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A case-control study of dietary intake and other lifestyle risk factors for hyperplastic polyps
GASTROENTEROLOGY 1997;113:423–429
A Case-Control Study of Dietary Intake and Other Lifestyle Risk Factors for Hyperplastic Polyps MARI´A ELENA MARTI´NEZ,* R. SUE MCPHERSON,* BERNARD LEVIN,§ and GARY A. GLOBER\ *Human Nutrition Center, University of Texas-Houston Health Science Center, School of Public Health, Houston; and §Division of Cancer Prevention and \Department of Gastrointestinal Medical Oncology and Digestive Diseases, University of Texas M. D. Anderson Cancer Center, Houston, Texas
Background & Aims: Despite the high prevalence of the hyperplastic polyp, little is known about its etiology. The aim of this study was to assess the relationship between diet and other lifestyle factors and the presence of colorectal hyperplastic polyps. Methods: Information on diet and other known or suspected risk factors for colorectal cancer or adenoma was collected among 81 subjects with hyperplastic polyps and 480 controls. Results: The multivariate-adjusted odds ratio (OR) for hyperplastic polyps for individuals in the upper vs. the lower quartile was 0.30 (95% confidence interval [CI], 0.10–0.88) for dietary fiber, 0.32 (95% CI, 0.11–0.96) for dietary calcium, 0.90 (95% CI, 0.27– 2.95) for total fat, and 2.02 (95% CI, 1.05–3.91) for alcohol consumption. Compared with individuals in the lower category, those in the upper category of body mass index had a higher risk for hyperplastic polyps (OR, 4.50; 95% CI, 1.84–10.97). Cigarette smoking was associated with a higher risk (OR, 1.97; 95% CI, 1.02–3.81 for ú20 pack-years vs. never), whereas an inverse association was seen for use of aspirin and other nonsteroidal anti-inflammatory drugs (OR, 0.29; 95% CI, 0.12–0.67 for once per day or more vs. never). Conclusions: Hyperplastic polyps share common lifestyle risk factors with colorectal adenomas and carcinomas.
A
lthough the adenomatous polyp is recognized as a precursor for colorectal cancer, the clinical significance of the hyperplastic polyp is questionable. In view of some similarities between hyperplastic polyps and colorectal carcinomas, including anatomic distribution1,2 and histochemical changes,3 – 7 some investigators have questioned the unimportance of these lesions.8,9 Unlike the adenomatous polyp, little is known about the etiology and natural history of the hyperplastic polyp, despite its high prevalence. Two proposals have been suggested to define the significance of hyperplastic polyps in the etiology of colorectal cancer: (1) hyperplastic polyps may be unimportant, and (2) hyperplastic polyps may act as markers for subsequent development of adenomas or carcinomas and may represent the first stage of / 5e1f$$0045
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the polyp-cancer sequence. Results of a recent molecular study found K-ras mutations to be equally prevalent in hyperplastic and dysplastic polyps,10 casting further doubt to the insignificance of these polyps. To our knowledge, only one epidemiological study has published results on the association of dietary and other lifestyle factors and the development of hyperplastic polyps.11 We hypothesized that these polyps have similar risk factors as adenomas and carcinomas of the large bowel. We conducted a case-control study of dietary and other lifestyle factors for colorectal polyps and report the findings for the hyperplastic polyps.
Materials and Methods Study Population Details regarding methodology of this study have been described in detail previously.12 – 14 The study population comprised white, black, and Hispanic individuals who underwent an endoscopy by one of eight collaborating gastroenterologists between September 1991 and June 1993. Approval for human subjects was obtained from each participating institution. Excluded were individuals with a history of colorectal polyps, familial polyposis coli, Gardner’s syndrome, hereditary nonpolyposis colorectal cancer, any cancer except nonmelanoma skin cancer, ulcerative colitis, inflammatory bowel disease and other colitides, human immunodeficiency virus infection, and chronic renal failure. Individuals whose residence was outside a 30-mile radius of the Texas Medical Center in Houston were also excluded. Case patients were individuals who met the eligibility criteria, had undergone a sigmoidoscopy or colonoscopy, and had a first-time histological diagnosis of hyperplastic polyps. Individuals with both adenomatous and hyperplastic polyps were excluded. The control group consisted of individuals who met the eligibility criteria but who were found to be negative for hyperplastic or adenomatous polyps. Eligible persons were identified by a review of medical records of individuals who had undergone endoscopy at any of Abbreviations used in this paper: BMI, body mass index; CI, confidence interval; FFQ, food frequency questionnaire; OR, odds ratio. q 1997 by the American Gastroenterological Association 0016-5085/97/$3.00
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the clinic sites. We reviewed 4698 medical records and identified 113 eligible case subjects and 719 eligible controls. The three primary reasons for ineligibility were history of polyps (38%), living outside the study area (33%), and history of cancer (26%). We contacted eligible individuals by telephone to explain the purpose of the study, to request their participation, and to schedule a personal interview at the physician’s office, the participant’s home, or place of employment. Interviews were conducted within 1 month after endoscopy. We could not contact 16 of the eligible case individuals (14%) and 83 of the eligible controls (11.5%) because of wrong or disconnected telephone numbers. Among the case patients contacted, 84.5% (82 of 97) participated in the study; among the controls, 83.6% (532 of 636) of those contacted participated. We excluded from subsequent analyses 5 controls with caloric intakes ú 5500 kcal/day and 1 control whose interview was unsatisfactory. In addition, because the youngest case was 34 years of age, we restricted the study population to individuals 35 years of age and older, which excluded 1 additional case and 46 controls from the analyses. The analysis was based on 81 subjects with hyperplastic polyps and 480 controls who were negative for colorectal polyps. Complete ascertainment on indications for endoscopy was not always available. According to the information available, rectal bleeding prompted endoscopy in 8% of the cases and 17.3% of the controls, and occult blood in the stool was the indication for 10% of the cases and 9% of the controls. Because the study population primarily comprised individuals seen for screening, 22% of the controls underwent total colonoscopy and the remaining 78% had only a sigmoidoscopy examination; among the case subjects, 58% underwent total colonoscopy and 42% only a sigmoidoscopy examination. This is in accordance with the recommendations of national authorities who do not advise colonoscopy if a hyperplastic polyp is found during sigmoidoscopy.15,16 Therefore, we do not have complete ascertainment of hyperplastic polyps in the proximal colon, although this number is likely to be low.9,17
Questionnaire Information Personal interviews were conducted to obtain information on age, sex, race, years of education, combined annual family income, height and current weight, physical activity, family history of colorectal cancer in first-degree relatives, use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), vitamin and mineral supplement use, cigarette smoking, and dietary intake (including alcohol consumption). We assessed dietary intake from a 138-item quantified food frequency questionnaire (FFQ) that inquired about diet during the month before the interview. We used common household measures and two- and three-dimensional food models to obtain serving sizes. The food list of the FFQ represents at least 90% of the foods that are in other validated FFQs with the differences being the addition of foods specific to calcium intake and to the triethnic population of Texas.18 Validation of the FFQ method has been well published, and this food list did not differ markedly from those in the literature.19 The
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FFQ specifically assessed mean daily intake of total calories, calcium, total fat, total dietary fiber, and alcohol. We computed nutrient intake by using the Food Frequency Data Entry and Analysis Program and nutrient and gram weight data from the U.S. Department of Agriculture Survey Nutrient Database.20,21
Data Analysis With the exception of age and use of aspirin and other NSAIDs, we converted continuous scaled variables to categorical variables based on the quartile distribution among the control group. We treated age as a continuous variable and categorized frequency of use of aspirin and other NSAIDs as none, less than daily, and at least daily and duration as none, less than 5 years, and 5 years or more. We used unconditional logistic regression analysis22 to control for variables that were a priori risk factors for colorectal cancer and adenoma. We included total kilocalories per day in the logistic regression models to adjust for energy intake.
Results The study population included 81 subjects with hyperplastic polyps (44 men and 37 women) and 480 controls (229 men and 251 women). The mean ages of the case and control subjects were 57 and 55 years, respectively. A total of 135 hyperplastic polyps were detected among the 81 case participants; 93% of these lesions were located in the distal colon and rectum. The risk factor characteristics of the study population by casecontrol status are shown in Table 1. Compared with the case group, the control individuals were significantly younger, had a lower proportion of whites, and consumed significantly more fiber and less alcohol. Overall, compared with the case group, participants in the control group had a risk factor pattern consistent with a lower risk profile for colorectal cancer and adenoma. These include a lower proportion of current smokers, a lower body mass index (BMI), a higher level of physical activity, a lower prevalence of family history of colorectal cancer, a higher proportion of users of aspirin and other NSAIDs, a lower intake of total fat, and a higher intake of fiber and calcium. A higher intake of total dietary fiber was associated with a lower risk of hyperplastic polyps (Table 2). Compared with individuals in the lower quartile, the multivariate odds ratio (OR) for those consuming ¢28 g of total dietary fiber per day was 0.30 (95% confidence interval [CI], 0.10–0.88). A significant trend was observed across the categories of fiber intake (P Å 0.02). Individuals in the upper category of calcium intake had an OR of 0.32 for hyperplastic polyps (95% CI, 0.11– 0.96) compared with individuals in the lower category (P for trend Å 0.05). A higher intake of total fat was WBS-Gastro
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RISK FACTORS FOR HYPERPLASTIC POLYPS 425
Table 1. Risk Factor Characteristics of Study Population According to Case-Control Status Case-control status Cases (n Å 81)
Risk factor a
Age (yr ) Male (%) White (%) ¢High school education (%) Current smoker (%) Past smoker (%) BMI (kg/m2)a Physical activity (kcal/wk)a Family history of colorectal cancer (%)b NSAID/aspirin use (%) Total fat (% energy)a Fiber (gr1000 kcal01rday01)a Calcium (mgr1000 kcal01rday01)a Alcohol (g/day)a
Controls (n Å 480)
57.3 { 9.7 54.3 77.8 90.1 19.8 40.7 28.2 { 4.3 1329 { 1170 18.5 19.8 34.4 { 4.9 10.1 { 2.3 389.5 { 121.3 8.6 { 15.0
54.7 { 9.8 47.7 62.3 86.7 11.9 34.6 27.2 { 5.3 1540 { 1262 16.5 29.4 33.0 { 6.1 10.9 { 3.0 408.1 { 131.9 5.0 { 9.8
P value 0.03 0.27 0.007 0.39 0.05 0.28 0.10 0.16 0.65 0.07 0.06 0.02 0.24 0.005
a
Mean { SD. Family history in first-degree relatives.
b
not associated with a higher risk of hyperplastic polyps (OR for the upper vs. the lower quartile, 0.90; 95% CI, 0.27–2.95). Alcohol consumption was positively associated with risk of hyperplastic polyps. Individuals consuming ú9.4 g of alcohol per day were more than twice as likely to have hyperplastic polyps compared with nondrinkers (OR, 2.02; 95% CI, 1.05–3.91; P for trend Å 0.01). The associations of BMI, physical activity, cigarette
smoking, and use of aspirin and other NSAIDs and hyperplastic polyps are presented in Table 3. A strong positive association was observed for BMI and risk of hyperplastic polyps. Individuals with a BMI ú29.8 kg/m2 had an OR of 4.50 for hyperplastic polyps (95% CI, 1.84– 10.97) compared with those with a BMI of õ23.4; a monotonic dose response was observed (P for trend Å 0.001). Physical activity was inversely associated with the presence of hyperplastic polyps; however, the negative
Table 2. OR for Hyperplastic Polyps of the Colorectum According to Intake of Total Dietary Fiber, Dietary Calcium, Total Fat, and Alcohol No. of cases
No. of controls
ORa (95% CI)
ORb (95% CI)
P trendc
25 15 15 16
120 120 120 120
1.00 0.80 (0.42–1.50) 0.42 (0.20–0.87) 0.47 (0.23–0.96)
1.00 0.78 (0.39–1.56) 0.36 (0.16–0.83) 0.30 (0.10–0.88)
0.02
22 22 23 14
120 120 120 120
1.00 0.75 (0.38–1.47) 0.74 (0.37–1.46) 0.41 (0.19–0.90)
1.00 0.72 (0.34–1.50) 0.69 (0.31–1.51) 0.32 (0.11–0.96)
0.05
21 15 23 22
120 120 120 120
1.00 0.65 (0.32–1.34) 0.96 (0.48–1.90) 0.90 (0.44–1.87)
1.00 0.65 (0.29–1.43) 0.88 (0.38–2.06) 0.90 (0.27–2.95)
0.13
32 13 12 24
224 85 85 85
1.00 1.06 (0.53–2.11) 1.01 (0.50–2.05) 2.01 (1.11–3.63)
1.00 1.01 (0.49–2.09) 0.94 (0.44–2.01) 2.02 (1.05–3.91)
0.01
Fiber (g/day) °15.8 15.9–22.0 22.1–27.9 ¢28.0 Calcium (mg/day) °558 559–775 776–1093 ¢1094 Total fat (g/day) °53.6 53.7–71.7 71.8–96.2 ¢96.3 Alcohol (g/day) 0 0.1–2.3 2.4–9.4 ú9.4 a
Adjusted for age, race, and sex. Adjusted for age, race, sex, energy intake, BMI, cigarette smoking, and use of aspirin and other NSAIDs. c Test for trend conducted by modeling the median category value as a continuous variable. b
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Table 3. OR for Hyperplastic Polyps of the Colorectum According to BMI, Physical Activity, Cigarette Smoking, and Use of Aspirin and Other NSAIDs
BMI (kg/m2) õ23.4 23.5–26.0 26.1–29.8 ú29.8 Activity (kcal/wk) õ600 601–1289 1290–2204 ¢2205 Cigarette smoking Never Past Current Pack-yearsd °10 11–20 ú20 NSAIDs Never Frequency (times/wk) 1–6 ¢7 Duration (yr) 0.3–4.9 ¢5
No. of cases
No. of controls
ORa (95% CI)
ORb (95% CI)
P trendc
8 19 30 24
120 120 120 120
1.00 2.57 (1.07–6.18) 4.11 (1.77–9.51) 3.79 (1.61–8.92)
1.00 2.93 (1.18–7.25) 4.97 (2.08–11.86) 4.50 (1.84–10.97)
0.001
24 23 21 13
120 120 120 120
1.00 0.91 (0.48–1.72) 0.90 (0.47–1.71) 0.50 (0.24–1.05)
1.00 1.01 (0.52–1.97) 0.91 (0.46–1.80) 0.55 (0.25–1.19)
0.60
32 33 16
257 166 57
1.00 1.15 (0.70–1.88) 2.10 (1.12–3.94)
1.00 1.33 (0.76–2.32) 2.45 (1.20–4.98)
17 11 21
97 48 76
1.41 (0.75–2.67) 1.76 (0.82–3.79) 1.97 (1.05–3.70)
1.21 (0.63–2.35) 1.71 (0.78–3.74) 1.97 (1.02–3.81)
63
339
1.00
9 7
47 94
0.92 (0.43–1.99) 0.32 (0.14–0.72)
1.21 (0.54–2.73) 0.29 (0.12–0.67)
0.01
6 10
85 56
0.33 (0.14–0.79) 0.76 (0.36–1.59)
0.34 (0.14–0.83) 0.77 (0.36–1.67)
0.53
0.04
1.00
a
Adjusted for age, race, and sex. Adjusted for age, race, sex, energy intake, fiber intake, alcohol consumption, and the other nondietary factors. c Test for trend conducted by modeling the median category value as a continuous variable. d Packs-years of ever (past and current) smoking. Excludes 2 control participants with missing information. b
association was confined to the upper quartile compared with the lower quartile (OR, 0.55; 95% CI, 0.25–1.19; P for trend Å 0.60). When BMI and physical activity were included in the model simultaneously (data not shown), the ORs for each were slightly attenuated (OR for the upper vs. the lower quartile, 4.24; 95% CI, 1.73– 10.39 for BMI; and OR, 0.56; 95% CI, 0.26–1.22 for physical activity). Cigarette smoking was positively associated with risk of hyperplastic polyps; a stronger risk was shown for current (OR, 2.45; 95% CI, 1.20–4.98) than past smokers (OR, 1.33; 95% CI, 0.76–2.32) compared with those who were never smokers. When we assessed the dose response of this relation by pack-years of ever (past and current) smoking, individuals who had smoked ú 20 pack-years were at almost twice the risk of having hyperplastic polyps compared with never smokers (OR, 1.97; 95% CI, 1.02–3.81; P for trend Å 0.04). Because of the small number of current smokers, we were unable to assess the dose response separately for past and current smokers. Individuals who used aspirin and other NSAIDs once per day or more were at significantly lower risk of having hyperplastic polyps compared with never users (OR, 0.29; 95% CI, 0.12–0.67), and a significant / 5e1f$$0045
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trend was observed across the categories (P Å 0.01). However, a longer duration of use of these drugs was not associated with a significantly lower risk of hyperplastic polyps (OR, 0.77; 95% CI, 0.36–1.67 for individuals in the highest category vs. the never users; P for trend Å 0.53).
Discussion The results of this study suggest that high intakes of dietary fiber and calcium and the use of aspirin and other NSAIDs reduce the risk of developing hyperplastic polyps, whereas an increased consumption of alcohol, cigarette smoking, and a high BMI increase this risk. A lower risk of hyperplastic polyps was also observed with a high level of physical activity, but no significant trend was apparent across the categories. To our knowledge, this is the first epidemiological study to show a relation between hyperplastic polyps and a wide array of risk factors also known to be associated with colorectal cancer and adenoma. Results of one prospective study11 found an inverse association with intake of folate and positive associations for alcohol consumption and cigarette smoking. We do not know whether the role of calcium, the WBS-Gastro
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RISK FACTORS FOR HYPERPLASTIC POLYPS 427
use of NSAIDs, or BMI were assessed in this study. Results of the study by Hoff et al.23 also showed an inverse association for dietary fiber and colorectal polyps; however, no distinction was made between adenomatous and hyperplastic polyps. In a necropsy study,17 age and, to a lesser extent, BMI, were positively associated with the presence of hyperplastic polyps. Because colorectal hyperplastic polyps are largely considered to be innocuous lesions, they have been less studied than adenomas. It is generally believed that hyperplastic polyps are not neoplastic lesions and do not give rise to carcinomas.24 The epithelial cells of hyperplastic polyps are morphologically well differentiated and cell replication is confined, as in normal mucosa, to a proliferative zone in the lower epithelial crypt.25 – 27 Arthur28 has suggested that hyperplastic polyps are benign neoplasms or hamartomas, a response to inflammation or trauma, or a degenerative change in the mucosa. Some investigators9,28 – 30 have suggested that both adenomatous and hyperplastic distal polyps are markers for proximal neoplasms; however, these studies lacked a control group free of distal polyps. Studies with an adequate control group and/or performed in asymptomatic individuals have failed to confirm this association.8,15,31 – 33 Warner et al.34 suggest that although diminutive hyperplastic polyps are benign, large hyperplastic polyps may be prone to dysplasia and malignant potential. Therefore, size may be a better marker than histology for assessing distal polyps as markers of proximal neoplasms. Results of The National Polyp Study16 indicate that a distal hyperplastic polyp is not a marker for proximal tumors. Most notably, based on its review of the evidence, the American College of Gastroenterology15 has recommended that a hyperplastic polyp found at proctosigmoidoscopy is not an indication for subsequent colonoscopy. Indirect evidence of a relationship between hyperplastic polyps and large-bowel cancer is suggested by the sequential increase in average age of individuals corresponding to the hierarchy of progression from hyperplastic polyps, followed by tubular adenomas, tubulovillous adenomas, villous adenomas, dysplastic lesions, and, finally, carcinomas.2 Ansher et al.9 have considered the hyperplastic polyp to be premalignant. Their suggestion is largely based on site distribution of hyperplastic polyps, which corresponds to that of colorectal cancer and common histochemical characteristics. Pennazio et al.35 suggest that hyperplastic polyps are good markers of exposure to ambient colorectal adenoma risk factors and refer to these as paraneoplastic lesions. Phenotypic features of hyperplastic polyps that differentiate them from normal mucosa are also displayed in neoplastic lesions. / 5e1f$$0045
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These include proliferative activity,36 p53 overexpression,37 and degree of hypomethylation in the c-myc gene.38 The levels of these markers are intermediate between those of normal and dysplastic tissue. Of considerable importance is the recent report of a prevalence of K-ras mutations at codons 12 and 13b in hyperplastic polyps equal to that of dysplastic polyps.10 Because ras mutations are considered to be early genetic events, hyperplastic polyps may play a role early in colorectal carcinogenesis. However, it has been noted39 that if a sequential relationship exists between hyperplastic polyps, adenomas, and carcinomas of the colorectum, it is likely that only a few of the hyperplastic lesions will progress to carcinoma given that only a small percentage of adenomas progress to carcinomas.40 An advantage of the present study was the selection of a control group that underwent endoscopy. The use of this group decreases the possibility of misclassification of control individuals given the high prevalence of polyps in an asymptomatic population.41 A high participation rate also strengthens the findings of our study (85% for case and 84% for control group). An additional strength was the ability to simultaneously adjust for risk factors known to be associated with colorectal adenoma and cancer. A limitation of the present study lies in the relatively small number of case subjects. This restricted stratified analysis by anatomic subsite, age, and sex, among other characteristics. However, we observed a risk factor pattern similar to that for adenomatous polyps as reported in our previous studies12 – 14 and others.42 – 46 Selection bias is an unlikely explanation for the observed findings given that both cases and controls were selected from the same population using the same set of criteria and procedures. Although the possibility of selection bias cannot be entirely excluded, it seems unlikely that differential participation might have occurred. Interviewer bias is also unlikely because the interviewer was blinded as to the case-control status of the participants. As noted earlier, 78% of the controls and 42% of the cases underwent only a sigmoidoscopy examination, given that this is the recommended procedure for screening and that it is not commonly accepted that patients with distal hyperplastic polyps undergo full colonoscopy.14,15 The potential for misclassification exists as a result of incomplete examination of the colon,31,47,48 which may be differential given that a greater proportion of the case subjects underwent a total colonoscopy. However, as previously noted, the majority of hyperplastic polyps tend to be distributed in the distal colon and rectum.9,17 This is in accordance with the results of our study in which 93% of these lesions were located in the WBS-Gastro
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distal colon and rectum; among participants who only had a total colonoscopy, 92% of the lesions were in this region. Furthermore, this type of bias is likely to result in an underestimate of our point estimates. If all participants had undergone a total colonoscopy, additional polyps would have been identified in the proximal colon; the individuals with these lesions would have been excluded from the control group, resulting in lower prevalence rates of the risk factors of interest (e.g., low fiber intake, cigarette smoking, and high BMI), which in turn would result in stronger odds ratios than those observed. In addition, when we included an indicator variable for endoscopy type in the multivariate models, no appreciable changes in the point estimates were observed. Thus, it is unlikely that our results are explained by misclassification bias. The results of this study indicate that hyperplastic polyps share similar lifestyle risk factors with adenomas and carcinomas of the colorectum. Whereas the clinical importance of hyperplastic polyps is unclear, our results suggest that their presence is associated with a risk profile characteristic of individuals at higher risk of developing an adenoma or carcinoma of the large bowel. Given these findings, it may be prudent for gastroenterologists and primary care providers to counsel individuals with hyperplastic polyps on a lifestyle aimed at reducing risk of colorectal cancer. Lifestyle changes include altering diet, smoking cessation, limiting alcohol consumption, and maintaining or achieving ideal body weight, preferably by means of increasing physical activity. Currently, there is insufficient evidence to recommend other measures such as augmentation of calcium intake or the regular use of aspirin. In addition, these results need to be confirmed by additional epidemiological studies.
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8. Provenzale D, Garrett JW, Condon SE, Sandler RS. Risk for colon adenomas in patients with rectosigmoid hyperplastic polyps. Ann Intern Med 1990;113:760–763. 9. Ansher AF, Lewis JH, Fleischer DE, Cattau EL, Collen MJ, O’Kieffe DA, Korman LY, Benjamin SB. Hyperplastic colonic polyps as a marker for adenomatous colonic polyps. Am J Gastroenterol 1989;84:113–117. 10. Jen J, Powell SM, Papadopoulos N, Smith KJ, Hamilton SR, Bogelstein B, Kinzler KW. Molecular determinants of dysplasia in colorectal lesions. Cancer Res 1994;54:5523–5526. 11. Kearny J, Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Ascherio A, Bleday R, Willett WC. Diet, alcohol, and smoking and the occurrence of hyperplastic polyps of the colon and rectum (United States). Cancer Causes Control 1995;6:45–56. 12. MartıB nez ME, McPherson RS, Annegers JF, Levin B. Cigarette smoking and alcohol consumption as risk factors for colorectal adenomatous polyps. J Natl Cancer Inst 1995;87:274–279. 13. MartıB nez ME, McPherson RS, Levin B, Annegers JF. Aspirin and other nonsteroidal anti-inflammatory drugs and risk of colorectal adenomatous polyps among endoscoped individuals. Cancer Epidemiol Biomarkers Prev 1995;4:703–707. 14. MartıB nez ME, McPherson RS, Annegers JF, Levin B. Association of diet and colorectal adenomatous polyp: dietary fiber, calcium, and total fat. Epidemiology 1996;7:264–268. 15. Bond JH, for the Parameters Committee of the American College of Gastroenterology. Polyp guideline: diagnosis, treatment, and surveillance for patients with nonfamilial colorectal polyps. Ann Intern Med 1993;119:836–843. 16. Zauber A, Winawer SJ, Diaz B. National Polyp Study (NPS): the association of colonic hyperplastic polyps and adenomas (abstr). Am J Gastroenterol 1988;83:1060. 17. Jass JR, Young PJ, Robinson EM. Predictors of presence, multiplicity, size, and dysplasia of colorectal adenomas: a necropsy study in New Zealand. Gut 1992;33:1508–1514. 18. Block G, Hartman AM, Presser CM, Carroll M, Gannon J, Gardner L. A data-based approach to diet questionnaire design and testing. Am J Epidemiol 1986;124:453–469. 19. Thompson FE, Byers T. Dietary assessment resource manual. J Nutr 1994;124:22455–23175. 20. Food Frequency Data Entry and Analysis Program, Version 1.0. Houston, TX: The University of Texas-Houston School of Public Health, 1991. 21. USDA, Human Nutrition Information Service. USDA Nutrient Data Base for Individual Intake Surveys. Release 6.0. Springfield, VA: National Technical Information Service, 1991. 22. Computing Resource Center. STATA Reference Guide. Version 3.1. College Station, TX: Stata Press, 1991. 23. Hoff G, Moen IE, Trygg K, Frolich W, Savar J, Vatn M. Epidemiology of polyps in the rectum and sigmoid colon: evaluation of nutritional factors. Scand J Gastroenterol 1986;21:199–204. 24. Fenoglio-Preiser CM, Hutter RVP. Colorectal polyps: pathologic diagnosis and clinical significance. CA Cancer J Clin 1985;35: 322–344. 25. Troncale F, Hertz R, Lipkin M. Nucleic acid metabolism in proliferating and differentiating colon cells of man and in neoplastic lesions of the colon. Cancer Res 1971;31:463–467. 26. Fenoglio CM, Lane N. The anatomic precursor of colorectal carcinoma. Cancer 1974;34:819–823. 27. Fenoglio CM, Richart RM, Kaye GI. Comparative electron microscopic features of normal, hyperplastic and adenomatous colonic epithelium. II: variations in surface architecture found by scanning electron microscopy. Gastroenterology 1975;69:100–109. 28. Arthur JF. Structure and significance of metaplastic nodules in rectal mucosa. J Clin Pathol 1968;21:735–743. 29. Achar E, Cary W. Small polyps found during fiberoptic sigmoidoscopy in asymptomatic patients. Ann Intern Med 1988;109:880– 883.
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30. Stoltenberg PH, Kirtley DW, Culp KS, LeSage GD, White JG. Are diminutive colorectal polyps (DCP) clinically significant (abstr)? Gastrointest Endosc 1988;34:172. 31. Foutch PG, DiSario JA, Pardy K, Mai HD, Manne RK. The sentinel hyperplastic polyp: a marker for synchrononous neoplasia in the proximal colon. Am J Gastroenterol 1991;86:1482–1485. 32. Brady PG, Straker RJ, McClave SA, Nord HJ, Pinkas M, Robinson BE. Are hyperplastic rectosigmoid polyps associated with an increased risk of proximal colonic neoplasms? Gastrointest Endosc 1993;39:481–485. 33. Rex DK, Smith JJ, Ulbright TM, Lehman GA. Distal colonic hyperplastic polyps do not predict proximal adenomas in asymtomatic average-risk subjects. Gastroenterology 1992;102:317–319. 34. Warner AS, Glick ME, Fogt F. Multiple large hyperplastic polyps of the colon coincident with adenocarcinoma. Am J Gastroenterol 1994;89:123–125. 35. Pennazio M, Arrigoni A, Risio M, Spandre M, Rossini FP. Small rectosigmoid polyps as markers of proximal neoplasms. Dis Colon Rectum 1993;36:1121–1125. 36. Risio M, Arrigoni A, Pennazio M, Agostinucci A, Spandre M, Rossini FP. Mucosal cell proliferation in patients with hyperplastic colorectal polyps. Scan J Gastroenterol 1995;30:344–348. 37. Rubio CA, Rodensjo M. p53 overexpression in flat serrated adenomas and flat tubular adenomas of the colorectal mucosa. J Cancer Res Clin Oncol 1995;121:571–576. 38. Sharrard RM, Royds JA, Rogers S, Shorthouse AJ. Patterns of methylation of the c-myc gene in human colorectal cancer progression. Br J Cancer 1992;65:667–672. 39. Teoh HH, Delahunt B, Isbister WH. Dysplastic and malignant areas in hyperplastic polyps of the large intestine. Pathology 1989;21:138–142. 40. Greenwald P, Sondik E: National Cancer Insitute’s strategy for colorectal cancer. In: Rozen P, Reich CB, Winawer SJ, eds. Large bowel cancer: policy, prevention, research and treatment. Front Gastrointest Res Basel: Karger, 1991:3–24. 41. Neugut AI. The use of endoscopy in screening for colorectal cancer in average-risk individuals. In: Rozen P, Reich CB, Winawer SJ, eds. Large bowel cancer: policy, prevention, research and treatment. Front Gastrointest Res Basel: Karger, 1991:157– 164. 42. Logan FRA, Little J, Hawtin PH, Hardcastle JD. Effect of aspirin and non-steroidal anti-inflammatory drugs on colorectal adenomas: case-control study of subjects participating in the Notting-
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43.
44.
45.
46.
47.
48.
ham faecal occult blood screening programme. B M J 1993; 285–289. Giovannucci E, Stampfer MJ, Colditz GA, Rimm EB, Willett WC. Relation of diet to the risk of colorectal adenoma in men. J Natl Cancer Inst 1992;84:91–98. Lee WC, Neugut AI, Garbowski GC, Forde KA, Treat MR, Waye JD, Fenoglio-Preiser C. Cigarettes, alcohol, coffee, and caffeine as risk factors for colorectal adenomatous polyps. Ann Epidemiol 1993;3:239–244. Giovannucci E, Stampfer MJ, Colditz GA, Willett WC. Physical activity, adiposity and risk of colorectal adenoma in women. Cancer Causes Control 1996;7:253–263. Giovannucci E, Stampfer MJ, Colditz GA, Rimm EB, Trichopoulos D, Rosner BA, Speizer FE, Willett WC. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst 1993;85:875–884. Foutch PG, Mai H, Pardy K, DiSario JA, Manne RK, Kerr D. Flexible sigmoidoscopy may be ineffective for secondary prevention of colorectal cancer in asymptomatic, average-risk men. Dig Dis Sci 1991;36:924–928. Stevenson G. Strategies for diagnosis of gastrointestinal cancers. In: Rozen P, Reigh CB, Winawer SJ, eds. Large bowel cancer: policy, prevention, research and treatment. Front Gastrointest Res Basel: Karger, 1991:165–180.
Received November 12, 1996. Accepted March 4, 1997. Address requests for reprints to: R. Sue McPherson, Ph.D., Human Nutrition Center, University of Texas-Houston School of Public Health, 1200 Herman Pressler, Houston, Texas 77030. Fax: (713) 500-9329. Supported by the National Dairy Board and administered in cooperation with the National Dairy Council. Dr. MartıB nez’s current affiliation is: Arizona Cancer Center, University of Arizona Health Sciences Center, Tucson, Arizona. The authors thank Drs. R. Winn and M. Nichaman for their assistance as coinvestigators; Drs. F. GarcıB a-Torres, J. Hughes, B. Kaplan, and F. S. O’Neil from Kelsey-Seybold Clinic; Drs. M. Bridges and D. Whitman from Diagnostic Clinic; Drs. M. Appel and F. L. Hochman from St. Luke’s Episcopal Hospital; the staff at the Gastrointestinal Medical Oncology Clinic at M. D. Anderson Cancer Center for providing access to the study participants; Dr. N. Kurumatani, R. Saliba, and C. Abla for their assistance in medical record abstraction and data collection; and Dr. M. Lynch for reviewing the pathology slides for quality control.
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A Case-Control Study of Dietary Intake and Other Lifestyle Risk Factors for Hyperplastic Polyps MARI´A ELENA MARTI´NEZ,* R. SUE MCPHERSON,* BERNARD LEVIN,§ and GARY A. GLOBER\ *Human Nutrition Center, University of Texas-Houston Health Science Center, School of Public Health, Houston; and §Division of Cancer Prevention and \Department of Gastrointestinal Medical Oncology and Digestive Diseases, University of Texas M. D. Anderson Cancer Center, Houston, Texas
Background & Aims: Despite the high prevalence of the hyperplastic polyp, little is known about its etiology. The aim of this study was to assess the relationship between diet and other lifestyle factors and the presence of colorectal hyperplastic polyps. Methods: Information on diet and other known or suspected risk factors for colorectal cancer or adenoma was collected among 81 subjects with hyperplastic polyps and 480 controls. Results: The multivariate-adjusted odds ratio (OR) for hyperplastic polyps for individuals in the upper vs. the lower quartile was 0.30 (95% confidence interval [CI], 0.10–0.88) for dietary fiber, 0.32 (95% CI, 0.11–0.96) for dietary calcium, 0.90 (95% CI, 0.27– 2.95) for total fat, and 2.02 (95% CI, 1.05–3.91) for alcohol consumption. Compared with individuals in the lower category, those in the upper category of body mass index had a higher risk for hyperplastic polyps (OR, 4.50; 95% CI, 1.84–10.97). Cigarette smoking was associated with a higher risk (OR, 1.97; 95% CI, 1.02–3.81 for ú20 pack-years vs. never), whereas an inverse association was seen for use of aspirin and other nonsteroidal anti-inflammatory drugs (OR, 0.29; 95% CI, 0.12–0.67 for once per day or more vs. never). Conclusions: Hyperplastic polyps share common lifestyle risk factors with colorectal adenomas and carcinomas.
A
lthough the adenomatous polyp is recognized as a precursor for colorectal cancer, the clinical significance of the hyperplastic polyp is questionable. In view of some similarities between hyperplastic polyps and colorectal carcinomas, including anatomic distribution1,2 and histochemical changes,3 – 7 some investigators have questioned the unimportance of these lesions.8,9 Unlike the adenomatous polyp, little is known about the etiology and natural history of the hyperplastic polyp, despite its high prevalence. Two proposals have been suggested to define the significance of hyperplastic polyps in the etiology of colorectal cancer: (1) hyperplastic polyps may be unimportant, and (2) hyperplastic polyps may act as markers for subsequent development of adenomas or carcinomas and may represent the first stage of / 5e1f$$0045
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the polyp-cancer sequence. Results of a recent molecular study found K-ras mutations to be equally prevalent in hyperplastic and dysplastic polyps,10 casting further doubt to the insignificance of these polyps. To our knowledge, only one epidemiological study has published results on the association of dietary and other lifestyle factors and the development of hyperplastic polyps.11 We hypothesized that these polyps have similar risk factors as adenomas and carcinomas of the large bowel. We conducted a case-control study of dietary and other lifestyle factors for colorectal polyps and report the findings for the hyperplastic polyps.
Materials and Methods Study Population Details regarding methodology of this study have been described in detail previously.12 – 14 The study population comprised white, black, and Hispanic individuals who underwent an endoscopy by one of eight collaborating gastroenterologists between September 1991 and June 1993. Approval for human subjects was obtained from each participating institution. Excluded were individuals with a history of colorectal polyps, familial polyposis coli, Gardner’s syndrome, hereditary nonpolyposis colorectal cancer, any cancer except nonmelanoma skin cancer, ulcerative colitis, inflammatory bowel disease and other colitides, human immunodeficiency virus infection, and chronic renal failure. Individuals whose residence was outside a 30-mile radius of the Texas Medical Center in Houston were also excluded. Case patients were individuals who met the eligibility criteria, had undergone a sigmoidoscopy or colonoscopy, and had a first-time histological diagnosis of hyperplastic polyps. Individuals with both adenomatous and hyperplastic polyps were excluded. The control group consisted of individuals who met the eligibility criteria but who were found to be negative for hyperplastic or adenomatous polyps. Eligible persons were identified by a review of medical records of individuals who had undergone endoscopy at any of Abbreviations used in this paper: BMI, body mass index; CI, confidence interval; FFQ, food frequency questionnaire; OR, odds ratio. q 1997 by the American Gastroenterological Association 0016-5085/97/$3.00
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the clinic sites. We reviewed 4698 medical records and identified 113 eligible case subjects and 719 eligible controls. The three primary reasons for ineligibility were history of polyps (38%), living outside the study area (33%), and history of cancer (26%). We contacted eligible individuals by telephone to explain the purpose of the study, to request their participation, and to schedule a personal interview at the physician’s office, the participant’s home, or place of employment. Interviews were conducted within 1 month after endoscopy. We could not contact 16 of the eligible case individuals (14%) and 83 of the eligible controls (11.5%) because of wrong or disconnected telephone numbers. Among the case patients contacted, 84.5% (82 of 97) participated in the study; among the controls, 83.6% (532 of 636) of those contacted participated. We excluded from subsequent analyses 5 controls with caloric intakes ú 5500 kcal/day and 1 control whose interview was unsatisfactory. In addition, because the youngest case was 34 years of age, we restricted the study population to individuals 35 years of age and older, which excluded 1 additional case and 46 controls from the analyses. The analysis was based on 81 subjects with hyperplastic polyps and 480 controls who were negative for colorectal polyps. Complete ascertainment on indications for endoscopy was not always available. According to the information available, rectal bleeding prompted endoscopy in 8% of the cases and 17.3% of the controls, and occult blood in the stool was the indication for 10% of the cases and 9% of the controls. Because the study population primarily comprised individuals seen for screening, 22% of the controls underwent total colonoscopy and the remaining 78% had only a sigmoidoscopy examination; among the case subjects, 58% underwent total colonoscopy and 42% only a sigmoidoscopy examination. This is in accordance with the recommendations of national authorities who do not advise colonoscopy if a hyperplastic polyp is found during sigmoidoscopy.15,16 Therefore, we do not have complete ascertainment of hyperplastic polyps in the proximal colon, although this number is likely to be low.9,17
Questionnaire Information Personal interviews were conducted to obtain information on age, sex, race, years of education, combined annual family income, height and current weight, physical activity, family history of colorectal cancer in first-degree relatives, use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), vitamin and mineral supplement use, cigarette smoking, and dietary intake (including alcohol consumption). We assessed dietary intake from a 138-item quantified food frequency questionnaire (FFQ) that inquired about diet during the month before the interview. We used common household measures and two- and three-dimensional food models to obtain serving sizes. The food list of the FFQ represents at least 90% of the foods that are in other validated FFQs with the differences being the addition of foods specific to calcium intake and to the triethnic population of Texas.18 Validation of the FFQ method has been well published, and this food list did not differ markedly from those in the literature.19 The
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FFQ specifically assessed mean daily intake of total calories, calcium, total fat, total dietary fiber, and alcohol. We computed nutrient intake by using the Food Frequency Data Entry and Analysis Program and nutrient and gram weight data from the U.S. Department of Agriculture Survey Nutrient Database.20,21
Data Analysis With the exception of age and use of aspirin and other NSAIDs, we converted continuous scaled variables to categorical variables based on the quartile distribution among the control group. We treated age as a continuous variable and categorized frequency of use of aspirin and other NSAIDs as none, less than daily, and at least daily and duration as none, less than 5 years, and 5 years or more. We used unconditional logistic regression analysis22 to control for variables that were a priori risk factors for colorectal cancer and adenoma. We included total kilocalories per day in the logistic regression models to adjust for energy intake.
Results The study population included 81 subjects with hyperplastic polyps (44 men and 37 women) and 480 controls (229 men and 251 women). The mean ages of the case and control subjects were 57 and 55 years, respectively. A total of 135 hyperplastic polyps were detected among the 81 case participants; 93% of these lesions were located in the distal colon and rectum. The risk factor characteristics of the study population by casecontrol status are shown in Table 1. Compared with the case group, the control individuals were significantly younger, had a lower proportion of whites, and consumed significantly more fiber and less alcohol. Overall, compared with the case group, participants in the control group had a risk factor pattern consistent with a lower risk profile for colorectal cancer and adenoma. These include a lower proportion of current smokers, a lower body mass index (BMI), a higher level of physical activity, a lower prevalence of family history of colorectal cancer, a higher proportion of users of aspirin and other NSAIDs, a lower intake of total fat, and a higher intake of fiber and calcium. A higher intake of total dietary fiber was associated with a lower risk of hyperplastic polyps (Table 2). Compared with individuals in the lower quartile, the multivariate odds ratio (OR) for those consuming ¢28 g of total dietary fiber per day was 0.30 (95% confidence interval [CI], 0.10–0.88). A significant trend was observed across the categories of fiber intake (P Å 0.02). Individuals in the upper category of calcium intake had an OR of 0.32 for hyperplastic polyps (95% CI, 0.11– 0.96) compared with individuals in the lower category (P for trend Å 0.05). A higher intake of total fat was WBS-Gastro
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RISK FACTORS FOR HYPERPLASTIC POLYPS 425
Table 1. Risk Factor Characteristics of Study Population According to Case-Control Status Case-control status Cases (n Å 81)
Risk factor a
Age (yr ) Male (%) White (%) ¢High school education (%) Current smoker (%) Past smoker (%) BMI (kg/m2)a Physical activity (kcal/wk)a Family history of colorectal cancer (%)b NSAID/aspirin use (%) Total fat (% energy)a Fiber (gr1000 kcal01rday01)a Calcium (mgr1000 kcal01rday01)a Alcohol (g/day)a
Controls (n Å 480)
57.3 { 9.7 54.3 77.8 90.1 19.8 40.7 28.2 { 4.3 1329 { 1170 18.5 19.8 34.4 { 4.9 10.1 { 2.3 389.5 { 121.3 8.6 { 15.0
54.7 { 9.8 47.7 62.3 86.7 11.9 34.6 27.2 { 5.3 1540 { 1262 16.5 29.4 33.0 { 6.1 10.9 { 3.0 408.1 { 131.9 5.0 { 9.8
P value 0.03 0.27 0.007 0.39 0.05 0.28 0.10 0.16 0.65 0.07 0.06 0.02 0.24 0.005
a
Mean { SD. Family history in first-degree relatives.
b
not associated with a higher risk of hyperplastic polyps (OR for the upper vs. the lower quartile, 0.90; 95% CI, 0.27–2.95). Alcohol consumption was positively associated with risk of hyperplastic polyps. Individuals consuming ú9.4 g of alcohol per day were more than twice as likely to have hyperplastic polyps compared with nondrinkers (OR, 2.02; 95% CI, 1.05–3.91; P for trend Å 0.01). The associations of BMI, physical activity, cigarette
smoking, and use of aspirin and other NSAIDs and hyperplastic polyps are presented in Table 3. A strong positive association was observed for BMI and risk of hyperplastic polyps. Individuals with a BMI ú29.8 kg/m2 had an OR of 4.50 for hyperplastic polyps (95% CI, 1.84– 10.97) compared with those with a BMI of õ23.4; a monotonic dose response was observed (P for trend Å 0.001). Physical activity was inversely associated with the presence of hyperplastic polyps; however, the negative
Table 2. OR for Hyperplastic Polyps of the Colorectum According to Intake of Total Dietary Fiber, Dietary Calcium, Total Fat, and Alcohol No. of cases
No. of controls
ORa (95% CI)
ORb (95% CI)
P trendc
25 15 15 16
120 120 120 120
1.00 0.80 (0.42–1.50) 0.42 (0.20–0.87) 0.47 (0.23–0.96)
1.00 0.78 (0.39–1.56) 0.36 (0.16–0.83) 0.30 (0.10–0.88)
0.02
22 22 23 14
120 120 120 120
1.00 0.75 (0.38–1.47) 0.74 (0.37–1.46) 0.41 (0.19–0.90)
1.00 0.72 (0.34–1.50) 0.69 (0.31–1.51) 0.32 (0.11–0.96)
0.05
21 15 23 22
120 120 120 120
1.00 0.65 (0.32–1.34) 0.96 (0.48–1.90) 0.90 (0.44–1.87)
1.00 0.65 (0.29–1.43) 0.88 (0.38–2.06) 0.90 (0.27–2.95)
0.13
32 13 12 24
224 85 85 85
1.00 1.06 (0.53–2.11) 1.01 (0.50–2.05) 2.01 (1.11–3.63)
1.00 1.01 (0.49–2.09) 0.94 (0.44–2.01) 2.02 (1.05–3.91)
0.01
Fiber (g/day) °15.8 15.9–22.0 22.1–27.9 ¢28.0 Calcium (mg/day) °558 559–775 776–1093 ¢1094 Total fat (g/day) °53.6 53.7–71.7 71.8–96.2 ¢96.3 Alcohol (g/day) 0 0.1–2.3 2.4–9.4 ú9.4 a
Adjusted for age, race, and sex. Adjusted for age, race, sex, energy intake, BMI, cigarette smoking, and use of aspirin and other NSAIDs. c Test for trend conducted by modeling the median category value as a continuous variable. b
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Table 3. OR for Hyperplastic Polyps of the Colorectum According to BMI, Physical Activity, Cigarette Smoking, and Use of Aspirin and Other NSAIDs
BMI (kg/m2) õ23.4 23.5–26.0 26.1–29.8 ú29.8 Activity (kcal/wk) õ600 601–1289 1290–2204 ¢2205 Cigarette smoking Never Past Current Pack-yearsd °10 11–20 ú20 NSAIDs Never Frequency (times/wk) 1–6 ¢7 Duration (yr) 0.3–4.9 ¢5
No. of cases
No. of controls
ORa (95% CI)
ORb (95% CI)
P trendc
8 19 30 24
120 120 120 120
1.00 2.57 (1.07–6.18) 4.11 (1.77–9.51) 3.79 (1.61–8.92)
1.00 2.93 (1.18–7.25) 4.97 (2.08–11.86) 4.50 (1.84–10.97)
0.001
24 23 21 13
120 120 120 120
1.00 0.91 (0.48–1.72) 0.90 (0.47–1.71) 0.50 (0.24–1.05)
1.00 1.01 (0.52–1.97) 0.91 (0.46–1.80) 0.55 (0.25–1.19)
0.60
32 33 16
257 166 57
1.00 1.15 (0.70–1.88) 2.10 (1.12–3.94)
1.00 1.33 (0.76–2.32) 2.45 (1.20–4.98)
17 11 21
97 48 76
1.41 (0.75–2.67) 1.76 (0.82–3.79) 1.97 (1.05–3.70)
1.21 (0.63–2.35) 1.71 (0.78–3.74) 1.97 (1.02–3.81)
63
339
1.00
9 7
47 94
0.92 (0.43–1.99) 0.32 (0.14–0.72)
1.21 (0.54–2.73) 0.29 (0.12–0.67)
0.01
6 10
85 56
0.33 (0.14–0.79) 0.76 (0.36–1.59)
0.34 (0.14–0.83) 0.77 (0.36–1.67)
0.53
0.04
1.00
a
Adjusted for age, race, and sex. Adjusted for age, race, sex, energy intake, fiber intake, alcohol consumption, and the other nondietary factors. c Test for trend conducted by modeling the median category value as a continuous variable. d Packs-years of ever (past and current) smoking. Excludes 2 control participants with missing information. b
association was confined to the upper quartile compared with the lower quartile (OR, 0.55; 95% CI, 0.25–1.19; P for trend Å 0.60). When BMI and physical activity were included in the model simultaneously (data not shown), the ORs for each were slightly attenuated (OR for the upper vs. the lower quartile, 4.24; 95% CI, 1.73– 10.39 for BMI; and OR, 0.56; 95% CI, 0.26–1.22 for physical activity). Cigarette smoking was positively associated with risk of hyperplastic polyps; a stronger risk was shown for current (OR, 2.45; 95% CI, 1.20–4.98) than past smokers (OR, 1.33; 95% CI, 0.76–2.32) compared with those who were never smokers. When we assessed the dose response of this relation by pack-years of ever (past and current) smoking, individuals who had smoked ú 20 pack-years were at almost twice the risk of having hyperplastic polyps compared with never smokers (OR, 1.97; 95% CI, 1.02–3.81; P for trend Å 0.04). Because of the small number of current smokers, we were unable to assess the dose response separately for past and current smokers. Individuals who used aspirin and other NSAIDs once per day or more were at significantly lower risk of having hyperplastic polyps compared with never users (OR, 0.29; 95% CI, 0.12–0.67), and a significant / 5e1f$$0045
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trend was observed across the categories (P Å 0.01). However, a longer duration of use of these drugs was not associated with a significantly lower risk of hyperplastic polyps (OR, 0.77; 95% CI, 0.36–1.67 for individuals in the highest category vs. the never users; P for trend Å 0.53).
Discussion The results of this study suggest that high intakes of dietary fiber and calcium and the use of aspirin and other NSAIDs reduce the risk of developing hyperplastic polyps, whereas an increased consumption of alcohol, cigarette smoking, and a high BMI increase this risk. A lower risk of hyperplastic polyps was also observed with a high level of physical activity, but no significant trend was apparent across the categories. To our knowledge, this is the first epidemiological study to show a relation between hyperplastic polyps and a wide array of risk factors also known to be associated with colorectal cancer and adenoma. Results of one prospective study11 found an inverse association with intake of folate and positive associations for alcohol consumption and cigarette smoking. We do not know whether the role of calcium, the WBS-Gastro
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RISK FACTORS FOR HYPERPLASTIC POLYPS 427
use of NSAIDs, or BMI were assessed in this study. Results of the study by Hoff et al.23 also showed an inverse association for dietary fiber and colorectal polyps; however, no distinction was made between adenomatous and hyperplastic polyps. In a necropsy study,17 age and, to a lesser extent, BMI, were positively associated with the presence of hyperplastic polyps. Because colorectal hyperplastic polyps are largely considered to be innocuous lesions, they have been less studied than adenomas. It is generally believed that hyperplastic polyps are not neoplastic lesions and do not give rise to carcinomas.24 The epithelial cells of hyperplastic polyps are morphologically well differentiated and cell replication is confined, as in normal mucosa, to a proliferative zone in the lower epithelial crypt.25 – 27 Arthur28 has suggested that hyperplastic polyps are benign neoplasms or hamartomas, a response to inflammation or trauma, or a degenerative change in the mucosa. Some investigators9,28 – 30 have suggested that both adenomatous and hyperplastic distal polyps are markers for proximal neoplasms; however, these studies lacked a control group free of distal polyps. Studies with an adequate control group and/or performed in asymptomatic individuals have failed to confirm this association.8,15,31 – 33 Warner et al.34 suggest that although diminutive hyperplastic polyps are benign, large hyperplastic polyps may be prone to dysplasia and malignant potential. Therefore, size may be a better marker than histology for assessing distal polyps as markers of proximal neoplasms. Results of The National Polyp Study16 indicate that a distal hyperplastic polyp is not a marker for proximal tumors. Most notably, based on its review of the evidence, the American College of Gastroenterology15 has recommended that a hyperplastic polyp found at proctosigmoidoscopy is not an indication for subsequent colonoscopy. Indirect evidence of a relationship between hyperplastic polyps and large-bowel cancer is suggested by the sequential increase in average age of individuals corresponding to the hierarchy of progression from hyperplastic polyps, followed by tubular adenomas, tubulovillous adenomas, villous adenomas, dysplastic lesions, and, finally, carcinomas.2 Ansher et al.9 have considered the hyperplastic polyp to be premalignant. Their suggestion is largely based on site distribution of hyperplastic polyps, which corresponds to that of colorectal cancer and common histochemical characteristics. Pennazio et al.35 suggest that hyperplastic polyps are good markers of exposure to ambient colorectal adenoma risk factors and refer to these as paraneoplastic lesions. Phenotypic features of hyperplastic polyps that differentiate them from normal mucosa are also displayed in neoplastic lesions. / 5e1f$$0045
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These include proliferative activity,36 p53 overexpression,37 and degree of hypomethylation in the c-myc gene.38 The levels of these markers are intermediate between those of normal and dysplastic tissue. Of considerable importance is the recent report of a prevalence of K-ras mutations at codons 12 and 13b in hyperplastic polyps equal to that of dysplastic polyps.10 Because ras mutations are considered to be early genetic events, hyperplastic polyps may play a role early in colorectal carcinogenesis. However, it has been noted39 that if a sequential relationship exists between hyperplastic polyps, adenomas, and carcinomas of the colorectum, it is likely that only a few of the hyperplastic lesions will progress to carcinoma given that only a small percentage of adenomas progress to carcinomas.40 An advantage of the present study was the selection of a control group that underwent endoscopy. The use of this group decreases the possibility of misclassification of control individuals given the high prevalence of polyps in an asymptomatic population.41 A high participation rate also strengthens the findings of our study (85% for case and 84% for control group). An additional strength was the ability to simultaneously adjust for risk factors known to be associated with colorectal adenoma and cancer. A limitation of the present study lies in the relatively small number of case subjects. This restricted stratified analysis by anatomic subsite, age, and sex, among other characteristics. However, we observed a risk factor pattern similar to that for adenomatous polyps as reported in our previous studies12 – 14 and others.42 – 46 Selection bias is an unlikely explanation for the observed findings given that both cases and controls were selected from the same population using the same set of criteria and procedures. Although the possibility of selection bias cannot be entirely excluded, it seems unlikely that differential participation might have occurred. Interviewer bias is also unlikely because the interviewer was blinded as to the case-control status of the participants. As noted earlier, 78% of the controls and 42% of the cases underwent only a sigmoidoscopy examination, given that this is the recommended procedure for screening and that it is not commonly accepted that patients with distal hyperplastic polyps undergo full colonoscopy.14,15 The potential for misclassification exists as a result of incomplete examination of the colon,31,47,48 which may be differential given that a greater proportion of the case subjects underwent a total colonoscopy. However, as previously noted, the majority of hyperplastic polyps tend to be distributed in the distal colon and rectum.9,17 This is in accordance with the results of our study in which 93% of these lesions were located in the WBS-Gastro
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distal colon and rectum; among participants who only had a total colonoscopy, 92% of the lesions were in this region. Furthermore, this type of bias is likely to result in an underestimate of our point estimates. If all participants had undergone a total colonoscopy, additional polyps would have been identified in the proximal colon; the individuals with these lesions would have been excluded from the control group, resulting in lower prevalence rates of the risk factors of interest (e.g., low fiber intake, cigarette smoking, and high BMI), which in turn would result in stronger odds ratios than those observed. In addition, when we included an indicator variable for endoscopy type in the multivariate models, no appreciable changes in the point estimates were observed. Thus, it is unlikely that our results are explained by misclassification bias. The results of this study indicate that hyperplastic polyps share similar lifestyle risk factors with adenomas and carcinomas of the colorectum. Whereas the clinical importance of hyperplastic polyps is unclear, our results suggest that their presence is associated with a risk profile characteristic of individuals at higher risk of developing an adenoma or carcinoma of the large bowel. Given these findings, it may be prudent for gastroenterologists and primary care providers to counsel individuals with hyperplastic polyps on a lifestyle aimed at reducing risk of colorectal cancer. Lifestyle changes include altering diet, smoking cessation, limiting alcohol consumption, and maintaining or achieving ideal body weight, preferably by means of increasing physical activity. Currently, there is insufficient evidence to recommend other measures such as augmentation of calcium intake or the regular use of aspirin. In addition, these results need to be confirmed by additional epidemiological studies.
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Received November 12, 1996. Accepted March 4, 1997. Address requests for reprints to: R. Sue McPherson, Ph.D., Human Nutrition Center, University of Texas-Houston School of Public Health, 1200 Herman Pressler, Houston, Texas 77030. Fax: (713) 500-9329. Supported by the National Dairy Board and administered in cooperation with the National Dairy Council. Dr. MartıB nez’s current affiliation is: Arizona Cancer Center, University of Arizona Health Sciences Center, Tucson, Arizona. The authors thank Drs. R. Winn and M. Nichaman for their assistance as coinvestigators; Drs. F. GarcıB a-Torres, J. Hughes, B. Kaplan, and F. S. O’Neil from Kelsey-Seybold Clinic; Drs. M. Bridges and D. Whitman from Diagnostic Clinic; Drs. M. Appel and F. L. Hochman from St. Luke’s Episcopal Hospital; the staff at the Gastrointestinal Medical Oncology Clinic at M. D. Anderson Cancer Center for providing access to the study participants; Dr. N. Kurumatani, R. Saliba, and C. Abla for their assistance in medical record abstraction and data collection; and Dr. M. Lynch for reviewing the pathology slides for quality control.
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