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Amsterdam UMC, University of Amsterdam, Department of Gastroenterology and Hepatology, Cancer Center Amsterdam, AmsterdamRadboudumc, Radboud University Medical Center, Department of Gastroenterology and Hepatology, Nijmegen, the Netherlands
Serrated polyposis syndrome (SPS) is the most prevalent colonic polyposis syndrome known and is associated with a high risk of colorectal cancer (CRC) if left untreated. Treatment consists of clearance of the initial polyp burden, followed by lifelong stringent endoscopic surveillance. However, the long-term safety and efficacy of surveillance and the natural disease course after initial clearance have not been described in detail.
We analyzed a single-center cohort of patients with SPS with over 10 years of prospective follow-up. Outcome measures were (1) CRC incidence, (2) postcolonoscopy adverse event rates, and (3) trends in polyp recurrence during endoscopic surveillance.
The cohort included 142 patients who underwent a median of 6 colonoscopies with a median of 47 months of prospective follow-up after initial polyp clearance. During surveillance (every 1-2 years), 1 case of CRC occurred (5-year CRC incidence, 1.0%; 95% confidence interval, 0%-2.9%). During 447 surveillance colonoscopies with 1308 polypectomies, 1 episode of postpolypectomy bleeding, 1 postpolypectomy syndrome, and no perforations occurred (adverse event rate, 0.45% per colonoscopy). During up to 9 rounds of surveillance, no upward or downward trend in polyp recurrence was observed.
In this prospective cohort with over 10 years of follow-up, endoscopic surveillance was effective and safe, with a low risk of CRC and colonoscopy-related adverse events. Furthermore, we show that the disease course of SPS is such that the polyp burden remains more or less equal during long-term surveillance, which advocates lifelong adherence to (personalized) surveillance guidelines and discourages de-intensifying surveillance intervals after multiple rounds of surveillance.
Serrated polyposis syndrome (SPS) is characterized by the presence of numerous serrated polyps (SPs) and is associated with an increased risk of colorectal cancer (CRC). Although previously considered rare, SPS is now believed to be the most prevalent polyposis syndrome known, with a prevalence of up to 1:111 in fecal immunochemical test (FIT)-based screening cohorts.
Recent cohort studies report that about 15% to 29% of patients with SPS are diagnosed with CRC at a certain point.
The diagnosis of SPS is based on clinical criteria defined by the World Health Organization (WHO): (1) ≥5 SPs proximal to the rectum, all ≥5 mm in size, with at least 2 ≥10 mm in size; or (2) >20 SPs of any size distributed throughout the large bowel, with ≥5 proximal to the rectum.
Current recommendations for the management of SPS separate a clearing and a surveillance phase. During the clearing phase, a patient is cleared from the initial polyp burden by removal of all potentially hazardous polyps, preferably by endoscopy or, if required, by surgical resection of affected bowel segments. The clearing phase is followed by endoscopic surveillance every 1 to 2 years.
This has impeded analysis of the long-term risks (eg, CRC development, colonoscopy-related adverse events) of endoscopic surveillance after initial polyp clearance. In addition, in the absence of long-term follow-up studies, the disease course of SPS has not yet been described in detail. It is therefore unknown whether patients should be advised to remain on the same stringent surveillance regimen for the rest of their lives, or whether the natural disease course of SPS is such that polyp recurrence will gradually fade away after several years of surveillance.
To address these questions, we analyzed a cohort of patients with SPS that we have prospectively followed for over 10 years. In this prospective cohort study, we aimed to describe the long-term risks and effectiveness of endoscopic surveillance. In addition, we aimed to describe the long-term natural disease course during endoscopic surveillance of SPS in terms of polyp burden after the initial clearing phase.
Study design and population
This was a post-hoc analysis of a prospective cohort of patients with SPS in the Amsterdam University Medical Centres (Amsterdam UMC) in the Netherlands. All patients with SPS in our center have undergone surveillance in the context of 2 prospective cohort studies, unless they met the exclusion criteria described below.
The data were prospectively collected by 4 consecutive research fellows (K.S.B., Y.H., J.E.G.IJ., A.G.C.B.).
The first prospective cohort study consecutively enrolled patients with SPS from January 2007 until December 2012, and assessed the yield of annual endoscopic surveillance after initial polyp clearance (Dutch Trial Register: www.trialregister.nl ID NL2629).
Subsequently, from January 2013 until April 2018, all patients were included in a second prospective cohort study, which assessed the safety and feasibility of a new individualized surveillance protocol (Dutch Trial Register: www.trialregister.nl, ID NL4476).
Prospective data entry in our database has continued until June 2019 awaiting initiation of new studies.
All patients were enrolled from our dedicated, weekly hereditary CRC outpatient clinic. This outpatient clinic has been staffed continuously by a professor in gastrointestinal oncology (E.D.) specialized in hereditary CRC syndromes, a staff gastroenterologist specialized in hereditary CRC syndromes (B.A.J.B.), a research nurse specialized in hereditary CRC syndromes (S.C.O.), and a research fellow specialized in SPS. This has ensured uninterrupted specialist care for all our patients with SPS. The attendance of the specialized research fellows ensured adherence to the surveillance protocols described below. Colonoscopies were performed by (or under direct supervision of) E.D. or B.A.J.B., or by a selected group of other GI endoscopists who had performed at least 1000 colonoscopies.
Because of the noninterventional nature of the current cohort study it fell beyond the legislation of the Medical Research Involving Human Subjects Act (Dutch: Wet Medisch Wetenschappelijk Onderzoek, WMO). In addition, the Amsterdam UMC’s Intitutional Review Board decided that both Hazewinkel et al’s
study fell outside of this legislation, and were therefore exempt from formal ethical approval.
Inclusion and exclusion criteria
Patients were included when they fulfilled the 2010 WHO diagnostic criteria I (≥5 SPs proximal to the sigmoid, with ≥2 measuring 10 mm) and/or III (>20 SPs of any size distributed throughout the colon).
Patients only fulfilling the 2010 criterion II (ie, any number of SPs proximal to the sigmoid colon in a first-degree relative of a patient with SPS) were not included.
Patients were eligible for inclusion if they were undergoing treatment in the Amsterdam UMC between January 2007 and June 2019, with at least one surveillance colonoscopy after initial polyp clearance. Initial polyp clearance was defined as clearance of all relevant polyps (ie, all sessile serrated lesions [SSLs], traditional serrated adenomas [TSAs], and conventional adenomas, as well as all hyperplastic polyps ≥5 mm in diameter). We excluded patients with inflammatory bowel disease or known CRC-related germline mutations (eg, GREM, PTEN, BMPR1A, SMAD4, ENG1 (bi-allelic), MutYH, or APC).
All patients were treated using uniform surveillance protocols. Between January 2007 and December 2012, patients were treated according to a surveillance protocol described by Hazewinkel et al.
Briefly, once clearance of the initial polyp burden was achieved, patients underwent annual endoscopic surveillance.
Between January 2013 and June 2019, all patients were treated using an updated protocol, in which patients were assigned to surveillance intervals of either 1 or 2 years, based on their most recent polyp burden. This protocol has been described in detail elsewhere.
Briefly, each consecutive surveillance colonoscopy was scheduled at an interval of 1 year when the most recent colonoscopy yielded ≥1 advanced SP, ≥1 advanced adenoma, or ≥5 nonadvanced clinically relevant lesions. When no advanced polyps and <5 clinically relevant lesions were found, patients were assigned to a 2-year interval. Clinically relevant lesions were defined as all polyps ≥5 mm and all polyps <5 mm but with the optical aspect of adenoma, TSA, or SSL. All colonoscopies had to be of sufficient quality, with a Boston bowel preparation score of 6 or higher and cecum intubation. If these criteria were not met, a repeat procedure was scheduled within 6 months.
Histopathologic assessment of all polyps was routinely performed by dedicated GI pathologists. In line with the most up-to-date WHO guidelines and with a recent review regarding the nomenclature of SPs,
SPs were classified as hyperplastic polyps, SSLs with/without dysplasia, and TSAs. SSL is synonymous with the frequently used terms “sessile serrated polyp (SSP)” and “sessile serrated adenoma/polyp (SSA/P).” Advanced serrated polyps (ASPs) were defined as any SP with dysplasia and/or with a diameter ≥10 mm, as well as all TSAs. Adenomas were classified as tubular adenomas or (tubulo)villous adenomas. Advanced adenomas (AAs) were defined as all adenomas ≥10 mm, with (tubulo)villous histology or high-grade dysplasia. Advanced neoplasia (AN) was defined as any ASP, AA, or CRC.
Aims and outcome parameters
We primarily aimed to describe the long-term safety and feasibility of endoscopic surveillance. To this end, we describe (1) the risk of CRC development and (2) the risk of colonoscopy-related adverse events per colonoscopy and per polypectomy. Our second aim was to assess whether or not polyp burden (AN, ASPs, and AAs) during surveillance followed a distinct upward or downward trend during the multiple rounds of surveillance after the initial polyp clearance phase. We performed these trend analyses on the entire cohort, as well as after stratification into (1) WHO subtype (fulfillment criterion I, III, or I and III), (2) smoking status (ie, nonsmoker or current/former smoker), (3) gender, and (4) indication for first colonoscopy (ie, screening or symptoms).
Colonoscopy-related adverse events were defined as events related to the colonoscopy occurring during or after the procedure (eg, perforation, bleeding, or postpolypectomy syndrome), leading to a change in management after the colonoscopy (eg, re-colonoscopy, surgery, admission, or antibiotic treatment). Perforations or bleeding that were resolved during the procedure and did not require additional treatment or admission were not considered colonoscopy-related adverse events. Adverse events were registered routinely in the adverse event registry of the Dutch Society of Gastroenterology until 2015. From January 2016, this registry was replaced by the Dutch Registration of Complications in Endoscopy. Occurrences of adverse events were identified by querying these 2 registries as well as the patient’s medical charts.
The presence of statistically significant trends in polyp burden was analyzed using a mixed effects logistic regression model in a per colonoscopy database, with the presence of any AN, any ASP, or any AA as independent variable. The numerical variable “round of surveillance” (1-9) was included in the model as a fixed effect; individual patients were included as a random effect to account for the repeated measurement for each patient. We defined a trend as a statistically significant association between the round of surveillance and the presence of AN, ASPs, or AAs, with a 2-sided P value of ≤.05. We present the results of this logistic regression model as the odds ratio (OR) with 95% confidence interval (CI), which should be interpreted as the OR of detecting AN for each additional round of surveillance. ORs >1.00 suggest an upward trend; ORs <1.00 suggest a downward trend.
Figures were produced using GraphPad Prism (version 7.03, GraphPad Software, La Jolla, Calif, USA).
Two hundred twelve potentially eligible patients were identified in our database, of whom 70 were excluded (Fig. 1). Patients were most frequently excluded because they had not yet undergone their first surveillance colonoscopy after the clearing phase (30) or because they did not fulfill WHO 2010 criterion I and/or III after careful review (11). Thus, 142 patients were included in the present study (Table 1).
The mean age at SPS diagnosis was 60.8 (± 9.7) years, and 65 (45.8%) were male. SPS diagnosis was made before 2010 in 39 (34.5%), between 2010 and 2014 in 68 (47%), and from 2015 onward in 25 (17.6%) patients. At the end of the clearing phase, 56 (39.4%) patients had a diagnosis of WHO criterion I, 50 (35.2%) had a diagnosis of WHO criterion III, and 36 (25.4%) fulfilled both criteria I and III. Fifty-two patients (36.7%) were diagnosed with CRC. Nine patients were additionally diagnosed with a second synchronous CRC, whereas 6 were later diagnosed with a second metachronous CRC. The median age at diagnosis of the first CRC was 59.5 years (range, 25-75 years). The patients underwent a median of 3 (interquartile range, 1-4) surveillance colonoscopies after clearing, with a median follow-up duration of 47 months (interquartile range, 15-71.5 months).
CRC during surveillance
One patient developed CRC while under endoscopic surveillance in our center, corresponding to a cumulative 5-year CRC incidence of 1.0% (95% CI, 0%-2.9%). This CRC was diagnosed in 2015 in a 55-year-old woman at surveillance colonoscopy 23 months after initial polyp clearance. She had a history of cervical cancer 17 years earlier, which was treated with abdominal radiotherapy. This patient had already undergone a right-sided hemicolectomy for a T4N0M0 cecal CRC that was diagnosed during the clearing phase. During the first surveillance colonoscopy after clearing, a tubulovillous adenoma with high-grade dysplasia was removed piecemeal from the transverse colon. During scar inspection 6 months later, the scar could not be located. The subsequent surveillance colonoscopy 6 months thereafter revealed a T3N0M0 CRC in the transverse colon, for which a proctocolectomy was performed. All surveillance colonoscopies were scheduled according to the surveillance protocol.
Adverse events during surveillance
In the 142 patients, a total of 447 surveillance colonoscopies and 1308 polypectomies were performed. Two adverse events occurred, which corresponds to an overall adverse event risk of 0.45% (95% CI, 0%-1.6%) per colonoscopy and 0.15% (95% CI, 0%-0.6%) per polypectomy.
One adverse event was postpolypectomy bleeding occurring 5 days after EMR of a 15-mm flat lesion, which required hospital admission, blood transfusion, and re-colonoscopy with clip placement. Histopathology showed this lesion was a tubular adenoma with low-grade dysplasia. This corresponds to a bleeding risk of 0.22% (95% CI, 0%-1.2%) per colonoscopy or 0.08% (95% CI, 0%-0.4%) per polypectomy.
The second adverse event was postpolypectomy syndrome consisting of fever and severe abdominal pain, which was managed conservatively with intravenous antibiotics during a 4-day hospital admission.
No patients presented with perforation, resulting in a per colonoscopy perforation rate of 0% (95% CI, 0%-0.8%) and a per-polypectomy perforation rate of 0% (95% CI, 0%-0.28%).
Polyp burden per surveillance round
The incidence of ASP differed per surveillance round between 2.9% (95% CI, 0.35%-9.9%) and 21.2% (95% CI, 9.0%-39.9%; Table 2), but the incidence did not follow a clear upward or downward trend over time (OR, 1.00; 95% CI, 0.82-1.23; Fig. 2A and Table 3). The incidence of AAs was lower and varied between 3.9% (95% CI, 1.1%-9.7%) and 12.9% (95% CI, 6.1%-23.0%). Similar to the incidence of ASP, no distinct upward or downward trend was seen in the incidence of AA over time (OR, 1.12; 95% CI, 0.73-1.74; Fig. 2A and Table 3). When stratified into fulfillment of WHO subtype, smoking status, and gender, the incidence of ASP and AA did not follow a distinct upward or downward trend either (Fig. 2B-D and Table 3). More detailed incidence rates for each surveillance round, stratified by WHO subtype, smoking status, gender, and indication for first colonoscopy are included in Supplementary Table 1 (available online at www.giejournal.org).
Screening: fecal occult blood test-based, primary or familial colorectal cancer.
The odds ratios should be interpreted as follows: odds ratios >1.0 suggest a positive trend, ie, increasing polyp burden over multiple rounds of surveillance; odds ratios <1.0 suggest a negative trend, ie, fading polyp burden over multiple rounds of surveillance.
When stratifying our cohort for the indication of their first colonoscopy, Figure 2E suggests a downward trend in the incidence of ASP in patients who underwent their first colonoscopy for a screening indication (fecal occult blood test-based, familial, or primary screening). Logistic regression analyses resulted in a nonsignificant downward trend with an OR of 0.42 (P =.10, Fig. 2E and Table 3). This trend was not observed for the incidence of AA.
In this post-hoc analysis of a large prospective cohort of patients with SPS in a tertiary referral center with a dedicated team of endoscopists and nurses, we assessed the long-term outcomes of endoscopic surveillance over more than 10 years of follow-up. First, we demonstrated that long-term endoscopic surveillance is effective, resulting in a low incidence of CRC. Second, we demonstrated that long-term endoscopic surveillance in such a setting is safe, with only 1 case colonoscopy-related bleeding and no perforations in 447 procedures. These findings are reassuring for clinicians and patients newly diagnosed with SPS. In addition, our results suggest that the natural disease course of SPS is such that the polyp burden remains more or less constant over many rounds of surveillance after initial polyp clearance. This finding supports lifelong adherence to current surveillance recommendations.
The median number of colonoscopies that was required to clear the colon of relevant polyps, before initiating endoscopic surveillance, was 3.5 in our study. This is in line with a recent prospective study by MacPhail et al,
in which 2 to 3 colonoscopies were needed to achieve initial polyp control. Furthermore, the low cumulative 5-year incidence of CRC (1.0%; 95% CI, 0%-2.9%) in our cohort was comparable with most recent cohort studies.
including 152 patients with SPS, reports a substantially higher incidence rate of 6.4% (95% CI, 0-13.6). Although we cannot explain the discrepancy between that study and our and other recent cohort studies, our results support the assumption that endoscopic surveillance every 1 to 2 years is effective for CRC prevention. These findings can be used to inform patients with SPS about a relatively favorable long-term prognosis once their initial polyp burden has been cleared, provided that surveillance protocols are adhered to, and surveillance is performed in an experienced center with high-quality colonoscopies (ie, adequate bowel preparation and cecum intubation). The low work of CRC during surveillance sharply contrasts with the high prevalence of CRC before diagnosis and/or initial polyp clearance (Table 1). The fact that the prevalence of CRC is high when SPS is undiagnosed and thus untreated, and the risk of CRC is low once proper treatment and surveillance are provided, suggests that CRC is mostly preventable in patients with SPS as long as proper treatment and surveillance are provided. This hypothesis is supported by the markedly lower incidence of CRC of 15% in our patients if we analyze the subgroup diagnosed with SPS after a regular (FIT-positive) screening colonoscopy. This highlights why early diagnosis of SPS before these patients develop CRC is so important. Therefore, adequate detection of SPs and careful application of the WHO diagnostic criteria are warranted.
Besides the low risk of CRC risk, the procedure-related risks of endoscopic surveillance were also reassuring. We demonstrated that surveillance procedures were safe, with a bleeding risk of only 0.22% (95% CI, 0%-1.6%) per colonoscopy and a perforation rate of 0% (95% CI, 0%-0.82%). Considering the large number of colonoscopies that patients with SPS undergo, the risks and benefits of such intensive surveillance regimens should be carefully weighed. This low adverse event rate is in line with a recent report of MacPhail et al,
in which no cases of perforation or delayed bleeding occurred in the management of 115 patients with SPS during clearing and subsequent surveillance procedures.
Finally, our study is the first to describe the disease course in patients with SPS after initial polyp clearance. We hypothesized that the polyp burden would gradually decrease after several rounds of endoscopic surveillance. This hypothesis was based on the assumption that the first few surveillance colonoscopies after initial polyp clearance are more likely to detect polyps that were missed during the initial polyp clearance, whereas during later surveillance colonoscopies, predominantly newly developed, less advanced polyps would be detected. Following this hypothesis, the incidence of larger, more advanced polyps would gradually become lower after multiple rounds of surveillance colonoscopies. However, our results do not suggest such a downward trend. Instead, we demonstrate that the polyp burden fluctuates from surveillance round to surveillance round without following a distinct upward or downward pattern. It remains unclear whether these advanced polyps occurring during later surveillance rounds represent polyps that were missed during earlier surveillance rounds, when they were still small, or whether these polyps newly developed between 2 surveillance colonoscopies. Regardless of the underlying mechanism, it seems plausible that patients with SPS are at increased risk of advanced polyps long after their initial polyp burden has been cleared. This advocates lifelong adherence to surveillance guidelines for all patients and discourages deintensifying surveillance after several rounds of surveillance.
Our study has several strengths. We used a large single-center cohort of patients with SPS with over 10 years of prospective follow-up. In addition, all patients were treated according to standardized surveillance protocols as part of 2 consecutive prospective cohort studies.
We could thus describe the natural disease course of SPS (while under endoscopic surveillance) with minimal risk of interfering factors such as variable treatment protocols and inter-endoscopist variation in polyp detection.
Nevertheless, several limitations have to be noted. First, we included patients with SPS over a large time span. This is important. Because 1:111 individuals with a positive FIT result might fulfill the diagnostic criteria of SPS, the introduction of the national FIT-based bowel cancer screening program in the Netherlands in 2014 has likely led to an increased number of patients with asymptomatic SPS.
Indeed, this hypothesis can be confirmed by stratifying our cohort into patients who underwent their first surveillance before 2014 or from 2014 onward: 3.8% versus 25.4% received their first colonoscopy because of a positive FIT result, respectively. The risk of CRC in FIT-positive, asymptomatic individuals may differ from patients who undergo their first colonoscopy because of symptoms. Another effect of including patients over such a large time span results from the fact that the detection of SPs by the participating endoscopists might have improved over the past 10 years, which might have made both clearing as well as surveillance colonoscopies more effective over the past few years. Second, although the single-center design of our study has minimized interference from inter-hospital and inter-endoscopist variation, the external validity would have been superior with a multicenter design. Third, all patients in our cohort were diagnosed according to the WHO 2010 diagnostic criteria, whereas the WHO recently (summer 2019) published their updated diagnostic criteria.
except that 2010 criterion II has been abandoned in the 2019 criteria. Because we excluded all patients fulfilling 2010 criterion II in this study, our cohort is representative of future patients diagnosed with SPS according to the 2019 criteria as well.
In conclusion, in this large single-center cohort study with over 10 years of prospective follow-up, we demonstrate that the long-term outcomes of patients with SPS under surveillance are favorable, with a low risk of the development of CRC and a low risk of colonoscopy-related adverse events. In addition, we demonstrate that the polyp burden remains rather stable throughout long-term surveillance and thus, lifelong adherence to surveillance recommendations seems warranted. Our findings can be used to inform patients about their long-term prognosis during surveillance that will follow clearance of their initial polyp burden.
This work was funded by grants from the Dutch Cancer Society (KWF). KWF was not involved in the design, collection, analysis, and interpretation of our data.
If you would like to chat with an author of this article, you may contact Professor Dekker at [email protected] .
DISCLOSURE: Dr Bastiaansen has received speaker’s fees from Olympus , Tillotts Pharma AG and Ovesco Endoscopy. Dr. Dekker has used endoscopic equipment on loan from Olympus and FujiFilm, and received a research grant from FujiFilm, honoraria for consultancy from FujiFilm, Tillots, Olympus, GI Supply, and Cancer Prevention Pharmaceuticals, and speaker’s fees from Olympus, Roche , and GI Supply. All other authors disclosed no financial relationships.
A challenging issue for endoscopists in colorectal cancer (CRC) surveillance is the management of polyposis syndromes.1 Serrated polyposis syndrome (SPS) in comparison with other polyposis syndromes may seem more challenging, owing in part to the relatively recent recognition of this disease. A recent study from a major referral center observed that ≤40% of SPS cases were not recognized by endoscopists.2 Many of the other polyposis syndromes are associated with a known genetic mutation, making identification of patients easier.