ICC]). Based on an estimated ICC of 0.7, the adjusted sample size was 194 biopsy specimens per group (24 patients). The ICC was estimated based on the standard premise that the range of reasonable outcomes divided by 4 is roughly equivalent to the standard deviation. To analyze the results, we used a mixed model (PROC GLIMMIX in SAS 9.1.3; SAS Inc, Cary, NC), with random intercept and a fixed effect of the biopsy forceps. We also included random effects of the subject and the subjectforceps interaction in the model. This allowed us to control for variation between patients and clustering of similar results by patient. We chose to use a fixed effect for the biopsy forceps, because we wanted to precisely estimate the effect of the forceps used. We chose to use random effects for the subject and subject-forceps interaction, because we wanted to control for these effects but did not want to precisely estimate the effect for an individual subject. Rather, our goal was to control for this effect to make our results generalizable to all patients with chronic colitis. As a secondary outcome, we evaluated the difference between the forceps in biopsy size (length) and fraction of biopsy specimens that penetrated the muscularis mucosa, controlling for patient, subject, and subjectforceps interaction. A similar statistical approach was used, with a mixed model, for this continuous outcome (PROC MIXED, SAS 9.1.3). This end point, because it uses a continuous outcome, has more power to detect a difference between the two forceps than the primary outcome; the sample size was more than sufficient for this end point. Point estimates and CIs for the adjusted mean biopsy length and adjusted probability of adequate biopsy specimens were generated after modeling with an LSMEANS statement in SAS 9.1.3.
Biopsy specimens in inflammatory bowel disease
biopsy specimen. The 95% upper CI for incremental cost was calculated by finding the difference between the lower CI for the number of adequate jumbo biopsy specimens and the upper CI for the number of adequate control biopsy specimens, and then dividing this value by the difference in cost between the forceps. The 95% lower CI for cost per additional adequate biopsy specimen was calculated by performing the same calculation with the upper CI for the number of adequate jumbo biopsy specimens and the lower CI for the number of adequate control biopsy specimens.
RESULTS Enrolled patient and disease characteristics are listed in Table 1. By design, no patients enrolled in this study had active colitis.
Biopsy specimens
A cost analysis of using the jumbo forceps instead of the control forceps was performed. This analysis evaluated the incremental cost of using the jumbo forceps as it relates to the number of additional adequate biopsy specimens that can be expected from using this forceps. The results are reported as the cost per additional adequate
The crude characteristics of biopsy specimens obtained with the control forceps and the jumbo forceps are listed in Table 2. Neither forceps resulted in crush artifact, presumably because of the large cup size of both devices. The probability of acquiring an adequate biopsy specimen with the jumbo forceps, controlling for variation between patients, was 0.67, 95% CI, 0.61-0.74. In comparison, the probability of acquiring an adequate biopsy specimen with the control forceps, controlling for variation between patients, was 0.48, 95% CI, 0.42-0.55. The difference was statistically significant (P ! .0001). The average length of biopsy specimen obtained with the jumbo forceps, controlling for variation between patients, was 4.00 mm, 95% CI, 3.81-4.20 mm. By comparison, the average length of biopsy specimen obtained with the control forceps, controlling for variation between patients, was 3.19 mm, 95% CI, 2.99-3.38 mm. The difference was statistically significant (P Z .0001). The probability of acquiring a biopsy specimen that penetrates into the muscularis mucosa with the jumbo forceps, controlling for variation between patients, was 77.8% (95% CI, 71.3%-83.6%), compared with 62.1% (95% CI, 54.6%-69.2%) with the control forceps. This difference was statistically significant (P Z .001). In multivariate analysis, the patient effect was significant. In other words, the variation between individual patients had a significant impact on the length and adequacy of their biopsy specimens. This was expected, because some patients have burned-out, tubular colons with ‘‘stiff ’’ mucosa, from which adequate biopsy specimens are difficult to obtain, whereas other patients have a softer mucosa that is more permissive of large biopsy specimens. We tested whether the jumbo forceps made a particular difference in the patients with the ‘‘more difficult’’ colon. The average jumbo forceps biopsy specimen length, sorted by whether the control forceps biopsy
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TABLE 1. Demographics and disease characteristics of patients Characteristics Crohn’s/ulcerative colitis Women (no./total)
10/13 (1 indeterminate colitis) 18/24 6/24
White (no./total)
23/24 (95.8%)
Median current age (y)
TABLE 2. Crude data on biopsy specimen characteristics by forceps
Characteristic
Control forceps
Jumbo forceps
Mean length, mm (SD)
3.2 (1.3)
4.0 (1.7)
61.7
77.9
None reported
None reported
Participants (n Z 24)
Men (no./total)
Mean age (y)
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Biopsy specimens penetrating MM (%) Crush artifact (%)
50.7 53 (range 29-76, IQR 40.0-59.5)
MM, Muscularis mucosa.
Location/type of disease (no./total) Left-sided ulcerative colitis
5/24
Ulcerative pancolitis
6/24
Crohn’s colitis
TABLE 3. Average jumbo forceps biopsy specimen length (sorted by tertile) Average biopsy specimen length, mm
10/24
Tertile
Control forceps
Jumbo forceps
Ulcerative colitis, unknown
2/24
Lowest
2.55
3.48
Indeterminate pancolitis
1/24
Middle
3.07
4.02
Highest
3.82
4.41
Mean duration of disease (y)
19.9
Median duration of disease (y)
17.5 (IQR 12-27)
Current steroid use (no./total)
2/24
IQR, Interquartile range.
specimen length was in the lowest, middle, or highest tertile, is listed in Table 3. Jumbo biopsy specimens are significantly larger in all 3 tertiles, indicating that the jumbo forceps obtain larger biopsy specimens even in patients with the ‘‘stiff ’’ mucosa phenomenon.
Patient characteristics and endoscopist effects We considered the effects of patient age, diagnosis of ulcerative colitis versus Crohn’s disease, duration, extent, and severity of colitis in the variation of biopsy length and adequacy. When tested in the multivariate model, none of these factors were significant predictors of biopsy specimen adequacy or length. A total of 13 endoscopists participated in this study. Endoscopist identity was not significant in the multivariate model, which suggested that endoscopist training and technique did not greatly influence the adequacy or length of biopsy specimen.
Cost analysis Based on the above results, 40 surveillance biopsy specimens obtained per colon with the jumbo forceps would yield an average of 26.9 adequate biopsy specimens. Forty surveillance biopsy specimens obtained with the control forceps would yield only 19.3 adequate biopsy specimens, resulting in an additional 7.6 adequate biopsy specimens per colonoscopy if the jumbo forceps is used. The average difference in cost between the jumbo forceps and the control forceps at our institution was $12. Therefore, the incremental cost for each additional adequate biopsy by using the jumbo forceps was $1.57. The 95% lower confidence bound for cost per additional adequate biopsy was $0.92 and the 95% upper confidence bound was $5.51. These results are illustrated in Table 4. Of note is that forceps pricing may vary significantly, depending on factors such as institution contract and purchase volume. Nevertheless, in 2006, the average price difference between a regular and a jumbo forceps in the United States was approximately $27. At this price difference, the incremental cost per additional adequate biopsy when using the jumbo forceps was $3.55, 95% CI, $2.11-$11.25.
Interobserver variation
No complications attributable to the jumbo forceps occurred in this study.
A subset of 80 biopsy specimens was also evaluated by a second pathologist. The Pearson correlation for length between pathologists was 0.256. The kappa values for muscularis mucosa penetration and adequacy could not be calculated because of scattered fixing of specimens per slide; we were unable to confidently ensure that the
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TABLE 4. Incremental cost analysis of jumbo versus control forceps
Forceps
Incremental cost per patient, US$
Probability of a diagnostically adequate biopsy specimen (95% CI)
Control
–
0.48 (0.42-0.55)
19.3 (16.8-22)
Jumbo
12
0.67 (0.61-0.74)
26.9 (24.4-29.6)
pathologists were comparing the same exact specimen. Pathologist no. 1 deemed 60% of biopsy specimens in the jumbo forceps subset adequate and 30% of biopsy specimens in the control subset adequate. Pathologist no. 2 deemed 42.5% of biopsy specimens in the jumbo forceps subset adequate and 12.5% of biopsy specimens in the control subset adequate. Therefore, as demonstrated in Table 5, both pathologists were 30% more likely to consider a jumbo forceps specimen adequate compared with a control specimen.
No. diagnostically adequate biopsy specimens per 40 (95% CI)
Incremental cost per diagnostically adequate biopsy specimens (95% CI), US$ – 1.57 (0.92-5.51)
TABLE 5. Comparison of difference in adequacy of biopsy specimens between forceps, by pathologist Adequate biopsy specimens, no./total (%) Pathologist no. 1 2
Control forceps
Jumbo forceps
Difference
5/40 (12.5)
17/40 (42.5)
þ30%
24/40 (60)
þ30%
12/40 (30)
DISCUSSION This prospective clinical trial demonstrated, with a high level of statistical significance, that the jumbo forceps was superior to a standard large-capacity forceps in obtaining diagnostically adequate IBD surveillance biopsy specimens, as defined in this study. On average, the jumbo forceps produced an additional 8 diagnostically adequate biopsy specimens per surveillance colonoscopy. Furthermore, jumbo biopsy specimens were longer, more likely to penetrate into the muscularis mucosa, and came at a modest increase in cost. These findings are clinically relevant because biopsy specimens obtained with the jumbo forceps are approximately 25% larger, which enabled the endoscopist to sample 25% additional mucosa during an IBD surveillance colonoscopy. Moreover, the jumbo forceps were particularly effective in obtaining adequate biopsy specimens from patients with chronic inflammation and fibrosis who develop ‘‘stiff ’’ colonic mucosa, a group that has traditionally been difficult to surveil. Therefore, although this study does not prove an increased dysplasia detection rate with the jumbo forceps, it does suggest a potential clinical benefit in using this forceps for IBD surveillance. Some patients with IBD will still develop colorectal cancer, despite enrollment in a surveillance program.7 This occurs because dysplasia may arise from endoscopically normal mucosa that cannot be uniformly and completely sampled during an individual procedure. Alternative surveillance strategies, such as using biologic markers8,9 or advanced imaging–targeted biopsies10-13 are being actively studied as a means of reducing the dysplasia-carcinoma miss rate. Until one of these strategies is proven superior and gains widespread support, however, random colonic
biopsies remain the standard of care. Use of the jumbo forceps to obtain these biopsy specimens may be a means of improving the diagnostic yield. In addition, if a targeted biopsy strategy becomes the standard of care, then highquality specimens will remain important to maximize diagnostic accuracy. There were no complications attributable to use of the jumbo forceps in this study. The RJ4-jumbo is a Food and Drug Administration–approved device in widespread clinical use in the United States, where adverse events related to the forceps have not been described. Nevertheless, given the relatively limited clinical experience with this forceps, we recommend that clinicians remain wary of potential complications, such as bleeding and perforation. Further studies and broader clinical experience will be necessary to establish the long-term safety profile of this forceps. This study had 2 important limitations. First, a validated outcome measure for the quality of GI biopsy specimens does not exist. The primary end point in this study is a combination of critical histopathologic criteria devised by our group of nationally recognized GI pathologists on the basis of substantial personal experience and published precedent. Validation of this outcome measure would be important in future GI tissue acquisition research. Second, the interobserver correlation between pathologists in this study was low. This finding was congruent with both GI and non-GI pathology studies that demonstrate a high level of interobserver variation.14-16 This suggests that interobserver variation is a general limitation of the field rather than a limitation that is unique to this study per se. Nevertheless, both pathologists deemed 30% more jumbo forceps specimens to be adequate compared with the
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control specimens, which suggests that the results of this study are reproducible and clinically applicable. In summary, the jumbo forceps is superior to a standard large-capacity forceps in obtaining diagnostically adequate IBD surveillance biopsy specimens. Because biopsy specimens obtained with the jumbo forceps are larger, an increased surface area of colonic mucosa can be sampled during a surveillance colonoscopy, potentially increasing the dysplasia detection rate. This projected increase in diagnostic yield with the jumbo forceps comes at a reasonable increase in cost. DISCLOSURE The following authors report that they have no disclosures relevant to this publication: B. J. Elmunzer, P. D. R. Higgins, Y. M. Kwon, C. Golembeski, J. K. Greenson, S. J. Korsnes. The following author has disclosed actual or potential conflicts: G. Elta consults for Ethicon, Avantis, Olympus, and MGI Pharma. This study was funded by an American Society for Gastrointestinal Endoscopy endoscopic research award. The experimental and control forceps were provided free of charge by Boston Scientific Corp.
REFERENCES 1. Fireman Z, Grossman A, Lilos P, et al. Intestinal cancer in patients with Crohn’s disease. A population study in central Israel. Scand J Gastroenterol 1989;24:346-50. 2. Woods K, Anand D, Cole R, et al. Influence of endoscopic biopsy forceps characteristics on tissue specimens: results of a prospective randomized trial. Gastrointest Endosc 1999;49:177-83. 3. Reid B, Weinstein W, Lewin K, et al. Endoscopic biopsy can detect high grade dysplasia or early adenocarcinoma in Barrett’s esophagus. Gastroenterology 1988;94:81-90. 4. Levine D, Haggitt R, Blount P, et al. An endoscopic biopsy protocol can differentiate high grade dysplasia from early adenocarcinoma in Barrett’s esophagus. Gastroenterology 1993;105:40-50. 5. Fantin A, Neuweiler J, Binek J, et al. Diagnostic quality of biopsy specimens: comparison between a conventional forceps and Multibite forceps. Gastrointest Endosc 2001;54:600-4.
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Elmunzer et al 6. Dolwani S, Saleem H, Thompson IW, et al. A comparison of three types of biopsy forceps in the endoscopic surveillance of Barrett’s oesophagus. Endoscopy 2002;34:946-9. 7. Rutter MD, Saunders BP, Wilkinson KH, et al. Thirty year analysis of a surveillance program for neoplasia in ulcerative colitis. Gastroenterology 2006;130:1030-8. 8. Burmer GC, Rabinovitch PS, Haggitt RC, et al. Neoplastic progression in ulcerative colitis: histology, DNA content, and loss of a p53 allele. Gastroenterology 1992;103:1602-10. 9. Lo¨fberg R, Brostro¨m O, Karle´n P, et al. DNA aneuploidy in ulcerative colitis: reproducibility, topographic distribution, and relation to dysplasia. Gastroenterology 1992;102:1149-54. 10. Klesslich R, Fritsch J, Holtmann M, et al. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2003;124:880-8. 11. Marion JF, Waye JD, Present DH, et al. Methylene blue dye-spray targeted biopsies are superior to standard colonoscopic surveillance biopsies for detecting dysplasia in patients with ulcerative and Crohn’s colitis: a prospective endoscopic trial [abstract]. Gastroenterology 2007;132:A-67. 12. Dekker E, van den Broek FJ, Reitsma JB, et al. Narrow-band imaging compared with conventional colonoscopy for the detection of dysplasia in patients with longstanding ulcerative colitis. Endoscopy 2007;39: 216-21. 13. Watanabe K, Machida H, Kamata N, et al. The efficacy of surveillance colonoscopy for patients with ulcerative colitis associated cancer or dysplasia by using NBI (narrow band imaging) as handy optical pancolonic chromoendoscopy [abstract]. Gastrointest Endosc 2007;65:AB333. 14. Kerkhof M, van Dekken H, Steyerberg EW, et al. Grading of dysplasia in Barrett’s oesophagus: substantial interobserver variation between general and gastrointestinal pathologists. Histopathology 2007;50: 920-7. 15. de Vet HC, Knipshild PG, Schouten HJA, et al. Interobserver variation in histopathologic grading of cervical dysplasia. J Clin Epidemiol 1990;43: 1395-8. 16. el-Zimaity HM, Graham DY, al-Assi MT, et al. Interobserver variation in the histopathological assessment of Helicobacter pylori gastritis. Hum Pathol 1996;27:35-41.
Received July 25, 2007. Accepted November 14, 2007. Current affiliations: Division of Gastroenterology (B.J.E., P.D.H., S.J.K., G.H.E.), Department of Medicine (Y.M.K.), Department of Pathology (C.G., J.K.G.), University of Michigan School of Medicine, Ann Arbor, Michigan, USA. Reprint requests: B. Joseph Elmunzer, MD, University of Michigan Medical Center, Department of Internal Medicine, Division of Gastroenterology, 3912 Taubman Center, Ann Arbor, MI 48109.
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