We evaluated the association between adenoma location at baseline with the risk of adenoma recurrence and the location of the recurrent adenoma in an attempt to assess differences in susceptibility to adenoma recurrence by location. Our study suggests three potential mechanisms underlying a lower protective effect of colonoscopy in the proximal colon. Firstly, we report that missed lesions are more common in the proximal colon. Secondly, recurrent adenoma and advanced adenoma are more likely to be in the proximal colon and thirdly, when compared with the participants with distal only adenoma at baseline, participants with proximal adenoma at baseline are more likely to have an adenoma and advanced adenoma recurrence, particularly in the proximal colon. Our sensitivity analyses investigating the effect of missed lesions suggest that missed lesions may not explain the differentially increased proportion of proximal adenoma at recurrence. This suggests the possibility of an underlying biological difference in susceptibility to recurrence of colonic neoplasia in the proximal and distal colon and identifies patients with a proximal adenoma as high-risk for recurrence. This may in part explain some of the observed differences in the efficacy of colonoscopy by colon subsite. Further studies on the role of tumor location in the natural history of colorectal neoplasia are needed.
We are not aware of any study that has evaluated the effect of missed lesions on the risk and location of adenoma recurrence for a direct comparison with our study. Missed lesions at colonoscopy are relatively common, and segmental unblinding of virtual colonoscopy results and tandem back to back colonoscopy have reported adenoma miss rates as high as 27%.22–27
A repeat colonoscopy after 1 year in our cohort of patients with a history of adenoma detected additional adenoma in 34.6% of patients and an advanced adenoma in 6% of patients. Per the design of PPT, these were regarded as missed lesions. However, the inclusion or exclusion of these lesions from our analysis did not affect the increased risk of adenoma recurrence we observed in association with previous proximal adenoma or the proximal location of recurrent adenoma. Also, we addressed the possibility that adenomas detected at T1 colonoscopy may be recurrent lesions because of the one year interval between T0 and T1 colonoscopy. We added the adenoma at T1 to the end-of-trial colonoscopic findings but the results were unchanged.
Our finding of proximal shift in metachronous adenoma is comparable to previous studies ().28–32
Although the magnitude of effect may differ, all the studies showed a consistent pattern of reduced percentage of distal adenoma at recurrence whereas the percentage of proximal adenoma increased. This mirrors the increased proportion of proximal only adenoma from 27% at baseline to 50.3% at recurrence reported in our study and suggests the possibility of different biological susceptibilities to neoplasia by colon subsite.
Previous studies that have evaluated adenoma location at baseline and at recurrence
The increased tendency for recurrence in the proximal colon may offer some explanation why the efficacy of colonoscopy may be lower in that location. However, the current postpolypectomy surveillance guidelines21
do not take adenoma location into consideration for surveillance interval recommendations. Prospective studies evaluating the optimal surveillance intervals after polypectomy in the distal versus the proximal colon and studies focusing on factors (including molecular markers) that reliably predict proximal neoplasia recurrence are needed.
Although missed adenomas did not affect proximal versus distal adenoma recurrence in our study, the importance of performing a good quality colonoscopic examination should be emphasized. Of note, we found more missed lesions in the proximal colon at T1 colonoscopy. The rates of missed lesions vary and are dependent on endoscopists' experience, withdrawal time, and attention to details. Optimal bowel preparation through splitting the bowel preparation laxatives so that some laxatives are consumed a few hours before the procedure is important as well as ongoing efforts to improve the technology of colonoscopy itself such as the use of high definition endoscopes, chromoendoscopy and cap fitted colonoscopy to minimize the risk of missing important lesions in clinical practice. A recent study reported that endoscopists with low adenoma detection rates perform colonoscopies that are associated with a higher risk of interval cancers.33
There are many strengths of our study. A unique feature of our study is the T1 colonoscopy performed in 93% of our study cohort to remove lesions that might have been missed at baseline colonoscopy which afforded us the opportunity to evaluate the effect of missed lesions. Our study population is from a large randomized controlled trial with participants recruited from geographically dispersed areas, information on candidate risk factors was prospectively gathered, all patients had planned colonoscopic assessment for recurrence after an adequate follow-up period and dedicated central pathologists with expertise in gastrointestinal tumors examined the adenomas, thereby ensuring consistency.
Our study also has limitations. The participants in the PPT were self-selected and may be healthier than comparable members of the general population. The design of the PPT also limited the degree of obesity of participants. Since obesity has been associated with an increased risk of colonic neoplasia,34
the yield of adenomas in our study may be lower than expected in the general population. We could not assess the effect of serrated polyps, flat, and depressed lesions in our study because they were not widely discussed at the time the trial was conducted. Furthermore, repeated colonoscopies may still miss lesions.
In conclusion, we observed an increased tendency for adenoma recurrence in the proximal colon supporting the current practice of the use of colonoscopy for surveillance regardless of the location of index adenoma. However, further studies are needed to elucidate whether this suggested biological difference warrants modification of postpolypectomy surveillance intervals.