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Adenoma characteristics as risk factors for recurrence of advanced adenomas
GASTROENTEROLOGY 2001;120:1077–1083
ALIMENTARY TRACT Adenoma Characteristics as Risk Factors for Recurrence of Advanced Adenomas MARI´A ELENA MARTI´NEZ,*,‡ RICHARD SAMPLINER,§,储 JAMES R. MARSHALL*,‡ ACHYUT K. BHATTACHARYYA,¶ MARY E. REID,*,‡ and DAVID S. ALBERTS*,‡,储 *Arizona Cancer Center, ‡College of Public Health, and Departments of 储Medicine and ¶Pathology, University of Arizona, Tucson, Arizona; and §Southern Arizona VA Health Care System, Tucson, Arizona
Background & Aims: The link between adenoma characteristics at baseline colonoscopy and adenoma recurrence is poorly understood. We assessed whether the number, size, location, or histology of resected adenomas was related to the probability of recurrence of advanced lesions. Methods: Analyses were based on 1287 men and women in the wheat bran fiber (WBF) study, a randomized, double-blind trial of WBF as a means of decreasing the probability of adenoma recurrence over a period of 3 years. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results: Recurrence of advanced adenomas (>1 cm or tubulovillous/villous histology) was higher among individuals with adenomas >1 cm compared with those with adenomas <0.5 cm (OR, 2.69; 95% CI, 1.34 –5.42) and among those with proximal than those with distal adenomas (OR, 1.65; 95% CI, 1.02–2.67). No association was observed for adenoma number or histology. A shift in location from the distal colon and rectum at baseline (54.6%) to more proximal recurrent adenomas (45.2%), including advanced lesions (42.8%), was observed. Conclusions: Large or proximally located adenomas are important indicators of recurrence of advanced lesions. Because most recurrences were detected in the proximal colon, careful surveillance of this area is warranted.
olorectal cancer represents the final stage of a slow, multistep carcinogenic process whose evolution involves the adenoma.1–3 Results of studies based on autopsy data and of high- or average-risk populations indicate that adenoma prevalence ranges from 20% to 60%.4 –10 Removal of adenomas is associated with a lower risk of colorectal cancer11; however, recurrence is common.11–13 Factors associated with recurrence of these lesions are not fully appreciated; furthermore, much less is known about the etiology of adenomas with advanced pathologic lesions, which represent an intermediate biologic endpoint of future colorectal malignancy. Although
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several studies have been published specifically addressing the role of adenoma characteristics (i.e., histology, size, multiplicity, and location) in the etiology of adenoma recurrence, interpretation of these data is difficult given the problems related to these studies: small number of participants, inclusion of lesions other than adenomas, variety of follow-up intervals, and low follow-up rates of study participants with regard to endpoint colonoscopies. Chemoprevention trials provide a unique opportunity to investigate the etiology of adenoma recurrence with respect to a variety of environmental and host factors, including the characteristics of the baseline adenoma. A major strength of these studies is the completeness of follow-up; endpoint colonoscopy data are available on the vast majority of the participants. The goal of this prospective study was to assess whether characteristics of adenomas detected at qualifying colonoscopy were related to the probability of recurrence, with particular emphasis on recurrence of advanced lesions.
Materials and Methods Study Population Analyses were conducted among participants in the wheat bran fiber (WBF) trial, whose details14 and results15 have been published. Because the WBF intervention had no significant effect on adenoma recurrence,15 we evaluated data from all participants in the trial. Briefly, the WBF study is a double-blind, phase III trial of high vs. low fiber, designed to measure the effects of 3 years of WBF supplementation on adenoma recurrence. Men and women 40 – 80 years of age who had 1 or more colorectal adenoma(s) 3 mm or larger removed Abbreviations used in this paper: CI, confidence interval; OR, odds ratio; WBF, wheat bran fiber. © 2001 by the American Gastroenterological Association 0016-5085/01/$35.00 doi:10.1053/gast.2001.23247
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at colonoscopy within 3 months before study entry were recruited from the 4 clinic sites in the Phoenix metropolitan area. We excluded individuals with a personal history of inflammatory bowel disease or hereditary colon cancer syndromes. Of 1429 participants randomized into the trial, 1303 (91%) successfully completed the study by undergoing 1 or more colonoscopic examinations after randomization. Self-administered questionnaires were used to obtain data on sociodemographic variables, family history of colorectal cancer in first-degree relatives, history of polyps before the baseline adenoma, and other risk factors related to colorectal neoplasia. The study was approved by the University of Arizona Human Subjects Committee and local hospital committees.
Adenoma Characteristics Endoscopic and pathologic reports were reviewed for the qualifying colonoscopy and each colonoscopy reported by the participant during the trial. Using standardized guidelines, data on number, size, and location of all neoplasms were abstracted from the endoscopy report. Histology of lesions and an additional size variable were obtained from the pathology report based on the review of the community pathologist. In addition, a study pathologist (A.K.B.) reviewed the original slide or one obtained from the paraffin-embedded tissue block. A high degree of agreement between the community and study pathologists was observed (92%) for identification of an adenoma vs. nonadenoma. Agreement between the community and study pathologists for classification of tubulovillous or villous histology was 65%. A potential reason for the discordance is that we were not always able to obtain the original slide reviewed by the community pathologist for review; thus, it was not always possible to examine the same polypoid tissue area. For histologic classification, we included data from the study pathologist’s review for reports with missing information from the community pathologist (n ⫽ 320). For individuals with more than 1 adenoma, the highest degree of villous component was used for classification. Adenoma size was determined using 2 sources: the endoscopy and community pathologist’s reports. Comparison of these sources showed that size based on the endoscopy report was significantly greater than that based on the pathology report (P ⬍ 0.001). Two recent publications16,17 indicated a higher degree of accuracy based on the pathology than on the endoscopy report. Therefore, in generating the best estimate of size, we used data from the pathology report, and when those data were missing, we used those from the endoscopy report. For individuals with more than 1 resected adenoma, the largest was used for classification of size. Adenoma location was classified as distal colon and rectum (rectum, rectosigmoid, sigmoid colon, descending colon, splenic flexure) or proximal colon (transverse colon, hepatic flexure, ascending colon, cecum). For individuals with more than 1 adenoma located in both sites, a separate category was created.
Follow-up The study protocol specified that 2 follow-up colonoscopies be performed after the qualifying colonoscopy. The first colonoscopy was to take place 1 year after randomization (to
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remove polyps missed at the qualifying colonoscopy) and the second 2 years thereafter. However, national recommendations for colorectal cancer screening changed during this trial,18,19 resulting in a decrease in 1-year colonoscopies among participants enrolled in the latter part of the trial, so that 889 of the 1303 participants had both a 1-year and an endpoint colonoscopy. Therefore, we considered a recurrence as 1 or more adenomas detected any time after randomization. Nine colon cancers, including 1 occurring without an accompanying adenoma recurrence, occurred during the follow-up period. No significant differences were shown for recurrence rates by clinic site: clinic 1, 48.1%; clinic 2, 52.4%; clinic 3, 49.2%; and clinic 4, 50.0%. The mean follow-up period was 36.8 (⫾16.0) months.
Statistical Analysis We explored the association between adenoma characteristics at qualifying colonoscopy and adenoma recurrence. Adenoma recurrence status (positive vs. negative) was used as the dependent variable for 1 set of statistical models. The presence of 1 or more advanced recurrent adenomas was used for the primary endpoint of interest. Advanced lesions comprised those ⬎1 cm in size, those with tubulovillous or villous histology, and all colon cancers. We used multiple logistic regression analysis20 to control for potential confounding variables. Initial models included age, gender, and number of study colonoscopies conducted after baseline. Simultaneous adjustment for all adenoma characteristics was conducted in the final statistical models. The importance of each independent variable was summarized by its odds ratio (OR) and 95% confidence interval (CI).
Results Of the 1303 participants with at least 1 colonoscopy after randomization, 1287 had data on baseline and recurrent adenoma characteristics of interest and made up the final study population. Of these, 625 (48.6%) had 1 or more recurrent adenomas, and 624 of these had complete data on all characteristics for classification of advanced recurrences. Of those with complete data, 146 were classified as having 1 or more advanced adenomas. Table 1 presents participant characteristics by recurrence status. Individuals with recurrence were significantly older and more likely to be male than those without recurrence. In addition, participants with a family history of colorectal cancer in first-degree relatives and those with a history of colorectal polyps before the baseline adenoma were more likely to have a recurrence; however, only the latter was statistically significant. Individuals with recurrence underwent a significantly higher number of colonoscopies than those without recurrence. Adenoma characteristics based on qualifying and follow-up colonoscopies are presented in Table 2. Compared with baseline adenomas, recurrent lesions were
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Table 1. Characteristics of Study Participants at Enrollment, According to Recurrence Status
Characteristic Age ( yr) ⬍67 [n (%)] ⱖ67 [n (%)] Sex Male [n (%)] Race White [n (%)] Family historyc [n (%)] History of previous polypsd [n (%)] No. of colonoscopies (mean ⫾ SD)
No recurrence (n ⫽ 662)
All recurrences (n ⫽ 625)
Advanced recurrencesa (n ⫽ 146)
322 (48.6) 340 (51.4)
260 (41.6) 365 (58.4)b
53 (36.3) 93 (63.7)b
409 (61.8)
455 (72.8)b
104 (71.2)b
635 (95.9)
602 (96.3)
142 (97.3)
101 (15.3)
117 (18.7)
31 (21.2)
193 (32.4)
252 (46.6)b
59 (47.6)b
1.8 ⫹ 0.7
2.3 ⫹ 0.9b
2.7 ⫹ 1.1b
recurrences include adenomas ⬎1 cm in size or with tubulovillous/villous histology or colon cancers. bP ⬍ 0.01 compared with no recurrence. cFamily history of colorectal cancer in a parent or sibling. dSelf-reported history of polyps before baseline adenomas. Data missing for 150 participants.
aAdvanced
more likely to be multiple, smaller in diameter, and of tubular histology. A shift in location from the distal colon and rectum at baseline (54.6%) to more proximal recurrent lesions (45.2%) was observed, such that more than 70% of study participants had at least 1 proximal adenoma at recurrence. By definition, advanced lesions were larger and more likely to be tubulovillous or villous. In addition, 42.8% of the advanced adenomas were proximally located, with no additional lesions located elsewhere in the colorectum. Exclusion of the 44 participants with incomplete examinations of the colon at follow-up did not materially change the results. Location of any recurrence was 27.3% for distal, 46.3% for proximal, and 26.4% for both; the corresponding figures for advanced recurrence were 19.2%, 46.2%, and 34.6%, respectively. Table 3 presents ORs for adenoma recurrence related to the characteristics of the baseline lesion. After adjustment for age, sex, number of colonoscopies, and the other adenoma characteristics, individuals with 3 or more adenomas had almost a 2-fold risk of any recurrence compared with those with a single lesion (OR, 1.91; 95% CI, 1.30 –2.79). Compared with participants with adenomas in the distal colon or rectum, those with proximal adenoma(s) had a higher risk of any recurrence (OR, 1.74; 95% CI, 1.32–2.31) and the risk was slightly higher for those with adenomas in both locations (OR, 1.89; 95% CI, 1.26 –2.82). Individuals with adenoma(s) ⬎1.0 cm in diameter had approximately a 50% increase in risk compared with those with adenomas ⬍0.5 cm (OR, 1.47;
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95% CI, 1.02–2.10). When we used advanced adenomas as the endpoint, adenoma number at baseline was not related to recurrence of these lesions. The presence of proximal adenomas at baseline was associated with a higher risk of recurrence of advanced lesions (OR, 1.65; 95% CI, 1.02–2.67), as was the presence of adenomas in both locations (OR, 2.69; 95% CI, 1.34 –5.42). A strong risk of recurrence for advanced adenomas was also shown for individuals with baseline adenomas ⬎1.0 cm compared with those with adenomas ⬍0.5 cm (OR, 2.27; 95% CI, 1.25– 4.14). No increase in risk of adenoma recurrence was shown for baseline villous polyp histology. When we included family history of colorectal cancer or history of previous polyps in the statistical models, results were not appreciably altered (data not shown). Likewise, exclusion of colon cancers from the analyses did not materially change the overall findings (data not shown). Because the recurrence rate is influenced by the degree of missed polyps at baseline, we also repeated analyses among 887 participants who underwent both a 1-year and an endpoint colonoscopy. Results of these analyses did not change the overall findings of our study (data not shown). Additionally, because of our use of 2 sources for histologic classification (community and study patholoTable 2. Adenoma Characteristics at Qualifying and Endpoint Colonoscopy
Characteristics No. of adenomas 1 2 ⱖ3 Locationb Distal colon and rectum Proximal Bothc Sized ⬍0.5 cm 0.6–1.0 cm ⬎1.0 cm Histologye Tubular Tubulovillous Villous Unspecified/incipient
Baseline All Advanced adenomas recurrences recurrencesa (n ⫽ 1287) (n ⫽ 625) (n ⫽ 146) 742 (57.7) 284 (22.1) 261 (20.2)
292 (46.8) 120 (19.2) 212 (34.0)
55 (37.9) 29 (20.0) 61 (42.1)
701 (54.6) 349 (27.2) 234 (18.2)
172 (27.7) 281 (45.2) 169 (27.1)
32 (22.1) 62 (42.8) 51 (35.2)
395 (30.7) 543 (42.4) 349 (27.1)
257 (41.3) 275 (44.1) 91 (14.6)
16 (11.0) 38 (26.2) 91 (62.8)
842 317 59 69
490 79 22 33
42 79 22 2
(65.4) (24.6) (4.6) (5.4)
(78.5) (12.7) (3.5) (5.3)
(29.0) (54.5) (15.2) (1.4)
NOTE. Data represent n (%). aAdvanced recurrences include adenomas ⬎1 cm in size or with tubulovillous/villous histology or colon cancers. bExcludes 3 participants with missing data for baseline adenomas and 2 participants with missing data for recurrence. cAdenomas in both distal colon and rectum and proximal colon. dSize of largest adenoma. Excludes 1 participant with missing data for recurrent adenomas. eHighest degree of histology.
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Table 3. Adenoma Characteristics at Qualifying Colonoscopy and Adenoma Recurrence
Characteristic No. of adenomas 1 2 ⱖ3
No recurrence (n ⫽ 662)
All recurrences (n ⫽ 625)
Advanced recurrencesa (n ⫽ 146)
433 140 89
309 144 172
All recurrences [ORb (95% CI)]
Advanced recurrences [OR (95% CI)]
86 28 32
1.00 1.23 (0.90–1.69) 1.91 (1.30–2.79) P trend ⫽ 0.001
1.00 0.76 (0.43–1.36) 1.01 (0.54–2.10) P trend ⫽ 0.98
Locationc Distal colon and rectum Proximal colon Bothd Sizee ⬍0.5 cm 0.6–1.0 cm ⬎1.0 cm
418 163 79
283 186 155
68 44 33
1.00 1.74 (1.32–2.31) 1.89 (1.26–2.82)
1.00 1.65 (1.02–2.67) 2.69 (1.34–5.42)
219 287 156
176 256 193
36 52 58
1.00 1.06 (0.80–1.42) 1.47 (1.02–2.10) P trend ⫽ 0.046
1.00 0.88 (0.52–2.14) 2.27 (1.25–4.14) P trend ⫽ 0.009
Histologyf Tubular Tubulovillous Villous Unspecified/incipient
439 156 28 39
403 161 31 30
92 41 9 4
1.00 1.01 (0.73–1.38) 0.72 (0.40–1.33) 1.11 (0.58–2.12)
1.00 1.10 (0.64–1.87) 0.41 (0.15–1.13) 0.47 (0.09–2.62)
recurrences include adenomas ⬎1 cm in size or with tubulovillous/villous histology or colon cancer. adjusted for age, sex, number of colonoscopies, and other adenoma characteristics. cExcludes 3 participants with missing data. dAdenomas in both distal colon and rectum and proximal colon. eSize of largest adenoma. fHighest degree of histology. aAdvanced bOR
gists), we repeated analyses using data only from the community pathologist; results were not appreciably altered for any recurrence or advanced recurrences (data not shown). Exclusion of the 44 participants with incomplete examinations at follow-up did not materially alter the results (data not shown). We compared risk factor characteristics of participants with proximal and those with distal adenomas at qualifying colonoscopy (Table 4). Compared with participants with only distal adenomas, those with only proximal adenomas were significantly older, were more likely to be male, and had a higher prevalence of polyps before baseline adenoma. The prevalence of family history of colorectal cancer was not statistically different between participants with distal and those with proximal adenomas. Proximal adenomas were smaller and less likely to contain a villous component than distal adenomas. As previously noted, when these characteristics were taken into account in the statistical models, the association between proximal adenomas and overall recurrence, as well as advanced recurrence, persisted.
Discussion To our knowledge, the present study is the largest to date providing evidence of the importance of adenoma characteristics as markers of recurrence as well as ad-
vanced recurrent lesions. These findings add to the published data,21–24 in that most individuals randomized into the study (91%) underwent follow-up colonoscopy, minimizing selection or detection bias. The results show that risk of adenoma recurrence, including advanced lesions, is linked to the characteristics of baseline lesions, which is in agreement with data from published studies. It is suspected that among individuals with adenomas, the risk of subsequent colorectal neoplasms is high, such that removal of the lesions should decrease morbidity and mortality from this malignancy. The risk of colorectal cancer has also been shown to vary with the characteristics of the adenomas25,26; however, among individuals with a single, small tubular adenoma, the incidence of advanced neoplasms (i.e., large, villous adenomas or carcinomas)27,28 or adenoma recurrence21 is low or no greater than would be expected in the general population. These results suggest that among these individuals, less costly and aggressive surveillance may be warranted. In agreement with numerous other studies,21–24,29 –33 the results of our study show adenoma recurrence to be associated with the presence of multiple adenomas; however, unlike the results of the National Polyp Study,32 adenoma number was not related to recurrence of advanced lesions. In a study with a design similar to ours,31 the strongest predictor of overall adenoma recurrence was
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Table 4. Characteristics of Participants According to Adenoma Location at Qualifying Colonoscopy Characteristic Age ( yr) ⬍67 ⱖ67 Male Family historyb History of previous polypsc No. of adenomas 1 2 ⱖ3 Sized ⬍0.5 cm 0.6–1.0 cm ⬎1.0 cm Histologye Tubular Tubulovillous Villous Unspecified/incipient
Distal (n ⫽ 701)
Proximal (n ⫽ 349)
351 (50.1) 350 (49.9) 446 (63.6) 106 (15.1) 178 (28.7)
145 (41.6) 204 (58.5)a 240 (68.8) 66 (18.9) 191 (61.2)a
503 (71.8) 134 (19.1) 64 (9.1)
236 (67.6) 67 (19.2) 46 (13.2)
201 (28.7) 296 (42.2) 204 (29.1)
157 (45.0) 133 (38.1) 59 (16.9)a
441 (62.9) 190 (27.1) 29 (4.1) 41 (5.9)
262 (75.1) 54 (15.5) 10 (2.8) 23 (6.6)a
NOTE. Data represent n (%). aP ⬍ 0.05 compared with distal. bFamily history of colorectal cancer in a parent or sibling. cSelf-reported history of polyps before baseline adenomas. Data missing for 117 participants. dSize of largest adenoma. eHighest degree of histology.
the number of index adenomas. According to data from St. Mark’s Hospital,30 in individuals who presented with multiple adenomas these lesions continued to grow as late as 15 years after follow-up; furthermore, their subsequent risk of colorectal cancer reached 1 in 14 at 5 years of follow-up and 1 in 8 at 10 years of follow-up. Clinically important adenomas include large (⬎1 cm) lesions, those with a high degree of dysplasia, and those with villous histology. In particular, adenoma size is considered an important marker of malignant potential, such that a larger adenoma at baseline is associated with a higher risk of colorectal cancer.25,26,28,34,35 Results of some21,24,31,32 but not all31 published studies also support the association of adenoma size and adenoma recurrence. Furthermore, results of our study show that the presence of large adenomas at baseline was an even stronger predictor of advanced recurrent adenomas. In the National Polyp Study,32 participants with a large adenoma (⬎1 cm) at enrollment were at increased risk, albeit nonsignificant, of recurrence of advanced lesions. Our results do not support the role of villous histology as predictive of subsequent overall recurrence or recurrence of advanced lesions. This can be the result of the low number of lesions with pure villous histology; conversely, misclassification resulting from our use of 2 sources (community and study pathologists) may be masking any true asso-
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ciation. However, data from some published studies,28,31 show no association between histology at baseline and recurrence of advanced adenomas. The presence of proximal adenomas was shown to be associated with higher risk of any recurrence as well as recurrence of advanced lesions. This characteristic has not been generally evaluated as a risk factor in the published literature. In one study,33 recurrence did not vary according to distribution of index lesions throughout the colorectum; however, the study sample was small (n ⫽ 109), included hyperplastic polyps, and the follow-up period was only 1 year. When we explored the characteristics of proximal lesions at baseline, we found these to be small and, for the most part, tubular in histology. Therefore, although the prediction would be that these lesions would not progress or recur based on these characteristics, they were found to be a marker of overall recurrence and recurrence of advanced lesions. Of particular importance, recurrent adenomas were more likely to be present in the proximal colon, as has also been reported in some studies.29,33 The importance of this finding is supported by data showing that colorectal cancer mortality is significantly higher among individuals with proximal adenomas than among those in the sigmoid or rectal areas (mortality ratio, 2.21; 95% CI, 1.18 – 4.16).26 In addition, although most cancers occur in the distal colon, in the last 3 decades, a progressive shift toward the proximal colon has occurred in the United States and other developed countries,36 –38 particularly among older white individuals,38 as is the case for our study population. These data suggest that the mucosa in the proximal colon is highly suitable for growth of new, more clinically important adenomas, regardless of the location of the baseline adenoma. Conversely, if these lesions represent missed polyps at baseline, this would imply that colonoscopic performance in this area needs to be improved. Our results also indicate that overall recurrence in the proximal colon was as common among individuals with baseline adenomas ⬍0.5 cm (48.5%) as in those with adenomas ⬎1 cm (47.9%). Additionally, the higher risk of recurrence of advanced lesions among individuals with proximal baseline adenomas suggests that this observation is real, given that large adenomas are less likely to represent missed polyps at baseline.39 – 41 A major strength of this study is in the high percentage of participants who underwent repeat colonoscopy. In several studies, only 11%– 60% of participants with a resected polyp returned for follow-up colonoscopy.21–24,30 Because it is possible that those who returned are different with respect to risk factors of interest than those who did not return for follow-up, the findings should be
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interpreted with caution. One limitation of the present study is that we did not collect data on indications for colonoscopy. Therefore, it is not possible to ascertain the extent to which these individuals were asymptomatic. Moreover, the study population is a group of healthconscientious white individuals, and the results may not be generalizable outside of the sociodemographic characteristics of this group. The findings of this study indicate that the presence of multiple adenomas, large adenomas (⬎1 cm), or adenomas in the proximal colon is a marker of future overall adenoma recurrence. More importantly, large or proximal adenomas at baseline were related to recurrence of advanced lesions. In addition, because most adenomas recurred in the proximal colon, careful examination of this area at follow-up by means of total colonoscopy is warranted. Currently, recommendations for surveillance after polypectomy take into account the size and number of polyps at baseline.18,42 The results of our study suggest that the finding of large or proximal adenomas warrants careful surveillance.
References 1. Fenoglio CM, Lane N. The anatomical precursor of colorectal carcinoma. Cancer 1974;34:819 – 823. 2. Morson BC. Evolution of cancer of the colon and rectum. Cancer 1974;34(suppl):845– 849. 3. Jackman RJ, Mayo CW. The adenoma-carcinoma sequence in cancer of the colon. Surg Gynecol Obstet 1951;93:327–330. 4. Bombi JA. Polyps of the colon in Barcelona, Spain: an autopsy study. Cancer 1988;61:1472–1476. 5. Vatn MH, Stalsberg H. The prevalence of polyps of the large intestine in Oslo. Cancer 1982;49:819 – 825. 6. Rickert RR, Auerbach O, Garfinkel L, Hammond EC, Frasch JM. Adenomatous lesions of the large bowel: an autopsy survey. Cancer 1979;43:1847–1857. 7. Restrepo C, Correa P, Duque E, Quello C. Polyps in a low risk colonic cancer population in Colombia, South America. Dis Colon Rectum 1981;24:29 –36. 8. Correa P, Strong JP, Reif A, Johnson WD. The epidemiology of colorectal polyps: prevalence in New Orleans and international comparisons. Cancer 1977;39:2258 –2264. 9. Webb WA, McDaniel L, Hones L. Experience with one thousand colonoscopic polypectomies. Ann Surg 1985;201:66626 – 66631. 10. Gillespie PE, Chambers TJ, Chan KW, Doronzo F, Morson BC Williams CB. Colonic adenomas—a colonoscopy survey. Gut 1979;20:240 –245. 11. Winawer SJ, Zauber AG, Ho MN, O’Brien MJ, Gottlieb LS, Sternberg SS, Waye JD, Schapiro M, Bond JH, Panish JF. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 1993;329:1977–1981. 12. Greenberg ER, Baron JA, Tosteson TD, Freeman DH, Beck GJ, Bond JH, Colacchio TA, Coller JA, Frankl HD, Haile RW. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. N Engl J Med 1994;331:141–147. 13. Baron JA, Beach M, Mandel JS, van Stolk RU, Haile RW, Sandler MD, Rothstein R, Summers RW, Snover DD, Beck GJ, Bond JH, Greenberg ER, Calcium Polyp Prevention Study Group. Calcium supplements for the prevention of colorectal adenomas. N Engl J Med 1999;340:101–107.
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14. Martı´nez ME, Reid ME, Guille´n-Rodrı´guez J, Marshall JR, Sampliner R, Aickin M, Ritenbaugh C, van Leeuwen B, Mason-Liddil N, Giuliano A, Vargas PA, Alberts DS. Design and baseline characteristics of study participants in the wheat bran fiber trial. Cancer Epidemiol Biomarkers Prev 1998;7:813– 816. 15. Alberts DS, Martinez ME, Roe DJ, Guillen-Rodriguez JM, Marshall JR, van Leeuwen B, Reid ME, Ritenbaugh C, Vargas PA, Bhattacharyya AB, Earnest DL, Sampliner RE, Parish D, Koonce K, Fales L. Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas. N Engl J Med 2000;342:1156 – 1162. 16. Schoen RE, Gerber LD, Marguiles C. The pathologic measurement of polyp size is preferable to the endoscopic estimate. Gastrointest Endosc 1997;46:492– 496. 17. Morales TG, Sampliner RE, Garewal HS, Fennerty MB, Aickin M. The difference in colon polyp size before and after removal. Gastrointest Endosc 1996;43:25–28. 18. Byers T, Levin B, Rothenberger D, Dodd GD, Smith RA. American Cancer Society guidelines for screening and surveillance for early detection of colorectal polyps and cancer: update 1997. CA Cancer J Clin 1997;47:154 –160. 19. Winawer SJ, Fletcher RH, Miller L, Godlee F, Stolar MH, Mulrow CD, Woolf SH, Glick SN, Ganiats TG, Bond JH, Rosen L, Zapka JG, Olsen SJ, Giardiello FM, Sisk JE, van Anturerp R, Brown-Davis C, Marcuriark DA, Mayer RJ. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997;112:594 – 642. 20. Hosmer DW, Lemeshow S. Applied logistic regression. New York: Wiley, 1989. 21. Fornasarig M, Valentini M, Poletti M, Carbone A, Bidoli E, Sozzi M, Cannizzaro R. Evaluation of the risk for metachronous colorectal neoplasms following intestinal polypectomy: a clinical, endoscopic and pathological study. Hepatogastroenterology 1998;45: 1565–1572. 22. Kellokumpu I, Husa A. Colorectal adenomas: morphologic features and the risk of developing metachronous adenomas and carcinomas in the colorectum. Scand J Gastroenterol 1987;22: 833– 841. 23. Neugut AI, Jacobson JS, Ahsan H, Santos J, Garbowski GC, Forde KA, Treat MR, Waye J. Incidence and recurrence rates of colorectal adenomas: a prospective study. Gastroenterology 1995;108: 402– 408. 24. Yang G, Zheng W, Sun Q-R, Shu X-O, Li W-D, Yu H, Shen G-F, Shen Y-Z, Potter JD, Zheng S. Pathologic features of initial adenomas as predictors for metachronous adenomas of the rectum. J Natl Cancer Inst 1998;90:1661–1651. 25. Otchy DP, Ransohoff DF, Wolff BG, Weaver A, Ilstrup D, Carlson H, Rademacher D. Metachronous colon cancer in persons who have had a large adenomatous polyp. Am J Gastroenterol 1996; 91:448 – 454. 26. Simons BD, Morrison AS, Lev R, Verhoek-Oftedahl W. Relationship of polyps to cancer of the large intestine. J Natl Cancer Inst 1992;84:962–966. 27. Atkin WS, Morson BC, Cuzick J. Long-term risk of colorectal cancer after excision of rectosigmoid adenomas. N Engl J Med 1992;326:658 – 662. 28. Grossman S, Milos ML, Tekawa IS, Jewell NP. Colonoscopic screening of persons with suspected risk factors for colon cancer: II. Past history of colorectal neoplasms. Gastroenterology 1989;96:299 –306. 29. Holfstad B, Vatn MH, Andersen SN, Huitfeldt HS, Rognum T, Larsen S, Osnes M. Growth of colorectal polyps: redetection and evaluation of unresected polyps for a period of three years. Gut 1996;39:449 – 456. 30. Morson BC, Bussey HJ. Magnitude of risk for cancer in patients with colorectal adenomas. Br J Surg 1985;72(suppl):23–25. 31. van Stolk RW, Beck GJ, Baron JA, Haile R, Summers R, Polyp Prevention Study Group. Adenoma characteristics at first
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32.
33.
34. 35.
36.
37. 38.
39.
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colonoscopy as predictors of adenoma recurrence and characteristics at follow-up. Gastroenterology 1998;115:13–18. Winawer SJ, Zauber AG, O’Brien MJ, Ho MN, Gottlieb L, Sternberg SS, Waye JD, Bond J, Schapiro M, Stewart ET, Panish J, Ackroyd F, Kurtz RC, Shike M, National Polyp Study Group. Randomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps. N Engl J Med 1993; 328:901–906. Woolfson IK, Eckholdt GJ, Wetzel CR, Gathright JB, Ray JE, Hicks TC, Timmcke AE, Ferrari BT. Usefulness of performing colonoscopy one year after endoscopic polypectomy. Dis Colon Rectum 1990;33:389 –393. Morson BC. The evolution of colorectal carcinoma. Clin Radiol 1984;35:425– 431. Noshirwani KC, van Stolk RU, Rybicki LA, Beck GJ. Adenoma size and number are predictive of adenoma recurrence: implications for surveillance colonoscopy. Gastrointest Endosc 2000;51:433– 437. Kee F, Wilson RH, Gilliland R, Sloan JM, Rowlands BJ, Moorehead RJ. Changing site distribution of colorectal cancer. BMJ 1992; 305:158. Mamazza J, Gordon PH. The changing distribution of large intestine cancer. Dis Colon Rectum 1982;25:558 –562. Nelson RL, Persky V, Turyk M. Time trends in distal colorectal cancer subsite location related to age and how it affects choice of screening modality. J Surg Oncol 1998;69:235–238. Hixson LS, Fennerty MB, Sampliner RE, McGee D, Garewal H. Prospective study of the frequency and size distribution of polyps missed by colonoscopy. J Natl Cancer Inst 1990;82: 1769 –1772.
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40. Rex DK, Cutler CS, Lemmel GT, Rahmani EY, Clark DW, Helper DJ, Lehman GA, Mark DG. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology 1997;112:24 –28. 41. Bensen S, Mott LA, Dain B, Rothstein R, Baron J, Polyp Prevention Study Group. The colonoscopic miss rate and true one-year recurrence of colorectal neoplastic polyps. Am J Gastroenterol 1999;94:194 –199. 42. Winawer SY, Fletcher RH, Miller L, Godlee F, Stolar MH, Mulrow CD, Woolf SH, Glick SN, Ganiats TG, Bond JH, Rosen L, Zapka JG, Olsen SJ, Giardiello FM, Sisk JE, van Antwerp R, Brown-Davis C, Marciniak DA, Mayer RJ. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997;112:594 – 642.
Received June 13, 2000. Accepted November 22, 2000. Address requests for reprints to: Marı´a Elena Martı´nez, Ph.D., University of Arizona, Arizona Cancer Center, P.O. Box 245024, Tucson, Arizona 85724. e-mail: [email protected]; fax: (520) 6269275. Supported in part by Public Health Service grants CA-41108 and CA-23074 from the National Cancer Institute, and by a Career Development Award (KO1 CA79069-10) from the National Cancer Institute (to M.E.M.). The authors thank Cheryl Kramer, Janine Einspahr, Nancy Hart, Denise J. Roe, Jose ´ Guille ´n-Rodriguez, and Barbara van Leeuwen for their expert assistance, and the staff at the Phoenix study sites and the Phoenix Colon Cancer Prevention Physicians’ Network for their valuable contributions.
Heidenhain of the Heidenhain Pouch
Rudolf Heidenhain (1834 –1897) was born at Marienwerder of a Prussian medical family; his father and 5 younger brothers were physicians. Following study at Berlin, Ko¨nigsberg, and Halle, in 1857 he acquired a lifetime post as professor of physiology and histology at Breslau. In his own time, he was best known for his contributions to the study of urine formation by the kidney. In addition, Heidenhain distinguished the various cell types in gastric mucosa and devised an experimental procedure in dogs whereby an externally drained pouch was wholly separated from the body of the stomach except for its blood supply (hence denervated), thus permitting investigation of uncontaminated gastric secretion. On this model, Ivan Pavlov (1849 –1936) devised a similar experimental gastric pouch in which innervation is preserved. Contributed by WILLIAM S. HAUBRICH, M.D., Scripps Clinic and Research Foundation, La Jolla, California Copyright holder unknown. Photo obtained from the National Library of Medicine website (http://www.nlm.nih.gov).
ALIMENTARY TRACT Adenoma Characteristics as Risk Factors for Recurrence of Advanced Adenomas MARI´A ELENA MARTI´NEZ,*,‡ RICHARD SAMPLINER,§,储 JAMES R. MARSHALL*,‡ ACHYUT K. BHATTACHARYYA,¶ MARY E. REID,*,‡ and DAVID S. ALBERTS*,‡,储 *Arizona Cancer Center, ‡College of Public Health, and Departments of 储Medicine and ¶Pathology, University of Arizona, Tucson, Arizona; and §Southern Arizona VA Health Care System, Tucson, Arizona
Background & Aims: The link between adenoma characteristics at baseline colonoscopy and adenoma recurrence is poorly understood. We assessed whether the number, size, location, or histology of resected adenomas was related to the probability of recurrence of advanced lesions. Methods: Analyses were based on 1287 men and women in the wheat bran fiber (WBF) study, a randomized, double-blind trial of WBF as a means of decreasing the probability of adenoma recurrence over a period of 3 years. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results: Recurrence of advanced adenomas (>1 cm or tubulovillous/villous histology) was higher among individuals with adenomas >1 cm compared with those with adenomas <0.5 cm (OR, 2.69; 95% CI, 1.34 –5.42) and among those with proximal than those with distal adenomas (OR, 1.65; 95% CI, 1.02–2.67). No association was observed for adenoma number or histology. A shift in location from the distal colon and rectum at baseline (54.6%) to more proximal recurrent adenomas (45.2%), including advanced lesions (42.8%), was observed. Conclusions: Large or proximally located adenomas are important indicators of recurrence of advanced lesions. Because most recurrences were detected in the proximal colon, careful surveillance of this area is warranted.
olorectal cancer represents the final stage of a slow, multistep carcinogenic process whose evolution involves the adenoma.1–3 Results of studies based on autopsy data and of high- or average-risk populations indicate that adenoma prevalence ranges from 20% to 60%.4 –10 Removal of adenomas is associated with a lower risk of colorectal cancer11; however, recurrence is common.11–13 Factors associated with recurrence of these lesions are not fully appreciated; furthermore, much less is known about the etiology of adenomas with advanced pathologic lesions, which represent an intermediate biologic endpoint of future colorectal malignancy. Although
C
several studies have been published specifically addressing the role of adenoma characteristics (i.e., histology, size, multiplicity, and location) in the etiology of adenoma recurrence, interpretation of these data is difficult given the problems related to these studies: small number of participants, inclusion of lesions other than adenomas, variety of follow-up intervals, and low follow-up rates of study participants with regard to endpoint colonoscopies. Chemoprevention trials provide a unique opportunity to investigate the etiology of adenoma recurrence with respect to a variety of environmental and host factors, including the characteristics of the baseline adenoma. A major strength of these studies is the completeness of follow-up; endpoint colonoscopy data are available on the vast majority of the participants. The goal of this prospective study was to assess whether characteristics of adenomas detected at qualifying colonoscopy were related to the probability of recurrence, with particular emphasis on recurrence of advanced lesions.
Materials and Methods Study Population Analyses were conducted among participants in the wheat bran fiber (WBF) trial, whose details14 and results15 have been published. Because the WBF intervention had no significant effect on adenoma recurrence,15 we evaluated data from all participants in the trial. Briefly, the WBF study is a double-blind, phase III trial of high vs. low fiber, designed to measure the effects of 3 years of WBF supplementation on adenoma recurrence. Men and women 40 – 80 years of age who had 1 or more colorectal adenoma(s) 3 mm or larger removed Abbreviations used in this paper: CI, confidence interval; OR, odds ratio; WBF, wheat bran fiber. © 2001 by the American Gastroenterological Association 0016-5085/01/$35.00 doi:10.1053/gast.2001.23247
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at colonoscopy within 3 months before study entry were recruited from the 4 clinic sites in the Phoenix metropolitan area. We excluded individuals with a personal history of inflammatory bowel disease or hereditary colon cancer syndromes. Of 1429 participants randomized into the trial, 1303 (91%) successfully completed the study by undergoing 1 or more colonoscopic examinations after randomization. Self-administered questionnaires were used to obtain data on sociodemographic variables, family history of colorectal cancer in first-degree relatives, history of polyps before the baseline adenoma, and other risk factors related to colorectal neoplasia. The study was approved by the University of Arizona Human Subjects Committee and local hospital committees.
Adenoma Characteristics Endoscopic and pathologic reports were reviewed for the qualifying colonoscopy and each colonoscopy reported by the participant during the trial. Using standardized guidelines, data on number, size, and location of all neoplasms were abstracted from the endoscopy report. Histology of lesions and an additional size variable were obtained from the pathology report based on the review of the community pathologist. In addition, a study pathologist (A.K.B.) reviewed the original slide or one obtained from the paraffin-embedded tissue block. A high degree of agreement between the community and study pathologists was observed (92%) for identification of an adenoma vs. nonadenoma. Agreement between the community and study pathologists for classification of tubulovillous or villous histology was 65%. A potential reason for the discordance is that we were not always able to obtain the original slide reviewed by the community pathologist for review; thus, it was not always possible to examine the same polypoid tissue area. For histologic classification, we included data from the study pathologist’s review for reports with missing information from the community pathologist (n ⫽ 320). For individuals with more than 1 adenoma, the highest degree of villous component was used for classification. Adenoma size was determined using 2 sources: the endoscopy and community pathologist’s reports. Comparison of these sources showed that size based on the endoscopy report was significantly greater than that based on the pathology report (P ⬍ 0.001). Two recent publications16,17 indicated a higher degree of accuracy based on the pathology than on the endoscopy report. Therefore, in generating the best estimate of size, we used data from the pathology report, and when those data were missing, we used those from the endoscopy report. For individuals with more than 1 resected adenoma, the largest was used for classification of size. Adenoma location was classified as distal colon and rectum (rectum, rectosigmoid, sigmoid colon, descending colon, splenic flexure) or proximal colon (transverse colon, hepatic flexure, ascending colon, cecum). For individuals with more than 1 adenoma located in both sites, a separate category was created.
Follow-up The study protocol specified that 2 follow-up colonoscopies be performed after the qualifying colonoscopy. The first colonoscopy was to take place 1 year after randomization (to
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remove polyps missed at the qualifying colonoscopy) and the second 2 years thereafter. However, national recommendations for colorectal cancer screening changed during this trial,18,19 resulting in a decrease in 1-year colonoscopies among participants enrolled in the latter part of the trial, so that 889 of the 1303 participants had both a 1-year and an endpoint colonoscopy. Therefore, we considered a recurrence as 1 or more adenomas detected any time after randomization. Nine colon cancers, including 1 occurring without an accompanying adenoma recurrence, occurred during the follow-up period. No significant differences were shown for recurrence rates by clinic site: clinic 1, 48.1%; clinic 2, 52.4%; clinic 3, 49.2%; and clinic 4, 50.0%. The mean follow-up period was 36.8 (⫾16.0) months.
Statistical Analysis We explored the association between adenoma characteristics at qualifying colonoscopy and adenoma recurrence. Adenoma recurrence status (positive vs. negative) was used as the dependent variable for 1 set of statistical models. The presence of 1 or more advanced recurrent adenomas was used for the primary endpoint of interest. Advanced lesions comprised those ⬎1 cm in size, those with tubulovillous or villous histology, and all colon cancers. We used multiple logistic regression analysis20 to control for potential confounding variables. Initial models included age, gender, and number of study colonoscopies conducted after baseline. Simultaneous adjustment for all adenoma characteristics was conducted in the final statistical models. The importance of each independent variable was summarized by its odds ratio (OR) and 95% confidence interval (CI).
Results Of the 1303 participants with at least 1 colonoscopy after randomization, 1287 had data on baseline and recurrent adenoma characteristics of interest and made up the final study population. Of these, 625 (48.6%) had 1 or more recurrent adenomas, and 624 of these had complete data on all characteristics for classification of advanced recurrences. Of those with complete data, 146 were classified as having 1 or more advanced adenomas. Table 1 presents participant characteristics by recurrence status. Individuals with recurrence were significantly older and more likely to be male than those without recurrence. In addition, participants with a family history of colorectal cancer in first-degree relatives and those with a history of colorectal polyps before the baseline adenoma were more likely to have a recurrence; however, only the latter was statistically significant. Individuals with recurrence underwent a significantly higher number of colonoscopies than those without recurrence. Adenoma characteristics based on qualifying and follow-up colonoscopies are presented in Table 2. Compared with baseline adenomas, recurrent lesions were
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Table 1. Characteristics of Study Participants at Enrollment, According to Recurrence Status
Characteristic Age ( yr) ⬍67 [n (%)] ⱖ67 [n (%)] Sex Male [n (%)] Race White [n (%)] Family historyc [n (%)] History of previous polypsd [n (%)] No. of colonoscopies (mean ⫾ SD)
No recurrence (n ⫽ 662)
All recurrences (n ⫽ 625)
Advanced recurrencesa (n ⫽ 146)
322 (48.6) 340 (51.4)
260 (41.6) 365 (58.4)b
53 (36.3) 93 (63.7)b
409 (61.8)
455 (72.8)b
104 (71.2)b
635 (95.9)
602 (96.3)
142 (97.3)
101 (15.3)
117 (18.7)
31 (21.2)
193 (32.4)
252 (46.6)b
59 (47.6)b
1.8 ⫹ 0.7
2.3 ⫹ 0.9b
2.7 ⫹ 1.1b
recurrences include adenomas ⬎1 cm in size or with tubulovillous/villous histology or colon cancers. bP ⬍ 0.01 compared with no recurrence. cFamily history of colorectal cancer in a parent or sibling. dSelf-reported history of polyps before baseline adenomas. Data missing for 150 participants.
aAdvanced
more likely to be multiple, smaller in diameter, and of tubular histology. A shift in location from the distal colon and rectum at baseline (54.6%) to more proximal recurrent lesions (45.2%) was observed, such that more than 70% of study participants had at least 1 proximal adenoma at recurrence. By definition, advanced lesions were larger and more likely to be tubulovillous or villous. In addition, 42.8% of the advanced adenomas were proximally located, with no additional lesions located elsewhere in the colorectum. Exclusion of the 44 participants with incomplete examinations of the colon at follow-up did not materially change the results. Location of any recurrence was 27.3% for distal, 46.3% for proximal, and 26.4% for both; the corresponding figures for advanced recurrence were 19.2%, 46.2%, and 34.6%, respectively. Table 3 presents ORs for adenoma recurrence related to the characteristics of the baseline lesion. After adjustment for age, sex, number of colonoscopies, and the other adenoma characteristics, individuals with 3 or more adenomas had almost a 2-fold risk of any recurrence compared with those with a single lesion (OR, 1.91; 95% CI, 1.30 –2.79). Compared with participants with adenomas in the distal colon or rectum, those with proximal adenoma(s) had a higher risk of any recurrence (OR, 1.74; 95% CI, 1.32–2.31) and the risk was slightly higher for those with adenomas in both locations (OR, 1.89; 95% CI, 1.26 –2.82). Individuals with adenoma(s) ⬎1.0 cm in diameter had approximately a 50% increase in risk compared with those with adenomas ⬍0.5 cm (OR, 1.47;
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95% CI, 1.02–2.10). When we used advanced adenomas as the endpoint, adenoma number at baseline was not related to recurrence of these lesions. The presence of proximal adenomas at baseline was associated with a higher risk of recurrence of advanced lesions (OR, 1.65; 95% CI, 1.02–2.67), as was the presence of adenomas in both locations (OR, 2.69; 95% CI, 1.34 –5.42). A strong risk of recurrence for advanced adenomas was also shown for individuals with baseline adenomas ⬎1.0 cm compared with those with adenomas ⬍0.5 cm (OR, 2.27; 95% CI, 1.25– 4.14). No increase in risk of adenoma recurrence was shown for baseline villous polyp histology. When we included family history of colorectal cancer or history of previous polyps in the statistical models, results were not appreciably altered (data not shown). Likewise, exclusion of colon cancers from the analyses did not materially change the overall findings (data not shown). Because the recurrence rate is influenced by the degree of missed polyps at baseline, we also repeated analyses among 887 participants who underwent both a 1-year and an endpoint colonoscopy. Results of these analyses did not change the overall findings of our study (data not shown). Additionally, because of our use of 2 sources for histologic classification (community and study patholoTable 2. Adenoma Characteristics at Qualifying and Endpoint Colonoscopy
Characteristics No. of adenomas 1 2 ⱖ3 Locationb Distal colon and rectum Proximal Bothc Sized ⬍0.5 cm 0.6–1.0 cm ⬎1.0 cm Histologye Tubular Tubulovillous Villous Unspecified/incipient
Baseline All Advanced adenomas recurrences recurrencesa (n ⫽ 1287) (n ⫽ 625) (n ⫽ 146) 742 (57.7) 284 (22.1) 261 (20.2)
292 (46.8) 120 (19.2) 212 (34.0)
55 (37.9) 29 (20.0) 61 (42.1)
701 (54.6) 349 (27.2) 234 (18.2)
172 (27.7) 281 (45.2) 169 (27.1)
32 (22.1) 62 (42.8) 51 (35.2)
395 (30.7) 543 (42.4) 349 (27.1)
257 (41.3) 275 (44.1) 91 (14.6)
16 (11.0) 38 (26.2) 91 (62.8)
842 317 59 69
490 79 22 33
42 79 22 2
(65.4) (24.6) (4.6) (5.4)
(78.5) (12.7) (3.5) (5.3)
(29.0) (54.5) (15.2) (1.4)
NOTE. Data represent n (%). aAdvanced recurrences include adenomas ⬎1 cm in size or with tubulovillous/villous histology or colon cancers. bExcludes 3 participants with missing data for baseline adenomas and 2 participants with missing data for recurrence. cAdenomas in both distal colon and rectum and proximal colon. dSize of largest adenoma. Excludes 1 participant with missing data for recurrent adenomas. eHighest degree of histology.
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Table 3. Adenoma Characteristics at Qualifying Colonoscopy and Adenoma Recurrence
Characteristic No. of adenomas 1 2 ⱖ3
No recurrence (n ⫽ 662)
All recurrences (n ⫽ 625)
Advanced recurrencesa (n ⫽ 146)
433 140 89
309 144 172
All recurrences [ORb (95% CI)]
Advanced recurrences [OR (95% CI)]
86 28 32
1.00 1.23 (0.90–1.69) 1.91 (1.30–2.79) P trend ⫽ 0.001
1.00 0.76 (0.43–1.36) 1.01 (0.54–2.10) P trend ⫽ 0.98
Locationc Distal colon and rectum Proximal colon Bothd Sizee ⬍0.5 cm 0.6–1.0 cm ⬎1.0 cm
418 163 79
283 186 155
68 44 33
1.00 1.74 (1.32–2.31) 1.89 (1.26–2.82)
1.00 1.65 (1.02–2.67) 2.69 (1.34–5.42)
219 287 156
176 256 193
36 52 58
1.00 1.06 (0.80–1.42) 1.47 (1.02–2.10) P trend ⫽ 0.046
1.00 0.88 (0.52–2.14) 2.27 (1.25–4.14) P trend ⫽ 0.009
Histologyf Tubular Tubulovillous Villous Unspecified/incipient
439 156 28 39
403 161 31 30
92 41 9 4
1.00 1.01 (0.73–1.38) 0.72 (0.40–1.33) 1.11 (0.58–2.12)
1.00 1.10 (0.64–1.87) 0.41 (0.15–1.13) 0.47 (0.09–2.62)
recurrences include adenomas ⬎1 cm in size or with tubulovillous/villous histology or colon cancer. adjusted for age, sex, number of colonoscopies, and other adenoma characteristics. cExcludes 3 participants with missing data. dAdenomas in both distal colon and rectum and proximal colon. eSize of largest adenoma. fHighest degree of histology. aAdvanced bOR
gists), we repeated analyses using data only from the community pathologist; results were not appreciably altered for any recurrence or advanced recurrences (data not shown). Exclusion of the 44 participants with incomplete examinations at follow-up did not materially alter the results (data not shown). We compared risk factor characteristics of participants with proximal and those with distal adenomas at qualifying colonoscopy (Table 4). Compared with participants with only distal adenomas, those with only proximal adenomas were significantly older, were more likely to be male, and had a higher prevalence of polyps before baseline adenoma. The prevalence of family history of colorectal cancer was not statistically different between participants with distal and those with proximal adenomas. Proximal adenomas were smaller and less likely to contain a villous component than distal adenomas. As previously noted, when these characteristics were taken into account in the statistical models, the association between proximal adenomas and overall recurrence, as well as advanced recurrence, persisted.
Discussion To our knowledge, the present study is the largest to date providing evidence of the importance of adenoma characteristics as markers of recurrence as well as ad-
vanced recurrent lesions. These findings add to the published data,21–24 in that most individuals randomized into the study (91%) underwent follow-up colonoscopy, minimizing selection or detection bias. The results show that risk of adenoma recurrence, including advanced lesions, is linked to the characteristics of baseline lesions, which is in agreement with data from published studies. It is suspected that among individuals with adenomas, the risk of subsequent colorectal neoplasms is high, such that removal of the lesions should decrease morbidity and mortality from this malignancy. The risk of colorectal cancer has also been shown to vary with the characteristics of the adenomas25,26; however, among individuals with a single, small tubular adenoma, the incidence of advanced neoplasms (i.e., large, villous adenomas or carcinomas)27,28 or adenoma recurrence21 is low or no greater than would be expected in the general population. These results suggest that among these individuals, less costly and aggressive surveillance may be warranted. In agreement with numerous other studies,21–24,29 –33 the results of our study show adenoma recurrence to be associated with the presence of multiple adenomas; however, unlike the results of the National Polyp Study,32 adenoma number was not related to recurrence of advanced lesions. In a study with a design similar to ours,31 the strongest predictor of overall adenoma recurrence was
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Table 4. Characteristics of Participants According to Adenoma Location at Qualifying Colonoscopy Characteristic Age ( yr) ⬍67 ⱖ67 Male Family historyb History of previous polypsc No. of adenomas 1 2 ⱖ3 Sized ⬍0.5 cm 0.6–1.0 cm ⬎1.0 cm Histologye Tubular Tubulovillous Villous Unspecified/incipient
Distal (n ⫽ 701)
Proximal (n ⫽ 349)
351 (50.1) 350 (49.9) 446 (63.6) 106 (15.1) 178 (28.7)
145 (41.6) 204 (58.5)a 240 (68.8) 66 (18.9) 191 (61.2)a
503 (71.8) 134 (19.1) 64 (9.1)
236 (67.6) 67 (19.2) 46 (13.2)
201 (28.7) 296 (42.2) 204 (29.1)
157 (45.0) 133 (38.1) 59 (16.9)a
441 (62.9) 190 (27.1) 29 (4.1) 41 (5.9)
262 (75.1) 54 (15.5) 10 (2.8) 23 (6.6)a
NOTE. Data represent n (%). aP ⬍ 0.05 compared with distal. bFamily history of colorectal cancer in a parent or sibling. cSelf-reported history of polyps before baseline adenomas. Data missing for 117 participants. dSize of largest adenoma. eHighest degree of histology.
the number of index adenomas. According to data from St. Mark’s Hospital,30 in individuals who presented with multiple adenomas these lesions continued to grow as late as 15 years after follow-up; furthermore, their subsequent risk of colorectal cancer reached 1 in 14 at 5 years of follow-up and 1 in 8 at 10 years of follow-up. Clinically important adenomas include large (⬎1 cm) lesions, those with a high degree of dysplasia, and those with villous histology. In particular, adenoma size is considered an important marker of malignant potential, such that a larger adenoma at baseline is associated with a higher risk of colorectal cancer.25,26,28,34,35 Results of some21,24,31,32 but not all31 published studies also support the association of adenoma size and adenoma recurrence. Furthermore, results of our study show that the presence of large adenomas at baseline was an even stronger predictor of advanced recurrent adenomas. In the National Polyp Study,32 participants with a large adenoma (⬎1 cm) at enrollment were at increased risk, albeit nonsignificant, of recurrence of advanced lesions. Our results do not support the role of villous histology as predictive of subsequent overall recurrence or recurrence of advanced lesions. This can be the result of the low number of lesions with pure villous histology; conversely, misclassification resulting from our use of 2 sources (community and study pathologists) may be masking any true asso-
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ciation. However, data from some published studies,28,31 show no association between histology at baseline and recurrence of advanced adenomas. The presence of proximal adenomas was shown to be associated with higher risk of any recurrence as well as recurrence of advanced lesions. This characteristic has not been generally evaluated as a risk factor in the published literature. In one study,33 recurrence did not vary according to distribution of index lesions throughout the colorectum; however, the study sample was small (n ⫽ 109), included hyperplastic polyps, and the follow-up period was only 1 year. When we explored the characteristics of proximal lesions at baseline, we found these to be small and, for the most part, tubular in histology. Therefore, although the prediction would be that these lesions would not progress or recur based on these characteristics, they were found to be a marker of overall recurrence and recurrence of advanced lesions. Of particular importance, recurrent adenomas were more likely to be present in the proximal colon, as has also been reported in some studies.29,33 The importance of this finding is supported by data showing that colorectal cancer mortality is significantly higher among individuals with proximal adenomas than among those in the sigmoid or rectal areas (mortality ratio, 2.21; 95% CI, 1.18 – 4.16).26 In addition, although most cancers occur in the distal colon, in the last 3 decades, a progressive shift toward the proximal colon has occurred in the United States and other developed countries,36 –38 particularly among older white individuals,38 as is the case for our study population. These data suggest that the mucosa in the proximal colon is highly suitable for growth of new, more clinically important adenomas, regardless of the location of the baseline adenoma. Conversely, if these lesions represent missed polyps at baseline, this would imply that colonoscopic performance in this area needs to be improved. Our results also indicate that overall recurrence in the proximal colon was as common among individuals with baseline adenomas ⬍0.5 cm (48.5%) as in those with adenomas ⬎1 cm (47.9%). Additionally, the higher risk of recurrence of advanced lesions among individuals with proximal baseline adenomas suggests that this observation is real, given that large adenomas are less likely to represent missed polyps at baseline.39 – 41 A major strength of this study is in the high percentage of participants who underwent repeat colonoscopy. In several studies, only 11%– 60% of participants with a resected polyp returned for follow-up colonoscopy.21–24,30 Because it is possible that those who returned are different with respect to risk factors of interest than those who did not return for follow-up, the findings should be
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interpreted with caution. One limitation of the present study is that we did not collect data on indications for colonoscopy. Therefore, it is not possible to ascertain the extent to which these individuals were asymptomatic. Moreover, the study population is a group of healthconscientious white individuals, and the results may not be generalizable outside of the sociodemographic characteristics of this group. The findings of this study indicate that the presence of multiple adenomas, large adenomas (⬎1 cm), or adenomas in the proximal colon is a marker of future overall adenoma recurrence. More importantly, large or proximal adenomas at baseline were related to recurrence of advanced lesions. In addition, because most adenomas recurred in the proximal colon, careful examination of this area at follow-up by means of total colonoscopy is warranted. Currently, recommendations for surveillance after polypectomy take into account the size and number of polyps at baseline.18,42 The results of our study suggest that the finding of large or proximal adenomas warrants careful surveillance.
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Received June 13, 2000. Accepted November 22, 2000. Address requests for reprints to: Marı´a Elena Martı´nez, Ph.D., University of Arizona, Arizona Cancer Center, P.O. Box 245024, Tucson, Arizona 85724. e-mail: [email protected]; fax: (520) 6269275. Supported in part by Public Health Service grants CA-41108 and CA-23074 from the National Cancer Institute, and by a Career Development Award (KO1 CA79069-10) from the National Cancer Institute (to M.E.M.). The authors thank Cheryl Kramer, Janine Einspahr, Nancy Hart, Denise J. Roe, Jose ´ Guille ´n-Rodriguez, and Barbara van Leeuwen for their expert assistance, and the staff at the Phoenix study sites and the Phoenix Colon Cancer Prevention Physicians’ Network for their valuable contributions.
Heidenhain of the Heidenhain Pouch
Rudolf Heidenhain (1834 –1897) was born at Marienwerder of a Prussian medical family; his father and 5 younger brothers were physicians. Following study at Berlin, Ko¨nigsberg, and Halle, in 1857 he acquired a lifetime post as professor of physiology and histology at Breslau. In his own time, he was best known for his contributions to the study of urine formation by the kidney. In addition, Heidenhain distinguished the various cell types in gastric mucosa and devised an experimental procedure in dogs whereby an externally drained pouch was wholly separated from the body of the stomach except for its blood supply (hence denervated), thus permitting investigation of uncontaminated gastric secretion. On this model, Ivan Pavlov (1849 –1936) devised a similar experimental gastric pouch in which innervation is preserved. Contributed by WILLIAM S. HAUBRICH, M.D., Scripps Clinic and Research Foundation, La Jolla, California Copyright holder unknown. Photo obtained from the National Library of Medicine website (http://www.nlm.nih.gov).