ARTICLE 1 Predictors of Metachronous Risk Polyps After COLON Index Colonoscopy Laura Carot, MD1,2,3, Gemma Navarro, PhD4, Dolores Naranjo-Hans, MD4, Mar Iglesias-Coma, MD, PhD4, Alba Dalmases, PhD4, Lierni Fernández, MS4, Agustín Seoane, MD1,3, Andrea Buron, MD, PhD3,5, Beatriz Bellosillo, MD, PhD2,4, Xavier Bessa, MD, PhD1,2,3, Montserrat Andreu, MD, PhD1,3 and Cristina Alvarez-Urturi, MD, PhD1,3 INTRODUCTION: Guidelines for surveillance after polypectomy are lacking in strong evidence. Our aim was to identify some precursors of colorectal cancer lesions at 3 years after polypectomy to improve stratification and surveillance programs. METHODS: We included patients with high-risk lesions (HRLs), defined as advanced adenoma (AA), large serrated polyps (SPs), and multiplicity (‡3 of any adenomas/SPs). Data on age, sex, cardiovascular risk factors, pharmacological treatment, and the histological characteristics in each individual, and mutations in genes involved in the most advanced index polyp, were collected. Parameters independently associated with a metachronous HRL diagnosis were evaluated through univariate and multivariate analyses. The results are reported as odds ratios and 95% confidence intervals along with P values. RESULTS: A total of 537 cases (median age: 60.7 years; 66% male) were included. Dyslipidemia and smoking correlated with metachronous HRLs. Multivariate logistic regression analysis showed that the presence of multiplicity with ‡3 polyps on the index colonoscopy was significantly associated with metachronous HRL, AA, proximal AA, and ‡3 polyps at 3 years. In addition, independent predictors of metachronous proximal AA were increasing age, female sex, and the loss of expression of the MLH1 protein. DISCUSSION: Multiplicity was a strong predictor of HRLs at 3 years, although the inclusion of other clinical variables (age, sex, smoking status, and dyslipidemia) improves surveillance recommendations. Without these risk factors, the surveillance could be extended to 5 years; we propose examining the somatic expression of MHL1 in all patients. SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/CTG/A498; http://links.lww.com/CTG/A499 Clinical and Translational Gastroenterology 2021;12:e00304. https://doi.org/10.14309/ctg.0000000000000304 INTRODUCTION is associated with different factors (9,10). Individuals with low- Advanced adenomas (AAs), defined as having more than 25% risk adenomas (LRAs) (1–2 in number, tubular, ,10 mm in size, villous histology and/or a size $10 mm, and/or high-grade dys- and with low-grade dysplasia) diagnosed during their first colo- plasia, are the main precursor of colorectal cancer (CRC) (1,2). noscopy have a 6.9% AA risk after 5 years from the procedure, Moreover, large serrated polyps (SPs) ($10 mm) are also con- whereas those with high-risk adenomas (HRAs) (AA and/or $3 sidered equally premalignant lesions responsible for approxi- synchronous adenomas) have a 15.5% risk after 5 years from the mately 15% of CRC cases (3,4). Endoscopic polypectomy reduces procedure (11). One analysis from a population-based colono- the incidence and mortality of CRC and remains the key to suc- scopy registry showed that patients observed with large SPs at cessful population screening programs (2,5,6). Recent evidence index colonoscopy had an increased risk of metachronous large confirms that individuals with AA and/or large SPs have a 3–4 SPs, and those with both HRAs and SPs had a considerably in- times higher risk of mortality due to CRC than individuals creased risk of metachronous HRAs (12). Colonoscopy remains without polyps (7,8). The risk of developing new lesions over time the main strategy for surveillance after index polypectomy. The 1 Gastroenterology Department, Hospital del Mar, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain; 2Medicine Department, Autonomous University of Barcelona, Barcelona, Spain; 3Colorectal Neoplasms Clinical and Translational Research Group, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain; 4Pathology Department, Hospital del Mar, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain; 5Epidemiology and Evaluation Department, Hospital del Mar, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. Correspondence: Cristina Alvarez-Urturi, MD, PhD. E-mail: 98907@parcdesalutmar.cat. Montserrat Andreu, MD, PhD. E-mail: 18219@parcdesalutmar.cat. Received May 19, 2020; accepted December 18, 2020; published online February 18, 2021 © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology American College of Gastroenterology Clinical and Translational Gastroenterology 2 Carot et al. intervals between colonoscopies are based on the size, number, Clinical and pathological data and histopathology of the removed polyps. However, the current We assessed the data on age, sex, the fecal immunochemistry method of risk stratification is not accurate enough because of the test before colonoscopy, body mass index, smoking history, lack of strong evidence (7,8,13,14). high blood pressure (25), type 2 diabetes mellitus, and dysli- COLON Some research has pointed to other factors significantly pidemia, defined as elevated plasma cholesterol, triglycerides, related to metachronous lesions, such as a family history of or both, or low HDL cholesterol. Data on the presence of CRC, sedentary lifestyle, smoking, and cardiovascular risk MetS, as defined by the World Health Organization (26), factors of metabolic syndrome (MetS) (15–17). Furthermore, administration of aspirin, nonsteroidal anti-inflammatory some somatic molecular polyp characteristics have been linked drugs, and statins and on any chronic treatment were also to metachronous lesions. It is well known that molecular al- collected. Furthermore, the number of polyps, their size, lo- terations occur during the progression of the adenoma- cation (distal or proximal to the splenic flexure), and histo- carcinoma sequence, which disturbs the cellular homeostasis. pathology at the basal and the surveillance colonoscopies were It has been postulated that these alterations can be a pre- recorded. disposition to new neoplasm development (18,19). In fact, the existence of the KRAS somatic mutation has been shown to be Molecular markers related to AA recurrences (20,21). For all of these reasons, The molecular study was performed on the most advanced applying the integrative concept of the “etiological field effect,” histological polyp in every patient. Two experienced patholo- which indicates that the interaction of multiple etiological and gists selected the relevant section of the paraffin-embedded exogenous factors contribute to the initiation and progression samples. of neoplasia, could help to improve the precision of risk strat- The genes most commonly involved in colorectal carcino- ification (22). genesis that have been linked to the risk of advanced or meta- The goal of surveillance after polypectomy was to identify chronous polyps were studied based on the pathway, metachronous high-risk lesions (HRLs), which are defined as AA, chromosomes, or microsatellite instabilities. These genes were large SPs, and/or having multiplicity ($3 adenomas and/or SPs), KRAS, NRAS, BRAF, APC, TP53, FBXW7, CTNNB1, SMAD4, Ki- for use as surrogate markers to signal the future risk of CRC 67, MLH-1, CYTOKERATIN 7, CYTOQUERATIN 20, and CDX2. (12). Thus, knowing the predictive factors of metachronous DNA was extracted from formalin-fixed, paraffin-embedded HRLs is essential and will improve stratification and surveillance blocks of the sample using the MagCore Genomic DNA FFPE programs. One-Step Kit—MagCore HF 16 Plus (24,25). Our aim was to identify the predictive factors for metachro- nous HRLs at 3 years after polypectomy. The study was con- Sequencing of the somatic mutation study. A sample library was ducted on a cohort drawn from a population-based CRC generated with a QIAseq Targeted DNA panel (Qiagen) con- screening program at the index colonoscopy. We incorporated an taining the coding region of the genes (see Supplementary evaluation of the environmental and clinical factors and the Digital Contents 1 and 2, Supplementary Tables 1, http://links. histopathological and somatic molecular changes based on the lww.com/CTG/A498, and http://links.lww.com/CTG/A499). most advanced index polyp. The resulting library was sequenced on the next-generation sequencing platform, MiSeq (Illumina, San Diego, CA), and METHODS analyzed with the QIASeq DNA pipeline. Variants obtained We conducted a single-center retrospective study on a cohort were filtered and annotated with Variant Studio v3.0 and vi- that had an average risk of CRC (asymptomatic individuals sualized with Integrative Genomics Viewer v2.4. The average between 50 and 69 years of age) from the Barcelona CRC depth of coverage was 1559 x. The frequent CRC-associated Screening Program 2009–2011. The selected individuals had variants in KRAS, BRAF, NRAS, APC, and TP53 genes with all been diagnosed with HRL through colonoscopy after a fecal variant allelic frequency ,5% were considered true variants. immunochemistry test (OC-sensor $20 mg Hb/g of feces) and Those variants with a variant allelic frequency .5% were who had undergone surveillance colonoscopy at 3 years 6 6 considered less frequent variants to minimize the probability months after polypectomy. We recorded which cases un- of false positive results. derwent more than one colonoscopy to ensure complete re- All mutations identified were verified against a catalogue of section of polyps. somatic mutations in the cancer database and VarSome (27). The Informed consent was obtained from all patients. The bi- mutation nomenclature used follows the Human Genome Vari- ological samples were obtained from Barcelona Parc de Salut ation Society’s recommendations. MAR Biobank (MARBiobanc), and the study was approved by the Hospital del Mar Clinical Research Ethics Committee (Ref. Immunohistochemistry technique 2016S004). All colonoscopies fulfilled the standard quality policy Tissue microarray construction. Representative hematoxylin- (23), and all endoscopists adhered to the recommended adenoma eosin stained sections from polyps were prepared by 2 expe- detection rate standards. rienced gastrointestinal pathologists. The most histopatho- Individuals with a personal and/or familial history of CRC logically advanced polyp area was selected for the construction or adenoma, inflammatory bowel disease, incomplete histo- of the tissue microarray (TMA) blocks using a tissue arrayer. pathological analysis of recovered polyps, and individuals who Each case was represented in the final TMA paraffin block by 2 did not provide informed consent were excluded. Individuals tissue cores, each being 1.5 mm in diameter. who were observed to have SPs exclusively at the index colo- Immunohistochemistry tests were performed on the noscopy were excluded because the number of SPs in such formalin-fixed paraffin-embedded TMA blocks. Sections were individuals was low. cut at 4 mm and then dewaxed and rehydrated. We used an Clinical and Translational Gastroenterology VOLUME 12 | FEBRUARY 2021 www.clintranslgastro.com Predictors of Metachronous Risk Polyps 3 COLON Figure 1. Study flow chart. Patients included in the analysis. FIT, fecal immunochemical test; HRL, high-risk lesions; SP, serrated polyps; TMA, tissue microarray. automatized panel of Roche Ventana antibodies (Benchmarkt) lesions were tested with the x2 test. Multivariate logistic re- (see Supplementary Digital Contents 1 and 2, Supplementary gression analysis was conducted to identify independent pa- Tables 1, http://links.lww.com/CTG/A498, and 2 http://links. rameters associated with metachronous HRLs. The results are lww.com/CTG/A499). Each marker was semiquantitatively expressed as odds ratios (ORs) with 95% confidence intervals assessed and scored by estimating the percentage of tumor cells (CIs). SPSS version 25 (IBM, Armonk, NY) was used for the showing characteristic staining. analyses. Membrane staining for CK7 and CK20 and nuclear staining for CDX-2 were considered positive when more than 5% of the RESULTS tumor cells showed a positive reaction for each marker; Ki-67 We identified 638 individuals with HRLs at the baseline colo- was considered positive when more than 5% of the nonbasal noscopy. We excluded 95 cases (14.8%) lacking surveillance located cells showed nuclear staining irrespective of intensity colonoscopy and 6 cases with exclusively index SPs. A total of 537 (28,29). Loss of MLH1 expression was considered when one or cases (85.2%) that met the inclusion and exclusion criteria (me- more clusters of tumor cells (minimal, focal, or multifocal) or dian age 60.7 6 5.2 years; 66% men) were analyzed. The median all dysplastic cells showed $50% non-nuclear staining, com- surveillance colonoscopy time was 38.8 months, and the study pared with positive nuclear staining in normal epithelial flow chart is presented in Figure 1. cells (30). Characteristics of the cohort included in the study are pre- sented in Table 1. Half of the study population had had some Statistical analysis exposure to tobacco, and 47% had been diagnosed with dyslipi- Differences between demographic, clinical, and molecular data demia. Of note, nearly 80% of the included individuals were among patients with and without metachronous advanced overweight or obese (Figure 2). American College of Gastroenterology Clinical and Translational Gastroenterology 4 Carot et al. Table 1. Baseline characteristics Colonoscopy Index Surveillance at 3 yr COLON Baseline characteristics Patients HRL No HRL Total no. of cases N 5 537 (%) N 5 103 (%) N 5 434 (%) Age 50–59 yr 229 (42.6) 39 (17.1) 190 (82.9) 60–69 yr 308 (57.4) 64 (20.8) 244 (79.2) Sex Men 355 (66) 70 (19.7) 285 (80.3) Woman 182 (44) 33 (18.2) 149 (81.8) Cigarette smoking status Never 268 (49.9) 40 (15.6) 228 (84.4) Smoker/former 269 (50.1) 61 (22.7) 208 (77.3) High blood pressure Yes 273 (50.8) 59 (21.6) 214 (78.4) Type 2 diabetes Yes 79 (15.9) 18 (22.8) 61 (77.2) Dyslipidemia Yes 247 (46.7) 60 (24.4) 186 (75.6) Body mass index (kg/m2) ,25 94 (19.6) 18 (19.8) 76 (80.9) 25–29 217 (45.2) 40 (18.4) 177 (81.6) $30 169 (35.2) 33 (19.5) 136 (80.5) Metabolic syndrome Yes 53 (11) 14 (26.4) 39 (73.5) Alcohol intake Yes 76 (17.2) 18 (23.7) 58 (76.3) NSAID treatment Yes 65 (13.2) 13 (20) 52 (80) Aspirin treatment Yes 75 (15.4) 14 (18.7) 61 (81.3) Statins treatment Yes 201 (38.7) 42 (21) 158 (79) More than one baseline colonoscopy Yes 137 (25.5) 38 (27.7) 99 (72.3) Advanced adenoma Yes 463 (86.2) 89 (19.3) 373 (80.7) Multiplicity ($3 polyps) 282 (52.5) 71 (25.2) 211 (74.8) Only adenomas 228 (42.5) 61 (26.8) 167 (73.2) Adenomas and or serrated polyps 60 (11.2) 10 (1.6) 44 (1.6) Adenoma size $10 mm 434 (80.8) 84 (19.4) 349 (80.6) Villous component $25% 310 (57.7) 52 (16.8) 257 (83.2) High grade dysplasia 111 (20.7) 22 (19.8) 89 (80.2) Location of advanced adenomas Distal to the splenic flexure 327 (70.7) 55 (16.8) 271 (83.2) Proximal splenic flexure 136 (29.3) 34 (25) 102 (75) HRL, high-risk lesion; NSAID, nonsteroidal anti-inflammatory drug. Clinical and Translational Gastroenterology VOLUME 12 | FEBRUARY 2021 www.clintranslgastro.com Predictors of Metachronous Risk Polyps 5 To achieve complete polyp resection, 137 cases (25.2%) re- 95% CI: 1.18–36.46), although the number of metachronous quired more than one colonoscopy, most of them because of large SPs was small. We evaluated the mutations individually control of the piecemeal removed lesions (70%) or for complete and in groups from the same polyp for the power to predict resection of the remaining polyps (30%). metachronous lesions at 3 years, which turned out to be poor in COLON The somatic molecular findings for the most histologically both cases. Loss of nuclear expression of the MLH1 gene at the advanced polyps in every individual are provided in Table 2. As time of baseline colonoscopy resulted in an 8-fold increased risk expected, most of the AAs had mutations in the APC gene. KRAS of proximal AAs (OR 5 8.68, 95% CI: 2.44–30.89) and up to a mutations were more frequent in AAs (P , 0.05). In addition, 5-fold increased risk of multiplicity (OR 5 5.02, 95% CI: although they were not too frequent, BRAF mutations and loss of 1.54–16) and HRLs (OR 5 4.59, 95% CI: 1.44–14.62) at the MLH1 expression were found in proximal AAs. The mutation follow-up colonoscopy. data for the genes analyzed are presented in Supplementary Ta- bles 1 and 2 (see Supplementary Digital Contents 1 and 2, http:// Multivariate analysis links.lww.com/CTG/A498, and http://links.lww.com/CTG/ Multivariate logistic regression analysis (Table 5) confirmed A499). that older individuals and women had a higher risk of being At surveillance colonoscopies, 103 cases (19%) were classi- diagnosed with metachronous proximal AAs (OR 5 3.59, 95% fied as HRLs. There were 54 patients with AAs (10.1%), with 29 CI: 1.29–9.93; OR 5 3.12, 95% CI: 1.31–7.69, respectively). of the AAs (5.4%) located in the proximal colon. In 73 cases Dyslipidemia and smoking history were associated with a (13.6%), we found multiplicity (63 cases with $3 adenomas and higher risk of developing HRLs (OR 5 1.68, 95% CI: 1.00–2.79; 10 cases with $3 adenomas plus large SPs). Nine patients (1.7%) OR 5 1.69, 95% CI: 1.00–2.86, respectively). Individuals with had large SPs in the proximal colon. The remaining 435 indi- index multiplicity were 3 times more likely to be diagnosed at viduals (81.0%) had normal colonoscopy findings at 3 years the 3-year surveillance of HRL (OR 5 2.35, 95% CI: 1.35–4.10), (48.9%) or had low-risk lesions (32.0%). No CRCs were AA (OR 5 3.01, 95% CI: 1.44–6.27), proximal AA (OR 5 4.42, diagnosed. 95% CI: 1.66–11.75), and multiplicity (OR 5 2.93, 95% CI: 1.48–5.81) than those with no multiplicity. From the molecular Risk of advanced lesions at the surveillance colonoscopy somatic analysis, the multivariable analysis showed that the The univariate analysis results are reported in Tables 3 and 4. expression of the MLH1 protein was significantly associated When we evaluated the clinical factors, the patients who were with proximal AAs at surveillance (OR 5 15.21, 95% CI: current or former smokers had a slightly but statistically sig- 3.07–76.58) and the mutation in NRAS was significantly as- nificantly increased metachronous HRL risk (OR 5 1.58, 95% sociated with any size of SP at surveillance 4.42 (95% CI: CI: 1.01–2.46) as did those with dyslipidemia (OR 5 1.74, 95% 1.31–14.91). CI: 1.12–2.70). A history of dyslipidemia or high blood pressure correlated with multiplicity at the surveillance colonoscopy (OR DISCUSSION 5 2.20, 95% CI: 1.32–3.67; OR 5 1.74, 95% CI: 1.05–2.91, re- This study confirms that multiplicity is a strong predictor of spectively). In addition, those presenting with multiplicity at the metachronous HRLs and also highlights the importance of index colonoscopy were more than twice as likely to develop factors such as a history of smoking, dyslipidemia, older age, metachronous AAs (OR 5 2.54, 95% CI: 1.36–4.74), proximal female sex, and loss of MLH1 protein expression. These results AAs (OR 5 2.46, 95% CI: 1.07–5.66), repeated multiplicity (OR reveal the need to optimize current surveillance guideline 5 2.49, 95% CI: 1.45–4.28), and HRLs (OR 5 2.36, 95% CI: strategies. 1.48–3.75). The need for additional colonoscopies after the in- At the 3-year follow-up, 19% of patients with HRL at the dex colonoscopy correlated with increased occurrence of index colonoscopy had metachronous HRLs. These results were metachronous AAs, multiplicity, and HRLs (OR 5 1.99, 95% CI: comparable with those of other studies (31). However, the 1.10–3.57; OR 5 1.86, 95% CI: 1.10–3.14; OR 5 1.91, 95% CI: variability in HRL recurrence in published studies is high be- 1.20–3.04, respectively). Of all the studied baseline character- cause it depends not only on individual risk factors but also on istics, large metachronous SPs were only significantly associated the colonoscopy quality and the subsequent polyps’ miss rate with the need for more than one index colonoscopy (OR 5 6.56, (MR) (9,32,33). In our cohort, we estimated a 13% MR for AAs, a Figure 2. Predictive factors of metachronous overall lesions. Multivariate analysis. AA, advanced adenoma; HBP, high blood pressure; OR, odds ratio. American College of Gastroenterology Clinical and Translational Gastroenterology 6 Carot et al. proportion higher the 9% MR published in the meta-analysis by Table 2. Molecular baseline characteristics Zhao et al. (34). Our MR was likely overestimated because we obtained it from surveillance colonoscopies performed to en- Mutation Patients % sure complete resection (46). COLON KRAS (n 5 441) Older age and female sex were robust predictors of meta- Wild type#5% 278 63 chronous proximal AAs (OR 5 3.59, 95% CI: 1.29–9.93; OR 5 3.12, 95% CI: 1.31–7.69, respectively). Older age has been iden- Mutation .5% 163 37 tified as an independent HRL risk factor (9,35), especially for BRAF (n 5 444) HRLs in the proximal colon (36). This might be because of de- Wild type#5% 425 95.7 creased immunity and genetic variations that occur with ad- Mutation .5% 19 4.3 vancing age (35). The Clinical Outcomes Research Initiative endoscopy database provides the opportunity to study the dif- NRAS (n 5 444) ferences in polyps and tumors with differences in age and sex. Wild type#5% 429 96.6 Using this, we found that women have a greater tendency of Mutation .5% 15 3.4 developing right-sided polyps. Indeed, hormonal factors may APC (n 5 434) explain a large percentage of the metachronous right-sided AAs observed in women (37) because estrogen exposure is a protective Wild type#5% 50 11.5 factor against the Microsatellite Instable high phenotype, which Mutation .5% 384 88.5 often accompanies right-sided tumors (38). Therefore, it is nec- TP53 (n 5 436) essary to emphasize that special attention must be given in the detection of proximal lesions in women older than the age of 60 Wild type#5% 345 79.1 years. Mutation .5% 91 20.9 There is limited information about the role of each of the CTNNB1 (B-catenin) (n 5 408) components of MetS in metachronous HRL development (16). Wild type#5% 391 95.8 Nevertheless, we found a higher proportion of new HRLs at surveillance colonoscopy in patients with dyslipidemia; up until Mutation .5% 17 4.2 now, the molecular mechanism behind this is not well understood SMAD4 (n 5 411) (38,39). Wild type#5% 400 97.3 Likewise, carcinogenic compounds in tobacco, mainly aro- Mutation .5% 11 2.7 matic amines, can cause mutations in genes implicated in CRC, such as KRAS and BRAF (40). In a retrospective study, higher FBXW7 (n 5 407) nicotine levels between the index and follow-up colonoscopies Wild type#5% 364 89.4 were correlated with metachronous colorectal neoplasia risk Mutation .5% 43 10.6 (41). These findings have important public health implications because they show that improving the plasma levels of MLH1 (n 5 455) cholesterol/triglycerides and giving up cigarette smoking would Normal expression 443 97.4 be effective measures for preventing colorectal metachronous Loss nuclear expression $50% 12 2.6 polyps. CDX2 (n 5 455) In our series, exposure to tobacco and the presence of dysli- pidemia had a higher risk of global metachronous HRL, whereas Normal expression 259 56.9 older age, female sex, and loss of MLH1 expression were signifi- Loss of any nuclear expression 196 36.5 cantly associated with HRLs on the right side (36,42). Thus, our Cytokeratin 7 (n 5 446) results could suggest that genetic factors have a greater effect on Normal expression 396 88.8 the proximal colon, whereas environmental factors have a more global effect (36,42). Cytoplasmatic expression 50 11.2 Some characteristics found in index polyps are indicative of Cytokeratin 20 (n 5 440) an increased risk of metachronous lesions. However, these Normal expression 377 85.7 findings are sufficiently helpful for planning early surveillance strategies, most likely because their effect could depend on la- Loss of cytoplasmatic 63 14.3 tency time. We did not find any histological characteristics that expression increased metachronous HRL risk. Nonetheless, we report that Ki-67 (n 5 332) multiplicity on index colonoscopy was a powerful predictor of Normal expression 2 0.6 HRL recurrence, possibly owing to genetic imbalance of cell Nuclear expression 330 99.4 proliferation in some individuals, which could lead to acceler- ated carcinogenesis on normal mucosa. Therefore, it is impor- APC 1 KRAS 142 32.7 tant to ensure that proper surveillance is performed on these APC 1 KRAS 1 TP53 37 8.5 individuals(43,44,46). APC 1 KRAS 1 NRAS 5 1.1 In addition, we found that NRAS mutations predicted the risk of SPs of any size 3 years after the polypectomy, and the loss of Clinical and Translational Gastroenterology VOLUME 12 | FEBRUARY 2021 www.clintranslgastro.com Predictors of Metachronous Risk Polyps 7 Table 3. Predictive factors of metachronous overall lesions (univariate analysis) Baseline characteristics Polyps Adenoma Serrated lesion COLON Variable n OR (95% CI) n OR (95% CI) n OR (95% CI) Age .60 yr 164 1.25 (0.89–1.77) 151 1.21 (0.86–1.72) 18 0.49 (0.26–0.91) Gender (female) 90 0.90 (0.63–1.29) 80 0.82 (0.57–1.17) 17 1.24 (0.65–2.35) Smoker/former 145 1.23 (0.88–1.74) 133 1.19 (0.84–1.68) 28 1.85 (0.96–3.55) High blood pressure 151 1.39 (0.99–1.95) 142 1.47 (1.04–2.07) 19 0.70 (0.37–1.31) Type 2 diabetes 45 1.28 (0.79–2.07) 43 1.36 (0.84–2.20) 7 1.11 (0.47–2.58) Dyslipidemia 142 1.61 (1.14–2.27) 136 1.80 (1.27–2.55) 22 1.18 (0.63–2.19) Body mass index $30 88 1.03 (0.80–1.32) 79 1.00 (0.78–1.29) 15 1.10 (0.69–1.73) Metabolic syndrome 35 1.92 (1.05–3.5) 34 2.14 (1.18–3.87) 3 0.64 (0.19–2.16) .1 colonoscopy 85 1.80 (1.21–2.68) 80 1.82 (1.23–2.70) 18 2.13 (1.13–4.02) $3 polyps 173 2.41 (1.70–3.42) 164 2.60 (1.83–3.69) 28 1.62 (0.85–3.07) AA 228 0.61 (0.37–1.01) 210 0.62 (0.38–1.02) 37 0.83 (0.35–1.93) Proximal AA 82 1.70 (1.14–2.54) 76 1.65 (1.11–2.45) 16 1.78 (0.93–3.42 Adenoma size $10 mm 208 0.51 (0.33–0.80) 192 0.55 (0.35–0.85) 33 0.68 (0.33–1.39) $20 mm 67 1.10 (0.73–1.64) 60 1.01 (0.67–1.51) 16 1.96 (1.02–3.75) Villous component$25% 172 0.82 (0.58–1.17) 138 0.78 (0.55–1.10) 25 0.95 (0.51–1.76) High grade dysplasia 56 0.95 (0.63–1.45) 52 0.97 (0.64–1.48) 10 1.12 (0.54–2.35) KRAS mutation 86 1.04 (0.70–1.54) 80 1.07 (0.73–1.58) 11 0.73 (0.35–1.53) NRAS mutation 8 1.05 (0.37–2.96) 7 0.95 (0.34–2.65) 4 3.96 (1.20–13.07) BRAF mutation 10 1.03 (0.41–2.59) 9 0.98 (0.39–2.47) 3 2.21 (0.61–7.99) APC mutation 198 1.07 (0.59–1.94) 182 0.98 (0.54–1.77) 31 1.01 (0.34–3.01) TP53 mutation 45 0.87 (0.55–1.39) 42 0.91 (0.57–1.45) 7 0.94 (0.39–2.21) CTNNB1 mutation 11 1.71 (0.62–4.72) 10 1.57 (0.58–4.22) 3 2.47 (0.67–9.08) SMAD4 mutation 5 0.74 (0.22–2.48) 4 0.61 (0.17–2.10) 2 2.38 (0.49–11.46) MLH1 8 1.92 (0.57–6.46) 8 2.26 (0.67–7.61) 2 2.39 (0.50–11.37) CDX2 127 0.82 (0.57–1.20) 118 0.87 (0.59–1.25) 15 0.52 (0.26–1.03) Cytokeratin 7 25 0.95 (0.52–1.71) 23 0.93 (0.51–1.68) 4 1.13 (0.38–3.37)) Cytokeratin 20 195 1.19 (069–203) 180 1.15 (0.67–1.97) 31 1.80 (0.53–6.08) Ki67 161 — 151 — 21 0.07 (0.004–1.13) APC and KRAS 74 1.01 (0.67–1.51) 68 1.00 (0.67–1.50) 9 0.67 (0.31–1.47) APC, KRAS, and p53 19 0.97 (0.49–1.91) 19 1.16 (0.59–2.28) 2 0.62 (0.14–2.68) APC, KRAS, and NRAS 2 0.60 (0.10–3.67) 2 0.71 (0.11–4.33) 1 2.89 (0.31–26.59) Significant values are represented in bold. AA, advanced adenoma; CI, confidence interval; OR, odds ratio. MLH1 protein expression was associated with proximal AA. period to identify molecular changes to predict recurrence (19). Limited data exist about the molecular profile of index polyps as a Juarez et al. found that polyps with KRAS mutations had a 2-fold predictive factor of metachronous lesions. Because several such higher risk of metachronous advanced lesions. Although we polyps represent early mutational changes, they could prove could not replicate this finding in our series, we found that KRAS useful in histological classification efforts, apart from their con- mutations were useful for diagnosing HRL. This discrepancy ventional use as carcinogenesis predictors. As expected, BRAF could be because the cohort was different and that they analyzed mutations were uncommon, although no patients with SPs were all polyps, whereas we analyzed the most advanced polyp of each analyzed. Nevertheless, we found that 4% of patients exhibited individual. BRAF mutation and loss of MLH1 protein expression. These This study has several strengths. The cohort was homogenous, polyps could reflect mixed polyps or serrated polyps mistakenly drawn from a CRC population screening program, and although classified as adenomas. Three years may have been a too short of a this was a retrospective study, baseline colonoscopies were American College of Gastroenterology Clinical and Translational Gastroenterology 8 Carot et al. Table 4. Predictive factors of metachronous risk lesions characterized by AA, multiplicity (‡3 polyps), high-risk lesion (AA and/or multiplicity), and advanced serrated polyps (univariate analysis) COLON Baseline characteristics Surveillance colonoscopy AA Proximal AA Multiplicity HRL Large SPs (‡10 mm) Variable n OR (95% CI) n OR (95%CI) n OR (95%CI) n OR (95% CI) n OR (95% CI) Age .60 yr 34 1.29 (0.72–2.31) 23 3.01 (1.18–7.40) 45 1.22 (0.73–2.03) 64 1.36 (0.87–2.12) 3 0.85(0.17–4.28) Gender (female) 22 1.40 (0.78–2.5) 15 2.22 (1.04–4.76) 22 0.82 (0.48–1.40) 33 0.90 (0.48–1.44) 9 2.12 (0.57–1.44) Smoker/former 31 1.45 (0.81–2.61) 12 0.70 (0.32–1.52) 42 1.44 (0.87–2.40) 61 1.58 (1.01–2.46) 10 1.44 (0.53–3.87) High blood pressure 23 0.68 (0.38–1.20) 13 0.76 (0.36–1.63) 46 1.74 (1.05–2.91) 58 1.36 (0.87–2.10) 4 2.00 (0.36–11.05) Type 2 diabetes 7 0.83 (0.36–1.92) 1 0.19 (0.02–1.46) 13 1.28 (0.66–2.47) 18 1.31 (0.73–2.33) 1 1.23 (0.14–10.81) Dyslipidemia 27 1.18 (0.67–2.07) 14 1.1 (0.52–2.32) 46 2.20 (1.32–3.67) 60 1.74 (1.12–2.70) 1 0.24 (0.02–2.10) Body mass index $30 17 1.03 (0.68–1.58) 8 0.94 (0.53–1.66) 24 1.05 (0.73–1.51) 33 1.00 (0.72–1.37) 1 0.72 (0.21–2.44) Metabolic syndrome 40 1.23 (0.49–3.07) 1 0.34 (0.46–2.60) 11 1.77 (0.86–3.65) 14 1.69 (0.87–3.26) 0 — .1 colonoscopy 21 1.99 (1.10–3.57) 12 2.12 (0.99–4.58) 27 1.86 (1.10–3.14) 38 1.91 (1.20–3.04) 4 6.56 (1.18–36.46) $3 polyps 39 2.54 (1.36–4.74) 21 2.46 (1.07–5.66) 52 2.49 (1.45–4.28) 71 2.36 (1.48–3.75) 5 5.32 (0.61–46.03) AA 45 0.76 (0.35–1.64) 24 0.74 (0.27–2.02) 63 0.99 (0.48–2.04) 89 1.08 (0.57–2.06) 5 0.76 (0.08–6.65) Proximal AA 16 1.26 (0.68–2.35) 9 1.33 (0.59–3.00) 24 1.53 (0.89–2.60) 34 1.56 (0.97–2.49) 2 1.75 (0.31–9.72) Adenoma size $10 mm 42 1.00 (0.53–1.88) 21 0.72 (0.25–1.40) 57 1.44 (0.79–2.59) 84 1.25 (0.99–1.57) 4 0.36 (0.07–1.83) $20 mm 15 1.28 (0.68–2.41) 21 1.02 (0.42–2.46) 19 1.16 (0.66–2.05) 27 1.23 (0.75–2.02) 4 1.60 (0.28–8.88) Villous component$25% 29 0.83 (0.47–1.46) 14 0.66 (0.31–1.39) 34 0.59 (0.36–0.97) 52 0.69 (0.45–1.07) 4 1.31 (0.23–7.27) High grade dysplasia 13 1.23 (0.63–2.40) 6 0.99 (0.39–2.49) 13 0.80 (0.42–1.52) 22 1.08 (0.63–1.82) 2 1.86 (0.33–10.35) KRAS mutation 15 0.81 (0.42–1.55) 8 0.66 (0.28–1.55) 21 0.88 (0.50–1.56) 34 1.21 (0.74–1.97) 3 2.58 (0.42–15.68) NRAS mutation 2 1.34 (0.29–6.14) 2 2.37 (0.50–11.07) 2 0.96 (0.21–4.37) 3 1.07 (0.25–3.38) 0 — BRAF mutation 3 1.70 (0.47–6.09) 3 3.11 (0.84–11.43) 4 1.75 (0.56–5.46) 5 1.58 (0.55–4.52) 3 — APC mutation 39 1.02 (0.38–2.72) 22 0.70 (0.23–2.13) 51 0.80 (0.35–1.81) 74 1.05 (0.49–2.26) 35 0.44 (0.04–4.10) TP53 mutation 8 0.77 (0.34–1.72) 5 0.80 (0.29–2.19) 12 0.83 (0.18–3.73) 14 0.73 (0.39–1.38) 8 — CTNNB1 mutation 1 0.51 (0.06–4.00) 0 — 2 0.93 (0.47–1.84) 2 0.56 (0.12–2.54) 3 6.72 (0.68–67.77) SMAD4 mutation 2 1.94 (0.40–9.28) 1 1.49 (0.18–12.12) 2 1.39 (0.29–6.60) 2 0.96 (0.20–4.53) 1 — MLH1 3 3.09 (0.80–11.8) 4 8.68 (2.44–30.89) 5 5.02 (1.54–16) 6 4.59 (1.44–14.62) 3 — CDX2 25 0.89 (0.48–1.65) 14 0.74 (0.34–1.59) 35 1.07 (0.61–1.86) 48 0.92 (0.57–1.48) 18 0.44 (0.07–2.66) Cytokeratin 7 6 1.28 (0.51–3.20) 4 1.39 (0.46–4.22) 4 0.51 (0.17–1.48) 8 0.77 (0.34–1.71) 4 — Cytokeratin 20 39 1.09 (0.44–2.71) 2 2.17 (0.50–9.43) 53 1.31 (0.56–3.03) 73 1.00 (0.51–1.98) 4 — Ki67 0 — 0 — 1 0.12 (0.01–1.94) 56 0.19 (0.01–3.18) 1 — APC and KRAS 14 0.93 (0.48–1.82) 7 0.71 (0.29–1.72) 19 0.96 (0.53–1.72) 30 1.25 (0.76–2.07) 12 3.04 (0.50–18.52) APC, KRAS, and p53 4 1.04 (0.35–3.08) 2 0.82 (0.18–3.62) 5 0.98 (0.36–2.64) 7 1.00 (0.42–2.37) 3 — APC, KRAS, and NRAS 1 2.20 (0.24–20.1) 1 3.82 (0.41–35.4) 2 4.31 (0.70–26.38) 2 2.91 (0.48–17.74) 2 — Significant values are represented in bold. AA, advanced adenoma; CI, confidence interval; OR, odds ratio; HRL, high-risk lesion; SP, serrated polyps. performed following an identical protocol of quality standards. This study also has certain limitations. Some clinical factors asso- Moreover, the integrity of both resections and polyp pathology ciated with the risk of metachronous lesions, such as diet and physical analyses was ensured via second-look colonoscopies when it was activity, were not studied, and they may be relevant. Furthermore, the deemed necessary, and the surveillance colonoscopy was performed CpG island methylator phenotype and microsatellite instability were at 3 years using the same quality standards. Finally, clinical in- not determined. Although these results would have been interesting, formation was obtained from computerized medical records. Thus, we instead analyzed BRAF mutations and MLH1 expression that also ours is a study with reliable results involving exhaustive analyses of reflect the serrated pathway, although the correlation is not always clinical, endoscopic, and molecular factors associated with advanced 100%. Likewise, a greater number of cases included in the study could metachronous lesions at 3 years after polypectomy. have helped to obtain more relevant results. Clinical and Translational Gastroenterology VOLUME 12 | FEBRUARY 2021 www.clintranslgastro.com Predictors of Metachronous Risk Polyps 9 Table 5. Predictive factors of metachronous risk lesions (multivariate analysis) Surveillance colonoscopy COLON AAs Proximal AA ‡3 polyps High risk lesions (AA and/or multiplicity) Large serrated lesions Basal characteristics OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) Age 60–69 1.55 (0.76–3.14) 3.59 (1.29–9.93) 1.34 (0.71–2.54) 1.51 (0.87–2.60) 0.91 (0.27–3.21) Gender (female) 2 (1–4) 3.12 (1.31–7.69) 1.21 (0.60–2.45) 1.40 (0.77–2.53) 2.84 (0.73–11.05) Smoker/former 1.74 (0.85–3.58) 0.95 (0.38–2.33) 1.64 (0.85–3.20 1.69 (1.00–2.86) 4.82 (1.05–22.02) Dyslipidemia 1.03 (0.53–2.02) 0.86 (0.37–2.01) 2.47 (1.33–4.57) 1.68 (1.00–2.79) 0.71 (0.20–2.45) $3 polyps 3.01 (1.44–6.27) 4.42 (1.66–11.75) 2.93 (1.48–5.81) 2.35 (1.35–4.10) 3.70 (0.81–16.83) .1 colonoscopy 1.21 (0.56–2.57) 1.82 (0.72–4.64) 1.74 (0.90–3.38) 1.64 (0.92–2.93) 3.64 (1.16–11.34) Adenoma size $20 mm 0.92 (0.41–2.09) 0.69 (0.23–2.02) 0.94 (0.46–1.94) 1.04 (0.56–1.93) 2.33 (0.68–8.8.03) NRAS 1.23 (0.25–6.07) 1.87 (0.35.9.93) 1.05 (0.18–5.96) 1.08 (0.26–4.49) 4.45 (0.43–46.51) MLH1 3.06 (0.57–16.21) 15.21 (3.07–76.58) 4.09 (0.88–18.95) 4.03 (0.99–16.43) AA, advanced adenoma; CI, confidence interval; OR, odds ratio. In conclusion, these results suggest that the ability to identify Study Highlights groups at risk of metachronous lesions remains challenging, as does the formulation of best follow-up recommendations. WHAT IS KNOWN Older age, female sex, smoking status, dyslipidemia, and baseline multiplicity significantly increased the risk of new ad- 3 The risk of developing new advanced lesions is associated vanced lesions at 3 years after polypectomy. The clinical with different factors. guidelines for patient surveillance after index polypectomy 3 Clinical follow-up recommendations are lacking in strong should consider incorporating these clinical factors to person- evidence, and surveillance strategies are based only on the alize surveillance recommendations. Because no cancer was size, number, and pathologic characteristics of the removed diagnosed at surveillance, we suggest that follow-up should be index polyps. performed at 5 years after the procedure if the individuals do not 3 Knowing clinical and molecular predictive factors of present with risk predictive factors. Regarding MLH1 expres- metachronous risk lesions would provide better risk stratification and improve surveillance programs. sion, we suggest examining it in all patients when conducting proximal HRL surveillance because it would be a cost-effective WHAT IS NEW HERE strategy because of the low price of the MLH1 immunohisto- chemistry technique. 3 Results regarding clinical, endoscopic, and molecular factors Future studies involving larger cohorts could further confirm associated with risk metachronous lesions at 3 years. these findings. 3 This study confirms that multiplicity is a strong predictor of metachronous HRLs, besides the relevance such factors as a history of smoking, dyslipidemia, older ager, female sex, and CONFLICTS OF INTEREST loss of MLH1 protein expression. Guarantor of the article: Alvarez-Urturi Cristina, MD, PhD. 3 These results expose the need to optimize current Specific author contributions: M.A.: conceived and designed this surveillance guidelines strategies. study. M.A., C.A.-U., L.C., and A.B.: gathered the data. A.S.-U.: TRANSLATIONAL IMPACT contributed to the performance and evaluation of colonoscopies. G.N., D.N.-H., M.I.-C., A.D., L.F., and B.B.: processed the samples 3 We suggest following up at 5 years if individuals do not present and carried out and analyzed the histopathological and molecular with clinical risk predictive factors. studies. M.A., C.A.-U., L.C., and X.B.: analyzed and interpreted the 3 We propose examining patients with HRLs considering that it data. M.A., C.A.-U., and L.C.: drafted the article. All authors would be a cost-effective strategy because of low price of the critically reviewed the draft and approved the final version of the MLH1 immunohistochemistry technique. article. Financial support: This work was supported by grants from the Instituto de Salud Carlos III-FEDER (PI14/00441) and (PT17/0015/ 0011); the Singular Project AECC (PS14152544ANDR); and the ACKNOWLEDGMENTS Xarxa de Bancs de Tumors sponsored by Pla Director d’Oncologia de We thank Xavier Duran for statistical analysis support. In addi- Catalunya (XBTC). AGAUR Research scholarship 2017SGR80. tion, we are deeply grateful to the patients who participated in this Potential competing interests: None to report. investigation. We would like to thank Editage (www.editage.com) Ethics approval: The study was approved by The Hospital del Mar for English language editing. This study will be part of Laura Clinical Research Ethics Committee (Ref. 2016S004). Carot Bastard’s doctoral thesis. American College of Gastroenterology Clinical and Translational Gastroenterology 10 Carot et al. REFERENCES 24. Carvajal-Carmona LG, Cazier JB, Jones AM, et al. Fine-mapping of 1. Atkin WS, Morson BC, Cuzick J. 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