ABSTRACT
Serrated polyps have been recognised in the last decade as important premalignant lesions accounting for between 15% and 30% of colorectal cancers. There is therefore a clinical need for guidance on how to manage these lesions; however, the evidence base is limited. A working group was commission by the British Society of Gastroenterology (BSG) Endoscopy section to review the available evidence and develop a position statement to provide clinical guidance until the evidence becomes available to support a formal guideline. The scope of the position statement was wide-ranging and included: evidence that serrated lesions have premalignant potential; detection and resection of serrated lesions; surveillance strategies after detection of serrated lesions; special situations-serrated polyposis syndrome (including surgery) and serrated lesions in colitis; education, audit and benchmarks and research questions. Statements on these issues were proposed where the evidence was deemed sufficient, and re-evaluated modified via a Delphi process until >80% agreement was reached. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) tool was used to assess the strength of evidence and strength of recommendation for finalised statements. Key recommendation: we suggest that until further evidence on the efficacy or otherwise of surveillance are published, patients with sessile serrated lesions (SSLs) that appear associated with a higher risk of future neoplasia or colorectal cancer (SSLs ≥10â mm or serrated lesions harbouring dysplasia including traditional serrated adenomas) should be offered a one-off colonoscopic surveillance examination at 3â years (weak recommendation, low quality evidence, 90% agreement).
Subject(s)
Humans , Colonic Polyps/diagnosis , Colitis/diagnosis , Intestinal Polyposis/diagnosis , Parasympatholytics/therapeutic use , Precancerous Conditions/diagnosis , Biomarkers/analysis , Colonoscopy , Feces/chemistryABSTRACT
Population-based screening for early detection and treatment of colorectal cancer (CRC) and precursor lesions, using evidence-based methods, can be effective in populations with a significant burden of the disease provided the services are of high quality. Multidisciplinary, evidence-based guidelines for quality assurance in CRC screening and diagnosis have been developed by experts in a project co-financed by the European Union. The 450-page guidelines were published in book format by the European Commission in 2010.â They include 10 chapters and over 250 recommendations, individually graded according to the strength of the recommendation and the supporting evidence. Adoption of the recommendations can improve and maintain the quality and effectiveness of an entire screening process, including identification and invitation of the target population, diagnosis and management of the disease and appropriate surveillance in people with detected lesions. To make the principles, recommendations and standards in the guidelines known to a wider professional and scientific community and to facilitate their use in the scientific literature, the original content is presented in journal format in an open-access Supplement of Endoscopy. The editors have prepared the present overview to inform readers of the comprehensive scope and content of the guidelines.
Subject(s)
Colorectal Neoplasms/diagnosis , Mass Screening/standards , Quality Assurance, Health Care , Early Detection of Cancer , Europe , Evidence-Based Medicine , HumansABSTRACT
Multidisciplinary, evidence-based guidelines for quality assurance in colorectal cancer screening and diagnosis have been developed by experts in a project coordinated by the International Agency for Research on Cancer. The full guideline document covers the entire process of population-based screening. It consists of 10 chapters and over 250 recommendations, graded according to the strength of the recommendation and the supporting evidence. The 450-page guidelines and the extensive evidence base have been published by the European Commission. The chapter on colonoscopic surveillance following adenoma removal includes 24 graded recommendations. The content of the chapter is presented here to promote international discussion and collaboration by making the principles and standards recommended in the new EU Guidelines known to a wider professional and scientific community. Following these recommendations has the potential to enhance the control of colorectal cancer through improvement in the quality and effectiveness of surveillance and other elements in the screening process, including multi-disciplinary diagnosis and management of the disease.
Subject(s)
Adenoma/surgery , Colonic Polyps/surgery , Colonoscopy/standards , Colorectal Neoplasms/diagnosis , Early Detection of Cancer/standards , Population Surveillance/methods , Quality Assurance, Health Care , Adenocarcinoma/diagnosis , Adenocarcinoma/prevention & control , Adenoma/pathology , Colonic Polyps/pathology , Colonoscopy/methods , Colorectal Neoplasms/prevention & control , Colorectal Neoplasms/surgery , Early Detection of Cancer/methods , European Union , Guideline Adherence/standards , Humans , Quality Assurance, Health Care/methods , Quality Assurance, Health Care/organization & administration , Quality Improvement , Recurrence , Risk AssessmentABSTRACT
Multidisciplinary, evidence-based guidelines for quality assurance in colorectal cancer screening and diagnosis have been developed by experts in a project coordinated by the International Agency for Research on Cancer. The full guideline document covers the entire process of population-based screening. It consists of 10 chapters and over 250 recommendations, graded according to the strength of the recommendation and the supporting evidence. The 450-page guidelines and the extensive evidence base have been published by the European Commission. The chapter on quality assurance in endoscopy includes 50 graded recommendations. The content of the chapter is presented here to promote international discussion and collaboration by making the principles and standards recommended in the new EU Guidelines known to a wider professional and scientific community. Following these recommendations has the potential to enhance the control of colorectal cancer through improvement in the quality and effectiveness of endoscopy and other elements in the screening process, including multidisciplinary diagnosis and management of the disease.
Subject(s)
Colonoscopy/standards , Colorectal Neoplasms/diagnosis , Early Detection of Cancer/standards , Mass Screening/standards , Quality Assurance, Health Care , Appointments and Schedules , Clinical Competence , Colonoscopy/instrumentation , Colonoscopy/methods , Colorectal Neoplasms/prevention & control , Conscious Sedation/standards , Early Detection of Cancer/methods , European Union , Humans , Informed Consent/standards , Mass Screening/methods , Mass Screening/organization & administration , Outcome and Process Assessment, Health Care , Patient Safety , Quality Assurance, Health Care/methods , Quality Assurance, Health Care/organization & administration , Quality Improvement , Sigmoidoscopy/instrumentation , Sigmoidoscopy/methods , Sigmoidoscopy/standardsABSTRACT
BACKGROUND: Bowel cancer is a serious health burden and its early diagnosis improves survival. The Bowel Cancer Screening Programme (BCSP) in England screens with the Faecal Occult Blood test (FOBt), followed by colonoscopy for individuals with a positive test result. Socioeconomic inequalities have been demonstrated for FOBt uptake, but it is not known whether they persist at the next stage of the screening pathway. The aim of this study was to assess the association between colonoscopy uptake and area socioeconomic deprivation, controlling for individual age and sex, and area ethnic diversity, population density, poor self-assessed health, and region. METHODS: Logistic regression analysis of colonoscopy uptake using BCSP data for England between 2006 and 2009 for 24 180 adults aged between 60 and 69 years. RESULTS: Overall colonoscopy uptake was 88.4%. Statistically significant variation in uptake is found between quintiles of area deprivation (ranging from 86.4 to 89.5%), as well as age and sex groups (87.9-89.1%), quintiles of poor self-assessed health (87.5-89.5%), non-white ethnicity (84.6-90.6%) and population density (87.9-89.3%), and geographical regions (86.4-90%). CONCLUSION: Colonoscopy uptake is high. The variation in uptake by socioeconomic deprivation is small, as is variation by subgroups of age and sex, poor self-assessed health, ethnic diversity, population density, and region.
Subject(s)
Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/economics , Early Detection of Cancer/methods , Patient Acceptance of Health Care/statistics & numerical data , Aged , Colonoscopy/economics , Colonoscopy/statistics & numerical data , Feces/chemistry , Female , Humans , Male , Middle Aged , National Health Programs , Occult Blood , Retrospective Studies , Risk Factors , Socioeconomic Factors , Survival Rate , United KingdomABSTRACT
OBJECTIVES: Evidence from existing UK screening programmes indicates disparities in uptake rates between UK ethnic minorities and the white majority population. The aim of this study was to explore barriers to the uptake of flexible sigmoidoscopy (FS) screening among UK ethnic minority populations. Specifically, beliefs about bowel cancer, perceived barriers to the test and ideas about ways to increase uptake were investigated. METHODS: Nine focus groups were conducted with a total of 53 participants from African-Caribbean, Gujarati Indian, Pakistani and white British communities. The topic guide was based on the Health Belief Model. Discussions were subject to framework analysis. RESULTS: Most participants expressed limited awareness of bowel cancer and cited this as a barrier to screening attendance. Anxiety regarding the invasiveness of the test, the bowel preparation and fear of a cancer diagnosis were common barriers across all ethnic groups. Language difficulties, failure to meet religious sensitivities and the expression of culturally influenced health beliefs were all discussed as specific barriers to uptake. Ethnically tailored health promotion and general practitioner involvement were recommended as ways of overcoming such barriers. CONCLUSIONS: The study was the first attempt to qualitatively explore barriers to FS bowel cancer screening in UK ethnic minorities. Most barriers were shared by all ethnic groups but health educators should supplement approaches designed for the majority to incorporate the specific needs of individual minority groups to ensure equitable access.
Subject(s)
Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/ethnology , Minority Groups/statistics & numerical data , Sigmoidoscopy/statistics & numerical data , Aged , Attitude to Health , Colorectal Neoplasms/psychology , Female , Humans , Male , Middle Aged , Minority Groups/psychology , United KingdomABSTRACT
Previous studies of patient experience with bowel screening tests, in particular CT colonography (CTC), have superimposed global rating scales and not explored individual experience in detail. To redress this, we performed qualitative interviews in order to characterize patient expectations and experiences in depth. Following ethical permission, 16 patients undergoing CTC, 18 undergoing colonoscopy and 15 undergoing barium enema agreed to a semi-structured interview by a health psychologist. Interviews were recorded, responses transcribed and themes extracted with the aim of assimilating individual experiences to facilitate subsequent development and interpretation of quantitative surveys of overall satisfaction with each diagnostic test. Transcript analysis identified three principal themes: physical sensations, social interactions and information provision. Physical sensations differed for each test but were surprisingly well tolerated overall. Social interactions with staff were perceived as very important in colouring the whole experience, particularly in controlling the feelings of embarrassment, which was critical for all procedures. Information provision was also an important determinant of experience. Verbal feedback was most common during colonoscopy and invariably reassuring. However, patients undergoing CTC received little visual or verbal feedback and were often confused regarding the test outcome. Barium enema had no specific advantage over other tests. Qualitative interviews provided important perspectives on patient experience. Our data demonstrated that models describing the quality of medical encounters are applicable to single diagnostic episodes. Staff interactions and information provision were particularly important. We found advantages specific to both CTC and colonoscopy but none for barium enema. CTC could benefit greatly from improved information provision following examination.
Subject(s)
Attitude to Health , Colonography, Computed Tomographic/psychology , Colonoscopy/psychology , Colorectal Neoplasms/diagnosis , Enema/psychology , Aged , Aged, 80 and over , Barium Sulfate , Colonography, Computed Tomographic/adverse effects , Colonoscopy/adverse effects , Colorectal Neoplasms/diagnostic imaging , Colorectal Neoplasms/psychology , Contrast Media , Enema/adverse effects , Female , Humans , Male , Middle Aged , Professional-Patient RelationsABSTRACT
BACKGROUND: The aim was to identify the patients with colorectal symptoms most likely to benefit from whole colonic imaging (WCI) to diagnose colorectal cancer and those for whom flexible sigmoidoscopy (FS) may be initially sufficient. METHODS: This prospective observational study (16 years) included 16 433 newly referred patients with symptoms or signs of colorectal cancer. RESULTS: Colorectal cancer was diagnosed in 946 patients (diagnostic yield 5.8 per cent), 815 (86.2 per cent) in the rectum or sigmoid (distal) and 131 (13.8 per cent) in the proximal colon. Some 15 829 patients (96.3 per cent) presented with symptoms alone (without iron deficiency anaemia or abdominal mass). Of 787 cancers in these patients, 750 (95.3 per cent) were distal. The prevalence of proximal cancer above and below the age of 60 years was 0.4 per cent (33 of 8249) and 0.1 per cent (four of 7580) respectively. Of 16 256 patients having FS, 5665 (34.8 per cent) had WCI. Of the other 10 591, five subsequently presented with proximal cancers. FS missed ten (1.3 per cent) of 796 cancers. CONCLUSION: Patients with iron deficiency anaemia or a mass require WCI. However, in patients with symptoms alone, FS detects 95 per cent of cancers, and the diagnostic yield of WCI after FS is very low. Alternative management strategies need to be developed to avoid unnecessary investigations in this low-risk group.
Subject(s)
Colorectal Neoplasms/diagnosis , Sigmoidoscopy/methods , Aged , Aged, 80 and over , Anemia/etiology , Cohort Studies , Diagnostic Errors , Enema , Female , Humans , Male , Middle Aged , Occult Blood , Prospective Studies , Referral and Consultation , Risk FactorsABSTRACT
Hyperplastic Polyposis (HPPS) is a poorly characterized syndrome that increases colorectal cancer (CRC) risk. We aimed to provide a molecular classification of HPPS. We obtained 282 tumours from 32 putative HPPS patients with >or= 10 hyperplastic polyps (HPs); some patients also had adenomas and CRCs. We found no good evidence of microsatellite instability (MSI) in our samples. The epithelium of HPs was monoclonal. Somatic BRAF mutations occurred in two-thirds of our patients' HPs, and KRAS2 mutations in 10%; both mutations were more common in younger cases. The respective mutation frequencies in a set of 'sporadic' HPs were 18% and 10%. Importantly, the putative HPPS patients generally fell into two readily defined groups, one set whose polyps had BRAF mutations, and another set whose polyps had KRAS2 mutations. The most plausible explanation for this observation is that there exist different forms of inherited predisposition to HPPS, and that these determine whether polyps follow a BRAF or KRAS2 pathway. Most adenomas and CRCs from our putative HPPS patients had 'classical' morphology and few of these lesions had BRAF or KRAS2 mutations. These findings suggest that tumourigenesis in HPPS does not necessarily follow the 'serrated' pathway. Although current definitions of HPPS are sub-optimal, we suggest that diagnosis could benefit from molecular analysis. Specifically, testing BRAF and KRAS2 mutations, and perhaps MSI, in multiple polyps could help to distinguish HPPS from sporadic HPs. We propose a specific model which would have diagnosed five more of our cases as HPPS compared with the WHO clinical criteria.
Subject(s)
Colorectal Neoplasms/genetics , Intestinal Polyposis/genetics , Adolescent , Adult , Aged , Cell Transformation, Neoplastic/genetics , Child , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/pathology , Female , Genetic Predisposition to Disease , Humans , Hyperplasia/genetics , Intestinal Mucosa/metabolism , Intestinal Polyposis/diagnosis , Intestinal Polyposis/pathology , Loss of Heterozygosity , Male , Middle Aged , Mutation , Neoplasm Proteins/genetics , Phenotype , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras) , ras Proteins/geneticsABSTRACT
AIM: To investigate interpretative accuracy and reporting time for radiologists performing computed tomography (CT) colonography in day-to-day non-academic clinical practice. MATERIALS AND METHODS: Thirteen radiologists from seven centres, who were reporting CT colonography in non-academic daily clinical practice, interpreted a dataset of 15 colonoscopically validated cases in a controlled environment. Ten cases had either a cancer or polyp >10mm; one case had a medium polyp and four were normal. Correct case categorization and interpretation times were compared using analysis of variance to aggregated results obtained from both experienced observers and observers recently trained using 50 cases, working in an academic environment. The effect of experience was determined using Spearman's rank correlation. RESULTS: Individual accuracy was highly variable, range 53% (95% CI 27-79%) to 93% (95% CI 68-100%). Mean accuracy overall was significantly inferior to experienced radiologists (mean 75 versus 88%, p=0.04) but not significantly different from recently trained radiologists (p=0.48). Interpretation time was not significantly different to experienced readers (mean 12.4 min versus 11.7, p=0.74), but shorter than recently trained radiologists (p=0.05). There was a significant, positive, linear correlation between prior experience and accuracy (p<0.001) with no plateau. CONCLUSION: Accuracy for sub-specialist radiologists working in a non-academic environment is, on average, equivalent to radiologists trained using 50 cases. However, there is wide variability in individual performance, which generally falls short of the average performance suggested by meta-analysis of published data. Experience improves accuracy, but alone is insufficient to determine competence.
Subject(s)
Clinical Competence/standards , Colonography, Computed Tomographic/standards , Colonic Neoplasms/diagnostic imaging , Colonic Polyps/diagnostic imaging , Humans , Image Interpretation, Computer-Assisted/methods , Observer Variation , Time FactorsABSTRACT
Bowel cancer is a major cause of morbidity and death and is a high cost to health care systems. Screening currently offers the best chance of improving outcomes from bowel cancer. When introducing screening, the problems encountered in other cancers need to be avoided to maximize benefits and minimize harms.
Subject(s)
Intestinal Neoplasms/diagnosis , Mass Screening/methods , Adenomatous Polyps/diagnosis , Adenomatous Polyps/surgery , Colonoscopy , Humans , Intestinal Polyps/diagnosis , Intestinal Polyps/surgery , Occult Blood , Patient Compliance , Patient Education as Topic , Reproducibility of Results , Risk Assessment , United KingdomABSTRACT
BACKGROUND AND STUDY AIMS: Adenoma detection rates (ADRs) at screening flexible sigmoidoscopy are known to vary between endoscopists. Variability in the technique used and in the quality of bowel preparation may explain this. The aim of this study was to establish whether there is a relationship between the grading of bowel preparation and the ADR. MATERIALS AND METHODS: The relationship between the ADR and assessment of bowel preparation was examined using the full United Kingdom Flexible Sigmoidoscopy Screening Trial data set (n = 38 601). The consistency of the bowel preparation classification was then investigated by six experienced endoscopists (video scorers), who examined 260 flexible sigmoidoscopy cases - 20 from each of the 13 trial endoscopists. RESULTS: Overall, the ADR was significantly higher in flexible sigmoidoscopy examinations with excellent or good bowel preparation ( P = 0.02). However, endoscopists with a higher ADR coded a smaller proportion of their examinations as having excellent/good preparation ( P = 0.002). Video scorers agreed with the trial endoscopists' definition of bowel preparation in 48.9 % of the readings, but they scored the quality of preparation as poorer than the trial endoscopists in 36.4 % and 40.6 %, respectively, in the intermediate-performance group (10 % < ADR < 14 %) and lower-performance group (ADR = 10 %) in comparison with only 12.9 % in the high-performance group (ADR > or =14 %). There was a significant linear trend between the proportion scored as having poor bowel preparation and the ADR ( P < 0.001), varying from 2.7 % in the higher-performance ADR group to 13.4 % in the lower-performance group. CONCLUSIONS: Endoscopists with a higher ADR are more likely to be critical of the quality of bowel preparation. Training in judgement processes such as non-acceptance of suboptimal bowel preparation is required in order to ensure universally high standards in screening procedures.
Subject(s)
Adenoma/diagnosis , Colorectal Neoplasms/diagnosis , Enema/standards , Sigmoidoscopy/standards , Chi-Square Distribution , Clinical Competence , Female , Humans , Linear Models , Male , Mass Screening , Quality Assurance, Health Care , United Kingdom , Video RecordingABSTRACT
BACKGROUND AND AIMS: Variation in the adenoma detection rate (ADR) at flexible sigmoidoscopy screening has been shown to be due to variation in endoscopist performance. There are no objective methods for scoring an endoscopist's performance reliably, and the aim of this study was to develop a valid and reliable objective scoring method using video footage of screening flexible sigmoidoscopies. METHODS: In a series of five experiments, experienced endoscopists (the scorers) independently scored a sample (n = 43) of the 40 000 flexible sigmoidoscopy extubations recorded as part of the United Kingdom Flexible Sigmoidoscopy Screening Trial (UK FSST). The scoring system, the parameters scored, and their definitions evolved over the course of the five experiments. The initial visual analogue score (range 0-100) used in the first two experiments evolved into a five-point score that ranged from 1 (E, poor) to 5 (A, excellent) in the last three experiments. The final parameters scored were: time spent viewing the mucosa, re-examination of poorly viewed areas, suctioning of fluid pools, distension of the lumen, lower rectal examination, and overall quality of the examination. The first four experiments scored one individual case per endoscopist; in experiment 5, an overall score was awarded for five cases performed by each endoscopist being assessed. RESULTS: Scoring five cases examined by an individual endoscopist using the A-E grading system was the most reliable method (interclass correlation coefficient 0.89). Cluster analysis demonstrated that the endoscopists in the high-scoring ADR group (ADR 14.7-15.9 %) could be differentiated from those in the intermediate- and low-scoring ADR groups (ADR 8.6-12.6 %). CONCLUSIONS: An objective scoring system for assessing the accuracy of performance at screening flexible sigmoidoscopy, based on video footage, is described. Endoscopists who might benefit from further training can be identified using this method.
Subject(s)
Adenoma/diagnosis , Clinical Competence , Colonic Neoplasms/diagnosis , Mass Screening , Sigmoidoscopy , Video Recording , Humans , Observer Variation , Sigmoidoscopy/standardsABSTRACT
Colorectal cancer is a common cancer and common cause of death. The mortality rate from colorectal cancer can be reduced by identification and removal of cancer precursors, adenomas, or by detection of cancer at an earlier stage. Pilot screening programmes have demonstrated decreased colorectal cancer mortality; as a result many countries are developing colorectal cancer screening programmes. The most common modalities being evaluated are faecal occult blood testing, flexible sigmoidoscopy and colonoscopy. Implementation of screening tests has been hampered by cost, invasiveness, availability of resources and patient acceptance. New technologies such at computed tomographic colonography and stool screening for molecular markers of neoplasia are in development as potential minimally invasive tools. This review considers who should be screened, which test to use and how often to screen.
Subject(s)
Colorectal Neoplasms/prevention & control , Mass Screening/methods , Colorectal Neoplasms/economics , Colorectal Neoplasms/mortality , Cost-Benefit Analysis , Forecasting , Humans , Mass Screening/economics , Mass Screening/mortality , Patient SelectionABSTRACT
BACKGROUND: Flexible sigmoidoscopy (FS) is a complex technical procedure performed in a variety of settings, by examiners with diverse professional backgrounds, training, and experience. Potential variation in technical quality may have a profound impact on the effectiveness of FS on the early detection and prevention of colorectal cancer. AIM: We propose a set of consensus and evidence based recommendations to assist the development of continuous quality improvement programmes around the delivery of FS for colorectal cancer screening. RECOMMENDATIONS: These recommendations address the intervals between FS examinations, documentation of results, training of endoscopists, decision making around referral for colonoscopy, policies for antibiotic prophylaxis and management of anticoagulation, insertion of the FS endoscope, bowel preparation, complications, the use of non-physicians as FS endoscopists, and FS endoscope reprocessing. For each of these areas, continuous quality improvement targets are recommended, and research questions are proposed.
Subject(s)
Colorectal Neoplasms/prevention & control , Mass Screening/methods , Sigmoidoscopy/standards , Antibiotic Prophylaxis/methods , Anticoagulants/therapeutic use , Colorectal Surgery/education , Early Diagnosis , Education, Medical, Continuing , Humans , Informed Consent , Medical Staff, Hospital/education , Patient Satisfaction , Referral and Consultation , Sensitivity and Specificity , Sigmoidoscopy/adverse effects , Sigmoidoscopy/methodsABSTRACT
OBJECTIVES: To assess the demographic and psychological mediators of gender differences in uptake of flexible sigmoidoscopy (FS) screening for colorectal cancer. SETTING: A subsample (n=5462) from a large community trial of FS in the UK. METHODS: Men and women randomized to screening as part of the UK Flexible Sigmoidoscopy Trial were sent a postal questionnaire assessing demographic characteristics and attitudes to screening six months before their screening appointment. Attendance at screening was recorded by the screening centres. RESULTS: More men than women attended screening (73% versus 67%). The higher male attendance was partially explained by their lower levels of socioeconomic deprivation, higher levels of marital status and lower perceived barriers to screening. CONCLUSIONS: Contrary to expectations, men were more likely than women to attend FS screening. This was partially explained by socioeconomic and attitudinal differences to screening, but additional research is needed to understand the key aspects of FS screening that will maximize screening uptake in men and women.
Subject(s)
Colorectal Neoplasms/prevention & control , Mass Screening/statistics & numerical data , Attitude to Health , Colorectal Neoplasms/diagnosis , Female , Humans , Male , Middle Aged , Randomized Controlled Trials as Topic , Risk Factors , Sex Distribution , Sigmoidoscopy/statistics & numerical data , Surveys and Questionnaires , United KingdomABSTRACT
BACKGROUND AND AIMS: Activating beta-catenin mutations in exon 3 have been implicated in colorectal tumorigenesis. Although reports to the contrary exist, it has been suggested that beta-catenin mutations occur more often in microsatellite unstable (MSI+) colorectal carcinomas, including hereditary non-polyposis colorectal cancer (HNPCC), as a consequence of defective DNA mismatch repair. We have analysed 337 colorectal carcinomas and adenomas, from both sporadic cases and HNPCC families, to provide an accurate assessment of beta-catenin mutation frequency in each tumour type. METHODS: Direct sequencing of exon 3 of beta-catenin. RESULTS: Mutations were rare in sporadic (1/83, 1.2%) and HNPCC adenomas (1/37, 2.7%). Most of the sporadic adenomas analysed (80%) were small (<1 cm), and our data therefore differ from a previous report of a much higher mutation frequency in small adenomas. No oncogenic beta-catenin mutations were identified in 34 MSI+ and 78 microsatellite stable (MSI-) sporadic colorectal cancers but a raised mutation frequency (8/44, 18.2%) was found in HNPCC cancers; this frequency was significantly higher than that in HNPCC adenomas (p=0.035) and in both MSI- (p<0.0001) and MSI+ (p=0.008) sporadic cancers. Mutations were more common in higher stage (Dukes' stages C and D) cancers (p=0.001). CONCLUSION: Exon 3 beta-catenin mutations are associated specifically with malignant colorectal tumours in HNPCC; mutations appear not to result directly from deficient mismatch repair. Our data provide evidence that the genetic pathways of sporadic MSI+ and HNPCC cancers may be divergent, and indicate that mutations in the HNPCC pathway of colorectal tumorigenesis may be determined by selection, not simply by hypermutation.