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.

Endoscopic subtypes of colorectal laterally spreading tumors (LSTs) and the risk of submucosal invasion: a meta-analysis.

BACKGROUND AND STUDY AIMS: Many studies have reported on laterally spreading tumors (LSTs), but systematic reviews of the data to determine their risk of containing submucosal invasion (SMI) are lacking. We systematically screened and analyzed the available literature to provide a more solid basis for evidence-based treatment. METHODS: We conducted a systematic search in PubMed, Embase, the Cochrane Library, and Scopus for published articles until July 2017. We estimated pooled prevalence or odds ratios (ORs) with 95 % confidence intervals (CIs), using random-effects models. We classified endoscopic subtypes into granular LST, which comprises the homogeneous and nodular mixed subtypes, and non-granular LST, which comprises the flat elevated and pseudodepressed subtypes. RESULTS: We identified 2949 studies, of which 48 were included. Overall, 8.5 % (95 %CI 6.5 % - 10.5 %) of LSTs contained SMI. The risk of SMI differed among the LST subtypes: 31.6 % in non-granular pseudodepressed LSTs (95 %CI 19.8 % - 43.4 %), 10.5 % in granular nodular mixed LSTs (95 %CI 5.9 % - 15.1 %), 4.9 % in non-granular flat elevated LSTs (95 %CI 2.1 % - 7.8 %), and 0.5 % in granular homogenous LSTs (95 %CI 0.1 % - 1.0 %). SMI was more common in distally rather than in proximally located LSTs (OR 2.50, 95 %CI 1.24 - 5.02). The proportion of SMI increased with lesion size (10 - 19 mm, 4.6 %; 20 - 29 mm, 9.2 %; ≥ 30 mm, 16.5 %). The pooled prevalence of patients with one or more LSTs in the general colonoscopy population was 0.8 % (95 %CI 0.6 % - 1.1 %). CONCLUSION: The majority of LSTs are non-invasive at the time of colonoscopic detection and can be treated with (piecemeal) endoscopic mucosal resection. Pretreatment diagnosis of endoscopic subtype, specifying areas of concern (nodule or depression), determines those LSTs at highest risk of containing SMI, where en bloc resection is the preferred therapy.

Post-Colonoscopy Complications: A Systematic Review, Time Trends, and Meta-Analysis of Population-Based Studies.

OBJECTIVES: Many studies around the world addressed the post-colonoscopy complications, but their pooled prevalence and time trends are unknown. We performed a systematic review and meta-analysis of population-based studies to examine the pooled prevalence of post-colonoscopy complications ("perforation", "bleeding", and "mortality"), stratified by colonoscopy indication. Temporal variability in the complication rate was assessed. METHODS: We queried Pubmed, Embase, and the Cochrane library for population-based studies examining post-colonoscopy complications (within 30 days), performed from 2001 to 2015 and published by 1 December 2015. We determined pooled prevalence of perforations, post-colonoscopy bleeding, post-polypectomy bleeding, and mortality. RESULTS: We retrieved 1,074 studies, of which 21 met the inclusion criteria. Overall, pooled prevalences for perforation, post-colonoscopy bleeding, and mortality were 0.5/1,000 (95% confidence interval (CI) 0.4-0.7), 2.6/1,000 (95% CI 1.7-3.7), and 2.9/100,000 (95% CI 1.1-5.5) colonoscopies. Colonoscopy with polypectomy was associated with a perforation rate of 0.8/1,000 (95% CI 0.6-1.0) and a post-polypectomy bleeding rate of 9.8/1,000 (95% CI 7.7-12.1). Complication rate was lower for screening/surveillance than for diagnostic examinations. Time-trend analysis showed that post-colonoscopy bleeding declined from 6.4 to 1.0/1,000 colonoscopies, whereas the perforation and mortality rates remained stable from 2001 to 2015. Overall, considerable heterogeneity was observed in most of the analyses. CONCLUSIONS: Worldwide, the post-colonoscopy complication rate remained stable or even declined over the past 15 years. The findings of this meta-analysis encourage continued efforts to achieve and maintain safety targets in colonoscopy practice.

Endoscopic characterization of sessile serrated adenomas/polyps with and without dysplasia.

BACKGROUND AND STUDY AIMS: Sessile serrated adenomas/polyps (SSA/Ps) are precursors of colorectal cancer (CRC), but their endoscopic detection can be difficult. We therefore examined the endoscopic characteristics of SSA/Ps with and without dysplasia in a cross-sectional study. PATIENTS AND METHODS: We reviewed clinical, endoscopic, and histopathologic data from patients undergoing colonoscopy between February 2008 and February 2012. We categorized colorectal polyps according to anatomic site, size, and shape, and classified serrated polyps using the World Health Organization (WHO) classification. Multiple logistic regression analyses examined potential differences regarding site, size, and shape between SSA/Ps and colorectal adenomas (overall and advanced only). RESULTS: We examined 7433 patients (mean age 59 years, 45.9 % men) with 5968 colorectal polyps. In total, we found 170 SSA/Ps (170/5968, 2.9 %), including 63 SSA/Ps with dysplasia (1.1 %) and 107 SSA/Ps without dysplasia (1.8 %). Compared with SSA/Ps with dysplasia, SSA/Ps without dysplasia were more often proximally located (odds ratio [OR] 3.3, 95 % confidence interval [95 %CI] 1.7 - 6.4), but less often < 6 mm in size (OR 0.6, 95 %CI 0.3 - 1.1). No significant differences were found regarding location between SSA/Ps with dysplasia and advanced adenomas (proximal colon, 47.6 % vs. 40.1 %). However, SSA/Ps with dysplasia were more often < 6 mm in size than advanced adenomas (OR 0.3, 95 %CI 0.2 - 0.5). Of the 63 dysplastic SSA/Ps, 6 (9.5 %) contained high grade dysplasia, but none invasive carcinoma. CONCLUSIONS: SSA/Ps with dysplasia are frequently < 6 mm in size, located throughout the colon and 9.5 % of them contain high grade dysplasia. These findings underscore the importance of high quality colonoscopic examination to maximize protection against CRC.

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.

Simple clinical risk score identifies patients with serrated polyps in routine practice.

Large, proximal, or dysplastic (LPD) serrated polyps (SP) need accurate endoscopic recognition and removal as these might progress to colorectal cancer. Herewith, we examined the risk factors for having ≥1 LPD SP. We developed and validated a simple SP risk score as a potential tool for improving their detection. We reviewed clinical, endoscopic, and histologic features of serrated polyps in a study of patients undergoing elective colonoscopy (derivation cohort). A self-administered questionnaire was obtained. We conducted logistic regression analyses to identify independent risk factors for having ≥1 LPD SP and incorporated significant variables into a clinical score. We subsequently tested the performance of the SP score in a validation cohort. We examined 2,244 patients in the derivation and 2,402 patients in the validation cohort; 6.3% and 8.2% had ≥1 LPD SP, respectively. Independent risk factors for LPD SPs were age of more than 50 years [OR 2.2; 95% confidence interval (CI), 1.3-3.8; P = 0.004], personal history of serrated polyps (OR 2.6; 95% CI, 1.3-4.9; P = 0.005), current smoking (OR 2.2; 95% CI, 1.4-3.6; P = 0.001), and nondaily/no aspirin use (OR 1.8; 95% CI, 1.1-3.0; P = 0.016). In the validation cohort, a SP score ≥5 points was associated with a 3.0-fold increased odds for LPD SPs, compared with patients with a score <5 points. In the present study, age of more than 50 years, a personal history of serrated polyps, current smoking, and nondaily/no aspirin use were independent risk factors for having LPD SPs. The SP score might aid the endoscopist in the detection of such lesions.

Tracking the molecular features of nonpolypoid colorectal neoplasms: a systematic review and meta-analysis.

OBJECTIVES: Nonpolypoid colorectal neoplasms (NP-CRNs) are proposed as a major contributor to the occurrence of interval cancers, but their underlying biology remains controversial. We conducted a systematic review and meta-analysis to clarify the major biological events in NP-CRNs. METHODS: We systematically searched for studies examining molecular characteristics of NP-CRNs. We performed random effect meta-analyses. We measured the heterogeneity among studies using I(2) and possible publication bias using funnel plots. RESULTS: Fifty-three studies on KRAS, APC, or BRAF mutations, microsatellite instability (MSI), CpG island methylator phenotype (CIMP), or DNA promoter hypermethylation were included. We observed less KRAS mutations (summary odds ratio (OR) 0.30, confidence interval (CI)=0.19-0.46, I(2)=77.4%, CI=70.1-82.9) and APC mutations (summary OR 0.42, CI=0.24-0.72, I(2)=22.6%, CI=0.0-66.7) in NP-CRNs vs. protruded CRNs, whereas BRAF mutations were more frequent (summary OR 2.20, CI=1.01-4.81, I(2)=0%, CI=0-70.8), albeit all with large heterogeneity. Less KRAS mutations were especially found in NP-CRNs subtypes: depressed CRNs (summary OR 0.12, CI=0.05-0.29, I(2)=0%, CI=0-67.6), non-granular lateral spreading tumors (LSTs-NG) (summary OR 0.61, CI=0.37-1.0, I(2)=0%, CI=0-74.6), and early nonpolypoid carcinomas (summary OR 0.11, CI=0.06-0.19, I(2)=0%, CI=0-58.3). MSI frequency was similar in NP-CRNs and protruded CRNs (summary OR 0.99, CI=0.21-4.71, I(2)=70.3%, CI=38.4-85.7). Data for promoter hypermethylation and CIMP were inconsistent, precluding meaningful conclusions. CONCLUSIONS: This meta-analysis provides indications that NP-CRNs are molecularly different from protruded CRNs. In particular, some subtypes of NP-CRNs, the depressed and LST-NG, are featured by less KRAS mutations than polypoid CRNs. Prospective, multicenter studies are needed to clarify the molecular pathways underlying nonpolypoid colorectal carcinogenesis and potential implications for surveillance intervals.

Chromosome 5q loss in colorectal flat adenomas.

PURPOSE: Flat adenomas are a subgroup of colorectal adenomas that have been associated with a more aggressive clinical behavior compared with their polypoid counterparts. Here, we aimed to compare one of the molecular changes most explicitly associated with adenoma to carcinoma progression, that is, chromosomal instability, between flat and polypoid colorectal adenomas. EXPERIMENTAL DESIGN: Consecutive series of 83 flat and 35 polypoid adenomas were analyzed for DNA copy number changes using a high-resolution array comparative genomic hybridization platform, microsatellite instability (MSI) status, and for mutations in the adenomatous polyposis coli (APC) gene. Immunohistochemical stainings for CD3, CD8, and FoxP3 expression were carried out. RESULTS: Patterns of DNA copy number changes differed between the two phenotypes, with significantly more frequent loss of 5q14.3 and 5q15-q31.1 in flat adenomas, whereas losses of 1p36.32-p35.3, 10q25.3, 17p12, and chromosome 18 were more frequent in polypoid adenomas (false discovery rate < 0.2). MSI was observed in one flat adenoma. As the 5q15-q31.1 region harbors the APC locus, APC mutation status was investigated, showing significantly less mutations in flat adenomas (P = 0.04). An initial exploration of a possible association of 5q loss with inflammation indicated that tumor-infiltrating lymphocytes were more abundant in the stroma of flat adenomas compared with that of polypoid adenomas. CONCLUSION: Flat and polypoid adenomas have partially distinct chromosomal profiles, consistent with differences in the biology underlying these phenotypes. Alterations more specific to flat adenomas, in particular 5q loss, may be associated with inflammation.

Endoscopic appearance of proximal colorectal neoplasms and potential implications for colonoscopy in cancer prevention.

BACKGROUND: In everyday practice, the use of colonoscopy for the prevention of colorectal cancer (CRC) is less effective in the proximal than the distal colon. A potential explanation for this is that proximal neoplasms have a more subtle endoscopic appearance, making them more likely to be overlooked. OBJECTIVE: To investigate the differences in endoscopic appearance, ie, diminutive size and nonpolypoid shape, of proximal compared with distal colorectal neoplasms. DESIGN: Cross-sectional, single-center study. SETTING: Endoscopists at the Maastricht University Medical Center in the Netherlands who were previously trained in the detection and classification of nonpolypoid colorectal lesions. PATIENTS: Consecutive patients undergoing elective colonoscopy. MAIN OUTCOME MEASUREMENTS: Endoscopic appearance, ie, diminutive size (<6 mm) or nonpolypoid shape (height less than half of the diameter) of colorectal adenomas and serrated polyps (SPs), with a focus on adenomas with advanced histology, ie, high-grade dysplasia or early CRC and SPs with dysplasia or large size. RESULTS: We included 3720 consecutive patients with 2106 adenomas and 941 SPs. We found that in both men and women, proximal adenomas with high-grade dysplasia/early CRC (n = 181) were more likely to be diminutive or nonpolypoid than distal ones (76.3% vs 26.2%; odds ratio [OR] 9.24; 95% CI, 4.45-19.2; P < .001). Of the proximal adenomas, 84.4% were diminutive or nonpolypoid compared with 68.0% of the distal ones (OR 2.66; 95% CI, 2.14-3.29; P < .001). Likewise, large/dysplastic SPs in the proximal colon were more often nonpolypoid than distal ones (66.2% vs 27.8%; OR 5.51; 95% CI, 2.79-10.9; P < .001). LIMITATIONS: Inclusion of both symptomatic and asymptomatic patients. CONCLUSIONS: Proximal colorectal neoplasms with advanced histology frequently are small or have a nonpolypoid appearance. These findings support careful inspection of the proximal colon, if quality of cancer prevention with the use of colonoscopy is to be optimized.

Nonpolypoid colorectal neoplasms: gender differences in prevalence and malignant potential.

OBJECTIVE: Colonoscopy may fail to prevent colorectal cancer, especially in the proximal colon and in women. Nonpolypoid colorectal neoplasms may potentially explain some of these post-colonoscopy cancers. In the present study, we aimed to examine the prevalence and malignant potential of nonpolypoid colorectal neoplasms in a large population, with special attention to gender and location. METHODS: We performed a cross-sectional study of all consecutive patients undergoing elective colonoscopy at a single academic medical center. The endoscopists were familiarized on the detection and treatment of nonpolypoid lesions. Advanced histology was defined by the presence of high-grade dysplasia or early cancer. RESULTS: We included 2310 patients (53.9% women, mean age 58.4 years) with 2143 colorectal polyps. Prevalences of colorectal neoplasms and nonpolypoid colorectal neoplasms were lower in women than in men (20.9% vs. 33.7%, p < 0.001 and 3.0% vs. 5.5%, p = 0.002). In women, nonpolypoid colorectal neoplasms were significantly more likely to contain advanced histology than polypoid ones (OR 2.89, 95% CI 1.24-6.74, p = 0.01), while this was not the case in men (OR 0.91, 95% CI 0.40-2.06, p = 0.83). Proximal neoplasms with advanced histology were more likely to be nonpolypoid than distal ones (OR 4.68, 95% CI 1.54-14.2, p = 0.006). CONCLUSION: Nonpolypoid mechanisms may play an important role in colorectal carcinogenesis, in both women and men. Although women have fewer colorectal neoplasms than men, they have nonpolypoid colorectal neoplasms, which frequently contain advanced histology.

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.

Development of expertise in the detection and classification of non-polypoid colorectal neoplasia: Experience-based data at an academic GI unit.

At its core, quality improvement in gastrointestinal (GI) practice relies on continuous training, education, and information among all health care providers, whether gastroenterologists, GI trainees, endoscopy nurses, or GI pathologists. Over the past few years, it became clear that objective criteria are needed to assess the quality of colonoscopy, such as cecum intubation rate, quality of bowel preparation, withdrawal time, and adenoma detection rate. In this context, development of competence among practicing endoscopists to adequately detect and treat non-polypoid colorectal neoplasms (NP-CRNs) deserves special attention. We describe a summary of the path to develop expertise in detection and management of NP-CRNs, based on experience at our academic GI unit.