Narrow-band imaging and high-definition white-light endoscopy in patients with serrated lesions not fulfilling criteria for serrated polyposis syndrome: a randomized controlled trial with tandem colonoscopy

Colorectal cancer (CRC) is the second leading cause of cancer death in western countries [1, 2]. Conventional polyps are considered to be precursor lesions of sporadic CRC. Serrated polyps cause 20 to 35% of all CRC cases and are associated with interval CRC, especially when they involve microsatellite instability and the CpG island methylator phenotype [3]. These polyps are difficult to identify on endoscopy due to their location in the right colon, their sessile or flat morphology, and their pale color with mucus capping [4].

According to the World Health Organization (WHO) of 2010, serrated polyposis syndrome (SPS) was defined by the presence of one out of the following criteria: [5] 1) at least five serrated polyps proximal to the sigmoid colon, with two or more of these larger than 10 mm in diameter; 2) any number of serrated polyps occurring proximal to the sigmoid colon in an individual with a first-degree relative with SPS; and 3) more than 20 serrated polyps of any size distributed throughout the colon. In June 2019, a new update on the WHO SPS criteria was made with small differences between criteria 1 and 3, and the abandonment of criterion 2: 1) five or more serrated polyps proximal to the rectum, all being ≥5 mm in size, with at least two being ≥10 mm in size; and 2) more than 20 serrated polyps of any size distributed throughout the large bowel, with ≥5 being proximal to the rectum [6]. Therefore, patients with SPS are considered to be at increased risk of CRC. Because of the substantial risk of polyp recurrence in these patients, surveillance is mandatory with 1- to 2-yearly colonoscopies [7].

The European Society of Gastrointestinal Endoscopy has published the first Guideline of Advanced Endoscopic Imaging for the detection and differentiation of colorectal neoplasia and recommends conventional chromoendoscopy or narrow-band imaging (NBI) in patients with SPS (strong recommendation, low quality evidence) [8]. A pilot study in patients with SPS showed a significantly lower polyp miss rate with NBI than with high-definition white-light endoscopy (HD-WLE). However, this finding was not confirmed in a subsequent multicentre randomized trial by the same group [9, 10]. A randomized controlled trial in patients undergoing their first colonoscopy reported a non-significant trend toward detection of more proximal colon serrated lesions with NBI than with HD-WLE [11]. Finally, in a retrospective selected case series [12] of individuals in a population-based screening program with proximal serrated lesions at the baseline colonoscopy, colonoscopy reassessment within 1 year using chromoendoscopy and high-definition endoscopes led to a three-fold increase in the diagnosis of SPS.

We hypothesized that NBI could improve the detection of serrated polyps compared with HD-WLE in patients with prior relevant (larger than 5 mm) serrated lesions not fulfilling the SPS criteria. Therefore, this study was designed to compare the serrated polyp detection rate of NBI versus HD-WLE in a randomized, cross-over trial of tandem colonoscopy.

In this randomized cross-over study, we found that the use of NBI versus HD-WLE in patients with a history of relevant serrated lesions not fulfilling SPS criteria was not superior in detecting polyps, including serrated lesions. However, reassessment of these patients, independently of the evaluated technique, allowed one-fifth of them to be reclassified as having SPS. In addition, we found no differences in the polyp miss rate on first evaluation with NBI or HD-WLE (21.3% versus 26.1%).

This prospective study confirms previously published results on the non-superiority of NBI in the detection of serrated lesions compared with HD-WLE. A multicenter randomized cross-over trial of NBI and HD-WLE in 51 patients with SPS concluded that the two techniques were similar, showing a non-significant trend in the polyp miss rate: 20% with NBI (95% CI, 15–27) versus 29% with HD-WLE (95% CI, 22–36), P = 0.065. This difference was driven by the lower HP miss rate with NBI [10]. Moreover, a recent randomized controlled trial with NBI and HD-WLE using the Olympus 190 series for the detection of proximal colon serrated lesions in routine colonoscopy patients showed no statistically significant differences, but found a trend toward higher detection of serrated lesions with NBI than with HD-WLE (0.51 versus 0.39 serrated lesions per patient, P = 0.085) [11].

One of the most salient findings of our randomized controlled study is that after the scheduled follow-up colonoscopy, nine patients (22%) were reassessed as meeting SPS criteria, both the 2010’s and the recently updated 2019’s criteria, with important clinical implications in these patients. A similar finding was observed in a retrospective study of a fecal immunochemical test (FIT)-based CRC screening program [12], in which a 1-year reassessment colonoscopy of arbitrary selected participants with previous serrated polyps detected by chromoendoscopy and high-definition endoscopes substantially improved SPS detection in those with proximal serrated lesions.

Without endoscopic reevaluation, most societies, such as the US Multi-Society Task Force, the European Society of Gastrointestinal Endoscopy and recently the British Society of Gastroenterology, classify these patients as high risk and recommend they undergo surveillance colonoscopy at a 3-yearly interval (patients with at least one sessile serrated lesion or a traditional serrated adenoma ≥10 mm or with a dysplastic component (weak recommendation, low quality evidence) [7, 19, 20]. The results of our study emphasize the clinical implications of the addition of high-quality endoscopic reassessment in patients with relevant serrated lesions, allowing around 20% of them to be reclassified as having SPS and to undergo close surveillance.

Of note, our inclusion criteria (more than one serrated lesion ≥10 mm or more than three serrated lesions proximal to the sigmoid colon) were not based on pre-established criteria but involved a high-risk group according to clinical guidelines. In the aforementioned retrospective study [12], the factors associated with SPS reassessment were five or more proximal serrated lesions or two or more sessile serrated polyps  ≥  10  mm. When we applied these criteria to our study, only 12 of our 41 (29.3%) patients met the threshold for endoscopic reevaluation, and two of the nine patients with SPS were misclassified.

These results have implications for participants in CRC screening programs. In a study of five European cohorts, the rate of any serrated lesion was between 15.1 and 27.2% (1.1 and 2.6% with at least one serrated lesion larger than 10 mm), with SPS being diagnosed in 0.4 to 0.8% after a follow-up colonoscopy (1:127 individuals were diagnosed with SPS during colonoscopy follow-up in the Spanish FIT-based CRC screening cohort) [21]. Identification of patients with SPS has important implications related to the higher risk of CRC. Indeed, in a large multicenter study conducted in Spain, CRC was diagnosed in 15.8% of all patients with SPS with a cumulative risk of CRC of 1.9% at 5 years [22]. Therefore, identifying patients who require close surveillance is essential to decrease the incidence of CRC.

This study has some limitations. First, it is a single-center study in a small number of patients based on a sample size calculation. However, given that we found no statistically significant differences, it is likely that a larger study would probably yield similar results. In addition, the study was underpowered to show differences in the detection of large SSL > 10 mm. Secondly, back-to-back colonoscopies were performed by the same endoscopist. Although it would have been better if two different endoscopists had performed each withdrawal colonoscopy, we considered this study design to be the most effective way to reduce interobserver variation [18] and to be the most feasible in practice. The main advantages are that the presence of a single endoscopist in the room eliminates other confounders such as differences in skill or experience between distinct endoscopists. Therefore, the withdrawal time and polyp/adenoma detection rate were identical for each endoscopist. Finally, although NBI is designed for use at a close distance from the mucosa to visualize vascular and pit patterns, our study was not designed to evaluate the accuracy of the endoscopists in characterizing detected lesions.

Our study shows that in patients with previously resected relevant serrated lesions there were no differences in the use of NBI or HD-WLE in the detection of serrated lesions, with the two techniques having a similar polyp miss rate. We suggest that NBI is an option in clinical practice but not necessarily as a matter of routine. Notably, the results of our study emphasize the importance of an exhaustive examination in patients with suspicion of relevant serrated lesions. Although further studies are needed to define the exact threshold for endoscopic reassessment of patients with relevant serrated lesions, the results of our prospective study, which confirm the substantial percentage of polyp miss rate and the clinical implications of SPS, suggest that a short reassessment colonoscopy interval would be suitable in these patients.