The rates of developing metachronous adenoma and advanced adenoma after polypectomy for colon polyps with HGD were 58% and 20%, respectively, in the current study. The clinical features of age, gender, stool occult blood positivity, size of polyp, morphology, pathology and location of polyps were not different between the patients who had developed recurrent adenomas and those who had not.
The odds ratios of developing metachronous adenoma and advanced adenoma were 4.32 (2.06–9.04 95% CI) and 2.55(1.11–5.89 95% CI), respectively, when comparing subjects with polyp number ≥ 3 and ≤ 2 at the index colonoscopy.
There was no metachronous adenocarcinoma observed during the period of this cohort. The incidence rate of adenomas was 35.9% in our patients who had undergone screening colonoscopy. The rate is higher than that of the Western population of 20% [14] and 8.13 to16.5% of Taiwanese and Chinese ethnic groups, respectively [15–17], because our study subjects were mostly referred on account of positivity for stool occult blood or symptomatic of gastrointestinal disorders.
The reported reduction rates of colon cancer after polypectomy were around 50–80% and the occurrence of interval cancers was located mostly in the right colon [18–20]. The reason accounting for higher recurrent rates of interval carcinoma in the right colon included incomplete colonoscopy study due to poor endoscopic technique [21], incomplete removal of the polyps [22], difficulty in visualization of smaller adenomas in the right colon [23–24], or sessile serrated adenoma in the proximal colon.
At screening colonoscopy, the prevalence of polyps with HGD was 2.2% (258/11565) in our patients, which is slightly lower than that of 3.5% in the general population of Chinese ethnic [26]. There was no interval cancer during the follow up period in the current study, because we performed the second look colonoscopy 6 to 12 months after piecemeal resection for advanced polyps or suspected incomplete resection to ensure complete resection of polyps and to decrease the rate of undetected adenomas at the index colonoscopies, as has been suggested by some endoscopists in treatment using the piecemeal method [25–26]. Recurrent adenomas after polypectomy were reported to be about 36 to 64% within 2 to 6 years [12, 27–30]. In the current study, the overall recurrence rate of metachronous adenomatous polyps was 58%, which is similar to that of 64% in Toll's study [12]. The rate of recurrent advanced adenomas was 20% in the current study which is lower than that of 40% in Toll’s report.
HGD in adenoma was considered following the adenoma-adenocarcinoma sequence and a precursor of adenocarcinoma [31]. However, the risk of future advanced adenomas in relation to HGD at index colonoscopy was reported to be small and variable.
In the meta-analysis study of Saini [32], the patients with HGD in polyps had a relative risk of advanced adenomas of 1.84 (95% CI 1.06–3.19) compared to those who had no HGD. Some other studies including a randomized controlled trial revealed no association of HGD with subsequent advanced adenomas during surveillance colonoscopy [33–36].
Two meta-analyses [37–38] have also shown that the presence of HGD had a small association with the risk of future advanced adenomas. On the multivariate analysis in these studies, the presence of HGD did not confer recurrence of metachronous adenomas. Most of the advanced adenomas are ≥ 1 cm [39]. However, if the adenomas with HGD can be removed completely, the risk for metachronous recurrence is probably dependent on the number of colon polyps and male gender as shown in this study. The rationale is also applicable to the association of villous histology of the resected adenomas with the risk of recurrent advanced adenomas. A cohort study had shown that the presence of villous adenomas at baseline colonoscopy had a relative risk of 1.8 of future adenomas [33]. Two other studies including one meta-analysis and a pooled analysis had found no association of villous histology with future adenomas [32, 14], which is in accordance with the present study result. The size of colonic adenomas has been shown to be closely related to the histological features of HGD and invasive cancer [40]. HGD in histology or prominent villous component was seen in 87.5% of large polyps (≥ 1 cm) [95% CI = 86–89.4]) [41]. The risk of recurrent advanced adenomas was shown to be corresponding with the size of polyps at index colonoscopy. In Martinez’s study [14], with polyp size of 0.5 cm as the reference group, the adenoma size of 1.0 to 1.9 cm or ≥ 2.0 cm at the baseline colonoscopy had a relative risk of 2.3 and 3.0, respectively, of recurrent advanced adenomas. There were four other studies showing an increase of relative risk of recurrent advanced adenomas in colonic adenomas greater than 1 cm at base-line [22, 32, 34–36]. The relative risk of polyps with HGD at baseline was 6.87 (95% CI 2.61–18.07) of interval advanced neoplasia in Lieberman’s study, in which 6 among 11 patients who had recurrent cancers or high-grade dysplasia were found in the portion of colon where the polyps were resected [22]. In the current study, the size of adenomas greater than 1 cm does not increase the risk of advanced adenomas on surveillance colonoscopy, which is in line with Saini’s meta-analysis [32]. Incomplete removal or missed adenomas [21–22] might account for the contradictory observations.
The number of adenomas ≥ 3 has been shown to increase the risk of recurrent advanced adenomas. The relative risk was between 1.5 and 5.0 [22, 32, 34–36] with one adenoma as the reference group. The current study in concert with the previous studies has found odds ratios of 2.45(1.22–4.93) on univariate analysis and 2.11(1.00-4.43) on multivariate analysis, respectively, when comparing adenoma number ≥ 3 to adenoma number ≤ 2. Male gender is also associated with advanced adenoma recurrence in his study with an odds ratio of 3.09, which is consistent with Zhang’s study that reported male gender and the number of adenoma ≥ 3 had high risk of advanced adenoma recurrence [17].
The natural history of colonic adenomas is still elusive. Two longitudinal follow up studies for small polyps (6–9 mm) using computed tomography showed the tumor progress rates of 22% [42] and 35% [43] during the follow up periods of 8 and 3 years, respectively. Advanced histology was seen in 47% of progressing polyps [43], which is similar to the rate of 40% in our patients with the baseline adenoma number ≥ 3. The high incidence rate of recurrent adenomas and advanced adenomas in patients with multiple adenomas is hard to explain solely on incomplete resection of adenomas. The multiple small polyps that were not detected on optical colonoscopy at baseline might have progressed slowly with time and became detectable on surveillance colonoscopy. The multiplicity or polyclonicity in patients with adenoma number ≥ 3 in number is a reasonable explanation but a longer observation with other non-invasive study modalities such as computed tomography or capsule endoscopy to detect missed adenomas may be required to elucidate the natural history of recurrent adenomas. The surveillance recommended by the United States Preventive Services Task Force (USPSTF) was 3 years after removal of advanced adenoma, traditional serrated adenoma, or advanced sessile serrate adenoma [44]. The European guidelines [45] recommended a more aggressive surveillance at 1 year for high risk polyps (≥ 20 mm). In the treatment with piecemeal resection, Walsh et al revealed a rate of 14% polyp recurrence after at least one negative examination, and the rate of CRC development was 17% in 65 patients with large flat polyps [46]. A second look examination for patients who underwent piecemeal resection or suspected incomplete resection may be warranted.
The current study had some limitations. We did not take into account the impact of diet change or life style change such as abstinence of smoking, alcohol drinking and the reduction of body mass index after polypectomy, as which might have some influences on the recurrence of adenomas or advanced adenomas [47–48]. The current study did not include the low risk patients as control group and the surveillance time of patients recruited was not the same. This might influence the rate of recurrent adenomas.