Joep E. G. IJspeert

Serrated neoplasia—role in colorectal carcinogenesis and clinical implications

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.

Detection rate of serrated polyps and serrated polyposis syndrome in colorectal cancer screening cohorts: a European overview

Objective The role of serrated polyps (SPs) as colorectal cancer precursor is increasingly recognised. However, the true prevalence SPs is largely unknown. We aimed to evaluate the detection rate of SPs subtypes as well as serrated polyposis syndrome (SPS) among European screening cohorts. Methods Prospectively collected screening cohorts of ≥1000 individuals were eligible for inclusion. Colonoscopies performed before 2009 and/or in individuals aged below 50 were excluded. Rate of SPs was assessed, categorised for histology, location and size. Age–sex–standardised number needed to screen (NNS) to detect SPs were calculated. Rate of SPS was assessed in cohorts with known colonoscopy follow-up data. Clinically relevant SPs (regarded as a separate entity) were defined as SPs ≥10 mm and/or SPs >5 mm in the proximal colon. Results Three faecal occult blood test (FOBT) screening cohorts and two primary colonoscopy screening cohorts (range 1.426–205.949 individuals) were included. Rate of SPs ranged between 15.1% and 27.2% (median 19.5%), of sessile serrated polyps between 2.2% and 4.8% (median 3.3%) and of clinically relevant SPs between 2.1% and 7.8% (median 4.6%). Rate of SPs was similar in FOBT-based cohorts as in colonoscopy screening cohorts. No apparent association between the rate of SP and gender or age was shown. Rate of SPS ranged from 0% to 0.5%, which increased to 0.4% to 0.8% after follow-up colonoscopy. Conclusions The detection rate of SPs is variable among screening cohorts, and standards for reporting, detection and histopathological assessment should be established. The median rate, as found in this study, may contribute to define uniform minimum standards for males and females between 50 and 75 years of age.

TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype

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.

Clinical risk factors of colorectal cancer in patients with serrated polyposis syndrome: a multicentre cohort analysis

Objective Serrated polyposis syndrome (SPS) is accompanied by an increased risk of colorectal cancer (CRC). Patients fulfilling the clinical criteria, as defined by the WHO, have a wide variation in CRC risk. We aimed to assess risk factors for CRC in a large cohort of patients with SPS and to evaluate the risk of CRC during surveillance. Design In this retrospective cohort analysis, all patients with SPS from seven centres in the Netherlands and two in the UK were enrolled. WHO criteria were used to diagnose SPS. Patients who only fulfilled WHO criterion-2, with IBD and/or a known hereditary CRC syndrome were excluded. Results In total, 434 patients with SPS were included for analysis; 127 (29.3%) were diagnosed with CRC. In a per-patient analysis ≥1 serrated polyp (SP) with dysplasia (OR 2.07; 95% CI 1.28 to 3.33), ≥1 advanced adenoma (OR 2.30; 95% CI 1.47 to 3.67) and the fulfilment of both WHO criteria 1 and 3 (OR 1.60; 95% CI 1.04 to 2.51) were associated with CRC, while a history of smoking was inversely associated with CRC (OR 0.36; 95% CI 0.23 to 0.56). Overall, 260 patients underwent surveillance after clearing of all relevant lesions, during which two patients were diagnosed with CRC, corresponding to 1.9 events/1000 person-years surveillance (95% CI 0.3 to 6.4). Conclusion The presence of SPs containing dysplasia, advanced adenomas and/or combined WHO criteria 1 and 3 phenotype is associated with CRC in patients with SPS. Patients with a history of smoking show a lower risk of CRC, possibly due to a different pathogenesis of disease. The risk of developing CRC during surveillance is lower than previously reported in literature, which may reflect a more mature multicentre cohort with less selection bias.

Colorectal Neoplasia Pathways : State of the Art

Colorectal cancer (CRC) is a heterogeneous disease and each CRC possesses a unique molecular tumor profile. The main pathways of oncogenesis are the chromosomal instability, microsatellite instability and serrated neoplasia pathway. Sessile serrated adenomas/polyps (SSA/Ps) may be the precursor lesions of CRC arising via the serrated neoplasia pathway. This has led to a paradigm shift because all SSA/Ps should be detected and resected during colonoscopy. The ability to accurately detect and resect only those polyps with a malignant potential could result in safer and cost-effective practice. Optimization of the endoscopic classification systems is however needed to implement targeted prevention methods.

Low prevalence of serrated polyposis syndrome in screening populations: a systematic review

BACKGROUND AND STUDY AIMS The most frequently cited prevalence for serrated polyposis syndrome (SPS) is 1 in every 3000 people screened, but this value is debated. Additionally, changes in 2010 in the World Health Organization (WHO) diagnostic criteria for SPS might affect reported prevalence. An updated estimate of SPS prevalence is necessary to predict the number of cases in screening programs. PATIENTS AND METHODS A systematic literature search was conducted in the PubMed, EMBASE, and Web of Science databases up to February 2014. Studies reporting the prevalence of SPS, as defined by WHO criteria, in screening populations were selected. RESULTS Six studies reported prevalence of SPS in screening populations, varying from 0 to 0.66 %. The highest prevalences (0.34 % and 0.66 %) were seen in studies from screening programs with patients pre-selected by fecal blood test. Primary colonoscopy-based screening programs, that have the lowest risk of bias, reported SPS prevalences ranging from 0 to 0.09 %. Across studies, 56 patients were diagnosed with SPS of whom 3 presented with synchronous colorectal cancer at index endoscopy. CONCLUSION The true prevalence of SPS is unclear because of the risk of bias across studies, but is likely to be below 0.09 % as derived from primary colonoscopy screening programs. The prevalence in pre-selected screening populations after positive fecal testing is higher, with reported values of 0.34 % and 0.66 %. Large and high quality primary colonoscopy screening studies, reporting SPS prevalence in adequately described populations, are necessary for better estimation of the true prevalence of SPS in average-risk patients.

Implementation of an e-learning module improves consistency in the histopathological diagnosis of sessile serrated lesions within a nationwide population screening programme.

Distinguishing premalignant sessile serrated lesions (SSLs) from hyperplastic polyps (HPs) is difficult for pathologists in daily practice. We aimed to evaluate nationwide variability within histopathology laboratories in the frequency of diagnosing an SSL as compared with an HP within the Dutch population‐based screening programme for colorectal cancer and to assess the effect of an e‐learning module on interlaboratory consistency.

Smoking status informs about the risk of advanced serrated polyps in a screening population

Background and study aims: Evidence has accumulated that approximately 15 % to 30 % of colorectal cancers (CRC) arise from serrated polyps (SP). Population screening, therefore, should be designated to detect advanced SP, in addition to advanced adenomas and CRC. We aimed to evaluate whether CRC risk factors also act as risk factors for advanced SP. Patients and methods: Data were collected in the colonoscopy arm of a multicenter randomized trial comparing colonoscopy with CT-colonography for primary population screening. Information on risk factors was obtained by screening participants before colonoscopy with a validated risk questionnaire. Advanced SP were defined as SP ≥ 10 mm and/or with dysplasia. Endoscopists were instructed to resect all detected lesions. Odds ratios (OR) for the detection of advanced SP as most advanced lesion were calculated using multiple logistic regression analysis. Results: Of 6 600 invited participants, 1 426 underwent a colonoscopy and 1 236 also completed the questionnaire. In 40 participants an advanced SP was the most advanced lesion detected. Multivariate analysis demonstrated a strong association between current smoking and the presence of at least one advanced SP (OR 4.50; 95 % CI 2.23 – 8.89; P < 0.001). A significant association was also demonstrated for higher fiber intake (OR 1.36 per 20 gram intake; CI 1.07 – 1.73; P = 0.01). Other clinical CRC risk factors did not show a significant association with the presence of at least one advanced SP in the univariate analyses. Fecal haemoglobin levels were also not significantly associated with the presence of advanced SPs (OR 1.00 per 10 ng/mL CI 0.97 – 1.03, P = 0.99). Conclusions: Current smoking is a strong clinical risk factor for the presence of advanced SPs. As such, smoking status could contribute to risk stratification in targeted CRC population screening. Dutch Trial Register: NTR1829 (www.trialregister.nl)

Optical Diagnosis of Sessile Serrated Polyps: Bottleneck for the Optical Diagnosis Paradigm?

Background: Optical diagnosis of diminutive (1 to 5 mm) polyps could result in a more cost-effective colonoscopy practice. Previous optical diagnosis studies did not incorporate the differentiation of sessile serrated polyps (SSPs). This study aimed to evaluate the impact of optical diagnosis of diminutive SSPs on the overall performance of endoscopic polyp differentiation in daily colonoscopy practice. Methods: Endoscopy data were prospectively collected between 2011 and 2014 in a colonoscopy center. Each endoscopist reported a real-time optical diagnosis (SSP, adenoma or hyperplastic polyp) for all lesions in a structured colonoscopy reporting system, using narrow band imaging at their discretion. Study outcomes were accuracy of optical diagnosis, surveillance interval agreement and negative predictive value for diminutive rectosigmoid neoplastic histology based on the optical diagnosis of diminutive polyps compared to histopathology. Results: Of 2853 removed diminutive polyps, 202 (7.1%) were histologically proven SSPs. Optical diagnosis of diminutive SSPs was accurate in 24.4%. Diminutive SSPs determined 6.9% of postpolypectomy surveillance assignments. Inaccurate optical diagnosis of diminutive SSPs led to lower surveillance interval agreement (78.1% vs. 53.3%, P<0.01) and pooled negative predictive value per polyp (84.3% vs. 50.0%; P<0.01) in patients with diminutive SSPs when compared to patients without diminutive SSPs. Accurate endoscopic identification of diminutive SSPs improved from 0% in 2011 to 47% in 2014 (P=0.02). Conclusions: Endoscopic characterization of diminutive SSPs is difficult, impairing overall performance of optical diagnosis in patients with diminutive SSPs. Future optical diagnosis studies should use validated trainings and classification algorithms that include differentiation of SSPs.

Impact of differences in adenoma and proximal serrated polyp detection rate on the long-term effectiveness of FIT-based colorectal cancer screening

BackgroundBoth the adenoma detection rate (ADR) and proximal serrated polyp detection rate (PSPDR) vary among endoscopists. It is unclear how these variations influence colorectal cancer (CRC) screening effectiveness. We evaluated the effect of variation in these detection rates on the long-term impact of fecal immunochemical test (FIT) based screening.MethodsThe Adenoma and Serrated pathway to Colorectal CAncer (ASCCA) model was set up to simulate the Dutch national biennial FIT-based CRC screening program between 2014 and 2044. Adherence to FIT and colonoscopy was 73 and 92%. Besides a ‘no screening scenario’, several screening scenarios varying in ADR and PSPDR were evaluated. Using the available literature on colonoscopy miss rates led to a base-case ADR of 59% and PSPDR of 11%, which were varied with intervals of 3 and 2%.ResultsCompared to no screening, FIT-screening in the base-case scenario reduced long-term mortality with 51.8%. At a fixed PSPDR of 11%, an increase in ADR from 44 to 62% would result in a 10.7% difference in mortality reduction. Using a fixed ADR of 59%, changing the PSPDR from 3 to 15% did not substantially influence long-term mortality (51.0 to 52.3%).ConclusionsAn increase in ADR gradually reduces CRC burden in a FIT-based screening program, whereas an increase in PSPDR only minimally influences long-term outcomes at a population-level. The limited effect of the PSPDR can be explained by the limited sensitivity of FIT for serrated polyps (SPs). Other triage modalities aiming to detect relevant SPs should be explored.