CT-Colonography vs. Colonoscopy for Detection of High-Risk Sessile Serrated Polyps.

OBJECTIVES: Sessile serrated polyps (SSPs) are suggested to be the precursors of 15-30% of all colorectal cancers (CRCs). Therefore, CRC screening modalities should also be designed to detect high-risk SSPs. We compared computed tomography colonography (CTC) with colonoscopy-based screening for the detection of high-risk SSPs in average-risk individuals. METHODS: Data from a randomized controlled trial that compared CTC with colonoscopy for population screening were used for the analysis. Individuals diagnosed at CTC with a lesion ≥10 mm in size were referred for colonoscopy. Individuals with only 6-9 mm lesions were offered surveillance CTC. This surveillance CTC was followed by a colonoscopy when a lesion ≥6 mm was detected. Yield of both was accumulated to mimic current American College of Radiology CTC referral strategy (referral of individuals with any lesion ≥6 mm). Per participant detection of ≥1 high-risk (dysplastic and/or ≥10 mm) SSP was compared with colonoscopy using multiple logistic regression analysis. RESULTS: In total, 8,844 individuals were invited to participate (in 2:1 allocation), of which 1,276 colonoscopy and 982 CTC invitees participated in the study. In the colonoscopy arm, 4.3% of individuals were diagnosed with ≥1 high-risk SSP, compared with 0.8% in the CTC arm (odds ratio (OR) 5.5; 95% confidence interval (CI) 2.6-11.6; P<0.001). In total, 3.1% of individuals in the colonoscopy arm were diagnosed with high-risk SSPs as most advanced lesion, compared with 0.4% in the CTC arm (OR 7.7; 95% CI 2.7-21.6; P<0.001). The current CTC strategy showed a marked lower detection for especially flat high-risk SSPs (17 vs. 0), high-risk SSP located in the proximal colon (32 vs. 1), and SSPs with dysplasia (30 vs. 1). CONCLUSIONS: In a randomized controlled setting, the detection rate of high-risk SSPs was significantly higher with colonoscopy than CTC. These results might have implications for CTC as a CRC modality for opportunistic screening in average-risk adults.

Molecular profiling of longitudinally observed small colorectal polyps: A cohort study.

BACKGROUND: Knowledge of the natural history of colorectal adenomas is limited because these lesions are removed upon detection. The few studies in which small adenomas have been left in situ for a limited period of time, have shown that most lesions remain stable or even completely regress. Specific DNA copy number changes ('cancer associated events' or CAEs) are associated with progression of adenomas to cancer. In this study we evaluated whether molecular features of progression correlated with growth of small polyps. METHODS: Small (6-9 mm) colorectal precursor lesions detected on CT-colonography (CTC) were left in situ and re-evaluated with CTC after three years. Based on volumetric change, polyps were classified as either grown, stable or regressed. Surveillance CTC was followed by colonoscopy, during which all lesions were resected. Using DNA isolated from FFPE polyp tissues, low-coverage whole genome sequencing was performed to determine DNA copy number profiles, as well as target enrichment mutation analysis and CpG island methylation phenotype (CIMP) analysis. Expression of DNA mismatch repair (MMR) proteins was determined by immunohistochemistry. Samples were marked as MMR proficient if all MMR proteins were expressed. FINDINGS: Out of 68 polyps resected at colonoscopy, for 65 (96%) material was available. Of these, 31 (48%) had grown, 27 (41%) remained stable and 7 (11%) regressed. Polyps with at least one CAE had higher growth rates compared to polyps without CAEs (difference 91% growth (95% CI 13-169), p = .023). CAEs were absent in lesions that had partially regressed. Mutations occurred in 94% of the polyps, with higher growth rates being associated with polyps having ≥2 mutations compared to lesions with only 0-1 mutations (difference 99% growth (95% CI 9-189), p = .032). All samples were MMR proficient. No relation between growth and CIMP was observed. INTERPRETATION: Molecular alterations associated with colorectal cancer, correlated with growth of small polyps and were absent in polyps that regressed. Therefore, this longitudinal study provides in vivo support in the human setting for the functional role of these molecular alterations, that have mostly been identified by cross sectional observations in tissue samples of colorectal adenomas and cancers. FUND: Alpe d'Huzes- Dutch Cancer Society (project number NKI2013-6338).