Subsequent Advanced Neoplasia Research Articles

Risk stratification for advanced colorectal neoplasia based on the findings of the index and first surveillance colonoscopies.

Risk stratification by index colonoscopy is well established for first surveillance endoscopy, but whether the previous two colonoscopies affect the subsequent advanced neoplasias has not been established. Therefore, the subsequent risk based on the findings of the index and first surveillance colonoscopies were investigated. This retrospective, cohort study was conducted in two clinics and included participants who had undergone two or more colonoscopies after index colonoscopy. High-risk was defined as advanced adenoma (≥ 1 cm, or tubulovillous or villous histology, or high-grade dysplasia). Based on the findings of the index and first surveillance colonoscopies, patients were classified into four categories: category A (both colonoscopy findings were normal), category B (no high-risk findings both times), category C (one time high-risk finding), and category D (high-risk findings both times). The incidence of subsequent advanced neoplasia was examined in each category. A total of 13,426 subjects were included and surveyed during the study periods. The subjects in category D had the highest risk of advanced neoplasia (27.4%, n = 32/117). The subjects in category A had the lowest risk (4.0%, n = 225/5,583). The hazard ratio for advanced neoplasia of category D compared to category A was 9.90 (95% Confidence interval 6.82–14.35, P<0.001). Classification based on the findings of index and first surveillance colonoscopies more effectively stratifies the risk of subsequent advanced neoplasia, resulting in more proper allocation of colonoscopy resources after two consecutive colonoscopies.

Associations between molecular characteristics of colorectal serrated polyps and subsequent advanced colorectal neoplasia.

BRAF mutation and DNA hypermethylation have linked sessile serrated adenomas/polyps (SSA/Ps) to serrated colorectal cancer (CRC) in cross-sectional studies, but they have not been evaluated in a longitudinal study. We aimed to evaluate the associations between molecular markers of serrated polyps and subsequent advanced colorectal neoplasia. Study subjects included Kaiser Permanente Washington members aged 20-75years who received an index colonoscopy between 1/1/1998 and 12/31/2007 and had hyperplastic polyps (HPs) or SSA/Ps according to study pathology review. Polyps from index colonoscopies were removed and assayed for BRAF mutation, CpG island methylator phenotype (CIMP), and MLH1 methylation. Pathology reports and biopsies from the subsequent lower gastrointestinal endoscopy through 1/1/2013 were reviewed for advanced colorectal neoplasia. We identified additional incident CRC cases through linkage to the Seattle-Puget Sound Surveillance Epidemiology and End Results registry. We used generalized estimating equations to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for subsequent advanced colorectal neoplasia, comparing index serrated polyps with different molecular markers. We included 553 individuals with index serrated polyps (420 HPs and 133 SSA/Ps) and 795 subsequent endoscopies. The prevalence of BRAF-mutant, CIMP-high, and MLH1-methylated serrated polyps were 51%, 4%, and 2%, respectively. BRAF and CIMP were not associated with subsequent advanced colorectal neoplasia. MLH1-methylated SSP/As were significantly more likely to have subsequent advanced neoplasia (OR = 4.66, 95% CI 1.06-20.51). Our results suggest that BRAF-mutant and CIMP-high serrated polyps are not associated with subsequent advanced colorectal neoplasia. Among SSA/Ps, MLH1 methylation may be an important marker to identify high-risk CRC precursors.

Risk stratification of advanced colorectal neoplasia after baseline colonoscopy: Cohort study of 17 Japanese community practices.

Background and AimIn Japan, risk stratification after baseline colonoscopy is not widely accepted. We investigated the findings of baseline colonoscopies at 17 community practices and evaluated the risk of the incidence of advanced neoplasia over a 5‐year period.MethodsThis retrospective cohort study enrolled 3115 subjects over 40 years of age who underwent baseline colonoscopies and had at least one repeated colonoscopy within 5 years. Each group was classified based on the endoscopic findings of the baseline colonoscopy: no neoplasia/diminutive polyp <5 mm (N/D); small adenoma <10 mm; advanced adenoma; invasive cancer, respectively. We examined the incidence of advanced neoplasia during these 5 years and investigated the relationship between the surveillance colonoscopy and newly detected advanced neoplasia.ResultsThe small adenoma group did not show any significant increased risk as compared to the N/D group (hazard ratio [HR]: 0.799. 95% CI 0.442–1.443). There was a significantly increased risk in the advanced adenoma and invasive cancer groups (HR: 4.996, 95% CI 2.940–8.491, HR: 3.737, 95% CI 1.309–10.666). Cancer incidences during the study period were 0.18% in the N/D group, and 1.9% in the invasive cancer group, respectively. Undergoing surveillance colonoscopies twice within 5 years decreased the risk of advanced neoplasia.ConclusionsThere was a close relationship between the endoscopic findings of baseline colonoscopies and subsequent advanced neoplasia development. Risk stratification for advanced neoplasia based on the baseline findings can serve as a useful index for determining the optimal interval and frequency of colonoscopies over a 5‐year period.

The predictive value of small versus diminutive adenomas for subsequent advanced neoplasia

Patients with previous colorectal adenomas are at increased risk of colorectal cancer. Current guidelines for postpolypectomy surveillance intervals treat all tubular adenomas 1 to 9mm in size with low-grade dysplasia as carrying the same level of risk. We evaluated whether 6 to 9mm adenomas detected at colonoscopy are associated with greater risk of advanced neoplasia at follow-up compared with baseline 1 to 5mm adenomas. We retrospectively evaluated a colonoscopy database at a single U.S. academic center. Patients with baseline examinations demonstrating tubular adenomas 1 to 9mm in size with low-grade dysplasia and no advanced adenomas were included. Follow-up colonoscopies were performed at least 200 days later and were assessed for incident advanced neoplasia (cancer, high-grade dysplasia, adenoma≥10mm in size, or villous elements). There were 2477 qualifying baseline colonoscopies. The absolute risk of metachronous advanced neoplasia increased from 3.6% in patients with 1 to 5mm adenomas to 6.9% in patients with at least 1 adenoma of 6 to 9mm (P= .001). Patients with 5 or more adenomas 1 of which was at least 6 to 9mm had the highest risk of advanced neoplasia at follow-up (10.4%, P= .006). When only screening colonoscopies were considered, all baseline groups (1-2 adenomas, 3-4 adenomas,≥5 adenomas) with adenomas 6 to 9mm in size had an increased risk for metachronous advanced neoplasia (odds ratio [OR], 4.07; 95% confidence interval [CI], 1.50-11.04; OR, 4.91; 95% CI, 1.44-16.75; OR, 4.71; 95% CI, 1.30-17.05, respectively). Patients with baseline small (6-9mm) adenomas have an increased risk of advanced lesions on follow-up compared with patients with only diminutive (1-5mm) adenomas. Postpolypectomy guidelines should consider risk stratification based on small versus diminutive adenomas.

Long-term Risk of Advanced Neoplasia After Colonic Low-grade Dysplasia in Patients With Inflammatory Bowel Disease: A Nationwide Cohort Study.

Background and AimsThe long-term risk of high-grade dysplasia [HGD] and colorectal cancer [CRC] following low-grade dysplasia [LGD] in inflammatory bowel disease [IBD] patients is relatively unknown. We aimed to determine the long-term cumulative incidence of advanced neoplasia [HGD and/or CRC], and to identify risk factors for advanced neoplasia in a nationwide IBD cohort with a history of LGD.MethodsThis is a nationwide cohort study using data from the Dutch National Pathology Registry [PALGA] to identify all IBD patients with LGD between 1991 and 2010 in the Netherlands. Follow-up data were collected until January 2016. We determined the cumulative incidence of advanced neoplasia and identified risk factors via multivariable Cox regression analysis.ResultsWe identified 4284 patients with colonic LGD with a median follow-up of 6.4 years after initial LGD diagnosis. The cumulative incidence of subsequent advanced neoplasia was 3.6, 8.5, 14.4 and 21.7%, after 1, 5, 10 and 15 years, respectively. The median time to develop advanced neoplasia after LGD was 3.6 years. Older age [≥ 55 years] at moment of LGD (hazard ratio [HR] 1.73, 95% confidence interval [CI] 1.44–2.06), male sex [HR 1.33, 95% CI 1.10–1.60], and follow-up at an academic [vs non-academic] medical centre [HR 1.37, 95% CI 1.07–1.76] were independent risk factors for advanced neoplasia following LGD.ConclusionsIn a large nationwide cohort with long-term follow-up of IBD patients with LGD, the cumulative incidence of advanced neoplasia was 21.7% after 15 years. Older age at LGD [≥55 years], male sex and follow-up by a tertiary IBD referral centre were independent risk factors for advanced neoplasia development after initial LGD.

Abstract 3310: Association between molecular characteristics of serrated polyps and subsequent advanced colorectal neoplasia

Abstract Purpose: Molecular characteristics, including BRAF mutation, MLH1 methylation, and CpG island methylator phenotype (CIMP), help identify aggressive subtypes of colorectal cancer (CRC), but their role is unclear for precursor lesions, especially in serrated polyps. Hyperplastic polyps (HPs) are serrated polyps that were considered to have no malignant potential, but a subset of HPs has been reclassified as sessile serrated polyps/adenomas (SSP/As), and SSP/As are now considered CRC precursors. In this study, we evaluated the association between molecular markers of serrated polyps and subsequent advanced colorectal neoplasia. Methods: Study subjects included Kaiser Permanente Washington members who were 20-75 years old, received an index colonoscopy between 1/1/98-12/31/07 with a diagnosis of HPs or SSP/As and were free of synchronous conventional adenomas, inflammatory bowel disease, familial CRC syndromes, and prior or prevalent CRC. All eligible participants received ≥1 subsequent endoscopy or a CRC diagnosis before 1/1/13. These subsequent endoscopy pathology reports and clinical biopsies were reviewed for advanced colorectal neoplasia, defined as CRC, conventional adenomas ≥10 mm, with ≥20% villous components, with high-grade dysplasia, or SSP/As with nuclear dysplasia. Incident CRC cases were also identified through linkage to the SEER registry. Polyps from index colonoscopies were assayed for BRAF mutation (V600E), MLH1 methylation, and CIMP (using an 8-marker panel). We used generalized estimating equations with a binomial distribution, logit link, and independent correlation structure to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for advanced colorectal neoplasia, comparing subgroups of serrated polyps with different molecular characteristics. Results: We included 733 subsequent endoscopies among 553 individuals with index serrated polyps (420 HPs and 133 SSP/As). The prevalence of BRAF mutation, MLH1 methylation, and CIMP-high among index serrated polyps were 51%, 2%, and 4% respectively. Compared to those without MLH1 methylation, those with MLH1methylated serrated lesions were more likely to have advanced colorectal neoplasia at a subsequent endoscopy, but the association was not statistically significant (adjusted OR = 1.95; 95% CI: 0.46-8.35). When restricted to index SSP/As, we observed a stronger association with MLH1 methylation (adjusted OR = 4.66, 95% CI: 1.06-20.51). BRAF and CIMP were also not statistically significantly associated with advanced colorectal neoplasia, even among those with SSP/As at the index colonoscopy. Conclusion: There was no association between the molecular characteristics of serrated polyps and subsequent advanced colorectal neoplasia. However, among index SSP/As, we observed a strong association between MLH1 methylation and subsequent advanced neoplasia. Citation Format: Xinwei Hua, Polly Newcomb, Jessica Chubak, Rachel Malen, Rebecca Ziebell, Aruna Kamineni, Lee-Ching Zhu, Melissa Upton, Hana Newman, Sheetal Hardikar, Andrea Burnett-Hartman. Association between molecular characteristics of serrated polyps and subsequent advanced colorectal neoplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3310.

Assessment of peri-polyp biopsy specimens of flat mucosa in patients with inflammatory bowel disease

When colon polyps are removed in the setting of inflammatory bowel disease (IBD) involving the large intestine, biopsy sampling of the flat mucosa surrounding such polyps have been recommended, but there are no data to support this practice. We reviewed endoscopic and pathologic findings in IBD patients who had dysplastic polyps removed and biopsy sampling of the adjacent flat mucosa. We assessed risk for subsequent neoplasia based on the presence or absence of dysplasia in the peri-polyp flat mucosa and based on number and grade of index polypoid lesions. Kaplan-Meier survival analysis was performed. Fifty-six IBD patients (68% ulcerative colitis [UC]) underwent 102 colonoscopies, in which 129 dysplastic polyps were resected. Five hundred three biopsy procedures of the surrounding flat mucosa were performed (mean, 3.9 biopsy samples per polyp), of which 16 (3.2%) were dysplastic. Thirty-four patients (21 UC) had follow-up in a median of 1.7 years (range, .02-15) and 147 colonoscopies. The presence of dysplasia in peri-polyp biopsy specimens during index colonoscopy was not associated with risk of developing high-grade dysplasia (HGD) or cancer (Pearson χ2 test= .19). The size and number of dysplastic polyps were not predictive of neoplastic outcomes, but the probability of developing subsequent advanced neoplasia for polypoid low-grade dysplasia was 18%, 29%, and 40% by 1, 3, and 5 years, respectively, and for polypoid HGD was 50%, 60%, and 70% by 1, 3, and 5 years, respectively (hazard ratio, 7.0; standard error, 4.8). In patients with IBD-associated colitis, biopsy sampling of the mucosa adjacent to discrete dysplastic polypoid lesions are low yield and do not predict findings in follow-up examinations. However, the grade of dysplasia of the polyp itself is predictive of subsequent advanced neoplasia.

A prognostic model for advanced colorectal neoplasia recurrence.

Following colonoscopic polypectomy, US Multisociety Task Force (USMSTF) guidelines stratify patients based on risk of subsequent advanced neoplasia (AN) using number, size, and histology of resected polyps, but have only moderate sensitivity and specificity. We hypothesized that a state-of-the-art statistical prediction model might improve identification of patients at high risk of future AN and address these challenges. Data were pooled from seven prospective studies which had follow-up ascertainment of metachronous AN within 3-5years of baseline polypectomy (combined n=8,228). Pooled data were randomly split into training (n=5,483) and validation (n=2,745) sets. A prognostic model was developed using best practices. Two risk cut-points were identified in the training data which achieved a 10 percentage point improvement in sensitivity and specificity, respectively, over current USMSTF guidelines. Clinical benefit of USMSTF versus model-based risk stratification was then estimated using validation data. The final model included polyp location, prior polyp history, patient age, and number, size and histology of resected polyps. The first risk cut-point improved sensitivity but with loss of specificity. The second risk cut-point improved specificity without loss of sensitivity (specificity 46.2% model vs. 42.1% guidelines, p<0.001; sensitivity 75.8% model vs. 74.0% guidelines, p=0.64). Estimated AUC was 65% (95% CI: 62-69%). This model-based approach allows flexibility in trading sensitivity and specificity, which can optimize colonoscopy over- versus underuse rates. Only modest improvements in prognostic power are possible using currently available clinical data. Research considering additional factors such as adenoma detection rate for risk prediction appears warranted.

Genetic Variants Associated with Colorectal Adenoma Susceptibility.

BackgroundCommon low-penetrance genetic variants have been consistently associated with colorectal cancer risk.AimTo determine if these genetic variants are associated also with adenoma susceptibility and may improve selection of patients with increased risk for advanced adenomas and/or multiplicity (≥ 3 adenomas).MethodsWe selected 1,326 patients with increased risk for advanced adenomas and/or multiplicity and 1,252 controls with normal colonoscopy from population-based colorectal cancer screening programs. We conducted a case-control association study analyzing 30 colorectal cancer susceptibility variants in order to investigate the contribution of these variants to the development of subsequent advanced neoplasia and/or multiplicity.ResultsWe found that 14 of the analyzed genetic variants showed a statistically significant association with advanced adenomas and/or multiplicity: the probability of developing these lesions increased with the number of risk alleles reaching a 2.3-fold risk increment in individuals with ≥ 17 risk alleles.ConclusionsNearly half of the genetic variants associated with colorectal cancer risk are also related to advanced adenoma and/or multiplicity predisposition. Assessing the number of risk alleles in individuals within colorectal cancer screening programs may help to identify better a subgroup with increased risk for advanced neoplasia and/or multiplicity in the general population.

PTU-067 The Fate Of Flat Low-grade Dysplasia In Ulcerative Colitis

IntroductionThe natural history of low- grade dysplasia (LGD) found during colonoscopic surveillance of ulcerative colitis is not clear. The optimum strategy, either continued surveillance or immediate colectomy, is debated. The...

Systematic review with meta‐analysis: the incidence of advanced neoplasia after polypectomy in patients with and without low‐risk adenomas

Patients with one to two tubular adenomas <1cm in size without high-grade dysplasia (low-risk group) are considered at low risk for colorectal cancer. However, it is uncertain whether they have the same risk of subsequent advanced neoplasia as those with no neoplasia at baseline colonoscopy. To compare incidence of metachronous advanced neoplasia between patients in the low-risk adenoma group and those without neoplasia at index colonoscopy. Relevant publications were identified by MEDLINE/EMBASE and other databases for the period 1992-2013. Studies comparing the incidence of post-polypectomy advanced neoplasia (adenomas ≥10mm/high-grade dysplasia/villous or cancer) between the low-risk group and patients without colorectal neoplasia at the first colonoscopy were included. Detection rates for advanced neoplasia at endoscopic surveillance were extracted. Study quality was ascertained according to Newcastle-Ottawa Scale. Forest plot was produced based on random-effect models. Inter-study heterogeneity was assessed using the I(2) statistic. Seven studies provided data on 11387 patients. Mean surveillance periods ranged between 2 and 5years. Altogether, 267 patients with post-polypectomy advanced neoplasia were detected in the two groups. The incidence of advanced neoplasia was 1.6% (119/7308) in those without neoplasia and 3.6% (148/4079) in those with low-risk adenoma, respectively, corresponding to a relative risk of 1.8 (95% CI: 1.3-2.6). Inter-study heterogeneity was only moderate (I(2) : 37%). No publication bias was present. Patients with low-risk adenomas at baseline had a higher risk of metachronous advanced neoplasia than the group with no adenomas at baseline, though the absolute risk was low in both groups.

Guidelines for Colonoscopy Surveillance After Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society

Adenomatous polyps are the most common neoplastic findings discovered in people who undergo colorectal screening or who have a diagnostic work-up for symptoms. It was common practice in the 1970s for these patients to have annual follow-up surveillance examinations to detect additional new adenomas and missed synchronous adenomas. As a result of the National Polyp Study report in 1993, which showed clearly in a randomized design that the first postpolypectomy examination could be deferred for 3 years, guidelines published by a gastrointestinal consortium in 1997 recommended that the first follow-up surveillance take place 3 years after polypectomy for most patients. In 2003 these guidelines were updated and colonoscopy was recommended as the only follow-up examination, stratification at baseline into low risk and higher risk for subsequent adenomas was suggested. The 1997 and 2003 guidelines dealt with both screening and surveillance. However, it has become increasingly clear that postpolypectomy surveillance is now a large part of endoscopic practice, draining resources from screening and diagnosis. In addition, surveys have shown that a large proportion of endoscopists are conducting surveillance examinations at shorter intervals than recommended in the guidelines. In the present report, a careful analytic approach was designed to address all evidence available in the literature to delineate predictors of advanced pathology, both cancer and advanced adenomas, so that patients can be stratified more definitely at their baseline colonoscopy into those at lower risk or increased risk for a subsequent advanced neoplasia. People at increased risk have either 3 or more adenomas, high-grade dysplasia, villous features, or an adenoma 1 cm or larger in size. It is recommended that they have a 3-year follow-up colonoscopy. People at lower risk who have 1 or 2 small (<1 cm) tubular adenomas with no high-grade dysplasia can have a follow-up evaluation in 5-10 years, whereas people with hyperplastic polyps only should have a 10-year follow-up evaluation, as for average-risk people. There have been recent studies that have reported a significant number of missed cancers by colonoscopy. However, high-quality baseline colonoscopy with excellent patient preparation and adequate withdrawal time should minimize this and reduce clinicians concerns. These guidelines were developed jointly by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society to provide a broader consensus and thereby increase the use of the recommendations by endoscopists. The adoption of these guidelines nationally can have a dramatic impact on shifting available resources from intensive surveillance to screening. It has been shown that the first screening colonoscopy and polypectomy produces the greatest effects on reducing the incidence of colorectal cancer in patients with adenomatous polyps.

Guidelines for Colonoscopy Surveillance after Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society,

Adenomatous polyps are the most common neoplastic findings uncovered in people who undergo colorectal screening or have a diagnostic workup for symptoms. It was common practice in the 1970s for these patients to have annual follow-up surveillance examinations to detect additional new adenomas as well as missed synchronous adenomas. As a result of the National Polyp Study report in 1993, which demonstrated clearly in a randomized design that the first postpolypectomy examination could be deferred for 3 years, guidelines published by a gastrointestinal consortium in 1997 recommended that the first follow-up surveillance be 3 years after polypectomy for most patients. In 2003, these guidelines were updated, colonoscopy was recommended as the only follow-up examination, and stratification at baseline into lower and higher risk for subsequent adenomas was suggested. The 1997 and 2003 guidelines dealt with both screening and surveillance. However, it has become increasingly clear that postpolypectomy surveillance is now a large part of endoscopic practice, draining resources from screening and diagnosis. In addition, surveys have demonstrated that a large proportion of endoscopists are conducting surveillance examinations at shorter intervals than recommended in the guidelines. In the present paper, a careful analytic approach was designed addressing all evidence available in the literature to delineate predictors of advanced pathology, both cancer and advanced adenomas, so that patients can be more definitely stratified at their baseline colonoscopy into those at lower or increased risk for a subsequent advanced neoplasia. People at increased risk have either three or more adenomas, or high-grade dysplasia, or villous features, or an adenoma > or =1 cm in size. It is recommended that they have a 3-year follow-up colonoscopy. People at lower risk who have one or two small (< 1 cm) tubular adenomas with no high-grade dysplasia can have a follow-up in 5 to 10 years, whereas people with hyperplastic polyps only should have a 10-year follow-up as average-risk people. Recent papers have reported a significant number of missed cancers by colonoscopy. However, high-quality baseline colonoscopy with excellent patient preparation and adequate withdrawal time should minimize this and reduce clinicians' concerns. These guidelines were developed jointly by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society to provide a broader consensus and thereby increase utilization of the recommendations by endoscopists. Adoption of these guidelines nationally can have a dramatic impact on shifting available resources from intensive surveillance to screening. It has been shown that the first screening colonoscopy and polypectomy produces the greatest effects on reducing the incidence of colorectal cancer in patients with adenomatous polyps.