Molecular pathways in post-colonoscopy versus detected colorectal cancers: results from a nested case-control study.

BACKGROUND: Post-colonoscopy colorectal cancers (PCCRCs) pose challenges in clinical practice. PCCRCs occur due to a combination of procedural and biological causes. In a nested case-control study, we compared clinical and molecular features of PCCRCs and detected CRCs (DCRCs). METHODS: Whole-genome chromosomal copy number changes and mutation status of genes commonly affected in CRC were examined by low-coverage WGS and targeted sequencing, respectively. MSI and CIMP status was also determined. RESULTS: In total, 122 PCCRCs and 98 DCRCs with high-quality DNA were examined. PCCRCs were more often located proximally (P < 0.001), non-polypoid appearing (P = 0.004), early stage (P = 0.009) and poorly differentiated (P = 0.006). PCCRCs showed significantly less 18q loss (FDR < 0.2), compared to DCRCs. No significant differences in mutations were observed. PCCRCs were more commonly CIMP high (P = 0.014) and MSI (P = 0.029). After correction for tumour location, only less 18q loss remained significant (P = 0.005). CONCLUSION: Molecular features associated with the sessile serrated lesions (SSLs) and non-polypoid colorectal neoplasms (CRNs) are more commonly seen in PCCRCs than in DCRCs. These together with the clinical features observed support the hypothesis that SSLs and non-polypoid CRNs are contributors to the development of PCCRCs. The future focus should be directed at improving the detection and endoscopic removal of these non-polypoid CRN and SSLs. CLINICAL TRIAL REGISTRATION: NTR3093 in the Dutch trial register ( www.trialregister.nl ).

Temporal trends and variability of colonoscopy performance in a gastroenterology practice.

BACKGROUND AND STUDY AIM: Quality measures for colonoscopy are operator dependent and vary. It is unclear whether quality measures change over time. In this study, time-dependent variation in colonoscopy performance was examined in a gastroenterology practice. PATIENTS AND METHODS: Colonoscopy and histopathology records that were collected at three hospitals (one university and two non-university hospitals) over three time periods (2007, 2010, and 2013) were reviewed. Data from colonoscopists performing at least 100 procedures per year were analyzed. Inter-colonoscopist variation in performance (i. e. adjusted cecal intubation rate [aCIR], adenoma detection rate [ADR], advanced ADR, mean adenomas per procedure [MAP], proximal ADR, nonpolypoid ADR, and serrated polyp detection rate) were examined using coefficients of variation. Logistic regression analyses were also performed, adjusting for covariates. RESULTS: A total of 23 colonoscopists performing 6400 procedures were included. Overall, the mean aCIR, ADR, MAP, and proximal ADR improved significantly over time, from 91.9 %, 22.5 %, 0.37, and 10.2 % in 2007 to 95.3 %, 25.8 %, 0.45, and 13.4 %, respectively, in 2013 (P < 0.05). The inter-colonoscopist variation in ADR decreased from 37 % in 2007 to 15 % in 2013 (P < 0.05). In the non-university hospitals, mean values for quality measures increased significantly over time, whereas they remained stable in the university hospital. CONCLUSIONS: Variability in performance among colonoscopists decreased significantly within the gastroenterology clinical practice. Core quality measures improved over time, mainly through improvement of the lower performers. Measurement of inter-colonoscopist variation in performance helps to identify factors that stimulate or hinder performance, and forms the basis for interventions. TRIAL REGISTRATION: http://www.trialregister.nl.

Metachronous colorectal cancers result from missed lesions and non-compliance with surveillance.

BACKGROUND: Several studies examined the rate of colorectal cancer (CRC) developed during colonoscopy surveillance after CRC resection (ie, metachronous CRC [mCRC]), yet the underlying etiology is unclear. OBJECTIVE: To examine the rate and likely etiology of mCRCs. DESIGN: Population-based, multicenter study. Review of clinical and histopathologic records, including data of the national pathology database and The Netherlands Cancer Registry. SETTING: National cancer databases reviewed at 3 hospitals in South-Limburg, The Netherlands. PATIENTS: Total CRC population diagnosed in South-Limburg from January 2001 to December 2010. INTERVENTIONS: Colonoscopy. MAIN OUTCOME MEASUREMENTS: We defined an mCRC as a second primary CRC, diagnosed >6 months after the primary CRC. By using a modified algorithm to ascribe likely etiology, we classified the mCRCs into cancers caused by non-compliance with surveillance recommendations, inadequate examination, incomplete resection of precursor lesions (CRC in same segment as previous advanced adenoma), missed lesions, or newly developed cancers. RESULTS: We included a total of 5157 patients with CRC, of whom 93 (1.8%) had mCRCs, which were diagnosed on an average of 81 months (range 7-356 months) after the initial CRC diagnosis. Of all mCRCs, 43.0% were attributable to non-compliance with surveillance advice, 43.0% to missed lesions, 5.4% to incompletely resected lesions, 5.4% to newly developed cancers, and 3.2% to inadequate examination. Age-adjusted and sex-adjusted logistic regression analyses showed that mCRCs were significantly smaller in size (odds ratio [OR] 0.8; 95% confidence interval [CI], 0.7-0.9) and more often poorly differentiated (OR 1.7; 95% CI, 1.0-2.8) than were solitary CRCs. LIMITATIONS: Retrospective evaluation of clinical data. CONCLUSION: In this study, 1.8% of all patients with CRC developed mCRCs, and the vast majority were attributable to missed lesions or non-compliance with surveillance advice. Our findings underscore the importance of high-quality colonoscopy to maximize the benefit of post-CRC surveillance.

Postcolonoscopy colorectal cancers are preventable: a population-based study.

OBJECTIVE: The quality of colonoscopy is key for ensuring protection against colorectal cancer (CRC). We therefore aimed to elucidate the aetiology of postcolonoscopy CRCs (PCCRCs), and especially to identify preventable factors. METHODS: We conducted a population-based study of all patients diagnosed with CRC in South-Limburg from 2001 to 2010 using colonoscopy and histopathology records and data from the Netherlands Cancer Registry. PCCRCs were defined as cancers diagnosed within 5 years after an index colonoscopy. According to location, CRCs were categorised into proximal or distal from the splenic flexure and, according to macroscopic aspect, into flat or protruded. Aetiological factors for PCCRCs were subdivided into procedure-related (missed lesions, inadequate examination/surveillance, incomplete resection) and biology-related (new cancers). RESULTS: We included a total of 5107 patients with CRC, of whom 147 (2.9% of all patients, mean age 72.8 years, 55.1% men) had PCCRCs diagnosed on average 26 months after an index colonoscopy. Logistic regression analysis, adjusted for age and gender, showed that PCCRCs were significantly more often proximally located (OR 3.92, 95% CI 2.71 to 5.69), smaller in size (OR 0.78, 95% CI 0.70 to 0.87) and more often flat (OR 1.70, 95% CI 1.18 to 2.43) than prevalent CRCs. Of the PCCRCs, 57.8% were attributed to missed lesions, 19.8% to inadequate examination/surveillance and 8.8% to incomplete resection, while 13.6% were newly developed cancers. CONCLUSIONS: In our experience, 86.4% of all PCCRCs could be explained by procedural factors, especially missed lesions. Quality improvements in performance of colonoscopy, with special attention to the detection and resection of proximally located flat precursors, have the potential to prevent PCCRCs.

Interval colorectal cancers: what and why.

An increasing number of studies now indicate that colonoscopic examination is not perfect in preventing colorectal cancer (CRC), especially of the proximal colon. Several factors can be implicated in the occurrence of interval CRCs--further referred to as postcolonoscopy CRCs-, such as missed, incompletely resected lesions and newly developed cancers. Missed lesions represent by far the dominant cause of postcolonoscopy CRCs, with nonpolypoid (flat or depressed) neoplasms and sessile serrated polyps playing a significant role. Molecular events underlying progression of such lesions may further augment the cancer risk. In this article, we review the literature about postcolonoscopy CRC risk and the most common explanations. We discuss potential implications, paying special attention to improvements required in education and training.

Metachronous neoplasms in patients with laterally spreading tumours during surveillance.

BACKGROUND: Laterally spreading tumours represent a major challenge for endoscopic detection and resection. OBJECTIVE: To examine synchronous and metachronous neoplasms in patients with laterally spreading tumours. METHODS: We prospectively collected colonoscopy and histopathology data from patients who underwent colonoscopy in our centre at up to 6 years' follow-up. Post-resection surveillance outcomes between laterally spreading tumours, flat colorectal neoplasms 10 mm or greater, and large polypoid colorectal neoplasms, polypoid colorectal neoplasms 10 mm or greater, were compared. RESULTS: Between 2008 and 2012, 8120 patients underwent colonoscopy for symptoms (84.6%), screening (6.7%) or surveillance (8.7%). At baseline, 151 patients had adenomatous laterally spreading tumours and 566 patients had adenomatous large polypoid colorectal neoplasms. Laterally spreading tumour patients had more synchronous colorectal neoplasms than large polypoid colorectal neoplasm patients (mean 3.34 vs. 2.34, p < 0.001). Laterally spreading tumour patients significantly more often developed metachronous colorectal neoplasms (71.6% vs. 54.2%, p = 0.0498) and colorectal neoplasms with high grade dysplasia/submucosal invasion than large polypoid colorectal neoplasm patients (36.4% vs. 15.8%, p < 0.001). After correction for age and gender, laterally spreading tumour patients were more likely than large polypoid colorectal neoplasm patients to develop a colorectal neoplasm with high grade dysplasia or submucosal invasion (hazard ratio 2.9, 95% confidence interval 1.8-4.6). The risk of metachronous colorectal cancer was not significantly different in laterally spreading tumours compared to large polypoid colorectal neoplasm patients. CONCLUSION: Patients with laterally spreading tumours developed more metachronous colorectal neoplasms with high grade dysplasia/submucosal invasion than large polypoid colorectal neoplasm patients. Based on these findings endoscopic treatment and surveillance recommendations for patients with laterally spreading tumours should be optimised.

Incidence and Classification of Postcolonoscopy Colorectal Cancers in Inflammatory Bowel Disease: A Dutch Population-Based Cohort Study.

BACKGROUND AND AIMS: Patients with inflammatory bowel disease [IBD] colitis are at increased risk for colorectal cancer [CRC]. We examined the proportion and most likely aetiology of potentially preventable postcolonoscopy CRCs [PCCRCs] in a population-based cohort. Furthermore, adherence to IBD surveillance guidelines was evaluated in both PCCRCs and the remainder of prevalent CRCs. METHODS: All IBD patients diagnosed from 1991 to 2011 in the South Limburg region of The Netherlands [i.e. IBDSL cohort] were included. CRC cases were cross-checked with the Dutch pathology database and cancer registry. PCCRCs were defined as cancers diagnosed within 6-60 months after a colonoscopy and were classified as attributable to 'inappropriate surveillance interval', 'inadequate bowel examination', 'incomplete resection', 'missed lesion' or 'newly developed cancer'. RESULTS: Twenty CRC cases were identified during 25,931 patient years of follow-up in 2,801 patients. The proportion of PCCRCs was 45.0%. Of these, 55.6% could be considered a 'missed lesion', while other possible aetiologies occurred only once. Considering both PCCRCs [n=9] and prevalent CRCs [n=11], ten were detected after publication of the surveillance guideline, but only three patients were enrolled. Moreover, 6 CRCs [30.0%] were detected before the recommended start of surveillance. CONCLUSIONS: In the IBDSL cohort, 45.0% of all CRCs were considered to be PCCRCs, mainly classified as missed lesions. Additionally, a large proportion of CRCs in our cohort were observed before a surveillance endoscopy was performed. Therefore, stringent adherence to IBD surveillance guidelines, improving endoscopy techniques and adjusting the surveillance program may lead to a decrease in CRC incidence.

Diverticulosis and colorectal polyps at younger age: a possible link?

OBJECTIVE: An association between diverticulosis and colorectal neoplasms may have implications for colonoscopic prevention of colorectal cancer. We aimed to examine the association between diverticulosis and colorectal polyps with special attention to the age at diagnosis, the anatomical location, and the histological subtype of colorectal polyps. METHODS: We included all consecutive patients referred for routine colonoscopy between February 2008 and February 2009. We recorded the presence of diverticulosis (defined as at least two diverticula) and colorectal polyps (adenomas and serrated polyps). RESULTS: We included 2310 patients (46.1% men, mean age 58.4 years), of which 37.0% had diverticulosis and 34.2% had one or more colorectal polyps. Multiple logistic regression analysis, including age, sex, and interaction terms with diverticulosis, showed that the association between diverticulosis and colorectal polyps was significantly influenced by age (P=0.009). In patients aged below 60 years, prevalence of colorectal polyps was significantly higher in those with diverticulosis compared with those without diverticulosis: 39.1% (79 of 202 patients) versus 19.6% (176 of 898 patients), adjusted odds ratio (OR) 1.87, 95% confidence interval (CI) 1.26-2.78, and P=0.002. This association was found for both proximal and distal polyps and for all histological subtypes, namely adenomas (adjusted OR 1.60, 95%CI 1.02-2.49, P=0.04), serrated polyps (adjusted OR 1.73, 95% CI 1.03-2.91, and P=0.04), and advanced neoplasms (adjusted OR 2.32, 95%CI 1.31-4.12, P=0.004). CONCLUSION: Presence of diverticulosis in patients aged below 60 years may be considered a 'red flag' for synchronous adenomas, serrated polyps, and advanced neoplasms. Diverticulosis may represent an indication for earlier initiation of colorectal cancer prevention programs.