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Gut Online First, published on November 24, 2015 as 10.1136/gutjnl-2015-310630
GI cancer


Clinical risk factors of colorectal cancer in patients
with serrated polyposis syndrome: a multicentre
cohort analysis
J E G IJspeert,1 S A Q Rana,2 N S S Atkinson,3 Y J van Herwaarden,4
B A J Bastiaansen,1 M E van Leerdam,5 S Sanduleanu,6 T M Bisseling,4
M C W Spaander,7 S K Clark,2 G A Meijer,8 N van Lelyveld,9 J J Koornstra,10
I D Nagtegaal,11 J E East,3 A Latchford,2 E Dekker,1 on behalf of the Dutch
workgroup serrated polyps & polyposis (WASP)

▸ Additional material is ABSTRACT
published online only. To view Objective Serrated polyposis syndrome (SPS) is Significance of this study
please visit the journal online
accompanied by an increased risk of colorectal cancer
gutjnl-2015-310630). (CRC). Patients fulfilling the clinical criteria, as defined
by the WHO, have a wide variation in CRC risk. We What is already known on this subject?
For numbered affiliations see
end of article. aimed to assess risk factors for CRC in a large cohort of ▸ Serrated polyposis syndrome is accompanied by
patients with SPS and to evaluate the risk of CRC during an increased risk of colorectal cancer.
Correspondence to surveillance. ▸ Patients fulfilling the clinical criteria for
Dr Evelien Dekker, Department Design In this retrospective cohort analysis, all patients
of Gastroenterology and
serrated polyposis syndrome have a wide
Hepatology, Academic Medical with SPS from seven centres in the Netherlands and two variation in colorectal cancer risk.
Centre, Meibergdreef 9, in the UK were enrolled. WHO criteria were used to ▸ Colorectal cancer risk factors in these patients
Amsterdam 1105 AZ, diagnose SPS. Patients who only fulfilled WHO criterion- are not yet well defined.
The Netherlands; 2, with IBD and/or a known hereditary CRC syndrome
were excluded. What are the new findings?
Results In total, 434 patients with SPS were included ▸ Serrated polyps containing dysplasia, advanced
Received 26 August 2015
Revised 23 September 2015 for analysis; 127 (29.3%) were diagnosed with CRC. In adenomas and/or a combined WHO criteria 1
Accepted 28 October 2015 a per-patient analysis ≥1 serrated polyp (SP) with and 3 phenotype are associated with colorectal
dysplasia (OR 2.07; 95% CI 1.28 to 3.33), ≥1 cancer in patients with serrated polyposis
advanced adenoma (OR 2.30; 95% CI 1.47 to 3.67) syndrome.
and the fulfilment of both WHO criteria 1 and 3 (OR ▸ Patients with serrated polyposis having a
1.60; 95% CI 1.04 to 2.51) were associated with CRC, history of smoking show a lower risk of
while a history of smoking was inversely associated with colorectal cancer, possibly due to a different
CRC (OR 0.36; 95% CI 0.23 to 0.56). Overall, 260 pathogenesis of disease.
patients underwent surveillance after clearing of all ▸ The risk of colorectal cancer during surveillance
relevant lesions, during which two patients were and after clearing of all relevant lesions is
diagnosed with CRC, corresponding to 1.9 events/1000 lower than suggested earlier.
person-years surveillance (95% CI 0.3 to 6.4). How might it impact on clinical practice in
Conclusion The presence of SPs containing dysplasia, the foreseeable future?
advanced adenomas and/or combined WHO criteria 1 ▸ The clinical risk factors that we discovered in
and 3 phenotype is associated with CRC in patients with the current study could help to risk stratify
SPS. Patients with a history of smoking show a lower patients with serrated polyposis for different
risk of CRC, possibly due to a different pathogenesis of surveillance intervals in order to decrease
disease. The risk of developing CRC during surveillance patient burden as well as the incidence of
is lower than previously reported in literature, which may colonoscopy interval colorectal cancer.
reflect a more mature multicentre cohort with less
selection bias.

than adenomas, via the serrated neoplasia
pathway.3–5 This pathway is characterised by several
BACKGROUND genetic and epigenetic changes of which the most
Colorectal cancer (CRC) is one of the main cancer- well-described alterations are a mutation in the
related causes of morbidity and mortality in the BRAF-oncogene and hypermethylation of promoter
To cite: IJspeert JEG,
Rana SAQ, Atkinson NSS,
Western world.1 As CRC arises from premalignant regions of tumour suppressor genes and subsequent
et al. Gut Published Online polyps, the detection and resection of these lesions silencing of these genes.6–9 The recent classification
First: [ please include Day decrease both CRC incidence and mortality.2 of the WHO classifies SPs into the subgroups
Month Year] doi:10.1136/ A growing body of evidence shows that 15%–30% hyperplastic polyps (HPs), sessile serrated aden-
gutjnl-2015-310630 of all CRCs arise from serrated polyps (SPs) rather omas/polyps (SSA/Ps) with or without dysplasia,
IJspeert JEG, et al. Gut 2015;0:1–7. doi:10.1136/gutjnl-2015-310630 1
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd (& BSG) under licence.

screening). presented to the local institutional review board (IRB) of the Missing data were assumed to be missing at random. Adenomas This is a retrospective international multicentre cohort study. since patient data were retrieved retrospectively whereas larger and/or proximally located HPs. due to polyps were included in the ‘at diagnosis’ group. In each participating centre. Data from 1993 to risk factors as well as colonoscopy risk factors were evaluated in 2015 were included for analysis.bmj. All HPs. ≥10 mm. Formal ethical committee approval was not potential. of which two are ≥10 mm in diameter (WHO the number.14–18 However. under annual surveil.bmj. et al. the time interval out the colorectum (WHO criterion-3). if applic- leads to a very heterogeneous group of patients with SPS. location and type of colonic polyps detected criterion-1).21 22 SPs were subdivided into SPs without dys- METHODS plasia and those with dysplasia. risk factors were dichotomised and treated as a who only fulfilled WHO criterion-2 were excluded from the binary variable. with high-grade dysplasia and/or a villous component Patients were enrolled from seven centres in the Netherlands were accounted as advanced adenomas.13 In fecal occult blood test (FOBT)-based population In each participating centre. screening. No centralised histopathology revision was performed. Both clinical registration of as much patients as possible. lesions that were detected lance. it study. smoking status and body mass index (BMI) were gathered from demonstrating the importance for endoscopists to recognise and medical charts. CRC risk for patients at their first diagnosis. Patients who ful. Multivariable logistic regression was used to with IBD and/or patients with a known germline adenomatous assess the adjusted associations between these risk factors and polyposis coli (APC) mutation. is important to characterise those patients with SPS at increased All detected lesions were assigned as SPs. Adenomas were subdivided into Study design and population non-advanced adenomas and advanced adenomas. none of the patients developed CRC during 5-year follow-up. irrespective of size.13 As germline mutations for SPS are and familial history records of CRC and extracolonic cancers. using a multivariable model. gender. the presence of one SP proximal to the sigmoid per patient. risk factors were handled as ordinal filled 2010 WHO criterion-1 and/or WHO criterion-3 for the or continuous variable. pathology and The primary objective of this study was to evaluate clinical risk endoscopy reports and hereditary CRC databases to enable the factors associated with CRC in patients with SPS. and two centres in the UK. Downloaded from http://gut. variability between pathologists in the differentiation of these polyp subtypes.0:1– GI cancer and traditional serrated adenomas (TSAs). the actual risk of CRC for patients with between the diagnosis of SPS and the clearing of all relevant SPS is probably overestimated in these small studies. In case of a median number of detected on a retrospective polyp count of all lesions. the prevalence of SPS may exceed 1:300 participants. This study was carried out accompanied by an increased risk of CRC. Subjects Act.Published by group. These reports were also used to define the initial and a first-degree relative (FDR) with SPS (WHO criterion-2) clinical presentation (symptomatic. A recent pro. unknown. as well as age at SPS diagnosis. SSA/Ps and TSAs were accounted as SPs lance protocols. Patients were included based a per-patient analysis. doi:10. a known mutation in one of the the presence of CRC. with the occurrence of CRC was calculated and presented as sented in online supplementary appendix 2 separately. The IRB decided on November 24. cohort but each site sought and received local research and terised by multiple SPs located throughout the colon and is development department approval. and all SSA/Ps and no additional interventions were performed for the purpose and TSAs are considered to possess a higher neoplastic of this study. but located through.10 Although WHO between colonoscopies.11 12 required for the UK sites for the same reasons as the Dutch Serrated polyposis syndrome (SPS) is a syndrome charac. anonymised per centre before being uploaded to a central spective study in 41 patients showed that. familial risk or population and/or 20 SPs or more. while several lance period was defined as the period after complete endo- retrospective studies have shown that these patients also have an scopic and/or surgical clearing of all clinically relevant SPs (all increased risk of developing CRC under endoscopic surveil. size. Data were retrieved from medical charts. In case of a median number of detected diagnosis of SPS were eligible for inclusion in this study. Multiple Academic Medical Centre for ethical approval. at SPS diagnosis or during surveillance. the number of colonoscopies.10 Diminutive HPs agreement with the Dutch Medical Research Involving Human located in the rectosigmoid are generally considered benign. The study protocol was the multivariable analyses. this clinical definition of the WHO as well as the reason for surgical colonic resections.19 Histopathology Large multicentre studies are needed to estimate the actual Histopathology was considered as the reference standard in this CRC incidence under surveillance in daily practice. Patients lesions of 0. in order to enable personalised treatment and surveil. the univariate association analysis. lesions per patient of >0. a search was performed for patients with multiple SPs in their medical Study outcomes and statistical analysis history. lesions above 5 mm). this disease has been clinically defined by the WHO Colonoscopy reports and surgery reports with corresponding by the presence of at least five SPs proximal to the sigmoid pathology reports were used to collect information regarding colon.20 SPS in the general population is largely unknown. lance. 2015 . was performed to that formal revision was not required for this study. As a result. All data were selection bias and non-structured surveillance. adenomas or as ‘other CRC risk. The clinical characteristics of these patients are pre.23 Analyses were performed using 10 2 IJspeert JEG. data on patient age.1136/gutjnl-2015-310630 . Moreover. however. Patients OR with 95% CI. type of polyp’. The surveil- presentation with SPS is reported up to 50%. given factors in a large cohort of patients with SPS and to evaluate the the retrospective design of this study and the high interobserver overall risk of CRC during surveillance. The aim of this study was to assess CRC risk but were not taken into account separately in the analyses.10 The prevalence of in accordance with the Helsinki Declaration. rates in colonoscopy screening populations of 1:2000 have been Clinical characteristics reported. with a able. All risk factors that showed a significant mismatch repair genes (Lynch syndrome) or a known biallelic association with CRC in the univariate analysis were included in Mut-YH mutation were also excluded. Medical charts were also used to gather patient diagnose this syndrome. Data were collected and stratified as follows: before SPS wide variation in CRC risk. Gut 2015. in adjust for missing values. database. the date of SPS diagnosis and the type criterion-2 is rarely used. For each risk factor.

No 409 (94. median (IQR) 2 (0–5) Patients with at least 1 adenoma.3%) were diagnosed Furthermore. 117 Smoking status. n (%) Symptoms 308 (71. ‘familial Missing 114 cancer risk’ for 69 patients (15. n (%) 114 (26.1) Overview of detected polyps per patient No.07). Table 1 Baseline characteristics These patients were excluded.05 was considered significant in the analyses. 324 patients (74. A two-sided p value chronous primary CRCs and 9/434 patients (2. n (%) No.bmj. body mass index. Kaplan–Meier survival analysis was used to 0–5). With regard to first of the WHO criteria for SPS (figure 1). Downloaded from http://gut. Of these 434 Male gender. of SPs.1%). doi:10.5) (31. Secondary objective of this study was to evaluate the (26. 44/179 RESULTS patients (24. n (%) (32.0%). Type 1 117 (27. n (%) 153 (35. SPS.7–67. 2015 . n (%) patients (27. the incidence rate of CRC during surveillance was with at least one advanced adenoma. 292 (67.2%) had a BMI ≥30.2%) diagnosed with both WHO criteria 1 and 3 In total. median (IQR) 3 (1–5) Patients with at least 1 SP ≥10 mm.21. resulting in a total of 434 patients Total cohort size. of SPs containing dysplasia.6) diagnosis and during surveillance) per patient was 29 (IQR 17– Missing 46 50). Overall.4%) with at least one SP patients diagnosed with CRC before diagnosed with SPS were ≥10 mm proximal to the rectosigmoid and 114 patients excluded. Type 3 179 (41. The median age at first diagnosis of CRC was 60.bmj. of advanced adenomas.8 (51. in which least one SP ≥10 mm. only 27 fulfilled WHO criterion-2.7).8 years (IQR Type 1+3 138 (31. n (%) 330 (76. measured.0) and 211 patients (48. 182 patients (56.0) Baseline characteristics of patients are presented in table 1. of SPs proximal to the rectosigmoid. 480 patients were identified who fulfilled at least one were diagnosed with CRC (p=0. metachronous CRCs (table 2). median 3 (0–5) (IQR) Patients with at least 1 SP ≥10 mm proximal to the 310 (71.0%) fulfilled WHO criterion-1 only.9%) had a ≥30 kg/m2 41 (16.0) No. of SPs ≥10 mm. median (IQR) 60.15. median (range) 0 (0–6) Patients with at least 1 advanced adenoma.0:1–7. 14 also had been diagnosed with IBD and 5 had a hereditary CRC syndrome (4 patients with Lynch syndrome and 1 with Mut-YH associated polyposis). SPs.3–84. CRC.9%) and ‘population screening’ BMI. 3 (IQR 1–5) for SPs Yes 25 (5. Yes 149 ( on November 24.7%) were also diagnosed with at calculate the 5-year cumulative incidence for CRC. n (%) 324 (74. 127/434 patients (29.Published by group. colorectal cancer. 310 patients (71. 41 patients (16.8) patients (38.0) (65.7) No. n (%) for SPs proximal to the rectosigmoid.6%) diagnosed with WHO criterion-3 and 50/138 Patient characteristics patients (36. 330 patients (76. FDR. tics (V. The median number of detected lesions was 14 (IQR 7–25) FDR with SPS.4) rectosigmoid. polyposis syndrome.3) No. first-degree relative.2%) diagnosed with WHO criterion-1. serrated polyposis syndrome.1136/gutjnl-2015-310630 3 .6) patients. No smoker 138 (43.2%) were diagnosed from 2010 onwards. least one adenoma and 153 patients (35. Of these patients. In GI cancer imputed datasets. n (%) with SPS (WHO criterion-1 and/or WHO criterion-3).8%) were diagnosed with two syn- Foundation for Statistical Computing). 149 <30 kg/m2 212 (83. In total.0) (The R of whom 8/434 patients (1. serrated polyps. Chicago. n (%) for 57 patients (13. of SPs ≥10 mm proximal to the rectosigmoid. 179 patients Current smoker 126 (39. et al. n (%) 211 (48.8) 51.8 years (range 20.9%) had at least one FDR that was also diagnosed FDR with CRC. of adenomas.6%) were male.3%) were diagnosed with CRC. Statistical analyses were performed using SPSS statis. SPS. IJspeert JEG. USA) and R (V. median (IQR) 14 (7–25) No.7%) in a British centre. Illinois.4) (41.9) Population screening 57 (13.1) entation was: ‘symptomatic’ for 308 patients (71.9) ≥10 mm and 3 (0–5) for SPs ≥10 mm proximal to the rectosig.3) Figure 1 Study flowchart. of whom 283 patients Age at diagnosis.1) moid. colorectal cancer. First clinical pres.2) The median age of patients at diagnosis was 60. median (range) 0 (0–18) Patients with at least 1 SP-containing dysplasia.0) Familial cancer risk 69 (15. n 434 eligible for inclusion in the analysis.1%) with two <0. A sensitivity analysis was performed.0%) were diagnosed with at Clinical presentation. median (IQR) 29 (17–50) No.8%) fulfilled both WHO criteria 1 and 3. The overall risk of developing CRC during surveillance after the clearing of median number of detected adenomas per patient was 2 (IQR all relevant lesions. serrated BMI. Gut 2015.3%) were included in a Dutch centre and 142 WHO subtype. CRC. SPSS. In total.7–67.3%) with at least one SP-containing dysplasia.2) history of smoking.2%) fulfilled WHO criterion-3 only and 138 patients Former smoker 56 (17. In total.4) The overall median number of detected SPs (detected up to No 239 (61.4%) had at least one FDR with CRC and 25 Missing 181 patients (5. In total 33/117 patients (28.2.

04 to 2. Caecum 14 (9. first-degree relative.49) 0. Univariate analyses showed an association with CRC in Patients with two synchronous primary CRCs.9%) was due to CRC.60. 95/403 84.7) for patients diagnosed with CRC proximal to the rectosig. n (%) 64 (50.51) 0.03 (0. In total.4%) during SPS surveillance.99 At least 1 SP containing dysplasia.1) 0.49 to 1.2–65. of SPs proximal to the rectosigmoid. p=0.74 (0.3) 139 (62. 95% CI 0.04 to 2.6) 95% CI 1. The cumulative number of SPs Criterion 1+3 50 (39.59 to 3.7) 2.70. Downloaded from http://gut.7).001).49.001 2. 8 (8. 95% CI WHO subtype.62.8%) who presented via (adjusted OR 0. 110/308 patients (35.bmj.60).1) 20 (6.95) and for men (adjusted population screening. 2015 . of SPs ≥10 mm proximal to the rectosigmoid.Published by group.001).7 (range 26. 95% CI 1. serrated polyps. n (%) 50 (39.05 *Referred to patients in which the variable was available. n (%) 8 (1.4) CRC (OR 0.62 (1.1) dysplasia (OR 2.67) < GI cancer Risk factors for CRC Table 2 Characteristics of patients with CRC Risk factors for CRC in patients with SPS are presented in All patients with CRC. 30 (31.07 (1. Subsequent analysis showed with symptoms and 4/69 patients (5.6%) needed surgery during the clearing phase.05 to 2.1136/gutjnl-2015-310630 .03 (1.30.4%) were detected before the diagnosis of performed sensitivity analysis showed no structural differences SPS.20). p<0.001 Male gender. patients (23.4) 88 (28.46.49. p<0.78 (0. of SPs ≥10 mm.5% vs which 56 (58. median (IQR)† 15 (8–27) 13 (7–25) 1. A history of smoking was inversely associated with During surveillance 2 (1.001).08) 0.6 (58.03). n (%)* 9 (10. 95% CI 0.9%) received clearing of all clinic- showed no statistically significant difference in the location of ally relevant lesions.01 No. of on November 24.3) 0.99 to 1. 95% CI 1.8 (20.00 (0. n (%) 1. median (IQR) 2 (1–5) 2 (0–5) 1.3–79.4 (48.0 (range 20.0) 0. 95% CI 1.78.03) 0.50 (0.01) 0. with a history of smoking had a lower risk of CRC (OR 0.6) 59.73. 13/57 patients (22.80.001 1. BMI. CRCs (1.02 1.29 At least one FDR with SPS.69 No.78) <0. Gut 2015.34 (1.001 Fulfilling WHO criteria 1 and 3.67 No.05) had an increased risk to be diagnosed with CRC. n (%)* 43 (44.001) and for Age at diagnosis first CRC. of moid ( p=0. 74 CRCs (51.5 months (IQR 0–8. p=0. median (IQR) 29 (18–46) 29 (17–52) 1. 68 CRCs (47. SPs.5) 2. 95% CI 0.47 to 3.23 to 0. SPS. Rectosigmoid 69 (47.07. p<0.51) <0.20 to 1.22 to 1.2%) at the time of diagnosis of SPS and 2 in the association between potential risk factors and CRC. 95% CI–7. CRC.56) <0.3–84.48 to 3. Location CRC (144 cancers).001) and patients who fulfilled Descending colon 6 (4. FDR.2) versus 63.6) 32 (19.59 to 3.6%) was due to 37.46 (1. p<0. n (%)* 38 (34. 95% CI 0. median (IQR)† 3 (1–5) 2 (1–4) 1.8) 66 (21.48 (0.01 to 1.001 BMI ≥30.3) 156 (50.05 to 2.33.4) SPS diagnosis when compared with patients without CRC At diagnosis SPS 68 (47.15 to 0.4%) was due to an unresectable polyp and 1 Table 3 Risk factors for CRC in 434 patients with SPS Patients with Patients without Univariate Multivariable CRC (n=127) CRC (n=307) OR (95% CI) p Value OR (95% CI) p Value Age at diagnosis SPS in years. Median age at diagnosis of CRC in these (table 4). n (%) 5 (4. median (range) 60.8) patients who were diagnosed with at least one SP-containing Patients with metachronous CRC.8) 0. serrated polyposis syndrome. In criterion-3 only (OR 1. of SPs.30 At least 1 advanced adenoma.9%) in the right-sided colon.9%) were diagnosed patients died from CRC before clearing was accomplished in the rectosigmoid.36 (0. n (%) 9 (2. SPS.bmj. et al. The different SPS phenotypes Of the 434 patients.7) Patients having at least one SP with dysplasia (OR 2.49 to 1.60 (1.0) teria 1 and 3 also showed an increased CRC risk (OR 1.98 to 1.28 to 3. Patients with CRC were significantly older at Before diagnosis SPS 74 (51. Criterion-3 44 (34. doi:10.48 to 3. median (IQR) 3 (1–5) 3 (1–5) 0.30 (1. No difference was found for gender (48.4) 1.01).10 to 2. polyp burden.96 to 1.74. p<0.09 At least one FDR with CRC.12) 0.28 to 3.8%) who were screened for that these patients significantly more often fulfilled WHO a familial CRC risk were diagnosed with CRC ( p<0. †Proximal is defined as proximal to the rectosigmoid. 28 patients were not yet cleared and 3 CRC ( p=0. CRC.00 (0.7%) who presented OR 0. serrated polyposis syndrome.05) <0.02). n (%) 48 (37.80) <0.96 to 1.2) both WHO criteria 1 and 3 (OR 1. body mass index.47 to 3. The decreased risk of CRC in patients with a history of smoking was found both for women clinical presentation.5) 1.01). at least one advanced adenoma (OR Transverse colon 24 (16.04 (1.02 to 1. p<0.51. n (%)* diagnosis of CRC.23 to 0.99 (0.00 (0. In total 69/144 CRCs (47.7) patients with at least one advanced adenoma (OR 2. The median time from diagnosis up to clearing of all patients was 58. colorectal cancer. Patients were included in the ‘at diagnosis’ group.2) 111 (40.06) <0. median (IQR) 63. n (%) 127 (29. 4 IJspeert JEG.01) 0.48. 95% CI Ascending colon 31 (21.1–69.03).23) 0.34.31 No.9– relevant lesions was 1. The total.0) 2.30 to 0.7) 1.60 (0.3) table 3. Patients who fulfilled both WHO cri- Criterion-1 33 (26.56. 75/144 CRCs (52. n (%) 55 (43.2) (p<0.36. n (%) Multiple logistic regression analysis showed similar results.4) as well as adenomas was not significantly associated with the Moment of diagnosis CRC (144 cancers).001).001 2.4) 89 (29.33) <0.01 0. colorectal cancer.30 to 0. 403 (92.07) 0. *Carcinomas detected between diagnosis of SPS and clearing of all relevant polyps adjusted for the confounder of age at SPS diagnosis.70) <0.16 A history of smoking.94 No.99 to 1.9) p<0.3% male. p=0.26 to 0.7) 0.1%) were located in the left-sided colon and 69/144 Clinical management of SPS (47. In total.53).04) 0.

multiple Unresectable polyp 4 (36. we evaluated risk factors asso. The 5-year cumulative Several studies have reported on the risk of CRC in patients incidence for CRC during surveillance was 1.0–1.1) cohort of patients to date. However. median 3. median (IQR) 0 (0–2) SPs. analyses were performed in the largest Perforation due to polypectomy 1 (1.2%) in the three largest cohorts till date (26%–29%). SPs. Downloaded from http://gut.9) imposing a risk of selection bias. As a result.9) CI 0. 4 patients due to an unresectable imposed selection bias. Second. we have decided to appraise all SSA/Ps. enabling robust estimates for both No. due to the same histopatho- 3. ably have resulted in biased and unreliable results.001). of large SPs.7%).1136/gutjnl-2015-310630 5 . The incidence rate of No. A third limitation in this study Patients with at least 1 SP ≥10 mm proximal to the 65 (25.7) to a different pathogenesis of disease. analysis for the risk of SSA/Ps and HPs separately would prob- CRC.0:1–7. Patients with at least 1 adenoma. quality assurance of retrieved Interval between surveillance colonoscopies (years).bmj. analysis based on polyp location.2) Several studies showed that the interobserver agreement Patients with at least 1 advanced adenoma. Taken these considerations patients were diagnosed with CRC during surveillance. median 1.21 22 24 25 Therefore. 2015 .2) tainment bias in patient selection. demonstrating a variable risk.7% of patients who presented with symptoms and 5.7%). These patients No.4) imputation enabled the evaluation of all patients in the multi- Perforation due to polypectomy 1 (9.3 to 6. The clinical characteristics of the two patients who 70%. (29%) was largely comparable with the risk that was presented plementary appendix 1. probably is a poor proxy for the real prevalence of disease. of SPs.5 (0–8.4) element of bias. median (IQR) 2 (0–7) documented prospective registry of SPS patients. n (%) design of the study. we demonstrated that the risk of CRC at presentation largely depends on the first clinical presentation. n (%) 20 (7.0) is the fact that histopathology of the colonic lesions was not rectosigmoid. which may have introduced another Polyp burden 5 (45. this study has a No.4) In the current study. two histopathological subclassification.26 The A total of 260 patients (59. median (IQR) 1.4). Nevertheless.2 years (IQR 1.Published by group. surveillance intervals were not based on copies of 1. years of surveillance (95% CI 0. of needed clearing colonoscopies. In the other centres. 5 However. The presence of at diagnosed with CRC ( p<0. the CRC prevalence in these studies polyp and 1 patient as result of a perforation after polypectomy. n (%) lesions was 1.9%) underwent surveillance after presence of dysplasia as well as polyp size was taken into clearing of all lesions >5 mm with a median follow-up of account in this guideline.7) hospitals in the Netherlands and the UK.1) variable analysis. median (IQR)* 2 (1–3) CRC risk factors as well as CRC incidence during surveillance. median (IQR) 7 (2–18) participating centres.9 events/1000 person.3 to 6. of patients who received clearing of all relevant lesions 403 smoking showed an inverse association with CRC. First. colorectal cancer. n (%) 11 (4. †Referred to the 260 patients who received surveillance after clearing of all polyps. et al. of patients who received surgery during surveillance. Conversely. 35. an established. logical restrictions. Most centres already had a well- No. due to the retrospective design of these studies and patients due to polyp burden.8% ciated with CRC in patients with SPS and assessed the overall of patients who were identified due to a familial CRC risk were risk of developing CRC during surveillance. serrated polyps. certain patients might have been missed.9 events/1000 person-years of surveillance (95% CRC 56 (58.4). due to logistic heterogeneity within Overview of detected polyps during surveillance per patient† centres. Unresectable polyp 8 ( on November 24. of SPs proximal to the rectosigmoid.14 27 30 needed surgery during surveillance: 1 patient due to CRC.2 years (IQR 1. doi:10. ing. 22.6) (table 4).6–5. Gut 2015.6) CRC during surveillance and after clearing of all relevant Reason surgery during clearing. To overcome this limitation. uniform surveillance proto- CRC 1 (9. due to the retrospective Reason surgery during surveillance. of patients who received surgery during clearing.8% of patients who presented via population screen- In this large multicentre study.1%) was as a result of a perforation caused by polypectomy.bmj.9) computer systems were used to identify patients with multiple No. individual *Referred to the 308 patients who did not receive surgery during clearing. No. Patients with at least 1 SP-containing dysplasia. at least one advanced Table 4 Clinical management of patients with serrated polyposis adenoma and/or a combined WHO criteria 1 and 3 phenotype syndrome was associated with CRC. which into account. possibly due Time from diagnosis up to clearing (months). the external validity of this study seems to be rea- corresponds to an incidence rate of 1.7) and a median interval between colonos.2 (1.5% (95% CI 0% with SPS. A total of 11/260 patients (4. several (IQR)† limitations have to be acknowledged.6–5. of adenomas. In DISCUSSION total. The same decision was made in the most recent median number of 2 clearing colonoscopies (IQR 1–3) were European Society of Gastrointestinal Endoscopy guideline for needed.2 (1. patients with a history of GI cancer least one SP-containing dysplasia. HPs as well as TSAs as identical lesions and to perform an overarching (1. Despite the challenge of missing data.1) col was not in place. median (IQR) 0 (0–1) form the vast majority in the analysis. n (%) 16 (6. corresponding to a 5-year cumulative risk of Polyp burden 30 (31.0–1. As mentioned. a plasia. n (%) 70 (26. In a subsequent analysis.5% (95% CI 0% to 3. sonably founded. These results suggest that the IJspeert JEG.14 17 18 27–31 The overall prevalence of CRC in our study developed CRC during surveillance are presented in online sup. size and the presence of dys- For those 308 patients who could be treated endoscopically.6) 1. of patients who received surveillance after clearing of all 260 This study has an international multicentre cohort design and polyps included both patients from academic and from non-academic Follow-up time since clearing of all polyps (years).7) between pathologists in the differentiation of SSA/Ps and HPs is considered moderate to low. post-polypectomy surveillance after the resection of SPs. n (%) revised centrally by a panel of gastrointestinal pathologists.6) (IQR)† data was limited and this study might be subject to certain ascer- No. we were unable to perform a uniform search within the No. local Patients with at least 1 SP ≥10 mm. For these centres. Also. ranging from 7% to to 3. of colonoscopies during surveillance. median (IQR)† 2 (1–4) retrospective design. n (%) 95 (23. n (%) 122 (46.

The authors described this phenomenon as ‘the smoking In conclusion. John Radcliffe Hospital. adjustments to the current WHO guidelines could help in stratified for phenotype: few large right-sided polyps. The Netherlands 2 design of this study. Downloaded from http://gut. University of Groningen. Radboud University Medical our earlier reports. statistical analysis: JEGI.11 12 This study confirms earlier results from our Netherlands group. St. Finally. many assigning those patients who are truly at risk of developing small left-sided polyps or a pancolonic phenotype. The Netherlands of the current WHO guidelines for the diagnosis of SPS.35. due to the retrospective University of Amsterdam. Netherlands Cancer Institute.03). This seems mainly driven by Contributors All authors have contributed to this article in the following way: the fact that diminutive HPs in the rectosigmoid should prob. Maastricht. It is not possible to exclude that a proportion of these CRCs may have arisen from an Funding KWF Kankerbestrijding (grant no. et al.5% that we have reported Department of Gastroenterology and GI cancer overall CRC risk in not-yet-diagnosed asymptomatic patients those SPs located in the rectosigmoid are of clinical importance. described in this study. Rotterdam. we showed that the incidence of CRC during on November 24. This suggests that the pathogenesis of SPS might be different in smokers and non-smokers. CRC arising in the rectosigmoid at a young age implies that Provenance and peer review Not commissioned. University Medical Centre Groningen. In this study a significant difference for CRC risk between ity of personalised treatment and surveillance for patients with the described phenotypes could not be detected. Centre. critical revision patients with CRCs located proximal to the rectosigmoid of the manuscript: all authors. research should be con- rectum and most of these patients probably fulfilled the WHO ducted to evaluate the effect of the discontinuation of smoking criteria for SPS. The lesions were not accounted as cancers developed during surveil. ED.19 Nieuwegein.04 to 2. we showed that SPs containing dysplasia. smoking. Future research should focus on the safety the current study patients with a history of smoking (current and feasibility of personalised treatment and surveillance for and former smokers) significantly more often fulfilled WHO patients with SPS. The Netherlands 5 during surveillance was 1. Furthermore. Oxford. UK structured surveillance is probably lower than assumed in one of 4 Department of Gastroenterology and Hepatology.15 to 0.32 CRC was diagnosed in 57 patients (38%). in order to decrease patient burden as well as criterion-3 only. rectal lesions are excluded from Netherlands the clinical diagnostic criteria and in criteria 1 and 2 lesions in the sigmoid colon are excluded. 6 IJspeert JEG. p=0. The Netherlands 8 Department of Pathology.32 a history of smoking is inversely associated with CRC in these Therefore.5% versus 6. compared with non-smokers (OR 1. The veillance. Amsterdam. Nuffield Department of Clinical Medicine. Nijmegen.bmj. Erasmus University Medical advice to clear all relevant lesions before the start of CRC sur. supervision: all authors. results from our study showed that 47.0 vs 63. Netherlands 7 lance. A potential beneficial Current smokers showed a markedly decreased risk of CRC result could contribute to provide assistance for patients to quit compared with non-smokers (OR 0. the risk in a given population of patients with patients. Academic Medical Centre. substantial contributions to the conception or design of the work. 1. CRCs diagnosed within 6 Division of Gastroenterology and Hepatology. Translational Gastroenterology Unit. Groningen.30 However. The Netherlands earlier. University of Oxford. which Department of Gastroenterology and Hepatology. These cancers were accuracy or integrity of any part of the work are appropriately investigated and detected in patients who were significantly younger than resolved. In a large cross-sectional study.Published by group. com. showing that annual colonoscopy surveillance after the 9 Department of Gastroenterology and Hepatology. The Netherlands 10 The results from this study raise questions about some aspects Department of Gastroenterology and Hepatology. in the near future. risk factors of CRC prolonged surveillance intervals. 95% CI 0. on the polyp burden in patients with SPS. (median 58. while observed on the development of diminutive polyps. The the current WHO guideline.7. However. This hypothesis is supported by the fact that in assessed in literature.7.14 Contrary to our prior study. could potentially help to risk stratify pared with patients who fulfilled WHO criterion-1 or WHO patients with SPS for different surveillance intervals. Final approval of the version published. CRC. we showed that the risk of developing increased CRC risk may be smaller in the smokers than in the CRC during non-structural surveillance is lower than earlier non-smokers. doi:10. criterion-3 only (adjusted OR 1. London. GROW School for Oncology and the period between SPS diagnosis and the clearing of all relevant Developmental Biology. One of the potential explanations for this paradox is advanced adenomas and/or a combined WHO criteria 1 and 3 the hypothesis that the effect of smoking may be mainly phenotype are associated with CRC in patients with SPS.1136/gutjnl-2015-310630 .bmj. Gut 2015. paradox’.30 These phe. Antonius Hospital.02). Unfortunately. we SPS in order to decrease patient burden as well as the incidence demonstrated that patients who fulfilled both WHO criteria 1 of colonoscopy interval CRCs. Netherlands Cancer Institute. The clinical risk factors. important intellectual content. as and 3 were at increased risk to be diagnosed with CRC. data analysis and interpretation: all authors. resection of all clinically relevant lesions is relatively safe. Furthermore.51.30 31 In a large into account their size and histopathology. for those individuals with and were evaluated in 151 patients with at least five SPs outside the without CRC risk factors.10 In 11 Department of Pathology.14 17 18 27–31 Few studies have tried to risk and not exclude lesions purely on their location without taking stratify SPS patients based on clinical risk factors. Agreement to However. 95% CI 1. with SPS is probably overestimated in previous studies as well as It would seem reasonable then to re-assess the WHO criteria in the current report.1 to 2. Drafting the work or revising it critically for ably not be taken into account for the diagnosis of SPS.82). analysis or interpretation of data. Amsterdam. the low risk of CRC during surveillance could also argue for p<0. Nijmegen. or the acquisition. adenoma rather than a SP but the substantial proportion of the Competing interests None declared. Hopefully these cohort of 115 patients with SPS. the risk of CRC was evaluated. 2015 .9% of all be accountable for all aspects of the work in ensuring that questions related to the CRCs were located in the rectosigmoid. a reliable differentiation between current The Polyposis Registry. Maastricht University Medical Centre.14 The 5-year cumulative incidence of CRC Centre. UK 3 and former smokers could not be made. St Mark’s Hospital. notypes largely overlap with those presented in the current Future studies should mainly focus on the safety and feasibil- study. UVA 2014-7500).0:1–7. Radboud University Medical Centre.14 This strategy aligns with international protocols. drafting the manuscript: JEGI. data acquisition: all authors. Amsterdam. p=0.05). Experimental Medicine Division.7. Conception and design: JEGI.60. externally peer reviewed. which might Author affiliations influence the options for therapy and surveillance for smokers 1 Department of Gastroenterology and Hepatology. 95% CI the number of colonoscopy interval CRCs.

Gut 2015. pathology and surveillance. 4 Toyota M. WHO surveillance: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Ahnen DJ. O’Brien MJ. Saunders BP. 5 Jass JR. Carneiro F.Published by group. Gut 2013. Serrated lesions of the colorectum: review and 27 Chow E. 30 Kalady MF. Axilbund JE.bmj. Virchows Arch 6 East JE. Colonoscopic polypectomy and patients with serrated polyposis syndrome who undergo annual endoscopic long-term prevention of colorectal-cancer deaths. resection. natural history. et al. 1997. Update on the serrated pathway to colorectal carcinoma. Gastrointest Endosc 2015. Leach B.45:842–51. Jarrar A. et al. Ahnen DJ.36:876–82. 2011. Serrated lesions in colorectal cancer screening: detection. phenotypic presentations and the role of MBD4 and MYH. for future guidelines based on a clinical study. Bilezikçi B. Albertsen H. 23 Streiner DL. Jaramillo E. 7 Leggett B. Histopathology 2007. Ohe-Toyota M. Virchows Arch syndrome.47:2101–4. Hyperplastic polyposis coli syndrome and 1 Siegel R. Rodríguez-Soler M.42:1–10.310:2191–4. et al. Drini M. Koornstra JJ. et al. Tytgat KM. et al. JAMA Gastroenterology 2005.81:517–24. Winawer SSJ. Samowitz W. Lyon. Am J Gastroenterol 2004.54:164– on November 24. determined by a colonoscopist with a high lesion detection rate and an experienced 8 Snover DC. Clin Gastroenterol Hepatol risk during follow-up in patients with hyperplastic polyposis syndrome: a multicentre 2013. eds. Gastroenterology quiz 1314. Gastroenterol Clin North Am 2008. et al. Downloaded from http://gut. Gut 2015. Role of the serrated pathway in colorectal cancer 24 Abdeljawad K. pathogenesis.62:404–8. et al. Sweet K. GI cancer REFERENCES 18 Rubio CA. et al. other research vagaries. cancer.62:10–29. Phenotypic characteristics and risk of Serrated Polyposis Syndrome: a series of 100 patients from genetics clinics. Baron JA. et al. Serrated polyps of the colon and rectum 9 Boparai KS. development of colorectal neoplasia. Ahuja N. Proc Natl Acad Sci USA 1999. CpG island methylator phenotype in 21 Ensari A. Baretton GB. Vieth M. traditional serrated predominates over the classic WNT pathway in patients with hyperplastic polyposis adenomas. Hylind LM. et al. Hyperplastic polyposis syndrome: recommendations from an expert panel. Polak MM. doi:10. cohort study.48:287–302. 160–5.131:30–9. Increased colorectal cancer molecular characteristics of serrated polyposis syndrome. Endoscopy 2013. classification of tumours of the digestive system. 11 Rex DK.59:1094–100.147:88–95.38:266–70.47:68–75. DiSario JA. molecular genetics. 12 Rosty C. Gastroenterology 2010. Quintero E. Serrated polyps of the large intestine: current 28 Lage P. et al. Am J cancer development in hyperplastic polyposis: Case series and literature review. Post-polypectomy colonoscopy serrated polyposis. sessile serrated adenomas.138:2088–100. Defining phenotypes and cancer risk in 15 Edelstein DL.bmj. Sporadic and syndromic hyperplastic polyps and 2014. Serrated polyps of the colon and rectum and 26 Hassan C. et al. Cancer statistics. Serrated polyposis: rapid and relentless hyperplastic polyposis syndrome. et al.37:25–46. Management of Portuguese patients with understanding of diagnosis. Stemme S. van Eeden S. World Medical Association Declaration of Helsinki: sample supports a CpG island methylator phenotype in colon cancer. Classification of colorectal cancer based on correlation of clinical. Cravo M. Hyperplastic polyposis and the risk of colorectal with multiple serrated polyps: a cross-sectional case series from genetics clinics. Defined morphological criteria allow reliable morphological and molecular features. Whitehall V. PLoS ONE 2010. et al. Sessile serrated polyp prevalence pathogenesis. Jass JR. 22 Rau TT. 1330. et al. 25 Aust DE. Kahi CJ. Lynch E. Sánchez-Fortún C. quiz e46.107:1315–29. et al. Anderson P. Hewett DG. In: Bosman T.5:1–7. Dumonceau J-M. 2012. Am J Gastroenterol 13 East JE. reproducible is their classification? Virchows Arch 2012. 10 Snover DC. 2004. Hruban R. Carneiro F. et al. et al. et al.178:2700–7. Endoscopy 2006.11:705–11. 2012. Agaimy A. 2010. Surg Pathol 2012. population-based 20 World Medical Association. Incidence of colonic neoplasia in 2 Zauber AGAAG. Gastroenterology 2014. 2006. serrated adenomas of the colon: classification. Lipton L. 3 Samowitz WS. Can J Psychiatry 2002. Naishadham D. Am J Gastroenterol 2012.1136/gutjnl-2015-310630 7 . Blasyk H. Dekker E. Gut 2010.64:991–1000. N Engl J Med 2012. Phenotype and Polyp Landscape in 16 Ferrández A. Mathus-Vliegen EMH.464:663–72.461:495–504. et al. Dis Colon Rectum 2011. Brown IS. Burt RW.99:2012–18. The case of the missing data: methods of dealing with dropouts and and clinical management.0:1–7. ethical principles for medical research involving human subjects.457:291–7. Buchanan DD.129:837–45. Clinical subtypes and 14 Boparai KS. et al. Evaluation of a large. 29 Guarinos C. Rex DK. diagnosis of colorectal serrated polyps and predict polyp genetics. 32 Buchanan DD. Risk factors for colorectal cancer in patients 17 Hyman NH. Am J Pathol 2011. Jemal A. 19 Hazewinkel Y. surveillance. J Gastroenterol hyperplastic polyposis and screening of at-risk first-degree relatives: a contribution 2013. 2015 . IJspeert JEG. A serrated colorectal cancer pathway (hyperplastic polyps. Hum Pathol pathologist.67:355–6.96:8681–6. 31 Rosty C. Walsh MD. Herrick J. et al. and mixed polyps)-proposal for diagnostic criteria. Dis Colon Rectum 2004. Vemulapalli KC. et al. CA Cancer J Clin colorectal carcinoma. Serrated polyps of the colon: how colorectal cancer.99:1779–84. and clinical management. Gehoff A.50:113–30. et al. Sousa R.

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