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Incidence of Colonic Neoplasia in Patients With Serrated Polyposis Syndrome Who Undergo Annual...
Transcript of Incidence of Colonic Neoplasia in Patients With Serrated Polyposis Syndrome Who Undergo Annual...
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Gastroenterology 2014;-:1–8
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CALAT
Incidence of Colonic Neoplasia in Patients With Serrated PolyposisSyndrome Who Undergo Annual Endoscopic SurveillanceYark Hazewinkel,1 Kristien M. A. J. Tytgat,1 Susanne van Eeden,2 Barbara Bastiaansen,1
Pieter J. Tanis,3 Karam S. Boparai,1 Paul Fockens,1 and Evelien Dekker1
Departments of 1Gastroenterology and Hepatology; 2Pathology; and 3Surgery, Academic Medical Center,Amsterdam, The Netherlands
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102CLINI
BACKGROUND & AIMS: Patients with serrated polyposis syn-drome (SPS) are advised to undergo endoscopic surveillancefor early detection of polyps and prevention of colorectal can-cer (CRC). The optimal surveillance and treatment regimen isunknown. We performed a prospective study to evaluate astandardized endoscopic treatment protocol in a large cohort ofpatients with SPS. METHODS: We followed a cohort of patientswith SPS who received annual endoscopic surveillance at theAcademic Medical Centre in Amsterdam, The Netherlands fromJanuary 2007 through December 2012. All patients underwentclearing colonoscopy with removal of all polyps �3 mm. Afterclearance, subsequent follow-up colonoscopies were scheduledannually. The primary outcomes measure was the incidence ofCRC and polyps. Secondary outcomes were the incidence ofcomplications and the rate of preventive surgery. RESULTS:Successful endoscopic clearance of all polyps �3 mm wasachieved in 41 of 50 (82%) patients. During subsequent annualsurveillance, with a median follow-up time of 3.1 years (inter-quartile range, 1.5�4.3 years), CRC was not detected. The cu-mulative risks of detecting CRC, advanced adenomas, or large(�10 mm) serrated polyps after 3 surveillance colonoscopieswere 0%, 9%, 34%, respectively. Twelve patients (24%) werereferred for preventive surgery; 9 at initial colonoscopy and 3during surveillance. Perforations or severe bleeding did notoccur. CONCLUSIONS: Annual surveillance with completeremoval of all polyps �3 mm with timely referral of selectedhigh-risk patients for prophylactic surgery prevents develop-ment of CRC in SPS patients without significant morbidity.Considering the substantial risk of polyp recurrence, closeendoscopic surveillance in SPS seems warranted. www.trialregister.nl ID NTR2757.
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Keywords: Colon Cancer; Serrated Neoplasia Pathway; CancerPrevention; Screening.
olorectal cancer (CRC) is one of the most common1
Abbreviations used in this paper: CRC, colorectal cancer; IRB, Institu-tional Review Board; SPS, serrated polyposis syndrome; WHO, WorldHealth Organization.
© 2014 by the AGA Institute0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2014.03.015
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Ccancers in the Western world. Until recently, thetraditional adenoma�carcinoma sequence was consideredto be the single pathway responsible for the development ofCRC. During the last decade, however, an alternativepathway of colorectal carcinogenesis has been recognized,that is, the serrated neoplasia pathway.2–8 This pathwayinvolves the malignant transformation of serrated polypsinto CRC, which, in turn, is associated with a poor prog-nosis.8 Alongside the adenoma�carcinoma sequence, this
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serrated pathway also plays a significant role in patientswith serrated polyposis syndrome (SPS).9,10
SPS is characterized by the presence of multipleserrated polyps spread throughout the colon and rectumand has been defined by the World Health Organization(WHO) as the presence of at least 5 serrated polyps prox-imal to the sigmoid colon, of which 2 measure at least10 mm in diameter (WHO criterion 1), any number ofserrated polyps occurring proximal to the sigmoid colon inan individual who has a first-degree relative with SPS (WHOcriterion 2), and/or >20 serrated polyps spread throughoutthe colon (WHO criterion 3).11 The prevalence of SPS wasrecently estimated to be in between 1:151 and 1:294among patients undergoing screening colonoscopy based onfecal immunochemical testing.12,13 Another estimation ofthe prevalence of SPS (1:3000) was based on data in anaverage risk screening population undergoing flexiblesigmoidoscopy.14 This makes the condition rather commonand more frequent in occurrence than other polyposissyndromes, such as familial adenomatous polyposis (prev-alence 1:13.000).15
SPS is associated with an increased personal and familialCRC risk. Previous published case series and cohort studiesreport CRC at first clinical presentation in up to 50% of SPSpatients.16–24 In addition, several retrospective studiesshowed that these patients can develop CRC under endo-scopic surveillance (interval cancers).16,19,20 Close endo-scopic surveillance to prevent malignant progression ofpolyps has therefore been advised by several expertgroups.4,6,16,19,25 Also the US Multi-Society Task Force onColorectal Cancer and the European Society of Gastrointes-tinal Endoscopy recently recommended a 1-year surveil-lance interval for these patients.26,27
However, due to a lack of prospective data, the optimaltreatment approach with regard to surveillance intervalsand polypectomy protocol is still largely unknown. As aconsequence, patients with SPS might still be inadequatelytreated and consequently be at risk for developing CRC
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CLINICALAT
under surveillance. Conversely, overtreatment with unnec-essary short surveillance intervals and removal of possibleharmless lesions, which can result in complications, shouldalso be avoided.
The aim of the present study was to prospectivelyevaluate a standardized endoscopic surveillance and poly-pectomy protocol in a consecutive cohort of SPS patients.Primary outcome was the incidence of CRC and polyps andsecondary outcomes were complication rate and percentageof patients referred for preventive colorectal surgery.
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MethodsPatients and Study Design
Consecutive patients, aged 18 years or older, fulfillingSPS WHO criteria 1 or 3, who presented at the AcademicMedical Centre, Amsterdam, the Netherlands, betweenJanuary 2007 and December 2012 were enrolled. WHOcriteria for SPS are as follows: �5 histologically diagnosedserrated polyps proximal to the sigmoid colon, of which 2measure �10 mm in diameter (WHO criterion 1), and/or�20 serrated polyps spread throughout the colon (WHOcriterion 3).28 The diagnosis of SPS was based on all pre-viously removed polyps at colonoscopies and/or surgeryand those that were removed at clearing colonoscopy. Asdefined by the WHO, only histologically confirmed serratedpolyps were counted for the diagnosis. Patients with aknown germline mutation in the MutYH (biallelic) or APCgene, as well as patients with Lynch syndrome, inflamma-tory bowel disease, or a total proctocolectomy wereexcluded. Additionally, patients were excluded when theywere not treated according to study protocol. Protocol vio-lations were defined as surveillance interval longer than2 years between 2 consecutive colonoscopies or the absenceof an experienced colonoscopist (ED, KT, and BB) duringclearing colonoscopy.
The study had a prospective cohort design. This studywas exempt from Institutional Review Board (IRB) reviewafter institutional IRB review. Our IRB decided that thestudy did not meet the requirements of the MedicalResearch Involving Human Subjects Act (WMO), as datawere collected during routine care and no additional patientinterventions were undertaken. Patients were verballyinformed about the surveillance protocol. Because the studywas exempt for IRB approval, written informed consent wasnot obtained. All authors had access to the study data andreviewed and approved the final manuscript. The study wasregistered on a publicly accessible website (Dutch TrialRegister: www.trialregister.nl ID NTR2757).
Endoscopic Surveillance and Treatment ProtocolAll SPS patients satisfying WHO criteria underwent
initial clearing colonoscopy with complete removal of allpolyps �3 mm. When this was not possible during oneprocedure, an additional clearing colonoscopy was per-formed, preferably within 6 months. After clearance, sub-sequent follow-up colonoscopies were scheduled annually,again with complete removal of all polyps �3 mm. Criteria
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for referring patients for preventive surgery were based onthe multiplicity, size, type, and shape of lesions seen duringcolonoscopy.
Demographic data of patients concerning age, sex, per-sonal history of CRC, and family history of CRC wereascertained. Family history of patients was obtained byexamining data from the Department of Clinical Genetics orby examining general medical records. These records werebased on self-reported information. During procedures,polyp variables were noted by an investigator or researchnurse by using a case record form. When there was no nurseor research fellow present, variables were recorded in thedigital colonoscopy report by one of the study colonoscop-ists. Subsequently, these data were linked with the pathol-ogy report and entered in a database. The following polypparameters were documented: size, location, morphology,and polypectomy technique. Complications were defined asperforations or post-procedure bleeding resulting in a hos-pital admission or repeat colonoscopy for hemostasis within30 days after colonoscopy.
All clearing colonoscopies were performed by 3 endo-scopists (ED, KT, and BB) specializing in polyposis syn-dromes and with an experience of >1000 colonoscopies.Procedures were performed using standard or high-resolution white-light endoscopy at a dedicated endoscopyprogram. A subset of consecutive patients underwent a tan-dem colonoscopywith high-resolutionwhite-light endoscopyand narrow band imaging as part of different studiescomparing polyp miss rates of both imaging modalities.29
Apart from these procedures, advanced imaging techniquesfor the detection of polyps (ie, chromoendoscopy) were notused.
Patients were prepared with a standard bowel prepa-ration, including a 4L polyethylene glycol solution or a 2Lhypertonic polyethylene glycol solution with an additional2�4 L transparent fluids and a low-fiber diet. Procedureswere performed under conscious sedation with midazolamand/or fentanyl or under propofol when indicated. Cecalintubation was confirmed by documentation of the cecallandmarks (cecal valve, appendix orifice, or intubation of theileum). The proximal colon was defined as proximal to sig-moid (descending, transverse, ascending colon, and cecum).
OutcomesPrimary outcome was the incidence of CRC and polyps
during annual colonoscopic surveillance. Secondary out-comes were the complication rate and percentage of pa-tients referred for preventive surgical resection.
Histopathologic evaluationTissue specimens were routinely processed and
reviewed by an expert gastrointestinal pathologist accord-ing to the Vienna criteria.30 Serrated polyps were classifiedas hyperplastic polyp, sessile serrated adenoma/polyp withor without cytological dysplasia, or traditional serrated ad-enoma based on histologic criteria initially proposed byTorlakovic Qet al, which are now incorporated into the WHOclassification for serrated polyps.11 A sessile serrated
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adenoma/polyp was defined by predominantly disorganizedand distorted crypts, including dilation or branching of thebasal portion of the crypt that often appears as a “boot” or“L” shape. Traditional serrated adenomas were defined by aprotuberant or pedunculated growth pattern with distortedviliform configurations with columnar cells having abundanteosinophlic cytoplasm or centrally located elongated nuclei.When it was impossible to differentiate between thedifferent serrated subtypes, for example, due to poororientation or severe cauterization artefacts, the lesion wasclassified as hyperplastic polyp. Advanced adenomas wereadenomas �10 mm, with villous structure or with high-grade dysplasia.
Statistical AnalysisNormal distributed variables are presented as means
(�SD), variables with skewed distribution are presented asmedian (interquartile range [IQR]). Categorical variablesare presented as frequencies (%). The cumulative proba-bility of events (CRC, advanced adenomas, and serratedpolyps �10 mm) during the study period was estimatedwith the Kaplan-Meier method, according to the sur-veillance colonoscopy number. Individuals where werecensored at their last surveillance colonoscopy. Statisticalanalysis was performed using SPSS 20.0 (IBM Corporation,Somers, NY).
Figure 1. Flow of patientsthroughout the studyperiod. Seventy-eight pa-tients with SPS were iden-tified. Fourteen patientswere excluded because ofprotocol violations, inflam-matory bowel disease, orLynch syndrome. Another14 (18%) patients werediagnosed with CRC at thetime of initial presentation.The remaining 50 patientsunderwent clearing colo-noscopy with intention toremove all polyps �3 mm.This was achieved in 41patients (82%), and9 (18%)patients were referredfor preventive surgery be-cause of an endoscopicallyuntreatable number ofpolyps. During subsequentsurveillance, another 3 pa-tients were referred forprophylactic surgery. CNS,colonoscopy.
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ResultsStudy Flow
Figure 1 details the flow of patients throughout thestudy period (January 2007�December 2012). A total of 78consecutive patients with SPS presented at our center.Fourteen patients were excluded because of protocol vio-lations (n ¼ Q9), concomitant inflammatory bowel disease(n ¼ 3), or Lynch syndrome (n ¼ 2). Protocol violationsincluded the following: absence of trained endoscopist atclearing colonoscopy (n ¼ 7) and surveillance intervallonger than 2 years between 2 consecutive colonoscopies(n ¼ 2). Another 14 patients (18%) were diagnosed withCRC at the time of initial presentation during the studyperiod. The remaining 50 patients underwent clearing co-lonoscopy with the intention to remove all polyps �3 mm.This was achieved in 41 patients (82%), and the other 9(18%) patients were referred for prophylactic surgerybecause of an endosopically untreatable number of polyps.
Endoscopic Treatment and SurveillanceThe 41 patients who were successfully cleared from all
polyps �3 mm entered the annual endoscopic surveillanceprogram. These 41 patients belonged to 39 families, including2 sisters and a sister and a brother. Baseline demographicsand colonoscopy details are displayed in Table 1. Mean age at
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Table 1.Baseline characteristics of serrated polyposissyndrome patients included in surveillanceprogram (n ¼ 41)
Age at diagnosis SPS, y, mean � SD (range) 56.5 � 10 (27�76)Age at inclusion surveillance program, y,
mean � SD (range)57.5 � 10 (27�76)
Male, n (%) 24 (59)WHO SPS classification, n (%)
I 6 (15)III 21 (51)Combined (IþIII) 14 (34)
Prior CRC, n (%) 13 (33)Age at diagnosis, y, mean � SD (range) 54 � 6 (41�61)Proximal, n 5Distal, n 8
Prior colonic surgery, n (%) 15 (37)Partial colonic resection, n 11Subtotal colectomy with ileorectal
anastomosis, n4
First-degree relative with CRC, n (%) 11 (27)Total no. of clearing colonoscopies 84No. of clearing colonoscopies per patient,
median (range)2 (1�4)
Total no. of surveillance colonoscopies 119No. of surveillance colonoscopies
per patient, median (range)3 (0�7)
Follow-up after first clearingcolonoscopy, y, median (range)
3.6 (0�5.3)
Follow-up after last clearingcolonoscopy, y, median (range)
3.1 (0�5.3)
Interval between surveillancecolonoscopies, y, median (range)
1.0 (0.6�1.7)
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start of the surveillance program was 57 years (�10 years)and 24 (59%) were male. Colonic resection before the firstclearing colonoscopy was performed in 15 patients (37%)because of previous CRC (n ¼ 13) or extensive polyposis(n ¼ 2). Consequently, 26 patients underwent clearing of anintact colon, 6 patients of the remaining colon proximal to therectosigmoid, 8 patients of the remaining distal colon, and 1
Table 2.Prevalence and number of polyps removed at clearing
Clearing(n ¼ 41) (n
Patients with CRC, n (%) 0 (0) 0Patients with �1 polyp, n (%) 38 (93) 35No. of polyps, median (range) 16 (0�72) 5Size of polyps, mm, median (range) 5 (3�25) 4Patients with �1 serrated polyp, n (%) 38 (93) 34Patients with �1 serrated polyp �10 mm, n (%) 21 (51) 4No. of serrated polyps, median (range) 12 (0�72) 4Size of serrated polyps, mm, median (range) 5 (3�25) 4Patients with �1 adenoma, n (%) 23 (56) 15Patients with �1 advanced adenoma, n (%) 11 (27) 2No. of adenomas, median (range) 1 (0�11) 0Size of adenomas, mm, median (range) 4 (3�25) 4
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patient of the remaining colon after a proximal segmentalresection. A research nurse/investigator was present during126 of 203 (62%) of all colonoscopies to record polyp vari-ables. During the remaining procedures, variables werenoted in the digital endoscopy report by one of studyendoscopists.
Clearing ColonoscopyMedian number of colonoscopies needed to clear the
colon from polyps �3 mm was 2 (IQR, 1�3; range, 1�4).A total of 773 polyps were detected; 441 (57%) hyper-plastic polyps, 242 (31%) sessile serrated adenomas/polyps, and 90 (12%) conventional adenomas. Detailedpolyp characteristics are outlined in Table 2. Median num-ber of polyps removed at clearing colonoscopy was 16(range, 0�72). At least 1 advanced adenoma or large (�10mm) serrated polyp was detected in 11 (29%) and 21(51%) patients, respectively (Table 3).
Follow-Up: Surveillance ColonoscopiesMedian follow-up from last clearing colonoscopy until
last surveillance colonoscopy of all 41 patients was 3.1years (IQR, 1.5�4.3; range, 0�5.3 years), with a median of 3(IQR, 2�4; range, 1�4) surveillance colonoscopies. Medianinterval between surveillance colonoscopies was 1.0 year(range, 0.6�1.7 years).
The incidence and number of polyps detected at eachsurveillance colonoscopy is displayed in Table 2. Polypcharacteristics are outlined in Table 3. A total of 37 patientsunderwent at least 1 surveillance colonoscopy; nonedeveloped CRC during follow-up. During 119 surveillancecolonoscopies, 575 polyps were detected; 346 (60%) hy-perplastic polyps, 135 (23%) sessile serrated adenomas/polyps, and 94 (16%) conventional adenomas. Traditionalserrated adenomas were not diagnosed. Polyps weredetected in at least 80% of patients at each follow-up timepoint. Most lesions were detected at first surveillancecolonoscopy, with a median number of 5 polyps
and each surveillance colonoscopy
Surveillance
First¼ 37)
Second(n ¼ 31)
Third(n¼ 26)
Fourth(n ¼ 15)
Fifth(n ¼ 2)
(0) 0 (0) 0 (0) 0 (0) 0 (0)(95) 27 (87) 23 (88) 12 (80) 2 (100)(0�22) 4 (0�20) 4 (0�15) 1 (0�20) 2 (1�3)(3�15) 4 (3�12) 4 (3�10) 3 (3�10) 4 (3�5)(92) 27 (87) 22 (81) 11 (73) 2 (100)(11) 5 (16) 3 (12) 1 (7) 0 (0)(0�19) 4 (0�20) 3 (0�14) 1 (0�19) 2 (1�3)(3�15) 4 (3�12) 4 (3�10) 4 (3�10) 4 (3�5)(41) 15 (48) 13 (50) 7 (47) 0 (0)(5) 1 (3) 0 (0) 0 (0) 0 (0)(0�10) 0 (0�3) 0.5 (0�4) 0 (0�4) 0 (0�0)(3�10) 3 (3�10) 3 (3�5) 3 (3�4) 0 (0�0)
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Table 3.Histology, size, location, and dysplasia of detectedpolyps at clearing and surveillance colonoscopies
HP SSA/P Adenoma Total
Clearing colonoscopy:no. of polyps
441 242 90 773
Size, n (%)3�5 mm 356 (81) 96 (40) 63 (70) 515 (67)6�9 mm 61 (14) 59 (24) 15 (17) 135 (17)>10 mm 24 (5) 87 (36) 12 (13) 123 (16)
Location,a n (%)Proximal 208 (47) 188 (78) 63 (70) 459 (59)Distal 159 (36) 42 (17) 18 (20) 219 (28)
Dysplasia, n (%)LGD 0 (0) 7 (3) 86 (96) 93 (12)HGD 0 (0) 0 (0) 4 (4) 4 (1)
Surveillancecolonoscopies:no. of polyps
346 135 94 575
Size, n (%)3�5 mm 298 (86) 93 (69) 87 (93) 478 (83)6�9 mm 39 (12) 29 (21) 5 (5) 75 (13)>10 mm 7 (2) 13 (10) 2 (2) 22 (4)
Location, n (%)Proximalb 176 (51) 107 (79) 79 (84) 362 (63)Distal 144 (42) 16 (12) 13 (14) 173 (30)
Dysplasia, n (%)LGD 0 (0) 14 (10) 93 (99) 107 (19)HGD 0 (0) 0 (0) 1 (1) 0 (0)
HGD, high-grade dysplasia; HP, hyperplastic polyp; LGD,low-grade dysplasia; MP, mixed polyp; SSA/P, sessileserrated adenoma/polyp.aSpecified for 678 of 773 polyps.bSpecified for 535 of 575 polyps.
Table 4.Calculated cumulative risk of detecting colorectalcancer or advanced polyps after 3 surveillancecolonoscopiesa
All patients(n ¼ 37)
With priorCRC (n ¼ 12)
Without priorCRCb (n ¼ 25)
Age, y, mean � SD 57 � 10 60 � 8 56 � 12Male sex (%) 21 (57) 6 (50) 15 (60)Colorectal cancer
(95% CI)0 (0�0) 0 (0�0) 0 (0�0)
Advanced adenoma(95% CI)
9 (0�17) 8 (0�23) 9 (0�20)
Serrated polyp�10 mm (95% CI)
34 (15�48) 27 (3�45) 38 (13�56)
NOTE. Subgroup analysis was performed for patients withand without a history of CRC before the start of the study.CI, confidence interval.aCumulative risk was analyzed by Kaplan-Meier survivalanalysis. Patients who did not reach the third surveillancecolonoscopy were censored from their last surveillancecolonoscopy.bTwenty-three of 25 patients had intact colons.
Figure 2. Kaplan-Meier curves for detecting CRC, advancedadenomas and large (�10 mm) serrated polyps during annualsurveillance.
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(range, 0�22). The range of detected polyps varied greatlyamong patients; considering all surveillance colonoscopies(except number 5), a minimum difference of 15 polyps wasobserved between the patient with the lowest and thehighest number of polyps.
During surveillance, advanced adenomas were detectedin 3 of 37 (8%) patients. Median interval between lastclearing colonoscopy and detection of these advanced ade-nomas was 13 months (range, 12�25 months). Thisincluded 1 tubular adenoma with high-grade dysplasia, 1tubulovillous adenoma, and 1 large (10 mm) tubular ade-noma. The calculated cumulative risk of detecting at least 1advanced adenoma after 3 surveillance colonoscopies was9% (Table 4 and Figure 2). When analyzing this risk sepa-rately for patients with and without a history of CRC, thecumulative risk was 8% and 9%, respectively. Largeserrated polyps (hyperplastic polyps or sessile serratedadenomas/polyps �10 mm) were detected in 11 of 37(30%) patients. Median interval between last clearing co-lonoscopy and detection of large serrated polyps was 21months (range, 12�39 months). The calculated cumulativerisk of detecting at least 1 large serrated polyp after 3surveillance colonoscopies was 34% (Table 4 and Figure 2).When analyzing this risk separately for patients with andwithout a history of CRC, the cumulative risk was 27% and
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38%, respectively. Detailed information regarding thenumber of patients at risk at each surveillance colonoscopywith corresponding cumulative risk estimates are summa-rized in Figure 2.
Prophylactic surgery after successful colonic clearanceof polyps was considered to be indicated in 3 of 37 (8%)patients. All 3 patients had an intact colon before the start ofthe surveillance program. A 62-year old male patient un-derwent 4 previous clearing colonoscopies. During these
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procedures 25 polyps were removed, including 3 advancedadenomas. At first surveillance colonoscopy (14 monthsafter last clearing colonoscopy), a proximal tubular ade-noma of 10 mm with at least high-grade dysplasia wasdetected, which was removed en bloc by endoscopicmucosal resection. Unfortunately, the depth of invasion intothe submucosal layer could not be reliably assessed by apanel of pathologists. For this reason, and because of thelarge burden of recurrent polyps, a subtotal colectomy withan ileorectal anastomosis was performed. The resectedspecimen showed 27 serrated polyps. No malignant ordysplastic polyps were observed. In 2 male patients (64 and54 years old), endoscopic treatment was no longer consid-ered safe and feasible because of recurrent extensive pol-yposis. In both patients, numerous small and large lesionswere seen throughout the entire colon. A subtotal colectomywith an ileorectal anastomosis was performed. The surgicalresection specimen showed >100 serrated polyps (all <10mm) without histologic dysplasia in the first patient, and>200 serrated polyps (all <12 mm) without histologicdysplasia in the second patient.
ComplicationsPerforations or post-procedural bleedings resulting in a
hospital admission or repeat colonoscopy for hemostasistherapy did not occur during 84 clearing and 119 surveil-lance colonoscopies. One patient was admitted within 24hours after colonoscopy with pneumococcal bacteremia ofunknown origin. The patient was treated with antibioticsand admitted for 3 days with an uneventful recovery. Twoother patients presented to the emergency room. The firstpatient reported minor rectal blood loss and fever. Labo-ratory findings showed normal hemoglobin and leukocytevalues. The second patient presented with abdominal painwithout perforation, but with signs of inflammation. A post-polypectomy syndrome was suspected. Both patients weremanaged conservatively without admission to the hospital.
SurgeryDuring the study period, 23 patients (median age, 60
years; 43% male) were referred for surgery on diagnosisand consequently not entered the endoscopic treatmentprotocol. Indications for surgery were CRC (n ¼ 14),extensive polyposis (n ¼ 8), and an endoscopically unre-sectable adenomatous polyp (n ¼ 1). Seven of the 8 patientswith extensive polyposis underwent a subtotal colectomywith ileorectal anastomosis. Median number of polyps in theresection specimens of these patients was 35 (range,20�93); no carcinomas were detected.
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DiscussionIn the present study, we prospectively evaluated the
outcomes of a standardized endoscopic treatment protocolin a large cohort of SPS patients with regard to endoscopicfindings, complications, and prophylactic surgery rate. Wedemonstrate that annual endoscopic surveillance withremoval of all polyps �3 mm with timely referral of selected
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high-risk patients for prophylactic surgery prevents devel-opment of CRC in SPS patients without significant morbidity.Considering the substantial risk of polyp recurrence in ourcohort, close endoscopic surveillance seems warranted.
Our study has several strengths. All patients underwenta standardized predefined treatment protocol and werefollowed in a prospective manner. In addition, all clearingcolonoscopies and most surveillance colonoscopies wereperformed by dedicated and experienced endoscopistsspecialized in polyposis syndromes. Several potential limi-tations should also be acknowledged. Due to the smallsample size and relatively short follow-up period, resultsshould be interpreted with caution, as they might not besufficiently representative for all patients with SPS. Also,lack of certain clinical and sociodemographic data likeobesity, smoking status, and ethnicity can potentially limitthe generalizability of our findings to other populations. Thepresent study is the largest prospective study available andthe current findings add substantially to our understandingof the longitudinal CRC risk in SPS patients under strictendoscopic surveillance. Another potential shortcoming ofthe study is that a subset of patients was diagnosed with SPSbefore the time period of this study and consequentlyalready received either endoscopic or surgical treatment.This might have affected the number of polyps detected atclearing colonoscopy. Another limitation is the fact that aproportion of patients underwent back-to-back colonoscopybecause they were enrolled in studies comparing narrowband imaging with high-resolution endoscopy. QDuring theseprocedures, each colonic segment was inspected twice,which might have positively influenced our polyp detectionrates. Lastly, as all patients were treated at a tertiary aca-demic referral center with extensive expertise in the man-agement of SPS, our findings cannot by default beextrapolated to general practice.
In a previous retrospective multicenter study from ourgroup, we calculated a worrisome cumulative CRC risk of7% at 5 years in patients with SPS undergoing endoscopicsurveillance.16 Also Edelstein et al recently reported asubstantial incidence of interval CRCs (5%) in this patientgroup.19 In contrast with the present study, screening in-tervals were not standardized in these studies, which mighthave resulted in different recommended surveillance in-tervals and incomplete removal of all polyps. In addition,because the clinical data of these studies dated back to 1982and 2001, it is likely that the association between multipleserrated polyps and colonic neoplasia was not always madeby endoscopists or was underestimated. As a consequence,these patients might have been treated insufficiently withthe development of CRC under surveillance in some of them.The present study reports the longest duration of prospec-tive follow-up and shows that the actual CRC risk is low inpatients with SPS who undergo annual surveillance of thecolon.
Considering the high polyp recurrence rate observed inour series, close endoscopic surveillance seems justified.Polyps were detected in at least 80% of patients at eachsurveillance colonoscopy. In addition, advanced adenomas,including one with high-grade dysplasia, and large serrated
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polyps were detected in 8% and 30% of patients duringfollow-up, respectively. Median interval between colonicclearing and the detection of these lesions was only 13months for advanced adenomas and 21 months for largeserrated lesions. Additionally, 2 (5%) patients developedsuch an extensive recurrent polyposis that endoscopiccontrol of polyps was no longer considered safe and feasible(>100 polyps were found in the surgical resection spec-imen). The detection of advanced lesions as well as the rapidrecurrence of numerous polyps suggests that SPS is asso-ciated with an increased neoplastic growth and progressionrate in at least a subset of patients. A future challenge willbe to investigate whether it is possible to separate thissubset of high-risk patients from patients with a minimumrisk of (recurrent) colonic neoplasia. This would allow for amore tailored endoscopic management with regard to sur-veillance intervals and preventive surgery. However, untildistinctive molecular and genetic differences have beenfound and as long as we cannot predict CRC risks in anassured manner, a strict surveillance regimen for all pa-tients who fulfill the WHO criteria for SPS is recommendedbased on our findings.
With regard to the feasibility of our protocol, completeendoscopic clearing of all polyps �3 mm was achieved in82% of patients, and 18% of patients were referred tosurgery because of an endoscopically untreatable number ofpolyps. Median number of polyps removed at clearing co-lonoscopy was 16 and >50% of patients had large serratedpolyps. It is therefore advisable that these clearing sessionsbe performed by endoscopists with experience in endo-scopic mucosal resection for complete and safe polypremoval. In addition, allowances should be made for suffi-cient procedure time, as the multiplicity of polyps and theuse of advanced polypectomy techniques leads to longerprocedure times.
Twelve patients (26%) (9 at initial colonoscopy and 3during surveillance) underwent a preventive surgicalresection. This decision for colectomy was made by anexpert endoscopist based on the multiplicity, size, type, andshape of lesions seen during colonoscopy. We would like toemphasize that we did not use a standard cut-off point forthe number of polyps because, in our opinion, the decisionfor a preventive colectomy needs to be individualized foreach patient. In this respect, it is advisable to centralizeendoscopic management of patients with SPS in institutionswith experience in this field to ensure optimal treatmentand follow-up.
The number of polyps found in 2 of the 3 patients whounderwent prophylactic surgery was much higher (>100polyps) than any of the polyp numbers found at any of thesurveillance colonoscopies. This might suggest that endos-copy misses many polyps in patients with SPS. Although wecannot exclude that lesions were missed, it is important torealize that polyps seen during the last colonoscopy beforesurgery in these 2 patients were not removed, as the deci-sion for surgery was made and these patients would un-dergo surgery anyway. At the time of surgery, these polypswere still in situ, which explains the relatively high numberof polyps found in the resection specimen. In addition,
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polyps <3 mm were not removed or counted duringendoscopy, and these polyps were counted in the colonicresection specimens by the pathologist.
Concerning the removal of polyps, previous studies haveshown that approximately 30%�50% of all CRCs in patientswith SPS arise via the serrated neoplasia pathway.9,10 Theother half presumably follows the traditionally adenoma�carcinoma sequence. In addition, it was shown thatadvanced neoplasia could be detected in polyps as small as4 mm in SPS.9 For this reason, removal of all type of polyps,including small lesions, seems advisable. On the other hand,overtreatment with unnecessary removal of possiblyharmless lesions should be avoided. We chose to clearpolyps �3 mm from the colon. Of note, 34% (339 of 993) ofall removed lesions between 3 and 5 mm were adenomas orsessile serrated adenomas/polyps, suggesting that removalof these diminutive lesions might prevent malignant pro-gression in SPS. None of these lesions contained high-gradedysplasia or invasive cancer. Considering that patients withSPS have many diminutive lesions, leaving these lesions insitu until they reach a certain size (ie, 6 mm) would sub-stantially reduce the workload of the endoscopist anddecrease the pathology costs, but the safety of this approachshould first be prospectively assessed.
In conclusion, results from this study suggest that pa-tients with SPS have a low risk of developing CRC when theyundergo annual surveillance of the colon with removal ofpolyps �3 mm. Additional follow-up studies are required toevaluate whether endoscopic surveillance can be performedat longer time intervals and additional studies are needed toidentify high-risk subgroups requiring prophylactic surgery.In addition, although removal of all larger polyps seemsnecessary in any case, future studies should evaluate thesafety of leaving diminutive lesions in situ, as this wouldcertainly save time and avoid overtreatment.
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Received November 4, 2013. Accepted March 14, 2014.
Reprint requestsQAddress requests for reprints to: Evelien Dekker, MD, PhD, Department of
Gastroenterology and Hepatology, Academic Medical Center, Meibergdreef 9,1105 AZ, Amsterdam, The Netherlands. e-mail: [email protected]; fax: þ31-20-691-7033.
Acknowledgments Qwww.trialregister.nl ID NTR2757.
Conflicts of interestQThe authors disclose no conflicts.
FundingQThis study was supported by the Dutch Cancer Society (UVA 2010-4717).
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