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Risk of Developing Metachronous Advanced Colorectal Neoplasia After Polypectomy in Patients With Multiple Diminutive or Small Adenomas

Kim, Nam Hee MD1; Jung, Yoon Suk MD, PhD2; Lee, Mi Yeon MPH3; Park, Jung Ho MD, PhD2; Park, Dong Il MD, PhD2; Sohn, Chong Il MD, PhD2

American Journal of Gastroenterology: October 2019 - Volume 114 - Issue 10 - p 1657–1664
doi: 10.14309/ajg.0000000000000296
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INTRODUCTION: Current post-polypectomy guidelines recommend a 3-year surveillance interval for ≥3 nonadvanced adenomas (NAAs) without discrimination between diminutive (1–5 mm) and small (6–9 mm) adenomas. We compared the risk of metachronous advanced colorectal neoplasia (ACRN) among these groups.

METHODS: We studied 9,733 patients who underwent ≥1 adenoma removal and follow-up colonoscopic surveillance. Patients were classified based on baseline adenoma characteristics: group 1, 1–2 NAAs (n = 8,051); group 2, ≥3 diminutive NAAs (n = 293); group 3, ≥3 small NAAs (n = 258); and group 4, advanced adenomas (AAs) (n = 1,131).

RESULTS: The mean age of the study population was 45.8 ± 8.2 years. In group 4, most patients (94.5%) had 1 AA. The 3- and 5-year cumulative incidence rates of metachronous ACRN in groups 1, 2, 3, and 4 were 0.9%, 2.8%, 3.5%, and 4.0% and 3.1%, 10.7%, 15.1%, and 8.5%, respectively. Groups 2, 3, and 4 had a higher risk of metachronous ACRN than group 1. Compared with those for group 1, adjusted hazard ratios (95% confidence interval) for metachronous ACRN were 2.07 (1.16–3.68), 3.29 (1.94–5.56), and 2.73 (2.00–3.72) for groups 2, 3, and 4, respectively. However, this relationship was statistically insignificant between groups 2, 3, and 4. Compared with those for group 2, adjusted hazard ratios (95% confidence intervals) for groups 3 and 4 were 1.59 (0.76–3.30) and 1.32 (0.72–2.42), respectively, and 0.83 (0.47–1.46) for group 4 compared with group 3. The results of patients aged ≥50 years were identical to those of all patients.

DISCUSSION: Risk of metachronous ACRN was not different between patients aged ≥50 years who underwent polypectomy of ≥3 diminutive NAAs, ≥3 small NAAs, and AA, thus supporting current guidelines that recommend a uniform surveillance interval for these lesions.

1Preventive Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea;

2Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea;

3Division of Biostatistics, Department of R&D Management, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.

Correspondence: Yoon Suk Jung, MD, PhD, E-mail: ys810.jung@samsung.com.

SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/A572

Received December 31, 2018

Accepted April 01, 2019

Online date: June 18, 2019

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INTRODUCTION

Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the fourth leading cause of cancer-related deaths in the world (1). Screening colonoscopy and polypectomy are the most effective strategies to reduce the incidence and mortality of CRC because they enable early detection of CRC and removal of precancerous lesions (2,3). The surveillance after polypectomy is also important to reduce CRC mortality because patients who undergo adenoma removal are at a higher risk of metachronous adenomas or cancer than patients without adenoma (4,5).

The current guidelines on post-polypectomy surveillance stratify adenomas into 2 risk groups based on the likelihood of developing advanced colorectal neoplasia (ACRN) during surveillance and recommend repeat colonoscopy at 5–10 years for patients with 1–2 tubular adenomas (TAs) measuring <10 mm in size (low-risk adenomas [LRAs]) and at 3 years for those with ≥3 adenomas or advanced adenomas (AAs) (high-risk adenomas [HRAs]) (5–7).

There is little doubt that if patients have 3 or more adenomas, and at least one is advanced, the risk of having ACRN during surveillance is high. One previous study demonstrated that these patients had a nearly 10-fold increased relative risk compared with patients with no adenoma and a 5-fold increased relative risk compared with those with LRA (8). However, previous studies have not subclassified subcentimeter (<1 cm) adenomas into diminutive (1–5 mm) vs small (6–9 mm) adenomas during the screening colonoscopy. There remains some doubt about whether patients who have ≥3 diminutive non-AAs (NAAs) (all ≤5 mm) really have an increased risk of interval ACRN during surveillance. Current guidelines recommend the same 3-year surveillance interval for patients with ≥3 NAAs without discrimination between diminutive and small adenomas (5,6). In other words, patients with ≥3 diminutive NAAs are recommended to follow the same surveillance interval as patients with AAs (5,6). However, it is questionable whether these recommendations are appropriate. The optimal surveillance intervals for patients with multiple diminutive or small NAAs remain unknown. Nevertheless, there have been few studies on this topic.

Therefore, in this study, we aimed at comparing the risk of developing metachronous ACRN at the follow-up colonoscopy, after endoscopic resection of adenomas at the index colonoscopy, among the LRA group and HRA subgroups (≥3 diminutive NAAs, ≥3 small NAAs, and AAs).

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METHODS

Study population

The Kangbuk Samsung Health Study is a cohort study comprising South Korean men and women aged ≥18 years who underwent a comprehensive annual or biennial health examination at clinics associated with the Kangbuk Samsung Hospital Total Healthcare Center in Seoul and Suwon, South Korea (9). The study population comprised a subset of the Kangbuk Samsung Health Study subjects who underwent colonoscopy as part of a comprehensive health examination between 2010 and 2017. We retrospectively analyzed data obtained from a prospectively established cohort.

The inclusion criteria for the study were as follows: patients who underwent endoscopic removal of one or more adenomas between January 2010 and December 2014 and those who underwent a follow-up surveillance colonoscopy at an interval of ≥1 year until December 2017. All polyps were removed endoscopically at the index colonoscopy.

Exclusion criteria were as follows: patients with a history of CRC or colorectal surgery, those with a history of inflammatory bowel disease, those diagnosed with CRC at index colonoscopy, those with >10 adenomas at index colonoscopy, those who underwent follow-up surveillance colonoscopy within 1 year, those aged <30 years, and those with poor bowel preparation at index or follow-up colonoscopy. Poor bowel preparation was defined as “large amounts of solid fecal matter observed in the bowel precluding a satisfactory study, unacceptable preparation, or a condition in which <90% of the mucosa could be adequately visualized” (10).

This study was approved by the Institutional Review Board of Kangbuk Samsung Hospital. The requirement for informed consent was waived because only deidentified data were retrospectively accessed.

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Colonoscopic and histological examinations

All colonoscopic examinations were performed using the EVIS LUCERA CV-260 colonoscope (Olympus Medical Systems, Tokyo, Japan) by board-certified endoscopists. Bowel cleansing was performed using 4 L of polyethylene glycol solution. All detected polyps were removed via biopsy, polypectomy, or endoscopic mucosal resection, and the specimens were histologically assessed by experienced pathologists. The size of each polyp was estimated using open biopsy forceps by endoscopists.

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Measurements and definitions of variables

Data on health-related behaviors and medical history were obtained through a self-administered questionnaire. Smoking status was categorized as never, former, or current smokers. Family history of CRC was defined as the occurrence of CRC in ≥1 first-degree relatives at any age. Self-reported use of nonsteroidal anti-inflammatory drugs regularly over the month before enrollment in the study was recorded.

A diminutive adenoma was defined as an adenoma 1–5 mm in diameter, and a small adenoma was defined as an adenoma 6–9 mm in diameter. AA was defined as an adenoma with size ≥10 mm, villous histology, or high-grade dysplasia (11). HRAs were defined as AAs or ≥3 adenomas, and LRAs were defined as 1 to 2 TAs measuring <10 mm in size (5). ACRN included AA and cancer (11). Sessile serrated polyps or traditional serrated adenomas were included in the definition of adenoma.

The primary end point in this study was the development of metachronous ACRN at the follow-up colonoscopy. We subclassified patients with HRAs based on the adenoma size (1–5 mm vs 6–9 mm) and the presence of AA. We then compared the risk of metachronous ACRN among the LRA group and HRA subgroups (≥3 diminutive NAAs, ≥3 small NAAs, and AAs). More specifically, patients are classified into 4 groups based on the number, size, and characteristics of the adenoma at the index colonoscopy: group 1, 1 or 2 NAAs (LRA group); group 2, 3 or more diminutive NAAs; group 3, 3 or more small NAAs; and group 4, AAs. The size was determined based on the largest adenoma.

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Statistical analysis

Baseline characteristics between the 4 groups were compared using the χ2 test and one-way analysis of variance for categorical variables and continuous variables, respectively. The cumulative incidence of metachronous ACRN was calculated using the Kaplan-Meier method, and the differences between groups were determined using the log-rank test. Furthermore, we estimated the hazard ratios (HRs) with 95% confidence intervals (CIs) for metachronous ACRN according to the risk groups using multivariable Cox proportional hazards regression models, adjusted for potentially confounding variables including age, sex, family history of CRC, nonsteroidal anti-inflammatory drug use, obesity, hypertension, and diabetes mellitus. All reported P values were 2 tailed, and P < 0.05 was considered statistically significant. SPSS software version 21 (IBM, Armonk, NY) was used to perform all statistical analyses.

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RESULTS

Baseline characteristics of the study population

A total of 12,458 patients who underwent endoscopic removal of ≥1 adenoma at the time of the index colonoscopy and who underwent follow-up surveillance colonoscopy were eligible for inclusion in this study. Among these, 2,725 patients were excluded based on the following criteria: those with a history of CRC or colorectal surgery (n = 97), those with a history of inflammatory bowel disease (n = 35), those diagnosed with CRC at index colonoscopy (n = 9), those with >10 adenomas at index colonoscopy (n = 3), those who underwent follow-up colonoscopy within 1 year (n = 278), those aged <30 years (n = 131), and those with poor bowel preparation (n = 2,172), Ultimately, 9,733 patients were analyzed. The patients were divided into 4 groups (as defined above) as follows: group 1, 1–2 NAAs, n = 8,051; group 2, ≥3 diminutive NAAs, n = 293; group 3, ≥3 small NAAs, n = 258; and group 4, AA, n = 1,131 (Figure 1).

Figure 1

Figure 1

The baseline characteristics of the 4 groups are described in Table 1. The mean age of the patients included in the study was 45.8 ± 8.2 years, and the proportion of men was 82.8%. The mean age was lower in group 1 than in groups 2, 3, and 4. The proportion of men was lower in group 4 than in groups 1, 2, and 3. The proportion of current smokers was higher in group 2 than in group 1. The proportion of hypertension and diabetes was higher in groups 2 and 3 than in group 1. The mean interval between the index and follow-up colonoscopies was 3.5 ± 1.4 years (median, 3.2 years; range, 1.0–7.5 years) and lowest in group 3. The prevalence of sessile serrated polyps or traditional serrated adenoma at the index colonoscopy was very low (2.4%, n = 235/9,733); it was 2.0%, 1.0%, 2.3%, and 6.1% in groups 1, 2, 3, and 4, respectively (P < 0.001).

Table 1

Table 1

In group 2, the mean number of diminutive NAAs was 3.3 ± 0.6 (range, 3–6), and the percentages of diminutive NAAs were 78.8%, 14.7%, 4.8%, and 1.7% for 3, 4, 5, and 6 diminutive NAAs, respectively. In group 3, the mean number of small or diminutive NAAs was 3.7 ± 1.2 (range, 3–8), and the percentages of diminutive NAAs were 61.6%, 19.8%, 8.5%, 4.7%, 4.3%, and 1.2% for 3, 4, 5, 6, 7, and 8, respectively. Most patients in groups 2 and 3 had 3–5 NAAs.

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Risk of metachronous advanced neoplasia according to baseline adenoma characteristics

During a median follow-up of 3.5 ± 1.4 years, ACRN developed in 236 patients (2.4%), and CRC developed in only 3 patients (0.03%). Two patients in group 1 (at 2.1 years and at 4.3 years) and 1 in group 4 (at 4.1 years) developed metachronous CRC. The comparison of the risk of development of metachronous ACRN on follow-up colonoscopy between the 4 groups is shown in Figure 2. The 3- and 5-year cumulative incidence rates of metachronous ACRN in groups 1, 2, 3, and 4 were 0.9%, 2.8%, 3.5%, and 4.0%, and 3.1%, 10.7%, 15.1%, and 8.5%, respectively. The cumulative incidence rates of metachronous ACRN in groups 2, 3, and 4 were higher than those in group 1 (all P < 0.001). However, the rate was not significantly different between groups 2, 3, and 4.

Figure 2

Figure 2

Table 2 shows the univariable and multivariable Cox regression analyses regarding factors associated with the development of metachronous ACRN. Similar results were obtained even after adjusting for potential confounders. Compared with those for group 1, the adjusted HRs (95% CIs) for metachronous ACRN were increased across the risk groups, which were 2.07 (1.16–3.68), 3.29 (1.94–5.56), and 2.73 (2.00–3.72) for groups 2, 3, and 4, respectively. However, this relationship was statistically insignificant among groups 2, 3, and 4 (Table 3). Compared with those for group 2, adjusted HRs (95% CIs) for group 3 and group 4 were 1.59 (0.76–3.30) and 1.32 (0.72–2.42), respectively. In addition, compared with that for group 3, adjusted HR (95% CI) for group 4 was 0.83 (0.47–1.46). Results of patients aged ≥50 years were identical to those of all patients. Among patients aged ≥50 years, the risk of metachronous ACRN was higher in groups 2, 3, and 4 than in group 1, but the risk was not significantly different between groups 2, 3, and 4. However, patients aged <50 years showed different results between the groups. Among patients aged <50 years, the risk of metachronous ACRN was not different between groups 1 and 2 (adjusted HR, 1.28; 95% CI, 0.47–3.49), but the risk was higher in group 3 than in group 2 (adjusted HR, 3.66; 95% CI, 1.12–11.92) (Table 3).

Table 2

Table 2

Table 3

Table 3

When group 2 and group 3 were combined into 1 group, the risk of metachronous ACRN in group 2 + group 3 was higher than that in group 1 (adjusted HR, 2.60; 95% CI, 1.73–3.92) and was not significantly different from that in group 4 (adjusted HR, 1.05; 95% CI, 0.67–1.65) (Table 3). These results were the same in both patients aged <50 years and ≥50 years.

Among the 8,051 patients in group 1, 1,301 (16.2%) had a surveillance interval of 5 years or more. The results for the comparison of the risk of metachronous ACRN between the 4 groups did not change even when group 1 was confined to 1,301 patients with a surveillance interval of 5 years or more (Supplementary Table 1, see Supplementary Digital Content 1, http://links.lww.com/AJG/A572). Among the 1,131 patients in group 4, 1,069 (94.5%) had 1 AA, and only 62 (5.5%) had 2 or more AAs. The results for the comparison of the risk of metachronous ACRN between the 4 groups did not change even when group 4 was confined to 1,069 patients with 1 AA (Supplementary Table 2, see Supplementary Digital Content 1, http://links.lww.com/AJG/A572). In addition, the results did not change even after excluding 3 patients who developed metachronous CRC.

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DISCUSSION

In this large-scale longitudinal study, we found that the risk of metachronous ACRN in patients with ≥3 NAAs and those with AA was higher than in patients with LRAs (1 or 2 NAAs). More specifically, the results of all patients and patients aged ≥50 years are summarized as follows: (i) the risk of metachronous ACRN in patients with ≥3 diminutive NAAs and those with ≥3 small NAAs was higher than that in patients with LRAs, (ii) among patients with ≥3 NAAs, the risk of metachronous ACRN was not different between those with diminutive and small NAAs, and (iii) the risk of metachronous ACRN in patients with ≥3 diminutive or small NAAs was not different from that in patients with AA. Although the lesions were not advanced, the multiplicity of diminutive adenomas showed clinical significance for risk of developing metachronous ACRN, and thus, 3 or more diminutive NAAs should be regarded as the HRA group in patients aged ≥50 years. Based on our results, it seems appropriate to recommend the same surveillance interval to patients aged ≥50 years with ≥3 diminutive NAAs, ≥3 small NAAs, and AA. Our findings support the current post-polypectomy guidelines recommending a uniform surveillance interval for these lesions.

However, in our cohort, most of the patients with AAs had only 1 AA (n = 1,069/1,131, 94.5%). The results for the comparison of the risk of metachronous ACRN between the groups did not change even when group 4 was confined to 1,069 patients with 1 AA (Supplementary Table 2, see Supplementary Digital Content 1, http://links.lww.com/AJG/A572). More precisely, our study showed that patients with 1 AA have a comparable risk of metachronous ACRN compared with patients with ≥3 diminutive or small NAAs. However, patients with 2 or more AAs might have a higher risk of metachronous ACRN compared with patients with ≥3 diminutive or small NAAs. One recent study demonstrated that the risk of metachronous ACRN in patients with ≥3 AAs was higher than that in patients with 1–2 AAs (12). These results support our hypothesis, and based on our results and hypothesis, the same surveillance interval can be recommended for patients with 1 AA and ≥3 diminutive or small NAAs, whereas more intensive surveillances may be recommended for patients with multiple AAs.

In the ≥3 diminutive NAAs group, the percentages of diminutive NAAs were 78.8%, 14.7%, 4.8%, and 1.7% for 3, 4, 5, and 6 diminutive NAAs, respectively. In other words, the range of the number of diminutive NAAs was 3–6, and most of them were distributed between 3 and 5. Our study revealed that even patients with 3–5 diminutive NAAs have a comparable risk of metachronous ACRN compared with patients with AA.

The detection rate of diminutive polyps has increased since high-definition colonoscopy has become widely available (13). Some studies have revealed that more than 70% of all polyps detected during colonoscopy were diminutive polyps (14–16). In addition, a significant proportion of diminutive polyps (up to 50%–64%) has been reported to be adenomas (15,17,18). In this situation, it is not uncommon to encounter patients with multiple diminutive adenomas. However, data for the risk of developing metachronous ACRN and the optimal surveillance intervals of these patients are extremely limited. Although the current post-polypectomy guidelines regard ≥3 diminutive NAAs, ≥3 small NAAs, and AAs as HRAs and recommend the same surveillance interval for these lesions (5–7), there remains doubt about whether patients who have ≥3 diminutive NAAs really have an increased risk of metachronous ACRN during surveillance. Most previous studies did not subclassify patients whose largest polyp was diminutive (1–5 mm) vs small (6–9 mm) on the screening colonoscopy.

Only a few studies compared the risk of metachronous ACRN between patients with multiple diminutive vs small NAAs (19–21). Similar to our results, Sneh Arbib et al. (19) demonstrated that among patients with ≥3 polyps with low-grade dysplasia, the risk of metachronous ACRN was not different between the 1–5-mm group vs the 6–9-mm group (n = 5/79, 6.3% vs n = 5/51, 9.8%; adjusted HR, 2.4; 95% CI, 0.7–8.5; P = 0.180). However, in their study, because patients with AAs (≥10 mm, villous histology, or high-grade dysplasia) were excluded, these patients were not compared with patients with ≥3 diminutive or small NAAs. Two other recent studies showed different results than ours (20,21). Moon et al. (20) reported that compared with patients with 1 or 2 TAs (<10 mm), those with 3–10 TAs including 3 or more small adenomas (adjusted HR, 2.4; 95% CI, 1.1–5.2) and AA (adjusted HR, 2.1; 95% CI, 1.5–3.1) had a higher risk of developing metachronous ACRN, whereas patients with 3–10 diminutive TAs (adjusted HR, 1.3; 95% CI, 0.6–2.9) and 3–10 TAs including 1 or 2 small adenomas (adjusted HR, 1.6; 95% CI, 0.8–2.9) did not. They concluded that the multiplicity of diminutive TAs, without advanced lesions, showed no clinical significance for risk of developing metachronous ACRN. However, the sample size of 3–10 diminutive TAs was too small to draw a firm conclusion (n = 117). Unlike our results, Kim et al. (21) also reported that patients with ≥3 diminutive NAAs had a borderline increased risk of metachronous ACRN compared with patients with LRAs (adjusted HR, 1.7; 95% CI, 0.99–2.9; P = 0.059), and they had a significantly lower risk of metachronous ACRN compared with those with AAs (adjusted HR, 0.3; 95% CI, 0.2–0.6; P < 0.001). In their study, however, there was no significant difference in the risk of developing metachronous ACRN between patients with ≥3 diminutive NAAs and ≥3 small NAAs, consistent with our findings (adjusted HR, 1.6; 95% CI, 0.8–3.1; P = 0.309). Our study showed that the risk of metachronous ACRN was not different between patients with ≥3 diminutive or small NAAs and those with AAs, whereas the study by Kim et al. showed that patients with AAs had a higher risk of metachronous ACRN compared with patients with ≥3 diminutive or small NAAs. One of the reasons for this discrepancy may be due to differences in the number of adenomas in patients with AAs (group 4) between the 2 studies. The number of adenomas in patients with AAs in our study was less than that reported by Kim et al. (2.1 ± 1.5 vs 3.3 ± 2.7, respectively). Although not directly comparable, it is highly likely that the number of AAs was also less in our study than the study by Kim et al. Therefore, the risk of metachronous ACRN in patients with AAs in our study might be lower than that in the study by Kim et al.

Another reason for the different results between the studies may be because of the small number of patients with multiple diminutive or small adenomas. In previous studies and our study, the number of patients with ≥3 diminutive or small NAAs was relatively small (20,21). Further large-scale studies including many of these patients are needed to clarify the association between the multiplicity of diminutive NAAs and the risk of metachronous ACRN.

In our cohort, the mean age of patients was younger than 50 years (46 years), which is younger than the recommended age for screening in the current guidelines, and the proportion of patients aged <50 years was higher than those aged ≥50 years (79% vs 21%). Therefore, we performed a subgroup analysis by age group (<50 and ≥50 years). The results of patients aged ≥50 years were identical to those of all patients overall. Our results indicate that current guidelines recommending the same surveillance interval for 3 diminutive NAAs, ≥3 small NAAs, and AA are appropriate for patients aged ≥50 years. Interestingly, patients aged <50 years showed different results. Among patients aged <50 years, the risk of metachronous ACRN was not different between patients with LRAs and ≥3 diminutive NAAs, and the risk was higher in patients ≥3 small NAAs than in patients ≥3 diminutive NAAs. These findings suggest that it may be inappropriate to recommend the same surveillance strategy to patients aged ≥50 years and <50 years. However, we confirmed that the risk of metachronous ACRN in patients with ≥3 diminutive or small NAAs (group 2 + group 3) was higher than that in patients with LRAs and was not different from that in patients with AA, both in patients older than 50 years and patients younger than 50 years. These results were the same in patients aged 40–49, 50–64, and ≥65 years. Even among patients aged 30–39 years, the risk of metachronous ACRN in patients with ≥3 diminutive or small NAAs (group 2 + group 3) tended to be higher than that in patients with LRAs, although there was no statistical significance (adjusted HR, 2.90; 95% CI, 0.89–9.44) and the risk was not significantly different from that in patients with AA (Supplementary Table 3, see Supplementary Digital Content 1, http://links.lww.com/AJG/A572). The uniqueness of our cohort, including a relatively large number of patients younger than 50 years, makes it possible to track the natural progression of young patients with LRAs, multiple diminutive or small adenomas, or AA. Our study provides valuable information on the situation in which the data on early-onset colorectal neoplasia are extremely limited. In particular, our study is timely and clinically important, given the increasing incidence of early-onset CRC (22).

However, our cohort was composed of ethnic Korean individuals only. Given that the incidence and mortality of CRC differs by race and ethnicity (23), the extent to which our findings can be applied to other races and ethnicities is unclear. Therefore, readers should exercise caution before generalizing to a broader population based solely on these findings. To reach a definitive conclusion, it will be necessary to conduct similar studies on individuals of other racial/ethnic groups, such as non-Hispanic whites and non-Hispanic blacks.

The current study has several limitations. First, this was a hospital-based study and not a population-based study and included asymptomatic Koreans who had undergone a health examination at 2 centers. In addition, most subjects were either employees of various companies and local governmental organizations or their spouses, which might cause some degree of selection bias. Second, because the study was conducted in a retrospective manner, the design might result in some methodological bias. For example, the interval between baseline and follow-up colonoscopy varied. However, we used survival models, including the Kaplan-Meier method and Cox hazards regression analysis, which can consider censored data during the follow-up. Third, the mean interval of surveillance was shorter than the intervals recommended in the current guidelines among patients with LRA (3.5 years). For these patients, surveillance colonoscopy is recommended at 5–10 years by the US guidelines (5) and at 5 years in the Korean guidelines (6). Early surveillance may have reduced the incidence of metachronous ACRN and thus may have been underestimated in these patients. However, among patients with LRA, the number of those with a surveillance interval of 5 years or more was not small (n = 1,301). Furthermore, we confirmed that the results for the comparison of the risk of metachronous ACRN between the groups did not change even when group 1 was confined to 1,301 patients with ≥5-year surveillance interval (Supplementary Table 1, see Supplementary Digital Content 1, http://links.lww.com/AJG/A572). Fourth, although our study included a large number of patients overall, the number of patients in groups 2 and 3 was relatively small, 293 and 258, respectively. The HR for metachronous ACRN for group 3 vs group 2 was 1.59, which was not statistically significant. However, this insignificant result may have been due to a lack of statistical power. Assuming that the risk of group 3 was 1.59 times higher than that of group 2, the estimated sample size needed to detect a significant difference between the 2 groups with a significance level of 0.05 and a power of 80% would be 2,268 and 1996 patients in groups 2 and 3, respectively. This shows that a larger sample size is needed. However, studies investigating the effect of multiple diminutive or small NAAs on the risk of metachronous ACRN are extremely limited, and our study is the largest on this topic. In the future, it is necessary to conduct prospective studies after estimating the sample size based on the results of our retrospective analysis. Finally, the measurement of polyp size may have been slightly different between endoscopists because it was roughly measured based on open biopsy forceps. However, interobserver variability and intraobserver variability for polyp size were not assessed in our cohort. A previous study demonstrated that the application of the open biopsy forceps method when measuring colon polyp size could help reduce interobserver differences and error rates (24). A total of 40 endoscopists participated in this study, and the overall intraclass correlation coefficient value for the forceps estimation was 0.804, which indicates an excellent interobserver agreement (24). Moreover, there would not be much difference between endoscopists when classifying the polyps as 1–5, 6–9, and ≥10 mm.

In conclusion, the risk of metachronous ACRN was not different between patients aged ≥50 years who underwent polypectomy of ≥3 diminutive NAAs, ≥3 small NAAs, and AA, thus supporting the current guidelines that recommend the same surveillance interval for these lesions. Our study suggests that in patients aged ≥50 years with 3 or more NAAs, it may not be necessary to distinguish between those that are 1–5 mm and 6–9 mm.

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CONFLICTS OF INTEREST

Guarantor of the article: Yoon Suk Jung, MD, PhD.

Specific author contributions: Study concept and design: Y.S.J. Acquisition of data: N.H.K. andY.S.J. Analysis and interpretation of data: N.H.K. andY.S.J. Drafting of themanuscript: N.H.K. andY.S.J. Critical revision of themanuscriptfor important intellectual content: J.H.P., D.I.P., and C.I.S. Statistical analysis: N.H.K.and M.Y.L. Study supervision: Y.S.J. Final approval of the article:all authors.

Financial support: None to declare.

Potential competing interests: None.

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Study Highlights

WHAT IS KNOWN

  • ✓ The current post-polypectomy guidelines consider ≥3 adenomas or AAs as HRAs and recommend the same 3-year surveillance interval for these lesions.
  • ✓ It is questionable whether patients who have ≥3 diminutive NAAs (all ≤5 mm) should be regarded as a high-risk group, and the optimal surveillance intervals for these patients remain unknown.
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WHAT IS NEW HERE

  • ✓ The risk of metachronous ACRN was not different between patients aged ≥50 years who underwent polypectomy of ≥3 diminutive NAAs (all ≤5 mm), ≥3 small NAAs (largest adenoma, 6–9 mm), and AA.
  • ✓ Although the lesions were not advanced, the multiplicity of diminutive NAAs had clinical significance for the risk of developing metachronous ACRN.
  • ✓ Our findings support current guidelines recommending the same surveillance interval for patients aged ≥50 years with ≥3 diminutive NAAs, ≥3 small NAAs, and AA without discrimination between diminutive and small adenomas.
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