- Email: [email protected]
Association of distal hyperplastic polyps and proximal neoplastic lesions: a prospective study of 5613 subjects
ORIGINAL ARTICLE
Association of distal hyperplastic polyps and proximal neoplastic lesions: a prospective study of 5613 subjects Martin C. S. Wong, MD, MPH,1,2 Jessica Y. L. Ching, MPH,1 Victor C. W. Chan, BSc,1 Thomas Y. T. Lam, MSc,1 Arthur K. C. Luk, BA,1 Sunny H. Wong, PhD,1 Siew C. Ng, PhD,1 Simon S. M. Ng, MD,1 Justin C. Y. Wu, MD,1 Francis K. L. Chan, MD,1 Joseph J. Y. Sung, MD, PhD1 Shatin, Hong Kong, HKSAR, China
Background and Aims: Current evidence of whether distal hyperplastic polyps (HPs) are markers of proximal neoplasia (PN) is mixed. We evaluated the association between distal neoplasia and synchronous PN in asymptomatic subjects. Methods: We recruited 5819 Chinese asymptomatic screening participants 50 to 70 years of age who underwent colonoscopy in Hong Kong from 2008 to 2014, of whom 206 subjects with distal advanced neoplasia or cancer were excluded. The association between distal pathology (tubular adenomas [TAs], HPs, no polyps) and proximal pathology (PN, proximal advanced neoplasia [PAN]) was assessed by multivariate regression models, overall and stratified by the Asia Pacific Colorectal Screening scoring system (scores of 4-7, high risk; scores of 0-3, lower risk). Results: The prevalence of PN in the no distal polyps group, distal HPs group, and distal TAs group was 14.8%, 19.3%, and 29.4%, respectively. The corresponding prevalence of PAN was 1.8%, 3.2%, and 3.5%. Participants with distal HPs did not have significantly higher odds of PN (adjusted odds ratio [AOR] 1.24; 95% confidence interval [CI], 0.97-1.59; P Z .089), and their association with PAN was marginally significant (AOR 1.77; 95% CI, 1.00-3.13; P Z .052), except in lower risk subjects for whom the odds of PAN were marginally higher in the distal HPs group than the no distal polyps group (AOR 1.97; 95% CI, 1.01-3.85; P Z .048). Overall, the distal polyps group had significantly lower odds of PN than the distal TAs group (AOR 0.55; 95% CI, 0.40-0.76; P < .001). The increased risk of PN and PAN among those with distal HPs was modest. Conclusions: A direct association between distal HPs and PN is lacking, and this implies a need for a multivariate assessment of the risk of PAN. Recommending colonoscopy for every patient with distal HPs detected by screening sigmoidoscopy is not supported by this study. (Gastrointest Endosc 2015;-:1-8.)
Colorectal cancer (CRC) affects 1.2 million people globally, accounting for 10% of all malignancies and 8% of all cancer deaths.1,2 Fecal occult blood tests, flexible sigmoidoscopy (FS), and colonoscopy could effectively reduce cancer-related mortality by up to 33%, 40%, and 68%, respectively.3-8
Compared with other screening modalities, use of FS is now becoming more widespread, especially in Europe and especially after the results of 4 landmark randomized, controlled trials were published.8-12 FS is a cost-effective strategy to reduce both the incidence and mortality of CRC.10,13 It also represents an attractive option in
Abbreviations: AOR, adjusted odds ratio; APCS, Asia Pacific Colorectal Screening; CI, confidence interval; CRC, colorectal cancer; FS, flexible sigmoidoscopy; HP, hyperplastic polyp; OR, odds ratio; PAN, proximal advanced neoplasia; PN, proximal neoplasia; TA, tubular adenoma.
Current affiliations: Institute of Digestive Disease (1), School of Public Health and Primary Care (2), Chinese University of Hong Kong, Shatin, Hong Kong, HKSAR, China.
DISCLOSURE: The Hong Kong Jockey Club Charities Trust provided full funding of this project. The Trust did not have any other role in this study. All authors disclosed no financial relationships relevant to this publication. Copyright ª 2015 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2015.06.049
Presented at the International Digestive Disease Forum, June 6-7, 2015, Hong Kong, HKSAR, China (Clin Gastroenterol Hepatol 2015;13:e86-7). Reprint requests: Joseph J.Y. Sung, MD, PhD, 7/F, Lui Che Woo Clinical Sciences Building, Prince of Wales Hospital, Shatin, Hong Kong, HKSAR, China. If you would like to chat with an author of this article, you may contact Professor Martin Wong at [email protected].
Received January 12, 2015. Accepted June 18, 2015.
www.giejournal.org
Volume
-,
No.
-
: 2015 GASTROINTESTINAL ENDOSCOPY 1
Association between proximal and distal lesions
Wong et al
resource-deprived countries where screening colonoscopy and gastroenterologists are not widely available. Studies have demonstrated that adequately trained family physicians and nurse endoscopists can perform screening FS as safely and effectively as gastroenterologists or surgeons.14-17 Whereas it was widely recognized that subjects with distal advanced neoplasia have higher risks of proximal neoplasia (PN) and proximal advanced neoplasia (PAN),18-20 whether distal hyperplastic polyps (HPs) are also markers of PN and PAN is under debate. Formal guidelines do not endorse distal HPs as markers of PN or PAN.20-22 Fourteen of 17 published colonoscopy studies reported no association between HP, PN, and PAN.23 However, recent pathology studies suggest that microvesicular HPs could develop into sessile serrated adenomas via microsatellite instability and MLH1 methylation pathways.24 Of 4 meta-analyses,23,25-27 2 concluded that there was an association between distal HPs and PN,23,25 1 demonstrated an association between distal adenomatous polyps and PN,26 and 1 showed no association between distal HPs and PN/PAN.27 The interpretation of these meta-analyses is mixed because the heterogeneity of the methodologies used by the original articles varied substantially. Treating distal HPs as normal colonoscopy findings has not been unanimously agreed on, as reflected by many physicians still referring patients with distal HPs alone for colonoscopy.28 There are thus far fewer large-scale colonoscopy studies that were prospectively conducted in asymptomatic individuals in Asia. Hence, the generalizability of the existing evidence to Eastern Asian populations is uncertain. The objective of this study was to evaluate the association between distal HPs and PN/PAN among CRC screening participants who underwent colonoscopy. Because a recent study reported that the detection of proximal serrated lesions at screening colonoscopy was independently associated with the risk of synchronous advanced colorectal neoplasia,29 we also examined the relationship between proximal serrated lesions and distal HPs.
METHODS The study setting has been described elsewhere.30-36 In 2008, a bowel cancer screening center was established in Hong Kong. It recruited eligible Hong Kong residents 50 to 70 years of age who were asymptomatic for CRC screening via media invitations. This study was approved by an ethics committee of the Chinese University of Hong Kong, and each participant provided informed consent.
Participant recruitment We prospectively recruited self-referred screening participants for CRC screening via telephone, fax, e-mail, or walk-in. Enrolled subjects were eligible if they (1) were 50 to 70 years of age; (2) had no existing or previous 2 GASTROINTESTINAL ENDOSCOPY Volume
-,
No.
-
: 2015
symptoms suggestive of CRC such as rectal bleeding, melena, anorexia, change in bowel habits in the past 4 weeks, and weight loss of more than 5 kg in the past 6 months; and (3) had not undergone any CRC screening tests in the past. Exclusion criteria included personal history of CRC, colonic adenoma, diverticular disease, inflammatory bowel disease, prosthetic heart valve, or vascular graft surgery. Subjects with contraindications to colonoscopy, including medical conditions such as cardiopulmonary insufficiency and the use of dual antiplatelet therapy, were also excluded. The participants were offered either a yearly fecal occult blood test or a colonoscopy for CRC screening. This study included all participants who underwent a colonoscopy (years 2008-2014).
Colonoscopy procedure A standardized bowel preparation regimen by using polyethylene glycol (Klean-Prep; Helsinn Birex Pharmaceuticals Ltd, Dublin, Ireland) was used. The colonoscopy was conducted at an endoscopy center in a major hospital, conducted by experienced colonoscopists. Before the colonoscopy, all subjects received a standard sedation regimen consisting of midazolam 2.5 mg (Groupe Panpharma, Beignon, France). Pethidine 25 mg (Martindale Pharma, Buckinghamshire, United Kingdom) was administered intravenously. A withdrawal time of at least 6 minutes was practiced for all subjects, which is in accordance with the current quality indicators for colonoscopy.37 All lesions were removed and underwent biopsies, as deemed appropriate by the endoscopists. In this study, the colonoscopists attempted to remove and perform biopsies on all lesions including benign-appearing HPs, except lesions that were smaller than 2 mm. These small lesions were also regarded as HPs in this analysis. The biopsy specimens were examined by gross and microscopic evaluation in a certified laboratory by experienced histopathologists.
Outcome variables and covariates The major outcome variable was the detection of PN and PAN. PAN is defined as any colorectal adenoma in the proximal colon 10 mm or greater in diameter having high-grade dysplasia and villous or tubulovillous histologic characteristics or any combination thereof. The secondary outcome variable was the detection of proximal serrated lesions, defined as HPs larger than 9 mm, those interpreted as sessile serrated adenomas or sessile serrated polyps, and traditional serrated adenomas in the proximal colon. The variables tested for association are distal tubular adenomas (TAs) and HPs, defined as TAs and HPs situated within the colonic mucosa in the rectum, the rectosigmoid junction, and the sigmoid colon. The covariates included participant age, sex, body mass index, smoking status, alcohol use, family history of CRC, concomitant comorbidities, and the use of aspirin and nonsteroidal anti-inflammatory drugs. www.giejournal.org
Wong et al
Statistical analyses We excluded participants with distal advanced neoplasia or adenocarcinoma from the analysis. All data were entered into a predesigned database with logistic checking by using Microsoft Access and analyzed by using SPSS software, version 18.0 (IBM, Chicago, Ill). We computed the absolute risks of PN and PAN according to the distal findings (no distal polyps vs distal HPs vs distal TAs). Each demographic characteristic of the subjects was tested for significance with distal findings by the Student t test and c2 test for continuous and categorical variables, respectively. Those variables found to be significant (P < .05) on univariate analysis were entered into a binary logistic regression model, with PN and PAN as outcome measures. In an additional subanalysis, we included all proximal serrated lesions as PN and studied its association with distal HPs. As part of sensitivity analysis, we selected the statistically significant (P < .05) variables in the multivariate regression analysis to fit into another binary logistic regression model. In addition, we repeated the above analysis by stratifying the study participants into average or moderate risk versus higher risk, according to the Asia Pacific Colorectal Screening (APCS) scoring system (scores of 4-7, high-risk; scores of 0-3, average or intermediate risk, thereafter referred to as lower risk).
RESULTS Participant characteristics A total of 5842 screening participants underwent colonoscopy. We excluded 206 subjects who were found to have distal advanced neoplasia or distal cancer, and 23 subjects who could not tolerate the laxative regimen or whose bowel preparation was poor. Their average SD age was 57.6 4.87 years (Table 1). The mean body mass index was 23.5 kg/m2, and the proportion of ever smokers and alcohol users was 7.7% and 9.4%, respectively. Among them, 13.9% had a first-degree relative with a history of CRC. The most common comorbidities included hypertension (22.6%), diabetes mellitus (7.3%), and GERD (5.3%). Most of them were of moderate risk (79.5%) as classified by the APCS scoring system. The detection rate of PN and PAN was 17.6% and 2.2%, respectively, whereas 74.6% had no distal polyps, 8.4% had distal HPs with no distal TAs, and 17.0% had distal TAs with or without distal HPs.
Absolute risk of PN The prevalence of PN was higher among those with distal TAs (29.4%) than subjects with distal HPs only (19.3%) and no distal polyps (14.8%) (Table 2). This decline in prevalence was similarly observed for PAN (3.5% vs 3.2% vs 1.8%) (Table 2). Stratification of all subjects into lower risk and high risk according to the APCS scores showed a similarly increasing prevalence of both types of proximal lesions. Three subjects (0.1%) had www.giejournal.org
Association between proximal and distal lesions
TABLE 1. Characteristics of study participants (N [ 5613) Age, y, mean SD
57.64 4.87
BMI, kg/m , mean SD
23.50 3.18
2
Male, no. (%)
2594 (46.2)
Family history of CRC in a first-degree relative, no. (%)
781 (13.9)
Ever smoked, no. (%)
430 (7.7)
Alcohol consumption, no. (%)
525 (9.4)
Diabetes mellitus, no. (%)
411 (7.3)
Hypertension, no. (%)
1267 (22.6)
IHD/heart disease, no. (%)
94 (1.7)
COAD, no. (%)
38 (0.7)
Stroke, no. (%)
37 (0.7)
Cirrhosis, no. (%)
8 (0.1)
GERD, no. (%)
295 (5.3)
Use of nonsteroidal anti-inflammatory drugs, no. (%)
263 (4.7)
Use of aspirin, no. (%)
131 (2.3)
APCS, no. (%) Low or moderate risk
4462 (79.5)
High risk
1151 (20.5)
Proximal neoplasia, no. (%)
990 (17.6)
Proximal advanced neoplasia, no. (%)
123 (2.2)
High-grade dysplasia
23 (0.4)
Villous or tubulovillous lesions
57 (1.0)
Adenoma size 10 mm No distal polyps, no. (%)
95 (1.7) 4187 (74.6)
Distal HPs with no distal TAs, no. (%)
472 (8.4)
Distal TAs with or without distal HPs, no. (%)
954 (17.0)
BMI, Body mass index; CRC, colorectal cancer; IHD, ischemic heart disease; COAD, chronic obstructive airway disease; APCS, Asia Pacific Colorectal Screening; HPs, hyperplastic polyps; TAs, tubular adenomas.
proximal HPs larger than 9 mm, 60 subjects (1.1%) had sessile serrated adenomas or sessile serrated polyps, and 269 subjects had traditional serrated adenomas (4.8%) in the proximal colon.
Association of demographic characteristics with distal lesions Compared with subjects having no distal polyps, participants with distal HPs had a higher body mass index (odds ratio [OR] 1.07; 95% confidence interval [CI], 1.041.10; P < .001); more were male (OR 1.53; 95% CI, 1.26-1.85; P < .001), ever smokers (OR 2.86; 95% CI, 2.16-3.78; P < .001), alcohol users (OR 1.43; 95% CI, 1.06-1.93; P Z .019); and had diabetes (OR 1.51; 95% CI, 1.08-2.11; P Z .016) and GERD (OR 1.50; 95% CI, 1.04–2.18; P Z .032) (Table 3). Subjects found to have distal TAs were younger (OR 0.97; 95% CI, 0.95-0.99; P Z .006) and were more likely to be ever smokers (OR 1.48; 95% CI, 1.07-2.04; P Z .017) compared with the distal HPs only group (Table 3). Volume
-,
No.
-
: 2015 GASTROINTESTINAL ENDOSCOPY 3
Association between proximal and distal lesions
Wong et al
TABLE 2. Absolute risk of PN according to distal findings*
Distal findings
All subjects, PN/no PN, no. (AR, %)
Moderate risk, PN/no PN, no. (AR, %)
High risk PN/no PN, no. (AR, %)
No distal polyps
619/3568 (14.8)
468/2936 (13.7)
151/632 (19.3)
Distal HPs with no distal TAs
91/381 (19.3)
61/287 (17.5)
30/94 (24.2)
Distal TAs with or without distal HPs
280/674 (29.4)
203/507 (28.6)
77/167 (31.6)
All subjects, PAN/no PAN, no. (AR, %)
Moderate risk, PAN/no PAN, no. (AR, %)
High risk, PAN/no PAN, no. (AR, %)
75/4112 (1.8)
52/3352 (1.5)
23/760 (2.9)
No distal polyps Distal HPs with no distal TAs
15/457 (3.2)
11/337 (3.2)
4/120 (3.2)
Distal TAs with or without distal HPs
33/921 (3.5)
20/690 (2.8)
13/231 (5.3)
PN, Proximal neoplasia; AR, absolute risk; HPs, hyperplastic polyps; TAs, tubular adenomas; PAN, proximal advanced neoplasia. *Proximal adenomatous lesions include advanced neoplasia and cancer, but the distal TAs group does not include distal advanced neoplasia and cancer. All P values were <.001 when the c2 test of trend was used to compare the absolute risks of proximal neoplasia among subjects with different distal findings.
TABLE 3. Association of the demographic characteristics between subjects with distal HPs only and those with distal TAs or no distal polyps Distal HPs only vs no distal polyps, OR (95% CI), P value
Distal TAs vs distal HPs only, OR (95% CI), P value
Age, y
1.02 (1.00–1.04), P Z .103
0.97 (0.95-0.99), P Z .006*
BMI, kg/m2
1.07 (1.04-1.10), P < .001*
1.01 (0.97-1.04), P Z .792
Male
1.53 (1.26–1.85), P < .001*
0.90 (0.72–1.12), P Z .356
Ever smoker
2.86 (2.16–3.78), P < .001*
1.48 (1.07–2.04), P Z .017*
Alcohol consumption
1.43 (1.06–1.93), P Z .019*
1.04 (0.74–1.47), P Z .807
Diabetes mellitus
1.51 (1.08–2.11), P Z .016*
0.88 (0.61–1.28), P Z .494
Family history of CRC in a first-degree relative
1.03 (0.79–1.36), P Z .813
0.90 (0.66–1.23), P Z .510
Hypertension
1.12 (0.89–1.40), P Z .339
0.92 (0.71–1.18), P Z .501
IHD/heart disease
1.37 (0.70–2.69), P Z .356
1.07 (0.49–2.31), P Z .873
COAD
1.78 (0.68–4.68), P Z .240
1.27 (0.41–3.89), P Z .680
Stroke
1.59 (0.61–4.14), P Z .342
2.54 (0.68–9.51), P Z .166
NA
NA
Characteristic
Cirrhosis GERD
1.50 (1.04–2.18), P Z .032*
1.51 (0.96–2.37), P Z .072
Use of nonsteroidal anti-inflammatory drugs
0.66 (0.39–1.12), P Z .124
0.61 (0.34–1.09), P Z .096
Use of aspirin
1.32 (0.73–2.38), P Z .358
0.87 (0.45–1.69), P Z .685
HPs, Hyperplastic polyps; OR, odds ratio; CI, confidence interval; TAs, tubular adenomas; BMI, body mass index; IHD, ischemic heart disease; COAD, chronic obstructive airway disease; NA, not available. *P < .05.
Independent associations between proximal lesions and distal findings On multivariate regression analysis controlling for potential confounders, it was found that participants with distal HPs did not have significantly higher odds of PN (AOR 1.24; 95% CI, 0.97-1.59; P Z .089), and the association with PAN (AOR 1.77; 95% CI, 1.00-3.13; P Z .052) was only of borderline significance compared with those with no distal polyps (Table 4). Compared with subjects having distal TAs, those with distal HPs had lower odds of PN (AOR 0.58; 95% CI, 0.44–0.76; P < .001) and statistically similar odds of PAN (AOR 0.93; 95% CI, 4 GASTROINTESTINAL ENDOSCOPY Volume
-,
No.
-
: 2015
0.50–1.73; P Z .808) (Table 4). There was no significant association between distal HPs and proximal serrated lesions (AOR 0.89; 95% CI, 0.21-3.82; P Z .875).
Sensitivity analysis As part of a sensitivity analysis, when regression analyses were conducted with significant covariates (defined as P < .05), defined in Table 4 as independent variables, the association between distal polyps (vs no distal polyps) and proximal lesions remained insignificant (Table 5). The significant association between distal TAs (vs distal polyps) and PN remained (AOR 0.578; 95% CI, www.giejournal.org
Wong et al
Association between proximal and distal lesions
TABLE 4. Adjusted odds ratio* of PN or PAN among subjects with distal HPs only and those with distal TAs versus no distal polyps PN AOR (95% CI), P value
PAN AOR (95% CI), P value
1.24 (0.97–1.59), P Z .089
1.77 (1.00–3.13), P Z .052
1.04 (1.01-1.06), P Z .007
1.02 (0.95-1.09), P Z .650
Male
1.57 (1.32-1.87), P < .001
0.99 (0.62-1.56), P Z .950
Ever smoker
1.21 (0.90-1.63), P Z .204
0.95 (0.41-2.19), P Z .904
Alcohol use
1.07 (0.81–1.40), P Z .639
1.27 (0.63–2.58), P Z .510
Diabetes mellitus
1.27 (0.94–1.71), P Z .117
0.65 (0.23–1.78), P Z .397
GERD
1.06 (0.74–1.51), P Z .766
2.23 (1.13–4.37), P Z .020
Distal HPs only vs no distal polyps BMI, kg/m2
0.58 (0.44–0.76), P < .001
0.93 (0.50–1.73), P Z .808
Age, y
1.06 (1.03-1.08), P < .001
1.04 (0.98-1.10), P Z .226
Ever smoker
1.78 (1.27–2.51), P Z .001
1.43 (0.66–3.11), P Z .369
Distal HPs only vs distal TAs
PN, Proximal neoplasia; PAN, proximal advanced neoplasia; AOR, adjusted odds ratio; CI, confidence interval; BMI, body mass index; IHD, ischemic heart disease; COAD, chronic obstructive airway disease; HPs, hyperplastic polyps; BMI, body mass index; TAs, tubular adenomas. *Potential covariates were found on univariate logistic regression with P < .05 (Table 3).
0.440–0.759). There were no interactions among the independent variables.
Association between proximal and distal lesions according to APCS scores When the screening participants were stratified into 2 groups according to the APCS scores (lower vs high risk), those with distal HPs were more likely to have PAN in the lower risk group (AOR 1.97; 95% CI, 1.01-3.85; P Z .048) (Table 6). Compared with those having distal TAs, subjects diagnosed with distal HPs were significantly less likely to have PN (AOR 0.55; 95% CI, 0.40–0.76; P < .001) in the lower-risk group. The respective association in the high-risk group was not significant (Table 6).
TABLE 5. Association between subjects with distal lesions and those with proximal lesions PN Distal HPs only vs no distal polyps Risk ratio (95% CI)
1.304 (1.069–1.590)*
1.774 (1.028–3.063)*
Crude OR (95% CI)
1.377 (1.079–1.757)*
1.800 (1.025–3.159)*
AOR with significant covariates of P values <.05
1.275 (0.995–1.633)
1.755 (0.998–3.085)
Risk ratio (95% CI)
0.657 (0.533–0.810)*
0.919 (0.507–1.674)
Crude OR (95% CI)
0.575 (0.440–0.751)*
0.916 (0.493–1.704)
AOR with significant covariates of P values <.05 (95% CI)
0.578 (0.440–0.759)*
0.916 (0.493–1.704)
Distal HPs only vs distal TAs
DISCUSSION Major findings and implications for clinical practice There are 2 principal findings from this study. First, distal HPs were not found to be predictive of PN or PAN. Although statistically there exists a significantly higher odd of detecting PAN in those with distal HPs versus no distal polyps when lower risk subjects were analyzed, the absolute difference in PAN was small (3.2% vs 1.5%). Second, subjects with distal TAs had higher odds of having PN than the distal polyps group irrespective of whether all subjects (29.4% vs 19.3%, P < .001) or moderate-risk subjects (28.6% vs 17.5%, P < .001) were analyzed. Therefore, these findings do not support colonoscopy arrangements for every patient with distal HPs detected by screening sigmoidoscopy. On the other hand, the study results support that detection of distal TAs is an indication for subsequent colonoscopy due to the high risk of proximal PN. However, the number of subjects in whom distal HPs were detected with PAN was relatively small, www.giejournal.org
PAN
PN, Proximal neoplasia; PAN, proximal advanced neoplasia; HPs, hyperplastic polyps; CI, confidence interval; OR, odds ratio; AOR, adjusted odds ratio; TAs, tubular adenomas. *P < .05.
making the value of statistical analysis less definite in this subanalysis.
Relationship with literature: the distribution of proximal and distal lesions The most recent meta-analysis, conducted by Dodou and de Winter23 in 2011 involving 32 studies reported that the absolute risk of PN and PAN was 27.2% (95% CI, 17.6%-38.0%) and 2.3% (95% CI, 1.6%-3.2%), respectively. The respective figures in the study by Lewis et al26 were 16.3% and 2% to 5%. These were statistically similar to our findings (17.6% and 2.2%, Volume
-,
No.
-
: 2015 GASTROINTESTINAL ENDOSCOPY 5
Association between proximal and distal lesions
Wong et al
TABLE 6. AOR* of PN or PAN among subjects with distal HPs only and those with distal TAs or no distal polyps by APCS risk tier PN AOR (95% CI), P value
PAN AOR (95% CI), P value
Distal HPs only vs no distal polyps
1.23 (0.91–1.65), P Z .184
1.97 (1.01–3.85), P Z .048*
Distal HPs only vs distal TAs
0.55 (0.40–0.76), P < .001*
1.14 (0.54–2.42), P Z .728
Distal HPs only vs no distal polyps
1.29 (0.81–2.04), P Z .282
1.33 (0.44–4.05), P Z .618
Distal HPs only vs distal TAs
0.64 (0.39–1.07), P Z .088
0.63 (0.20–1.99), P Z .427
Lower risk (low or moderate risk according to APCS score)
High risk
AOR, Adjusted odds ratio; CI, confidence interval; PN, proximal neoplasia; PAN, proximal advanced neoplasia; APCS, Asia Pacific Colorectal Screening; HPs, hyperplastic polyps; TAs, tubular adenomas. *Potential covariates were found on univariate logistic regression with P < .05 (Table 3).
P > .05). The absolute risk of PN and PAN in our study was, however, lower than that reported by Dave et al,25 who included 18 studies, and the overall risk of PN and PAN was 21% to 25% and 4% to 5%, respectively. Similarly, a meta-analysis conducted by Lin et al27 reported pooled risks of PN and PAN of 26% and 4.4%, respectively. The differences in the prevalence of PN and APN in all of these studies might be accounted for by study participants of different ethnicities and inclusion of different subgroups, such as participants with symptoms versus those with no symptoms, the use of different meta-analytic techniques in the analysis, and the quality of the study.
Relationship with medical literature: the association between distal HPs and proximal neoplasia Our study showed that distal HPs were not significantly associated with PN, and their association with PAN was of borderline significance. This is in accord with findings from 2 meta-analyses,26,27 but not in agreement with the other 2 meta-analyses.23,25 It should be noted that in these meta-analyses, some original studies were retrospective, and the validity of the findings may be doubtful. In addition, some studies were relatively small scale and could potentially lead to type II errors. Higher-quality studies are more likely to report that distal HPs were not markers of proximal lesions.27 Many lower-quality studies tended to be small scale and compared the prevalence of PN in patients with distal HPs versus those with no distal HPs or those with distal TAs, but not both. It cannot be overemphasized that to determine whether there exists an association between distal HPs and PN, comparisons of the prevalence of PN should be made among the 3 distal pathology groups (no distal HPs, distal HPs only, distal TAs with or without HPs). Studies that involved comparisons of those with distal HPs and those with no distal HPs may only demonstrate that the risk of PN is higher in the former group than the latter group. Without knowing the risk of PN in the distal TA group, one may wrongly recommend that people with distal HPs should have their proximal colon examined.27 6 GASTROINTESTINAL ENDOSCOPY Volume
-,
No.
-
: 2015
Our findings showed that when analysis was limited to the lower-risk group (APCS scores of 0-3), the association between distal HPs and PN became significant. This is similar to the finding of Dodou and de Winter,23 in which PN lesions were better predicted in populations with a low PAN prevalence (ie, the lower risk group). One possible explanation is that patients diagnosed at a younger age are more likely to have advanced malignancies, possibly due to genetic predispositions.38,39
Study strengths and limitations This was a large-scale, prospective study conducted in more than 5600 asymptomatic subjects. Determination of the eligibility criteria, data collection procedures, and colonoscopies was performed to the highest possible standard at accredited endoscopy centers and laboratories according to international guidelines. This study is the largest single study of the association of distal HPs and PN in a specific, relatively homogeneous population and using a recently validated risk scoring system for advanced colorectal neoplasia as a stratification tool in subgroup analysis. Nevertheless, some of the limitations should be addressed. First, this study included self-referred screening participants, and their health-seeking behavior and lifestyle habits might be different from those of the general public.40,41 Also, misclassification biases and false-positive results might occur, and it has been shown that missed lesion could occur in as many as 26% and 13% in adenomas smaller than 5 mm and between 5 and 10 mm, respectively. Furthermore, between-physician variation in the adenoma detection rate might exist. Last, critics might argue that this study used colonoscopy to understand how FS would work. Colonoscopy uses sedation, involves a more-invasive bowel preparation, and fully visualizes the entire colon to the splenic flexure; all of these factors might affect polyp detection relative to FS.
CONCLUSION These study results support the lack of a direct effect between distal HPs and PN and imply a need for www.giejournal.org
Wong et al
multivariate assessment of the risk of PAN. These findings are important to inform physicians on the subsequent management of distal HPs detected by screening sigmoidoscopy. Without randomized, controlled trials, the study findings do not imply that sigmoidoscopy is adequate for all patients with distal HPs because each screening participant has his or her own risk threshold in deciding whether a subsequent colonoscopy is warranted. Therefore, we recommend that physicians discuss the risk of PN with the patient, adopting a shared decision-making approach. Our findings are in line with existing guidelines in which detection of HPs on screening FS should not automatically prompt a subsequent colonoscopy.
REFERENCES 1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893-917. 2. Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer, 2010. Available at: http://globocan.iarc.fr. Accessed July 18, 2015. 3. Hardcastle JD, Chamberlain JO, Robinson MH, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996;348:1472-7. 4. Jorgensen OD, Kronborg O, Fenger C. A randomised study of screening for colorectal cancer using faecal occult blood testing: results after 13 years and seven biennial screening rounds. Gut 2002;50:29-32. 5. Mandel JS, Church TR, Ederer F, et al. Colorectal cancer mortality: effectiveness of biennial screening for fecal occult blood. J Natl Cancer Inst 1999;91:434-7. 6. Nishihara R, Wu K, Lochhead P, et al. Long-term colorectal-cancer incidence and mortality after lower endoscopy. N Engl J Med 2013;369: 1095-105. 7. Zauber AG, Winawer SJ, O'Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med 2012;366:687-96. 8. Bretthauer M. Colorectal cancer screening. J Intern Med 2011;270: 87-98. 9. Hoff G, Grotmol T, Skovlund E, et al. Risk of colorectal cancer seven years after flexible sigmoidoscopy screening: randomized controlled trial. BMJ 2009;338:b1846. 10. Atkin WS, Edwards R, Kralj-Hans I, et al. Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet 2010;375:1624-33. 11. Segnan N, Senore C, Andreoni B, et al. Baseline findings of the Italian multicentre randomised controlled trial of “once-only sigmoidoscopy” dSCORE. J Natl Cancer Inst 2002;94:1763-72. 12. Weissfeld JL, Schoen RE, Pinsky PF, et al. Flexible sigmoidoscopy in the PLCO cancer screening trial: results from the baseline screening examination of a randomized trial. J Natl Cancer Inst 2005;97:989-97. 13. Schoen RE, Pinsky PF, Weissfeld JL, et al. Colorectal-cancer incidence and mortality with screening flexible sigmoidoscopy. N Engl J Med 2012;366:2345-57. 14. Shaukat MS, Ramirex FC. The utilization of flexible sigmoidoscopy by family practitioners after residency training. Gastrointest Endosc 2000;52:45-7. 15. Williams J, Russell I, Dural D, et al. Effectiveness of nurse delivered endoscopy: findings from randomised multi-institution nurse endoscopy trial (MINuET). BMJ 2009;338:b231. 16. Limoges-Gonalez M, Singh N, Al-Juburi Amar, et al. Comparisons of screening colonoscopy performed by a nurse practitioner and gastroenterologists. Gastroenterol Nurs 2011;34:210-6.
www.giejournal.org
Association between proximal and distal lesions 17. Wallace MB, Kemp JA, Meyer F, et al. Screening for colorectal cancer with flexible sigmoidoscopy by nonphysician endoscopists. Am J Med 1999;107:214-8. 18. Benson VS, Patnick J, Davies AK, et al. Colorectal cancer screening: a comparison of 35 initiatives in 17 countries. Int J Cancer 2008;122: 1357-67. 19. Winawer SJ, Zauber AG. The advanced adenoma as the primary target of screening. Gastrointest Endosc Clin N Am 2002;12:1-9. 20. Winawer SJ, Zauber AG, Fletcher RH, et al. Guidelines for colonoscopy surveillance after polypectomy: a consensus update by the US MultiSociety Task Force on Colorectal Cancer and the American Cancer Society. CA Cancer J Clin 2006;56:143-59. 21. Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US MultiSociety Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin 2008;58:130-60. 22. Institute for Clinical Systems Improvement. Health care guideline: colorectal cancer screening. Thirteenth edition, 2010. Available at: http:// www.icsi.org/colorectal_cancer_screening/colorectal_cancer_screening_ 5.html. Accessed July 18, 2015. 23. Dodou D, de Winter JC. The relationship between distal and proximal colonic neoplasia: a meta-analysis. J Gen Intern Med 2011;27: 361-70. 24. Rex DK, Ahnen DJ, Baron JA, et al. Serrated lesions of the colorectum: review and recommendations from an expert panel. Am J Gastroenterol 2012;107:1315-29. 25. Dave S, Hui S, Kroenke K, et al. Is the distal hyperplastic polyp a marker for proximal neoplasia? A systematic review. J Gen Intern Med 2003;18: 128-37. 26. Lewis JD, Ng K, Hung KE, et al. Detection of proximal adenomatous polyps with screening sigmoidoscopy. A systematic review and meta-analysis of screening colonoscopy. Arch Intern Med 2003;163: 413-20. 27. Lin OS, Gerson LB, Soon MS, et al. Risk of proximal colon neoplasia with distal hyperplastic polyps. A metaanalysis. Arch Intern Med 2005;165: 382-90. 28. Mysliwiec PA, Brown ML, Klabunde CN, et al. Are physicians doing too much colonoscopy? A national survey of colorectal surveillance after polypectomy. Ann Intern Med 2004;141:264-71. 29. Ng SC, Ching JY, Chan VC, et al. Association between serrated polyps and the risk of synchronous advanced colorectal neoplasia in averagerisk individuals. Aliment Pharmacol Ther 2015;41:108-15. 30. Wong MC, Hirai HW, Luk AK, et al. The knowledge of colorectal cancer symptoms and risk factors among 10,078 screening participants: are high risk individuals more knowledgeable? PLoS One 2013;8:e60366. 31. Wong MC, Ching JY, Hirai HH, et al. Perceived obstacles of colorectal cancer screening and their associated factors among 10,078 Chinese participants. PLoS One 2013;8:e70209. 32. Wong MCS, John GK, Hirai HW, et al. Changes in the choice of colorectal cancer screening tests in primary care settings from 7,845 prospectively collected surveys. Cancer Causes Control 2012;23:1541-8. 33. Wong MC, Lam TYT, Tsoi KKF, et al. A validated tool to predict colorectal neoplasia and inform screening choice for asymptomatic subjects. Gut 2014;63:1130-6. 34. Ng SC, Ching JYL, Chan VCW, et al. Diagnostic accuracy of fecal immunochemical test for screening individuals with a family history of colorectal cancer. Aliment Pharmacol Ther 2013;38:835-41. 35. Wong MCS, Ching JY, Lam TY, et al. Prospective cohort study of compliance with faecal immunochemical tests for colorectal cancer screening in Hong Kong. Prev Med 2013;57:227-31. 36. Wong MCS, Tsoi KKF, Ng SSM, et al. A Comparison of the acceptance of Immunochemical faecal occult blood test and colonoscopy in colorectal cancer screening: a prospective study among Chinese. Aliment Pharmacol Ther 2010;32:74-82.
Volume
-,
No.
-
: 2015 GASTROINTESTINAL ENDOSCOPY 7
Association between proximal and distal lesions
Wong et al
37. Rex DK, Petrini JL, Baron TH, et al. Quality indicators for colonoscopy. Gastrointest Endosc 2006;63:S16-28. 38. Negri E, Braga C, La Vecchia C, et al. Family history of cancer and risk of colorectal cancer in Italy. Br J Cancer 1998;77:174-9. 39. Slattery ML, Friedman GD, Potter JD, et al. A description of age, sex, and site distributions of colon carcinoma in three geographic areas. Cancer 1996;78:1666-70.
8 GASTROINTESTINAL ENDOSCOPY Volume
-,
No.
-
: 2015
40. Thiis-Evensen E, Hoff GS, Sauar J, et al. Flexible sigmoidoscopy or colonoscopy as a screening modality for colorectal adenomas in older age groups? Findings in a cohort of the normal population aged 63– 72 years. Gut 1999;45:834-9. 41. Farrands PA, Hardcastle JD, Chamberlain J, et al. Factors affecting compliance with screening for colorectal cancer. Community Med 1984;6:12-9.
www.giejournal.org
Association of distal hyperplastic polyps and proximal neoplastic lesions: a prospective study of 5613 subjects Martin C. S. Wong, MD, MPH,1,2 Jessica Y. L. Ching, MPH,1 Victor C. W. Chan, BSc,1 Thomas Y. T. Lam, MSc,1 Arthur K. C. Luk, BA,1 Sunny H. Wong, PhD,1 Siew C. Ng, PhD,1 Simon S. M. Ng, MD,1 Justin C. Y. Wu, MD,1 Francis K. L. Chan, MD,1 Joseph J. Y. Sung, MD, PhD1 Shatin, Hong Kong, HKSAR, China
Background and Aims: Current evidence of whether distal hyperplastic polyps (HPs) are markers of proximal neoplasia (PN) is mixed. We evaluated the association between distal neoplasia and synchronous PN in asymptomatic subjects. Methods: We recruited 5819 Chinese asymptomatic screening participants 50 to 70 years of age who underwent colonoscopy in Hong Kong from 2008 to 2014, of whom 206 subjects with distal advanced neoplasia or cancer were excluded. The association between distal pathology (tubular adenomas [TAs], HPs, no polyps) and proximal pathology (PN, proximal advanced neoplasia [PAN]) was assessed by multivariate regression models, overall and stratified by the Asia Pacific Colorectal Screening scoring system (scores of 4-7, high risk; scores of 0-3, lower risk). Results: The prevalence of PN in the no distal polyps group, distal HPs group, and distal TAs group was 14.8%, 19.3%, and 29.4%, respectively. The corresponding prevalence of PAN was 1.8%, 3.2%, and 3.5%. Participants with distal HPs did not have significantly higher odds of PN (adjusted odds ratio [AOR] 1.24; 95% confidence interval [CI], 0.97-1.59; P Z .089), and their association with PAN was marginally significant (AOR 1.77; 95% CI, 1.00-3.13; P Z .052), except in lower risk subjects for whom the odds of PAN were marginally higher in the distal HPs group than the no distal polyps group (AOR 1.97; 95% CI, 1.01-3.85; P Z .048). Overall, the distal polyps group had significantly lower odds of PN than the distal TAs group (AOR 0.55; 95% CI, 0.40-0.76; P < .001). The increased risk of PN and PAN among those with distal HPs was modest. Conclusions: A direct association between distal HPs and PN is lacking, and this implies a need for a multivariate assessment of the risk of PAN. Recommending colonoscopy for every patient with distal HPs detected by screening sigmoidoscopy is not supported by this study. (Gastrointest Endosc 2015;-:1-8.)
Colorectal cancer (CRC) affects 1.2 million people globally, accounting for 10% of all malignancies and 8% of all cancer deaths.1,2 Fecal occult blood tests, flexible sigmoidoscopy (FS), and colonoscopy could effectively reduce cancer-related mortality by up to 33%, 40%, and 68%, respectively.3-8
Compared with other screening modalities, use of FS is now becoming more widespread, especially in Europe and especially after the results of 4 landmark randomized, controlled trials were published.8-12 FS is a cost-effective strategy to reduce both the incidence and mortality of CRC.10,13 It also represents an attractive option in
Abbreviations: AOR, adjusted odds ratio; APCS, Asia Pacific Colorectal Screening; CI, confidence interval; CRC, colorectal cancer; FS, flexible sigmoidoscopy; HP, hyperplastic polyp; OR, odds ratio; PAN, proximal advanced neoplasia; PN, proximal neoplasia; TA, tubular adenoma.
Current affiliations: Institute of Digestive Disease (1), School of Public Health and Primary Care (2), Chinese University of Hong Kong, Shatin, Hong Kong, HKSAR, China.
DISCLOSURE: The Hong Kong Jockey Club Charities Trust provided full funding of this project. The Trust did not have any other role in this study. All authors disclosed no financial relationships relevant to this publication. Copyright ª 2015 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2015.06.049
Presented at the International Digestive Disease Forum, June 6-7, 2015, Hong Kong, HKSAR, China (Clin Gastroenterol Hepatol 2015;13:e86-7). Reprint requests: Joseph J.Y. Sung, MD, PhD, 7/F, Lui Che Woo Clinical Sciences Building, Prince of Wales Hospital, Shatin, Hong Kong, HKSAR, China. If you would like to chat with an author of this article, you may contact Professor Martin Wong at [email protected].
Received January 12, 2015. Accepted June 18, 2015.
www.giejournal.org
Volume
-,
No.
-
: 2015 GASTROINTESTINAL ENDOSCOPY 1
Association between proximal and distal lesions
Wong et al
resource-deprived countries where screening colonoscopy and gastroenterologists are not widely available. Studies have demonstrated that adequately trained family physicians and nurse endoscopists can perform screening FS as safely and effectively as gastroenterologists or surgeons.14-17 Whereas it was widely recognized that subjects with distal advanced neoplasia have higher risks of proximal neoplasia (PN) and proximal advanced neoplasia (PAN),18-20 whether distal hyperplastic polyps (HPs) are also markers of PN and PAN is under debate. Formal guidelines do not endorse distal HPs as markers of PN or PAN.20-22 Fourteen of 17 published colonoscopy studies reported no association between HP, PN, and PAN.23 However, recent pathology studies suggest that microvesicular HPs could develop into sessile serrated adenomas via microsatellite instability and MLH1 methylation pathways.24 Of 4 meta-analyses,23,25-27 2 concluded that there was an association between distal HPs and PN,23,25 1 demonstrated an association between distal adenomatous polyps and PN,26 and 1 showed no association between distal HPs and PN/PAN.27 The interpretation of these meta-analyses is mixed because the heterogeneity of the methodologies used by the original articles varied substantially. Treating distal HPs as normal colonoscopy findings has not been unanimously agreed on, as reflected by many physicians still referring patients with distal HPs alone for colonoscopy.28 There are thus far fewer large-scale colonoscopy studies that were prospectively conducted in asymptomatic individuals in Asia. Hence, the generalizability of the existing evidence to Eastern Asian populations is uncertain. The objective of this study was to evaluate the association between distal HPs and PN/PAN among CRC screening participants who underwent colonoscopy. Because a recent study reported that the detection of proximal serrated lesions at screening colonoscopy was independently associated with the risk of synchronous advanced colorectal neoplasia,29 we also examined the relationship between proximal serrated lesions and distal HPs.
METHODS The study setting has been described elsewhere.30-36 In 2008, a bowel cancer screening center was established in Hong Kong. It recruited eligible Hong Kong residents 50 to 70 years of age who were asymptomatic for CRC screening via media invitations. This study was approved by an ethics committee of the Chinese University of Hong Kong, and each participant provided informed consent.
Participant recruitment We prospectively recruited self-referred screening participants for CRC screening via telephone, fax, e-mail, or walk-in. Enrolled subjects were eligible if they (1) were 50 to 70 years of age; (2) had no existing or previous 2 GASTROINTESTINAL ENDOSCOPY Volume
-,
No.
-
: 2015
symptoms suggestive of CRC such as rectal bleeding, melena, anorexia, change in bowel habits in the past 4 weeks, and weight loss of more than 5 kg in the past 6 months; and (3) had not undergone any CRC screening tests in the past. Exclusion criteria included personal history of CRC, colonic adenoma, diverticular disease, inflammatory bowel disease, prosthetic heart valve, or vascular graft surgery. Subjects with contraindications to colonoscopy, including medical conditions such as cardiopulmonary insufficiency and the use of dual antiplatelet therapy, were also excluded. The participants were offered either a yearly fecal occult blood test or a colonoscopy for CRC screening. This study included all participants who underwent a colonoscopy (years 2008-2014).
Colonoscopy procedure A standardized bowel preparation regimen by using polyethylene glycol (Klean-Prep; Helsinn Birex Pharmaceuticals Ltd, Dublin, Ireland) was used. The colonoscopy was conducted at an endoscopy center in a major hospital, conducted by experienced colonoscopists. Before the colonoscopy, all subjects received a standard sedation regimen consisting of midazolam 2.5 mg (Groupe Panpharma, Beignon, France). Pethidine 25 mg (Martindale Pharma, Buckinghamshire, United Kingdom) was administered intravenously. A withdrawal time of at least 6 minutes was practiced for all subjects, which is in accordance with the current quality indicators for colonoscopy.37 All lesions were removed and underwent biopsies, as deemed appropriate by the endoscopists. In this study, the colonoscopists attempted to remove and perform biopsies on all lesions including benign-appearing HPs, except lesions that were smaller than 2 mm. These small lesions were also regarded as HPs in this analysis. The biopsy specimens were examined by gross and microscopic evaluation in a certified laboratory by experienced histopathologists.
Outcome variables and covariates The major outcome variable was the detection of PN and PAN. PAN is defined as any colorectal adenoma in the proximal colon 10 mm or greater in diameter having high-grade dysplasia and villous or tubulovillous histologic characteristics or any combination thereof. The secondary outcome variable was the detection of proximal serrated lesions, defined as HPs larger than 9 mm, those interpreted as sessile serrated adenomas or sessile serrated polyps, and traditional serrated adenomas in the proximal colon. The variables tested for association are distal tubular adenomas (TAs) and HPs, defined as TAs and HPs situated within the colonic mucosa in the rectum, the rectosigmoid junction, and the sigmoid colon. The covariates included participant age, sex, body mass index, smoking status, alcohol use, family history of CRC, concomitant comorbidities, and the use of aspirin and nonsteroidal anti-inflammatory drugs. www.giejournal.org
Wong et al
Statistical analyses We excluded participants with distal advanced neoplasia or adenocarcinoma from the analysis. All data were entered into a predesigned database with logistic checking by using Microsoft Access and analyzed by using SPSS software, version 18.0 (IBM, Chicago, Ill). We computed the absolute risks of PN and PAN according to the distal findings (no distal polyps vs distal HPs vs distal TAs). Each demographic characteristic of the subjects was tested for significance with distal findings by the Student t test and c2 test for continuous and categorical variables, respectively. Those variables found to be significant (P < .05) on univariate analysis were entered into a binary logistic regression model, with PN and PAN as outcome measures. In an additional subanalysis, we included all proximal serrated lesions as PN and studied its association with distal HPs. As part of sensitivity analysis, we selected the statistically significant (P < .05) variables in the multivariate regression analysis to fit into another binary logistic regression model. In addition, we repeated the above analysis by stratifying the study participants into average or moderate risk versus higher risk, according to the Asia Pacific Colorectal Screening (APCS) scoring system (scores of 4-7, high-risk; scores of 0-3, average or intermediate risk, thereafter referred to as lower risk).
RESULTS Participant characteristics A total of 5842 screening participants underwent colonoscopy. We excluded 206 subjects who were found to have distal advanced neoplasia or distal cancer, and 23 subjects who could not tolerate the laxative regimen or whose bowel preparation was poor. Their average SD age was 57.6 4.87 years (Table 1). The mean body mass index was 23.5 kg/m2, and the proportion of ever smokers and alcohol users was 7.7% and 9.4%, respectively. Among them, 13.9% had a first-degree relative with a history of CRC. The most common comorbidities included hypertension (22.6%), diabetes mellitus (7.3%), and GERD (5.3%). Most of them were of moderate risk (79.5%) as classified by the APCS scoring system. The detection rate of PN and PAN was 17.6% and 2.2%, respectively, whereas 74.6% had no distal polyps, 8.4% had distal HPs with no distal TAs, and 17.0% had distal TAs with or without distal HPs.
Absolute risk of PN The prevalence of PN was higher among those with distal TAs (29.4%) than subjects with distal HPs only (19.3%) and no distal polyps (14.8%) (Table 2). This decline in prevalence was similarly observed for PAN (3.5% vs 3.2% vs 1.8%) (Table 2). Stratification of all subjects into lower risk and high risk according to the APCS scores showed a similarly increasing prevalence of both types of proximal lesions. Three subjects (0.1%) had www.giejournal.org
Association between proximal and distal lesions
TABLE 1. Characteristics of study participants (N [ 5613) Age, y, mean SD
57.64 4.87
BMI, kg/m , mean SD
23.50 3.18
2
Male, no. (%)
2594 (46.2)
Family history of CRC in a first-degree relative, no. (%)
781 (13.9)
Ever smoked, no. (%)
430 (7.7)
Alcohol consumption, no. (%)
525 (9.4)
Diabetes mellitus, no. (%)
411 (7.3)
Hypertension, no. (%)
1267 (22.6)
IHD/heart disease, no. (%)
94 (1.7)
COAD, no. (%)
38 (0.7)
Stroke, no. (%)
37 (0.7)
Cirrhosis, no. (%)
8 (0.1)
GERD, no. (%)
295 (5.3)
Use of nonsteroidal anti-inflammatory drugs, no. (%)
263 (4.7)
Use of aspirin, no. (%)
131 (2.3)
APCS, no. (%) Low or moderate risk
4462 (79.5)
High risk
1151 (20.5)
Proximal neoplasia, no. (%)
990 (17.6)
Proximal advanced neoplasia, no. (%)
123 (2.2)
High-grade dysplasia
23 (0.4)
Villous or tubulovillous lesions
57 (1.0)
Adenoma size 10 mm No distal polyps, no. (%)
95 (1.7) 4187 (74.6)
Distal HPs with no distal TAs, no. (%)
472 (8.4)
Distal TAs with or without distal HPs, no. (%)
954 (17.0)
BMI, Body mass index; CRC, colorectal cancer; IHD, ischemic heart disease; COAD, chronic obstructive airway disease; APCS, Asia Pacific Colorectal Screening; HPs, hyperplastic polyps; TAs, tubular adenomas.
proximal HPs larger than 9 mm, 60 subjects (1.1%) had sessile serrated adenomas or sessile serrated polyps, and 269 subjects had traditional serrated adenomas (4.8%) in the proximal colon.
Association of demographic characteristics with distal lesions Compared with subjects having no distal polyps, participants with distal HPs had a higher body mass index (odds ratio [OR] 1.07; 95% confidence interval [CI], 1.041.10; P < .001); more were male (OR 1.53; 95% CI, 1.26-1.85; P < .001), ever smokers (OR 2.86; 95% CI, 2.16-3.78; P < .001), alcohol users (OR 1.43; 95% CI, 1.06-1.93; P Z .019); and had diabetes (OR 1.51; 95% CI, 1.08-2.11; P Z .016) and GERD (OR 1.50; 95% CI, 1.04–2.18; P Z .032) (Table 3). Subjects found to have distal TAs were younger (OR 0.97; 95% CI, 0.95-0.99; P Z .006) and were more likely to be ever smokers (OR 1.48; 95% CI, 1.07-2.04; P Z .017) compared with the distal HPs only group (Table 3). Volume
-,
No.
-
: 2015 GASTROINTESTINAL ENDOSCOPY 3
Association between proximal and distal lesions
Wong et al
TABLE 2. Absolute risk of PN according to distal findings*
Distal findings
All subjects, PN/no PN, no. (AR, %)
Moderate risk, PN/no PN, no. (AR, %)
High risk PN/no PN, no. (AR, %)
No distal polyps
619/3568 (14.8)
468/2936 (13.7)
151/632 (19.3)
Distal HPs with no distal TAs
91/381 (19.3)
61/287 (17.5)
30/94 (24.2)
Distal TAs with or without distal HPs
280/674 (29.4)
203/507 (28.6)
77/167 (31.6)
All subjects, PAN/no PAN, no. (AR, %)
Moderate risk, PAN/no PAN, no. (AR, %)
High risk, PAN/no PAN, no. (AR, %)
75/4112 (1.8)
52/3352 (1.5)
23/760 (2.9)
No distal polyps Distal HPs with no distal TAs
15/457 (3.2)
11/337 (3.2)
4/120 (3.2)
Distal TAs with or without distal HPs
33/921 (3.5)
20/690 (2.8)
13/231 (5.3)
PN, Proximal neoplasia; AR, absolute risk; HPs, hyperplastic polyps; TAs, tubular adenomas; PAN, proximal advanced neoplasia. *Proximal adenomatous lesions include advanced neoplasia and cancer, but the distal TAs group does not include distal advanced neoplasia and cancer. All P values were <.001 when the c2 test of trend was used to compare the absolute risks of proximal neoplasia among subjects with different distal findings.
TABLE 3. Association of the demographic characteristics between subjects with distal HPs only and those with distal TAs or no distal polyps Distal HPs only vs no distal polyps, OR (95% CI), P value
Distal TAs vs distal HPs only, OR (95% CI), P value
Age, y
1.02 (1.00–1.04), P Z .103
0.97 (0.95-0.99), P Z .006*
BMI, kg/m2
1.07 (1.04-1.10), P < .001*
1.01 (0.97-1.04), P Z .792
Male
1.53 (1.26–1.85), P < .001*
0.90 (0.72–1.12), P Z .356
Ever smoker
2.86 (2.16–3.78), P < .001*
1.48 (1.07–2.04), P Z .017*
Alcohol consumption
1.43 (1.06–1.93), P Z .019*
1.04 (0.74–1.47), P Z .807
Diabetes mellitus
1.51 (1.08–2.11), P Z .016*
0.88 (0.61–1.28), P Z .494
Family history of CRC in a first-degree relative
1.03 (0.79–1.36), P Z .813
0.90 (0.66–1.23), P Z .510
Hypertension
1.12 (0.89–1.40), P Z .339
0.92 (0.71–1.18), P Z .501
IHD/heart disease
1.37 (0.70–2.69), P Z .356
1.07 (0.49–2.31), P Z .873
COAD
1.78 (0.68–4.68), P Z .240
1.27 (0.41–3.89), P Z .680
Stroke
1.59 (0.61–4.14), P Z .342
2.54 (0.68–9.51), P Z .166
NA
NA
Characteristic
Cirrhosis GERD
1.50 (1.04–2.18), P Z .032*
1.51 (0.96–2.37), P Z .072
Use of nonsteroidal anti-inflammatory drugs
0.66 (0.39–1.12), P Z .124
0.61 (0.34–1.09), P Z .096
Use of aspirin
1.32 (0.73–2.38), P Z .358
0.87 (0.45–1.69), P Z .685
HPs, Hyperplastic polyps; OR, odds ratio; CI, confidence interval; TAs, tubular adenomas; BMI, body mass index; IHD, ischemic heart disease; COAD, chronic obstructive airway disease; NA, not available. *P < .05.
Independent associations between proximal lesions and distal findings On multivariate regression analysis controlling for potential confounders, it was found that participants with distal HPs did not have significantly higher odds of PN (AOR 1.24; 95% CI, 0.97-1.59; P Z .089), and the association with PAN (AOR 1.77; 95% CI, 1.00-3.13; P Z .052) was only of borderline significance compared with those with no distal polyps (Table 4). Compared with subjects having distal TAs, those with distal HPs had lower odds of PN (AOR 0.58; 95% CI, 0.44–0.76; P < .001) and statistically similar odds of PAN (AOR 0.93; 95% CI, 4 GASTROINTESTINAL ENDOSCOPY Volume
-,
No.
-
: 2015
0.50–1.73; P Z .808) (Table 4). There was no significant association between distal HPs and proximal serrated lesions (AOR 0.89; 95% CI, 0.21-3.82; P Z .875).
Sensitivity analysis As part of a sensitivity analysis, when regression analyses were conducted with significant covariates (defined as P < .05), defined in Table 4 as independent variables, the association between distal polyps (vs no distal polyps) and proximal lesions remained insignificant (Table 5). The significant association between distal TAs (vs distal polyps) and PN remained (AOR 0.578; 95% CI, www.giejournal.org
Wong et al
Association between proximal and distal lesions
TABLE 4. Adjusted odds ratio* of PN or PAN among subjects with distal HPs only and those with distal TAs versus no distal polyps PN AOR (95% CI), P value
PAN AOR (95% CI), P value
1.24 (0.97–1.59), P Z .089
1.77 (1.00–3.13), P Z .052
1.04 (1.01-1.06), P Z .007
1.02 (0.95-1.09), P Z .650
Male
1.57 (1.32-1.87), P < .001
0.99 (0.62-1.56), P Z .950
Ever smoker
1.21 (0.90-1.63), P Z .204
0.95 (0.41-2.19), P Z .904
Alcohol use
1.07 (0.81–1.40), P Z .639
1.27 (0.63–2.58), P Z .510
Diabetes mellitus
1.27 (0.94–1.71), P Z .117
0.65 (0.23–1.78), P Z .397
GERD
1.06 (0.74–1.51), P Z .766
2.23 (1.13–4.37), P Z .020
Distal HPs only vs no distal polyps BMI, kg/m2
0.58 (0.44–0.76), P < .001
0.93 (0.50–1.73), P Z .808
Age, y
1.06 (1.03-1.08), P < .001
1.04 (0.98-1.10), P Z .226
Ever smoker
1.78 (1.27–2.51), P Z .001
1.43 (0.66–3.11), P Z .369
Distal HPs only vs distal TAs
PN, Proximal neoplasia; PAN, proximal advanced neoplasia; AOR, adjusted odds ratio; CI, confidence interval; BMI, body mass index; IHD, ischemic heart disease; COAD, chronic obstructive airway disease; HPs, hyperplastic polyps; BMI, body mass index; TAs, tubular adenomas. *Potential covariates were found on univariate logistic regression with P < .05 (Table 3).
0.440–0.759). There were no interactions among the independent variables.
Association between proximal and distal lesions according to APCS scores When the screening participants were stratified into 2 groups according to the APCS scores (lower vs high risk), those with distal HPs were more likely to have PAN in the lower risk group (AOR 1.97; 95% CI, 1.01-3.85; P Z .048) (Table 6). Compared with those having distal TAs, subjects diagnosed with distal HPs were significantly less likely to have PN (AOR 0.55; 95% CI, 0.40–0.76; P < .001) in the lower-risk group. The respective association in the high-risk group was not significant (Table 6).
TABLE 5. Association between subjects with distal lesions and those with proximal lesions PN Distal HPs only vs no distal polyps Risk ratio (95% CI)
1.304 (1.069–1.590)*
1.774 (1.028–3.063)*
Crude OR (95% CI)
1.377 (1.079–1.757)*
1.800 (1.025–3.159)*
AOR with significant covariates of P values <.05
1.275 (0.995–1.633)
1.755 (0.998–3.085)
Risk ratio (95% CI)
0.657 (0.533–0.810)*
0.919 (0.507–1.674)
Crude OR (95% CI)
0.575 (0.440–0.751)*
0.916 (0.493–1.704)
AOR with significant covariates of P values <.05 (95% CI)
0.578 (0.440–0.759)*
0.916 (0.493–1.704)
Distal HPs only vs distal TAs
DISCUSSION Major findings and implications for clinical practice There are 2 principal findings from this study. First, distal HPs were not found to be predictive of PN or PAN. Although statistically there exists a significantly higher odd of detecting PAN in those with distal HPs versus no distal polyps when lower risk subjects were analyzed, the absolute difference in PAN was small (3.2% vs 1.5%). Second, subjects with distal TAs had higher odds of having PN than the distal polyps group irrespective of whether all subjects (29.4% vs 19.3%, P < .001) or moderate-risk subjects (28.6% vs 17.5%, P < .001) were analyzed. Therefore, these findings do not support colonoscopy arrangements for every patient with distal HPs detected by screening sigmoidoscopy. On the other hand, the study results support that detection of distal TAs is an indication for subsequent colonoscopy due to the high risk of proximal PN. However, the number of subjects in whom distal HPs were detected with PAN was relatively small, www.giejournal.org
PAN
PN, Proximal neoplasia; PAN, proximal advanced neoplasia; HPs, hyperplastic polyps; CI, confidence interval; OR, odds ratio; AOR, adjusted odds ratio; TAs, tubular adenomas. *P < .05.
making the value of statistical analysis less definite in this subanalysis.
Relationship with literature: the distribution of proximal and distal lesions The most recent meta-analysis, conducted by Dodou and de Winter23 in 2011 involving 32 studies reported that the absolute risk of PN and PAN was 27.2% (95% CI, 17.6%-38.0%) and 2.3% (95% CI, 1.6%-3.2%), respectively. The respective figures in the study by Lewis et al26 were 16.3% and 2% to 5%. These were statistically similar to our findings (17.6% and 2.2%, Volume
-,
No.
-
: 2015 GASTROINTESTINAL ENDOSCOPY 5
Association between proximal and distal lesions
Wong et al
TABLE 6. AOR* of PN or PAN among subjects with distal HPs only and those with distal TAs or no distal polyps by APCS risk tier PN AOR (95% CI), P value
PAN AOR (95% CI), P value
Distal HPs only vs no distal polyps
1.23 (0.91–1.65), P Z .184
1.97 (1.01–3.85), P Z .048*
Distal HPs only vs distal TAs
0.55 (0.40–0.76), P < .001*
1.14 (0.54–2.42), P Z .728
Distal HPs only vs no distal polyps
1.29 (0.81–2.04), P Z .282
1.33 (0.44–4.05), P Z .618
Distal HPs only vs distal TAs
0.64 (0.39–1.07), P Z .088
0.63 (0.20–1.99), P Z .427
Lower risk (low or moderate risk according to APCS score)
High risk
AOR, Adjusted odds ratio; CI, confidence interval; PN, proximal neoplasia; PAN, proximal advanced neoplasia; APCS, Asia Pacific Colorectal Screening; HPs, hyperplastic polyps; TAs, tubular adenomas. *Potential covariates were found on univariate logistic regression with P < .05 (Table 3).
P > .05). The absolute risk of PN and PAN in our study was, however, lower than that reported by Dave et al,25 who included 18 studies, and the overall risk of PN and PAN was 21% to 25% and 4% to 5%, respectively. Similarly, a meta-analysis conducted by Lin et al27 reported pooled risks of PN and PAN of 26% and 4.4%, respectively. The differences in the prevalence of PN and APN in all of these studies might be accounted for by study participants of different ethnicities and inclusion of different subgroups, such as participants with symptoms versus those with no symptoms, the use of different meta-analytic techniques in the analysis, and the quality of the study.
Relationship with medical literature: the association between distal HPs and proximal neoplasia Our study showed that distal HPs were not significantly associated with PN, and their association with PAN was of borderline significance. This is in accord with findings from 2 meta-analyses,26,27 but not in agreement with the other 2 meta-analyses.23,25 It should be noted that in these meta-analyses, some original studies were retrospective, and the validity of the findings may be doubtful. In addition, some studies were relatively small scale and could potentially lead to type II errors. Higher-quality studies are more likely to report that distal HPs were not markers of proximal lesions.27 Many lower-quality studies tended to be small scale and compared the prevalence of PN in patients with distal HPs versus those with no distal HPs or those with distal TAs, but not both. It cannot be overemphasized that to determine whether there exists an association between distal HPs and PN, comparisons of the prevalence of PN should be made among the 3 distal pathology groups (no distal HPs, distal HPs only, distal TAs with or without HPs). Studies that involved comparisons of those with distal HPs and those with no distal HPs may only demonstrate that the risk of PN is higher in the former group than the latter group. Without knowing the risk of PN in the distal TA group, one may wrongly recommend that people with distal HPs should have their proximal colon examined.27 6 GASTROINTESTINAL ENDOSCOPY Volume
-,
No.
-
: 2015
Our findings showed that when analysis was limited to the lower-risk group (APCS scores of 0-3), the association between distal HPs and PN became significant. This is similar to the finding of Dodou and de Winter,23 in which PN lesions were better predicted in populations with a low PAN prevalence (ie, the lower risk group). One possible explanation is that patients diagnosed at a younger age are more likely to have advanced malignancies, possibly due to genetic predispositions.38,39
Study strengths and limitations This was a large-scale, prospective study conducted in more than 5600 asymptomatic subjects. Determination of the eligibility criteria, data collection procedures, and colonoscopies was performed to the highest possible standard at accredited endoscopy centers and laboratories according to international guidelines. This study is the largest single study of the association of distal HPs and PN in a specific, relatively homogeneous population and using a recently validated risk scoring system for advanced colorectal neoplasia as a stratification tool in subgroup analysis. Nevertheless, some of the limitations should be addressed. First, this study included self-referred screening participants, and their health-seeking behavior and lifestyle habits might be different from those of the general public.40,41 Also, misclassification biases and false-positive results might occur, and it has been shown that missed lesion could occur in as many as 26% and 13% in adenomas smaller than 5 mm and between 5 and 10 mm, respectively. Furthermore, between-physician variation in the adenoma detection rate might exist. Last, critics might argue that this study used colonoscopy to understand how FS would work. Colonoscopy uses sedation, involves a more-invasive bowel preparation, and fully visualizes the entire colon to the splenic flexure; all of these factors might affect polyp detection relative to FS.
CONCLUSION These study results support the lack of a direct effect between distal HPs and PN and imply a need for www.giejournal.org
Wong et al
multivariate assessment of the risk of PAN. These findings are important to inform physicians on the subsequent management of distal HPs detected by screening sigmoidoscopy. Without randomized, controlled trials, the study findings do not imply that sigmoidoscopy is adequate for all patients with distal HPs because each screening participant has his or her own risk threshold in deciding whether a subsequent colonoscopy is warranted. Therefore, we recommend that physicians discuss the risk of PN with the patient, adopting a shared decision-making approach. Our findings are in line with existing guidelines in which detection of HPs on screening FS should not automatically prompt a subsequent colonoscopy.
REFERENCES 1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893-917. 2. Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer, 2010. Available at: http://globocan.iarc.fr. Accessed July 18, 2015. 3. Hardcastle JD, Chamberlain JO, Robinson MH, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996;348:1472-7. 4. Jorgensen OD, Kronborg O, Fenger C. A randomised study of screening for colorectal cancer using faecal occult blood testing: results after 13 years and seven biennial screening rounds. Gut 2002;50:29-32. 5. Mandel JS, Church TR, Ederer F, et al. Colorectal cancer mortality: effectiveness of biennial screening for fecal occult blood. J Natl Cancer Inst 1999;91:434-7. 6. Nishihara R, Wu K, Lochhead P, et al. Long-term colorectal-cancer incidence and mortality after lower endoscopy. N Engl J Med 2013;369: 1095-105. 7. Zauber AG, Winawer SJ, O'Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med 2012;366:687-96. 8. Bretthauer M. Colorectal cancer screening. J Intern Med 2011;270: 87-98. 9. Hoff G, Grotmol T, Skovlund E, et al. Risk of colorectal cancer seven years after flexible sigmoidoscopy screening: randomized controlled trial. BMJ 2009;338:b1846. 10. Atkin WS, Edwards R, Kralj-Hans I, et al. Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet 2010;375:1624-33. 11. Segnan N, Senore C, Andreoni B, et al. Baseline findings of the Italian multicentre randomised controlled trial of “once-only sigmoidoscopy” dSCORE. J Natl Cancer Inst 2002;94:1763-72. 12. Weissfeld JL, Schoen RE, Pinsky PF, et al. Flexible sigmoidoscopy in the PLCO cancer screening trial: results from the baseline screening examination of a randomized trial. J Natl Cancer Inst 2005;97:989-97. 13. Schoen RE, Pinsky PF, Weissfeld JL, et al. Colorectal-cancer incidence and mortality with screening flexible sigmoidoscopy. N Engl J Med 2012;366:2345-57. 14. Shaukat MS, Ramirex FC. The utilization of flexible sigmoidoscopy by family practitioners after residency training. Gastrointest Endosc 2000;52:45-7. 15. Williams J, Russell I, Dural D, et al. Effectiveness of nurse delivered endoscopy: findings from randomised multi-institution nurse endoscopy trial (MINuET). BMJ 2009;338:b231. 16. Limoges-Gonalez M, Singh N, Al-Juburi Amar, et al. Comparisons of screening colonoscopy performed by a nurse practitioner and gastroenterologists. Gastroenterol Nurs 2011;34:210-6.
www.giejournal.org
Association between proximal and distal lesions 17. Wallace MB, Kemp JA, Meyer F, et al. Screening for colorectal cancer with flexible sigmoidoscopy by nonphysician endoscopists. Am J Med 1999;107:214-8. 18. Benson VS, Patnick J, Davies AK, et al. Colorectal cancer screening: a comparison of 35 initiatives in 17 countries. Int J Cancer 2008;122: 1357-67. 19. Winawer SJ, Zauber AG. The advanced adenoma as the primary target of screening. Gastrointest Endosc Clin N Am 2002;12:1-9. 20. Winawer SJ, Zauber AG, Fletcher RH, et al. Guidelines for colonoscopy surveillance after polypectomy: a consensus update by the US MultiSociety Task Force on Colorectal Cancer and the American Cancer Society. CA Cancer J Clin 2006;56:143-59. 21. Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US MultiSociety Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin 2008;58:130-60. 22. Institute for Clinical Systems Improvement. Health care guideline: colorectal cancer screening. Thirteenth edition, 2010. Available at: http:// www.icsi.org/colorectal_cancer_screening/colorectal_cancer_screening_ 5.html. Accessed July 18, 2015. 23. Dodou D, de Winter JC. The relationship between distal and proximal colonic neoplasia: a meta-analysis. J Gen Intern Med 2011;27: 361-70. 24. Rex DK, Ahnen DJ, Baron JA, et al. Serrated lesions of the colorectum: review and recommendations from an expert panel. Am J Gastroenterol 2012;107:1315-29. 25. Dave S, Hui S, Kroenke K, et al. Is the distal hyperplastic polyp a marker for proximal neoplasia? A systematic review. J Gen Intern Med 2003;18: 128-37. 26. Lewis JD, Ng K, Hung KE, et al. Detection of proximal adenomatous polyps with screening sigmoidoscopy. A systematic review and meta-analysis of screening colonoscopy. Arch Intern Med 2003;163: 413-20. 27. Lin OS, Gerson LB, Soon MS, et al. Risk of proximal colon neoplasia with distal hyperplastic polyps. A metaanalysis. Arch Intern Med 2005;165: 382-90. 28. Mysliwiec PA, Brown ML, Klabunde CN, et al. Are physicians doing too much colonoscopy? A national survey of colorectal surveillance after polypectomy. Ann Intern Med 2004;141:264-71. 29. Ng SC, Ching JY, Chan VC, et al. Association between serrated polyps and the risk of synchronous advanced colorectal neoplasia in averagerisk individuals. Aliment Pharmacol Ther 2015;41:108-15. 30. Wong MC, Hirai HW, Luk AK, et al. The knowledge of colorectal cancer symptoms and risk factors among 10,078 screening participants: are high risk individuals more knowledgeable? PLoS One 2013;8:e60366. 31. Wong MC, Ching JY, Hirai HH, et al. Perceived obstacles of colorectal cancer screening and their associated factors among 10,078 Chinese participants. PLoS One 2013;8:e70209. 32. Wong MCS, John GK, Hirai HW, et al. Changes in the choice of colorectal cancer screening tests in primary care settings from 7,845 prospectively collected surveys. Cancer Causes Control 2012;23:1541-8. 33. Wong MC, Lam TYT, Tsoi KKF, et al. A validated tool to predict colorectal neoplasia and inform screening choice for asymptomatic subjects. Gut 2014;63:1130-6. 34. Ng SC, Ching JYL, Chan VCW, et al. Diagnostic accuracy of fecal immunochemical test for screening individuals with a family history of colorectal cancer. Aliment Pharmacol Ther 2013;38:835-41. 35. Wong MCS, Ching JY, Lam TY, et al. Prospective cohort study of compliance with faecal immunochemical tests for colorectal cancer screening in Hong Kong. Prev Med 2013;57:227-31. 36. Wong MCS, Tsoi KKF, Ng SSM, et al. A Comparison of the acceptance of Immunochemical faecal occult blood test and colonoscopy in colorectal cancer screening: a prospective study among Chinese. Aliment Pharmacol Ther 2010;32:74-82.
Volume
-,
No.
-
: 2015 GASTROINTESTINAL ENDOSCOPY 7
Association between proximal and distal lesions
Wong et al
37. Rex DK, Petrini JL, Baron TH, et al. Quality indicators for colonoscopy. Gastrointest Endosc 2006;63:S16-28. 38. Negri E, Braga C, La Vecchia C, et al. Family history of cancer and risk of colorectal cancer in Italy. Br J Cancer 1998;77:174-9. 39. Slattery ML, Friedman GD, Potter JD, et al. A description of age, sex, and site distributions of colon carcinoma in three geographic areas. Cancer 1996;78:1666-70.
8 GASTROINTESTINAL ENDOSCOPY Volume
-,
No.
-
: 2015
40. Thiis-Evensen E, Hoff GS, Sauar J, et al. Flexible sigmoidoscopy or colonoscopy as a screening modality for colorectal adenomas in older age groups? Findings in a cohort of the normal population aged 63– 72 years. Gut 1999;45:834-9. 41. Farrands PA, Hardcastle JD, Chamberlain J, et al. Factors affecting compliance with screening for colorectal cancer. Community Med 1984;6:12-9.
www.giejournal.org