Mariëlle Bouwens

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.

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.

Endoscopic red flags for the detection of high-risk serrated polyps: an observational study

BACKGROUND AND STUDY AIMS In routine practice, colonoscopy may fail to prevent colorectal cancer (CRC), especially in the proximal colon. A better endoscopic recognition of serrated polyps is important, as this pathway may explain some of the post-colonoscopy cancers. In this study, the endoscopic characteristics of serrated polyps were examined. PATIENT AND METHODS This was a cross-sectional, single-center study of all consecutive patients referred for elective colonoscopy during 1 year. The endoscopists were familiarized with the detection and treatment of nonpolypoid colorectal lesions. Serrated polyps were classified into high risk serrated polyps, defined as dysplastic or large (≥ 6 mm) proximal nondysplastic serrated polyps, and low risk serrated polyps including the remaining nondysplastic serrated polyps. Advanced colorectal neoplasms were defined as multiple (at least three),≥ 10 mm in size, high grade dysplastic adenomas or CRC. RESULTS A total of 2309 patients were included (46.1 % men, mean age 58.4 years), of whom 2.5 % (57) had at least one high risk serrated polyp and 13.9 % (322) had at least one advanced neoplasm. Overall, serrated polyps were more often nonpolypoid than adenomas (16.2 % vs. 11.1 %; P = 0.002). In total, 65 high risk serrated polyps were found, of which 43.1 % (28) displayed a nonpolypoid endoscopic appearance. Patients with advanced neoplasms were more likely to have synchronous high risk serrated polyps than patients without advanced neoplasms: OR 3.66 (95 % CI 2.03 - 6.61, P < 0.001). CONCLUSIONS High risk serrated polyps are frequently nonpolypoid and are associated with synchronous advanced colorectal neoplasms. Advanced colorectal neoplasms may therefore be considered red flags for the presence of high risk serrated polyps. Detection, diagnosis, and treatment of high risk serrated lesions may be important targets to improve the quality of colonoscopic cancer prevention.

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.

Optical diagnosis of colorectal polyps using high-definition i-scan: An educational experience

AIM To examine performances regarding prediction of polyp histology using high-definition (HD) i-scan in a group of endoscopists with varying levels of experience. METHODS We used a digital library of HD i-scan still images, comprising twin pictures (surface enhancement and tone enhancement), collected at our university hospital. We defined endoscopic features of adenomatous and non-adenomatous polyps, according to the following parameters: color, surface pattern and vascular pattern. We familiarized the participating endoscopists on optical diagnosis of colorectal polyps using a 20-min didactic training session. All endoscopists were asked to evaluate an image set of 50 colorectal polyps with regard to polyp histology. We classified the diagnoses into high confidence (i.e., cases in which the endoscopist could assign a diagnosis with certainty) and low confidence diagnoses (i.e., cases in which the endoscopist preferred to send the polyp for formal histology). Mean sensitivity, specificity and accuracy per endoscopist/image were computed and differences between groups tested using independent-samples t tests. High vs low confidence diagnoses were compared using the paired-samples t test. RESULTS Eleven endoscopists without previous experience on optical diagnosis evaluated a total of 550 images (396 adenomatous, 154 non-adenomatous). Mean sensitivity, specificity and accuracy for diagnosing adenomas were 79.3%, 85.7% and 81.1%, respectively. No significant differences were found between gastroenterologists and trainees regarding performances of optical diagnosis (mean accuracy 78.0% vs 82.9%, P = 0.098). Diminutive lesions were predicted with a lower mean accuracy as compared to non-diminutive lesions (74.2% vs 93.1%, P = 0.008). A total of 446 (81.1%) diagnoses were made with high confidence. High confidence diagnoses corresponded to a significantly higher mean accuracy than low confidence diagnoses (84.0% vs 64.3%, P = 0.008). A total of 319 (58.0%) images were evaluated as having excellent quality. Considering excellent quality images in conjunction with high confidence diagnosis, overall accuracy increased to 92.8%. CONCLUSION After a single training session, endoscopists with varying levels of experience can already provide optical diagnosis with an accuracy of 84.0%.

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. Cancer Prev Res; 6(8); 855–63. ©2013 AACR.

Large proximal serrated polyps: natural history and colorectal cancer risk in a retrospective series.

To the Editor: As colonoscopy with the removal of precancerous lesions reduces the incidence and mortality of colorectal cancer,1 serious concerns have been raised by studies showing only limited effectiveness of colonoscopy in the prevention of proximal cancer.2 One of the many potential explanations for these postcolonoscopy cancers is the serrated neoplastic pathway, through which a subset of serrated polyps, namely sessile serrated adenomas/polyps and traditional serrated adenomas, might develop into colorectal cancer.3 The large variation in the detection of these lesions among endoscopists in conjunction with the difficulties in histologic classification by pathologists4 might explain the gaps in knowledge about the biology of serrated polyps. Serrated polyps are currently classified according to the WHO classification into hyperplastic polyps, sessile serrated adenomas/polyps with or without cytological dysplasia, and traditional serrated adenomas.5 International guidelines now endorse the need for accurate diagnosis and treatment of these lesions. We need to realize that data currently available about their biological behavior and cancer risk are scarce.6 Such information is crucial, as it may form the basis for evidence-based surveillance recommendations. Herewith, we present our experience with regard to the natural history and colorectal cancer risk in a small series of large proximal serrated polyps, after incomplete removal and a follow-up of at least 14 years. We retrospectively analyzed all patients diagnosed with at least 1 serrated polyp at our center, between January 1, 1991 and December 31, 1998, using a national pathology database. The group of serrated polyps comprised hyperplastic polyps, sessile serrated adenomas/polyps, and traditional serrated adenomas. Endoscopic records regarding size, number, location, and removal techniques of large proximal serrated polyps were retrieved. Proximal location was defined as proximal to the splenic flexure. Serrated polyps were defined as large, when sized Z6mm, as measured endoscopically. In our study, we used a cut-off value of 6mm for large serrated polyps for several reasons. Overall, serrated polyps are smaller in size than adenomas and are usually <6mm.7 In addition, nearly 50% of all sessile serrated adenomas/polyps seem to be sized 6 to 9mm.8 Moreover, serrated polyps often have indistinct borders, which may lead to underestimation of their size. A total of 689 patients who underwent colonoscopy were diagnosed with at least 1 serrated polyp during the study period. We excluded patients with incomplete clinicopathologic records (n=132), those who underwent sigmoidoscopy only (n=208), those with a personal history of colorectal cancer (n=50), prior colonic surgery (n=5), Lynch syndrome (n=1), or patients in whom histologic revision refuted the diagnosis of a serrated polyp (n=28). None of the patients fulfilled the diagnostic criteria for the serrated polyposis syndrome.9 Complete data of 265 patients with 482 serrated polyps were retrieved, of which we finally examined 18 patients with 21 large proximal serrated polyps, which were biopsied only, without complete removal, at the index colonoscopy. Of them, 3 patients developed colorectal cancer at the same anatomic location as the large proximal serrated polyp after 3, 5, and 9 years, respectively, whereas 1 patient developed colorectal cancer in the distal colon after 2 years. Sizes of the large proximal serrated polyps, which might have evolved into proximal colorectal cancer, in the 3 patients were 6, 6, and 10mm, respectively. Patients with large proximal serrated polyps significantly more often developed colorectal cancer compared with those with smaller proximal serrated polyps or serrated polyps in the distal colon (22.2% vs. 1.6%, P=0.001, Fisher exact test). Histologic revision of the original slides by 2 experienced (R.G.R., A.D.) and 1 expert gastrointestinal pathologist (F.T.B.) revealed that all large proximal serrated polyps of the patients who developed colorectal cancer were hyperplastic polyps. The 3 cases of colorectal cancer arising in the proximal colon were characterized by BRAFmutation, CIMP-H, and in 1 case microsatellite instability. A total of 14 patients with 16 large proximal serrated polyps (ie, in 1 case, the diagnosis of serrated polyp could not be confirmed by revision) did not develop colorectal cancer. Of these serrated polyps, 83.3% (10/12) were CIMP-H, 54.5% (6/11) BRAF mutated, and 100.0% (11/11) microsatellite stable. In our experience, 3 out of 18 (17%) patients with large proximal serrated polyps, biopsied only at the index colonoscopy, developed colorectal cancer in the proximal colon. The molecular characteristics of the large proximal serrated polyps and metachronous colorectal cancers support the involvement of the serrated neoplastic pathway. Although several studies suggest that large proximal serrated polyps, especially sessile serrated adenomas/polyps, are precursors of colorectal cancer, data about their natural history are still sparse and controversial. As clinical awareness about the relevance of large proximal serrated polyps has substantially increased over the past years, it remains questionable whether we will be truly able to clarify their cancer risk in the future. Circumstantial evidence, although imperfect, is the best we can achieve. In this retrospective series, histologic revision showed that all 4 large proximal serrated polyps in the patients who developed colorectal cancer were hyperplastic polyps. Although revision was performed on biopsy material only, we cannot exclude the former lesions were in fact sessile serrated adenomas/polyps. Moreover, the histologic distinction of sessile serrated adenomas/polyps from hyperplastic polyps remains difficult in routine practice,10 especially when limited material is available for diagnosis. Of note, several authors postulated that hyperplastic polyps and sessile serrated adenomas/polyps might in fact represent a morphological continuum.11 Our findings further support this concept, indicating that recognition and removal of all large proximal serrated polyps, irrespective of histologic classification, might be a more realistic target in routine practice. In the present study, large proximal serrated polyps were incompletely removed during the index colonoscopy. The authors declare that they have nothing to disclose. LETTERS TO THE EDITOR

Significantly higher rates of multiple and proximally located adenomas among patients with diabetes mellitus: A cross-sectional population-based study

Background Diabetes mellitus (DM) is associated with a greater risk for colorectal cancer (CRC). Objective The objective of this article is to examine the endoscopic phenotype and histopathology of colorectal polyps in patients with vs without DM. Methods We conducted a cross-sectional study of patients who underwent colonoscopy at our university hospital and who completed a questionnaire. We collected endoscopy and histopathology data regarding colorectal adenomas and serrated polyps. Cox regression analyses were used to estimate adjusted prevalence ratios (PRs). Results We examined a total of 3654 patients (mean age (SD): 62 (12) years, 47% males). Of them, 360 (9.9%) had DM. Overall, the prevalence of colorectal adenomas (42% vs 32%, p < 0.01), multiple (≥3) adenomas (12% vs 7%, p = 0.01) and proximal adenomas (30% vs 19%, p < 0.01) was higher in patients with vs without DM. Multivariable analysis showed that the prevalence of adenomas (PR 1.17, 95% CI; 1.02–1.34), multiple (PR 1.37, 95% CI; 1.00–1.86) and proximal (PR 1.37, 95% CI; 1.16–1.62) adenomas was higher in patients with vs without DM, especially in men. Conclusion Patients with DM harbor more frequently multiple and proximal adenomas than those without DM. Close colonoscopic surveillance of DM patients is important to maximize the effectiveness of colonoscopic CRC prevention.

Tu1890 Serrated Polyposis Syndrome: Incidence Rates and Clinicopathologic Characteristics in a Population-Based Study

posing risk for colorectal cancer development following a screening colonoscopy. Main objective of this study was a decade-long observation of patients after initial removal of adenomatous polyp(s), mainly in search for presence of recurrent adenomas. Another goal was to study the genetic profile of the most common somatic DNA mutations and their possible relation to adenoma recurrence potential. Material and methods: Patients included in the study were subjected to initial colonoscopy with polypectomy performed between 2002 and 2006. The tissue sample was always initially inspected by pathologist, followed by extraction of DNA and mutation detection directed at a panel of CRC mutation panel (APC, TP53, KRAS and BRAF). A subgroups of patients were then subjected to colonoscopy in recommended intervals with focus on relation between removed adenoma mutation and presence of recurrent adenomas. The followup intervals were either i) less than 3 years or ii) 3 years or longer depending on the initial adenoma level of risk. Results: 48 patients (39 men and 9 women, mean age of 62 years) undergoind initial colonoscopy with poylpectomy were enrolled in the study. Follow-up colonoscopies were gthen performed on 30 patients. Recurrence adenoma within 3 years was diagnosed in 11 (37%) of cases. 19 patients (63%) had no adenoma presence or the interval of recurrence adenoma was longer than 3 years. Somatic mutations were found in 10 patient in the first and 8 patients in the second group, respectively (90% and 42%; p=0.0249). Mutations were observed in 60% (29/48) of patients with advanced adenoma (size ≥ 10mm, villous structure, high grade dysplasia) and in 28% (8/28) with early adenoma. Conclusion: Follow-up with recommended intervals is the important tool for prevention of colorectal cancer development, especially in an important subgroup of patients susceptible to recurrent adenoma development. The pilot results imply that the chromosomal instability phenotype (CIN), uncovered by genetic testing of the autonomous tissue, may represent the independent factor of such recurrences increased risk. Supported by the Czech Ministry of Health Grant No. 14383

Tu1163 Macroscopic Features of Neuroendocrine Colorectal Cancers: A 10-Year Retrospective Study

vs. jejunum 90% vs. ileum 93%, p< 0.001). There was no significant difference in mean age at diagnosis, sex, or the number of additional primary cancers between the three primary sites. Using KM methods, five-year survival was marginally better for duodenal and ileal lesions than jejunal lesions (duodenum 67% vs. jejunum 66% vs. ileum 61%, p=0.045). However, on CPH analysis, duodenal lesions had significantly better survival than jejunal or ileal lesions (jejunum vs. duodenumHR 1.845 [95% CI 1.461-2.329] p<0.001, ileum vs. duodenal HR 1.665 [95% CI 1.388-1.999], p<0.001), controlling for age, stage, year of diagnosis, sex, race, marital status, and cancer-directed surgery. Conclusion: Epidemiology and survival patterns of SICs vary based on intestinal location. As duodenal lesions are diagnosed at an earlier stage and associated with significantly improved survival than jejunal or ileal lesions, it may be possible to avoid high-risk surgery for selected lesions in these patients.