Colorectal cancer (CRC) is considered a heterogeneous disease, both regarding pathogenesis and clinical behaviour. Four decades ago, the adenoma-carcinoma pathway was presented as the main pathway ...towards CRC, a conclusion that was largely based on evidence from observational morphological studies. This concept was later substantiated at the genomic level. Over the past decade, evidence has been generated for alternative routes in which CRC might develop, in particular the serrated neoplasia pathway. Providing indisputable evidence for the neoplastic potential of serrated polyps has been difficult. Reasons include the absence of reliable longitudinal observations on individual serrated lesions that progress to cancer, a shortage of available animal models for serrated lesions and challenging culture conditions when generating organoids of serrated lesions for in vitro studies. However, a growing body of circumstantial evidence has been accumulated, which indicates that ≥15% of CRCs might arise through the serrated neoplasia pathway. An even larger amount of post-colonoscopy colorectal carcinomas (carcinomas occurring within the surveillance interval after a complete colonoscopy) have been suggested to originate from serrated polyps. The aim of this Review is to assess the current status of the serrated neoplasia pathway in CRC and highlight clinical implications.
Sessile serrated adenomas/polyps (SSA/Ps) are the precursors of 15 % - 30 % of colorectal cancers (CRC). We aimed to determine the prevalence and distribution of SSA/Ps and to evaluate the ...association between SSA/Ps and the risk of synchronous advanced neoplasia at a high quality colonoscopy center.
Data from all colonoscopies performed within one dedicated colonoscopy center between 2011 and 2015 were prospectively retrieved using an automated reporting system. All lesions were assessed by an experienced gastrointestinal pathologist. Multiple logistic regression was used to evaluate influence of age, gender, and colonoscopy indication on prevalence of SSA/Ps, and to assess the association between SSA/Ps and synchronous advanced neoplasia.
In total 4251 histologically confirmed polyps were resected in 3364 patients; 399 polyps were SSA/Ps (9.4 %). The prevalence of SSA/Ps was 8.2 % overall, increasing to 9.0 % for individuals older than 50 years. SSA/P detection rate varied between 2.5 % and 13.6 % among endoscopists. Increased SSA/P prevalence was associated with colonoscopy indications "familial CRC risk" (odds ratio OR 1.52, 95 % confidence interval 95 %CI 1.05 - 2.22; P = 0.03) and "surveillance" (OR 1.73, 95 %CI 1.20 - 2.49; P < 0.01), when compared with the indication "symptoms." The presence of synchronous advanced neoplasia was associated with SSA/Ps overall (OR 1.71, 95 %CI 1.25 - 2.34; P = 0.001), as well as with high risk SSA/Ps (defined as ≥ 10 mm and/or with dysplasia) (OR 2.70, 95 %CI 1.56 - 4.67; P < 0.001) CONCLUSION: SSA/Ps are more common than previously reported and are associated with the presence of synchronous advanced neoplasia. Endoscopists should be assiduous in identifying SSA/Ps in daily practice and should carefully look for synchronous advanced neoplasia when an SSA/P has been recognized. RESULTS from this study can guide detection standards in general colonoscopy practice adapted to the type of patient that may predominate in an individual department.
Accurate endoscopic differentiation would enable to resect and discard small and diminutive colonic lesions, thereby increasing cost-efficiency. Current classification systems based on narrow band ...imaging (NBI), however, do not include neoplastic sessile serrated adenomas/polyps (SSA/Ps). We aimed to develop and validate a new classification system for endoscopic differentiation of adenomas, hyperplastic polyps and SSA/Ps <10 mm.
We developed the Workgroup serrAted polypS and Polyposis (WASP) classification, combining the NBI International Colorectal Endoscopic classification and criteria for differentiation of SSA/Ps in a stepwise approach. Ten consultant gastroenterologists predicted polyp histology, including levels of confidence, based on the endoscopic aspect of 45 polyps, before and after participation in training in the WASP classification. After 6 months, the same endoscopists predicted polyp histology of a new set of 50 polyps, with a ratio of lesions comparable to daily practice.
The accuracy of optical diagnosis was 0.63 (95% CI 0.54 to 0.71) at baseline, which improved to 0.79 (95% CI 0.72 to 0.86, p<0.001) after training. For polyps diagnosed with high confidence the accuracy was 0.73 (95% CI 0.64 to 0.82), which improved to 0.87 (95% CI 0.80 to 0.95, p<0.01). The accuracy of optical diagnosis after 6 months was 0.76 (95% CI 0.72 to 0.80), increasing to 0.84 (95% CI 0.81 to 0.88) considering high confidence diagnosis. The combined negative predictive value with high confidence of diminutive neoplastic lesions (adenomas and SSA/Ps together) was 0.91 (95% CI 0.83 to 0.96).
We developed and validated the first integrative classification method for endoscopic differentiation of small and diminutive adenomas, hyperplastic polyps and SSA/Ps. In a still image evaluation setting, introduction of the WASP classification significantly improved the accuracy of optical diagnosis overall as well as SSA/P in particular, which proved to be sustainable after 6 months.
The heterogeneous nature of colorectal cancer (CRC) complicates prognosis and is suggested to be a determining factor in the efficacy of adjuvant therapy for individual patients. Based on gene ...expression profiling, CRC is currently classified into four consensus molecular subtypes (CMSs), characterized by specific biological programs, thus suggesting the existence of unifying developmental drivers for each CMS. Using human organoid cultures, we investigated the role of such developmental drivers at the premalignant stage of distinct CRC subtypes and found that TGFβ plays an important role in the development of the mesenchymal CMS4, which is of special interest due to its association with dismal prognosis. We show that in tubular adenomas (TAs), which progress to classical CRCs, the dominating response to TGFβ is death by apoptosis. By contrast, induction of a mesenchymal phenotype upon TGFβ treatment prevails in a genetically engineered organoid culture carrying a BRAFV600E mutation, constituting a model system for sessile serrated adenomas (SSAs). Our data indicate that TGFβ signaling is already active in SSA precursor lesions and that TGFβ is a critical cue for directing SSAs to the mesenchymal, poor‐prognosis CMS4 of CRC.
Synopsis
Sessile serrated adenomas (SSAs)—precursor lesions of the serrated neoplasia pathway to colorectal cancer (CRC)—are predicted to give rise to either the good‐ or the poor‐prognosis CRC consensus molecular subtype (CMS1 and CMS4, respectively).
Organoid cultures from patient‐derived pre‐neoplastic lesions and genetically engineered organoid cultures present valuable model systems for early stage disease.
An organoid culture genetically engineered to carry the BRAFV600E mutation served as a model system for the earliest stage of the serrated neoplasia pathway.
A TGFβ signature separated patient‐derived tubular adenomas—precursor lesions of the classical path to CRC—from SSAs.
High activity of the TGFβ signaling pathway was detected in SSAs that would likely have—judged by gene expression‐based prediction—developed to CMS4‐like CRCs.
Sessile serrated adenomas (SSAs)—precursor lesions of the serrated neoplasia pathway to colorectal cancer (CRC)—are predicted to give rise to either the good‐ or the poor‐prognosis CRC consensus molecular subtype (CMS1 and CMS4, respectively).
Serrated polyposis syndrome (SPS) is associated with an increased risk of colorectal cancer (CRC). International guidelines recommend surveillance intervals of 1-2 years. However, yearly surveillance ...likely leads to overtreatment for many. We prospectively assessed a surveillance protocol aiming to safely reduce the burden of colonoscopies.
Between 2013 and 2018, we enrolled SPS patients from nine Dutch and Spanish hospitals. Patients were surveilled using a protocol appointing either a 1-year or 2-year interval after each surveillance colonoscopy, based on polyp burden. Primary endpoint was the 5-year cumulative incidence of CRC and advanced neoplasia (AN) during surveillance.
We followed 271 SPS patients for a median of 3.6 years. During surveillance, two patients developed CRC (cumulative 5-year incidence 1.3%95% CI 0% to 3.2%). The 5-year AN incidence was 44% (95% CI 37% to 52%), and was lower for patients with SPS type III (26%) than for patients diagnosed with type I (53%) or type I and III (59%, p<0.001). Most patients were recommended a 2-year interval, and those recommended a 2-year interval were not at increased risk of AN: AN incidence after a 2-year recommendation was 15.6% compared with 24.4% after a 1-year recommendation (OR 0.57, p=0.08).
Risk stratification substantially reduced colonoscopy burden while achieving CRC incidence similar to previous studies. AN incidence is considerable in SPS patients, but extension of surveillance intervals was not associated with increased AN in those identified as low-risk by the protocol. We identified SPS type III patients as low-risk group that might benefit from even less frequent surveillance.
The study was registered on http://www.trialregister.nl; trial-ID NTR4609.
Background and Aims The adenoma detection rate (ADR) is the most important surrogate quality parameter for colorectal cancer (CRC) prevention. However, serrated polyps also are precursors of CRC. ...Large, prospective studies comparing the detection rate of serrated polyps among endoscopists in an era of awareness about the malignant potential of serrated polyps have not yet been performed. We aimed to compare the proximal serrated polyp (PSP) detection rate and the clinically relevant serrated polyp (RSP) detection rate among endoscopists and to analyze the association between these parameters and the ADR. Methods Colonoscopy data were retrieved in one expert center between January 2011 and July 2014 by using a structured reporting system, enabling prospective and automatic quality assessment. Endoscopists who performed at least 50 colonoscopies within the timeframe were included for analysis. Multivariate logistic regression was used to compare the ADR, PSP detection rate, and RSP detection rate among endoscopists. The association among these parameters was calculated by using the Pearson r correlation coefficient. All lesions were assessed by an expert pathologist. Results In total, 16 endoscopists and 2088 colonoscopies were included for analysis. The PSP detection rate ranged from 2.9% to 18.6% (mean 10.4%) among endoscopists. Corrected for confounders, the odds ratio to detect ≥1 PSP, compared with endoscopists with the highest detection rate, ranged from 0.79 (95% confidence interval CI, 0.41-1.52) to 0.12 (95% CI, 0.03-0.55). The PSP detection rate was highly correlated with the RSP detection rate (ρ 0.94; P < .001), ranging from 4.3% to 20.9% (mean 13.9%). The PSP detection rate moderately correlated with the ADR (0.55; P = .03), which ranged from 23.2% to 49.2% (mean 35.2%). Conclusions The PSP detection rate is widely variable among endoscopists, strongly correlated with the RSP detection rate, and moderately correlated with the ADR. These results suggest a high miss rate of RSPs among endoscopists with low rates of PSP detection. Future research should determine the association between endoscopists’ PSP detection rates and the risk of interval cancer.
For decades, conventional adenomas were the only known precursor lesions of colorectal cancer (CRC). Accordingly, education and research regarding CRC prevention were mainly focused on adenomas. The ...groundbreaking discovery that serrated polyps (SPs) also have the potential to develop into CRCs, and seem to account for a considerable proportion of sporadic CRCs, has led to a paradigm shift in the prevention, diagnosis, and treatment of CRC. Studies in recent years have led to our current understanding of SPs and associated CRC, but a lot of work is still to be done to further improve knowledge about this serrated neoplasia pathway and the clinical management of SPs and serrated polyposis syndrome (SPS). In this review, we reflect on the current understanding of SPs with respect to terminology, detection, resection, and surveillance and reflect on the management of SPS.
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