Endoscopic indicators in patients with familial adenomatous polyposis undergoing duodenal resections – a nationwide Danish cohort study with long-term follow-up

Endoscopic indicators in patients with familial adenomatous polyposis undergoing duodenal resections – a nationwide Danish cohort study with long-term follow-up | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Endoscopic indicators in patients with familial adenomatous polyposis undergoing duodenal resections – a nationwide Danish cohort study with long-term follow-up John Gásdal Karstensen, Mads Wewer, Steffen Bülow, Thmas Van Overreem Hansen, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4363426/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Jul, 2024 Read the published version in Familial Cancer → Version 1 posted 9 You are reading this latest preprint version Abstract Background Familial adenomatous polyposis (FAP) predisposes individuals to duodenal adenomas. This study describes the histopathological features of endoscopic and surgical specimens from the duodenum, as well as genotype-phenotype associations. Methods All known FAP patients were included from the Danish Polyposis Register. FAP patients were defined as having more than 100 cumulative colorectal adenomas and/or having a known germline pathogenic variant in the APC gene. Endoscopic procedures, histopathology, and genetics were evaluated. Results Of 500 FAP patients, 70.6% underwent esophagogastroduodenoscopy (EGD) at least once. Of these, 59.2% presented with detectable duodenal adenomas. The most severe morphology was tubular in 62.7% patients, tubulovillous in 25.4%, and villous in 12.0%, while the most severe dysplasia was low-grade in 67.5% patients, high-grade in 25.4%, and 6.7% had adenocarcinoma. Seventeen of 500 patients (3.4%) developed duodenal adenocarcinoma, of which 47% were advanced at diagnosis. In 6.2% of FAP patients, duodenal resection was recommended, including 29% with duodenal adenocarcinoma. The risk of duodenal surgery was 1.31 per 1,000 person-years (median age: 53 years). The predominant reason for surgery was extensive polyposis (67.7%). Of the patients who underwent duodenal resection, a median of six (IQR: 4–8) EGDs were performed within five years prior to surgery, but 67.6% and 83.9% never underwent a duodenal polypectomy or endoscopic mucosa resection, respectively. Genetic evaluations revealed various pathogenic variants in the APC gene, with no strong genotype-phenotype association. Conclusions The prevalence of duodenal adenomas and cancer in FAP warrants vigilant endoscopic surveillance. Nevertheless, the need for duodenal surgery persists. Future studies should evaluate whether invasive endoscopy can reduce the need for duodenal resections. Familial adenomatous polyposis endoscopy duodenal adenomatosis adenocarcinoma genetic variants Figures Figure 1 Figure 2 Figure 3 Introduction Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disorder, which in addition to colorectal polyposis predisposes individuals to duodenal adenomatosis and cancer 1 – 5 . In the twentieth century, prophylactic colectomy was introduced for FAP patients and it decreased the risk of colorectal cancer and resulted in prolonged life expectancy 6 . Consequently, the importance of duodenal manifestations has increased. To prevent the development of duodenal cancer, it is essential to identify high-risk cases early on and refer them for surgical intervention before they undergo malignant transformation. Presently, the Spigelman classification system offers a comprehensive approach for endoscopic staging of duodenal adenomatosis and for assessing the risk of duodenal cancer. This system integrates factors such as the number and size of the adenomas, along with their morphology and the extent of dysplasia 7 . Although the Spigelman classification has been validated, it tends to underestimate the importance of ampullary lesions and does not closely correlate with the risk of duodenal cancer 8 – 11 . Additionally, it requires obtaining biopsies from duodenal lesions that many endoscopists would prefer to remove completely, either by simple polypectomy or endoscopic mucosal resection (EMR) 12 – 14 . Duodenal resection is indicated in the event of a localized duodenal cancer, as well as prophylactically in cases with severe polyposis and/or an assumed high risk of cancer where endoscopic surveillance and treatment is considered insufficient 15 16 . However, the threshold for duodenal resection is not clearly defined and the need for prophylactic surgical resection might be reduced with increased use of invasive endoscopic techniques. In Denmark, all known patients with FAP have been meticulously registered in the Danish Polyposis Register for the last 40 years, which includes data about endoscopic and surgical procedures, as well as genetic reports 17 . The register is free of referral and selection bias, which helps to ensure reliable estimations for the risk of needing duodenal surgery, as well as preoperative endoscopic interventions and other risk factors. We evaluated the histopathological severity of duodenal polyposis in the surgical specimens and compared it with previous endoscopic examinations, as well as genotypes. Furthermore, we examined whether the need for duodenal resections has been reduced in recent decades, possibly as a benefit of endoscopic interventions. Methods The Danish Polyposis Register was established in 1971 and became nationwide in 1974 17 . It comprises all Danish FAP patients. Endoscopic, surgical, and histopathological reports are all included, together with pedigrees and genetic test results. We conducted a cohort study of all known patients with FAP. No ethics approval or informed written consent were needed as this was a cohort study. Definitions FAP patients were defined as having 100 cumulative colorectal adenomas or more and/or having a known germline pathogenic variant in the APC gene (pathogenic or likely pathogenic, according to the American Society of Genetics) 18 . Patients with more than 100 colorectal adenomas and a known non- APC- related genetic etiology were excluded from the register and this study. FAP cohort The cohort consisted of all verified FAP patients registered in the Danish Polyposis Register up until April 22nd, 2021. Patients needed to have been alive on January 1st 1990 and should not have undergone duodenal surgery or developed duodenal cancer before initiation of the study. Patients with a duodenal resection (Whipple procedure or total pancreatectomy) due to pancreatic premalignant lesions or cancer were excluded. Since 1968, all Danish individuals have had a unique, 10-digit personal identification number 19 . We submitted the identification numbers of the FAP patients to Statistics Denmark, which enabled us to extract a complete list of endoscopic and surgical procedures from the National Patient Register (Supplementary Material 1), alongside the histopathological results from the Danish Pathology Register (Supplementary Material 2). Additionally, genotypes and indications for surgery were provided by the Polyposis Register. Outcomes The primary outcome was duodenal resection due to duodenal adenomatosis or cancer defined as risk per 1,000 person-years. Pancreatic indications were excluded. Secondary outcomes included the risk of developing duodenal adenomas and their morphology and grade of dysplasia. Additionally, the associations between surgical and endoscopic findings, in terms of adenoma morphology, grade of dysplasia, and adenocarcinoma, were analyzed, together with the risk of duodenal surgery. The most severe morphology and grade of dysplasia in each patient were counted. The most severe morphology was defined as villous, followed by tubulovillous, then tubular. Surgical and endoscopic modalities for the treatment of duodenal adenomas were assessed. Finally, the genotypes for all patients with duodenal resections were noted. According to the regulations of Statistics Denmark, absolute numbers of groups smaller than three were omitted. Statistical methods Follow-up of patients started on the date of their FAP diagnosis or on January 1st, 1990, whichever was most recent. Follow-up ended on the date of duodenal resection, death, loss to follow-up, or the end of the study, whichever occurred first. Baseline characteristics of the cohort were described using medians and interquartile ranges (IQR) for numerical variables and counts and proportions for categorical variables. A two-sided P value < .05 was considered significant. R version 4.2.1 (R Foundation for Statistical Computing, Vienna, Austria) was used to perform all statistical analyses. Results Characteristics of patients with familial adenomatous polyposis The cohort comprised 500 eligible FAP patients; 235 were female (47%) (Table 1 ). The genotype was known in 439 (87.8%) patients, and 176 were probands (35%). Of the 500 patients, 17 (3.4%) developed duodenal cancer (adenocarcinoma), 14 of which were identified in biopsies taken during an esophagogastroduodenoscopy (EGD). The remaining three cases of adenocarcinomas were found in the resected specimens in patients with high-grade dysplasia (HGD) in the endoscopic biopsies prior to surgery. Table 1 Danish nationwide cohort of familial adenomatous polyposis cohort characteristics Cohort characteristics FAP patients, N = 324 Female 235 (47%) Year of birth 2000 40 (8.0%) Probands 176 (35.2%) Genotype Yes 439 (87.8%) No 61 (12.2%) Number of patients with duodenal surgery 31 (6.2%) Median (IQR) time to duodenal surgery (years) 52 (40, 59) FAP, familial adenomatous polyposis; IQR, inter quartile range Endoscopy During the follow-up period, 60.8% (304/500) of patients received at least one EGD, 53.0% (265/500) an EGD with biopsies of duodenal polyps, and 70.6% (353/500) either at least one EGD or an EGD with biopsies. Of those who did not receive an EDG, two out of three were either below the age where duodenal surveillance is initiated or died due to CRC before initiating duodenal surveillance. Duodenal polypectomy was performed in 9.4% of the FAP patients (47/500), while 4.8% (24/500) underwent endoscopic mucosal resection (EMR)/endoscopic submucosal dissection (ESD)/argon plasma coagulation of duodenal lesions (Fig. 1 ). In 59.2% (209/353) of patients who underwent at least one EGD, the histopathology from either an endoscopic biopsy or a resection showed adenoma. The most severe morphology in these patients included 62.7% (131/209) with tubular adenomas, 25.4% (53/209) with tubulovillous adenomas, and 12.0% (25/209) with villous adenomas (Fig. 2 ). There was low-grade dysplasia (LGD) in 67.5% (141/209) and HGD in 25.4% (53/209) of patients (Fig. 2 ). The histopathological diagnosis was adenocarcinoma in 3.9% of FAP patients who received at least one EGD (14/353), corresponding to 6.7% of patients with known duodenal adenomatosis (14/209). Of the 14 patients with malignant histopathology, 57.1% (8/14) did not undergo surgery due to disseminated disease. Duodenal surgery During the follow-up period, 6.2% (31/500) of FAP patients underwent duodenal resection, corresponding to a risk of 1.31 per 1,000 person-years. The median age at surgery was 53 years (IQR = 41–62 years) and 39% (12/31) of patients were female. A Whipple procedure was performed in 67.7% (21/31), while the remaining patients underwent a pancreas-preserving duodenectomy. The histopathology in the resected specimens included adenocarcinoma in 29% (9/31) of the cases and benign histology in the remaining 22 cases (71%). In three of the nine patients diagnosed with adenocarcinoma, the endoscopic biopsies prior to surgery showed HGD as the most severe morphology. However, upon surgical resection, adenocarcinoma was identified in the specimens. In all benign cases, the histopathology showed adenomas with HGD in 86.3% (19/22) of cases and LGD in 13.6% (3/22) of cases. Indication for duodenal surgery The indication for duodenal resection was extensive duodenal adenomatosis prohibiting safe endoscopic surveillance or treatment in 67.7% (21/31) of patients. In the remaining cases, there was an endoscopic suspicion of either an ampullary (22.6%) or luminal (6.5%) cancer. Of these cases, the suspicion of malignancy was confirmed in 88.9% by histopathological examination of the surgical specimen. The indication was not clear in 3.2% of cases. For patients receiving surgery with the indication of extensive polyposis, 9.5% were operated upon between 1990–1999, 38.1% between 2000–2009, and 52.3% between 2010–2019. Genetics Patients undergoing duodenal resection or developing unresectable duodenal cancer comprised 28 families; the pathogenic variant was known in 89.7% (35/39) of patients. Three variants (p.(Glu1309Aspfs*4), p.(Glu1156Glyfs*8) and p.(Gln161*)) were detected in more than one family, but otherwise each family carried a different variant. All pathogenic variants were frameshift, nonsense, or splice variants, including single nucleotide variants, smaller or larger deletions or duplications, or large rearrangements (including whole APC gene deletion in one family) (Fig. 3 ). A need for duodenal resection or unresectable duodenal cancer was identified in six patients from one family who were carrying the c.2626C > T, p.(Arg876*) variant. Two families had a variant that was located 5’ of codon 168 in an area associated with A-FAP, while no variants were detected in other A-FAP regions in the APC gene, including codon 312–412 (alternative part of exon 9) and 3’ of codon 1580 (Fig. 3 ). Additionally, one family had a variant in the codon 976–1067 region. Most pathogenic variants were localized in exon 16. We failed to identify any firm genotype-phenotype correlation. Endoscopic findings prior to surgery Prior to the surgical procedure, all patients had received at least one EGD. Of the nine patients with adenocarcinoma in their surgical specimen, 66.7% (6/9) had endoscopic biopsies with adenocarcinoma, while 33.3% (3/9) had HGD in the endoscopic biopsies prior to surgery. In cases with a benign surgical pathology, endoscopic biopsies or polypectomy/EMR specimens before surgery included LGD in 27.3% (6/22) of cases and HGD in 72.7% (16/22) of cases (Table 2 ). A median of six (IQR: 4–8) EGDs were performed within the five years prior to surgery and 35.5% (11/31) had villous adenomas (Table 2 ). In 67.6% (21/31) of cases, the patient never underwent a duodenal polypectomy and EMR/ESD/APC were not carried out in 83.9% (26/31) of patients. Table 2 Most severe endoscopic morphology and dysplasia of duodenal adenomas in familial adenomatous polyposis patients prior to potential surgery. Specific pathology FAP patients without duodenal surgery N = 469 FAP patients with duodenal surgery N = 31 * p -values Morphology < 0.001 Tubular adenoma 125 (26.7%) 6 (19.4%) Tubulovillous adenoma 39 (8.3%) 14 (45.2%) Villous adenoma 14 (3.0%) 11 (35.5%) Dysplasia < 0.001 Low-grade dysplasia 135 (28.8%) 6 (19.4%) High-grade dysplasia 35 (7.5%) 19 1 (61.3%) Adenocarcinoma 8 (1.7%) 6 (19.4%) FAP: familial adenomatous polyposis *Fisher’s exact test 1 Three patients undergoing duodenal surgery had adenocarcinoma in the surgical specimen and high-grade dysplasia in the endoscopic biopsies Discussion In this nationwide cohort study of all known Danish FAP patients, we found that during a 30-year period the risk of duodenal surgery was 1.31 per 1,000 person-years with a median age at surgery of 53, and an increasing number of resections being carried out during this period. In 71.0% of FAP patients undergoing duodenal surgery, the indications, as well as the final histopathology, were benign. However, two-out-of-three patients never underwent a duodenal polypectomy before surgery, and only 16% had a duodenal EMR, thus emphasizing that the full potential of endoscopic interventions might not have been thoroughly explored. Studies have reported a lifetime risk of duodenal adenomatosis in up to 90% of individuals with FAP 2 . The progression from adenoma to adenocarcinoma in the duodenum, albeit slower than in the colon and rectum, remains a significant cause of morbidity and mortality 3 6 . A recent study demonstrated that FAP patients had a 14-fold higher risk of developing duodenal/small bowel cancer compared to the general population 1 . Thus, regular surveillance for duodenal lesions is paramount. In addition to surveillance, a growing body of evidence suggests that endoscopic techniques can obviate the need for surgery in a significant proportion of patients 13 20 21 . However, challenges remain. While EMR is efficient in removing larger lesions, duodenal EMR has its own set of adverse events such as bleeding, perforation, and post-polypectomy syndrome. Nevertheless, recent studies evaluating the use of cold snares for EMR have shown promising results, with fewer adverse events and few recurrent lesions 22 – 24 . Likewise, duodenal polypectomy, either with hot or cold snares, seems very safe and might remove duodenal lesions before they advance 13 25 . In our study, we found that only a minority of patients had undergone endoscopic removal of duodenal lesions before surgery. While our study’s analyses cannot definitively determine if some surgeries could have been avoided, the data strongly suggest that most patients did not receive the full benefit of currently available endoscopic therapies. Endoscopic techniques, while reducing the need for surgery, cannot always replace it, especially for ampullary lesions extending into the pancreatic or common bile duct. In FAP patients with duodenal lesions, choices often oscillate between the Whipple procedure, known for its comprehensive resection and associated complications, and the less invasive pancreas-preserving duodenectomy. The latter, while preserving pancreatic function, can raise the risk of recurrence and limit lymph node clearance in cases of malignancy 26 . Our study showed that two-thirds of patients underwent a Whipple procedure, probably reflecting the presence or suspicion of a malignant lesion. Notably, while the number of Whipple procedures seems to be on the rise, there is a declining trend in pancreas-preserving duodenectomies. This may complicate post-operative endoscopic management, as deep small bowel enteroscopy is needed to inspect the Roux-en-Y limb because of the Whipple operation. The cause of this trend remains undetermined. It might be influenced by surgical preferences, or the future risk of requiring a Whipple procedure due to ampullary adenomatosis 26 . The FAP patients who received a duodenal resection, together with those who developed disseminated duodenal cancer, represent the most severe phenotype. We analyzed the pathogenic APC variants in all these patients and found that only one family had a variant in the codon 976–1067, which has previously been associated with a 3-4-fold risk of developing duodenal adenomatosis 27 . Furthermore, one variant identified in two families was somewhat surprisingly located in an area of the gene which has previously been associated with a less severe phenotype (attenuated FAP) 28 – 30 . Nevertheless, the number of families/patients were too few for us to conclude there is a firm phenotype-genotype correlation; hence, endoscopic surveillance and treatment cannot be stratified according to specific pathogenic variants in the APC gene based on the present data. The evolving role of endoscopic interventions, particularly polypectomy, EMR and endoscopic papillectomy in managing duodenal lesions in FAP cannot be understated 20 31 32 . While they offer significant advantages over surgical modalities, a comprehensive, individualized approach is crucial to ensure optimal patient outcomes 12 . Further studies, preferably comparative, that focus on long-term outcomes and newer endoscopic techniques, are eagerly awaited. Of note, in our study the number of endoscopic resection was limited, hence, the FAP cohort may be considered representing the long-term natural course of duodenal adenomatosis under endoscopic surveillance. This study is limited by the small number of patients undergoing duodenal resection. Furthermore, our knowledge of the endoscopic surveillance before referral for surgery is limited to procedural codes and details such as Spigelman classification and possible reasons for omitting duodenal surveillance are not available. However, the study’s strengths include a national database free of referral and selection bias, as well as access to pathology reports after both endoscopy and surgery for comparison. Finally, endoscopic technology has been improved considerably during the study period, which might have improved the optical diagnoses. Our nationwide cohort study encompassing the entire Danish FAP population revealed a risk of duodenal surgery of 1.31 per 1,000 person-years, with patients undergoing surgery at a median age of 53 years. Strikingly, two-thirds of the patients referred for surgical intervention had not previously received a duodenal polypectomy, and even fewer an EMR. Furthermore, most patients were found to have a benign histopathology in their surgical specimen. These findings emphasize the importance of future studies evaluating the potential benefit of endoscopic interventions and their role in the management of duodenal lesions in FAP patients. Declarations Disclosures: JGK is a consultant for SNIPR BIOME. The other authors have no conflicts of interest to declare. Grant Support: The Misse and Valdemar Risom Foundation References Karstensen JG, Bulow S, Hojen H, et al. Cancer in Patients With Familial Adenomatous Polyposis: A Nationwide Danish Cohort Study With Matched Controls. 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Endoscopy 2023;55(8):709-18. doi: 10.1055/a-2029-2935 [published Online First: 2023/02/07] Additional Declarations Competing interest reported. JGK is a consultant for SNIPR BIOME. The other authors have no conflicts of interest to declare. Supplementary Files Supplementarymaterial.docx Cite Share Download PDF Status: Published Journal Publication published 24 Jul, 2024 Read the published version in Familial Cancer → Version 1 posted Editorial decision: Revision requested 14 Jun, 2024 Reviews received at journal 13 Jun, 2024 Reviews received at journal 29 May, 2024 Reviewers agreed at journal 24 May, 2024 Reviewers agreed at journal 15 May, 2024 Reviewers invited by journal 05 May, 2024 Submission checks completed at journal 04 May, 2024 Editor assigned by journal 04 May, 2024 First submitted to journal 03 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4363426","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":299773393,"identity":"a57930d9-55b3-4d02-8cf7-3c73432a8c2b","order_by":0,"name":"John Gásdal Karstensen","email":"data:image/png;base64,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","orcid":"","institution":"Copenhagen University Hospital - Amager and Hvidovre","correspondingAuthor":true,"prefix":"","firstName":"John","middleName":"Gásdal","lastName":"Karstensen","suffix":""},{"id":299773395,"identity":"0c5bb503-c0d8-4cc3-825d-47a73aab0107","order_by":1,"name":"Mads Wewer","email":"","orcid":"","institution":"Copenhagen University Hospital - Amager and Hvidovre","correspondingAuthor":false,"prefix":"","firstName":"Mads","middleName":"","lastName":"Wewer","suffix":""},{"id":299773397,"identity":"af979b3a-e304-4390-8078-9a5983620152","order_by":2,"name":"Steffen Bülow","email":"","orcid":"","institution":"Copenhagen University Hospital - Amager and Hvidovre","correspondingAuthor":false,"prefix":"","firstName":"Steffen","middleName":"","lastName":"Bülow","suffix":""},{"id":299773399,"identity":"c1d0a3e4-ba69-46c5-b6ee-1ec59bc31f7c","order_by":3,"name":"Thmas Van Overreem Hansen","email":"","orcid":"","institution":"University of Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Thmas","middleName":"Van Overreem","lastName":"Hansen","suffix":""},{"id":299773400,"identity":"af587ed6-895f-4b56-89e3-f504b4f8d536","order_by":4,"name":"Helle Højen","email":"","orcid":"","institution":"Copenhagen University Hospital - Amager and Hvidovre","correspondingAuthor":false,"prefix":"","firstName":"Helle","middleName":"","lastName":"Højen","suffix":""},{"id":299773401,"identity":"2f9a0809-c2e2-4392-b04a-7c5df04cf084","order_by":5,"name":"Anne Marie Jelsig","email":"","orcid":"","institution":"Copenhagen University Hospital - Rigshospitalet","correspondingAuthor":false,"prefix":"","firstName":"Anne","middleName":"Marie","lastName":"Jelsig","suffix":""},{"id":299773402,"identity":"23355251-eb6a-44be-a1d5-69a37a565d12","order_by":6,"name":"Tine Plato Kuhlmann","email":"","orcid":"","institution":"University of Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Tine","middleName":"Plato","lastName":"Kuhlmann","suffix":""},{"id":299773403,"identity":"c7381ba2-67a9-4ee5-9a48-142e70580d9a","order_by":7,"name":"Johan Burisch","email":"","orcid":"","institution":"Copenhagen University Hospital - Amager and Hvidovre","correspondingAuthor":false,"prefix":"","firstName":"Johan","middleName":"","lastName":"Burisch","suffix":""},{"id":299773404,"identity":"669e26c8-c7e2-4521-9104-d26a9fe368bb","order_by":8,"name":"Hans Christian Pommergaard","email":"","orcid":"","institution":"University of Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Hans","middleName":"Christian","lastName":"Pommergaard","suffix":""}],"badges":[],"createdAt":"2024-05-03 10:13:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4363426/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4363426/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10689-024-00415-x","type":"published","date":"2024-07-24T16:16:01+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":56396207,"identity":"852c182d-2276-4744-9cf5-9d1b7ef6a786","added_by":"auto","created_at":"2024-05-13 15:43:29","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":506512,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart for a Danish nationwide cohort of patients with familial adenomatous polyposis *FAP: familial adenomatous polyposis; EGD: esophagogastroduodenoscopy; EMR: endoscopic mucosal resection; ESD: endoscopic submucosal dissection; APC: argon plasma coagulation\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4363426/v1/9e9b957e2e4e6503bf083ad5.png"},{"id":56396208,"identity":"ce22129c-1f70-4c31-9deb-e098c5358ec7","added_by":"auto","created_at":"2024-05-13 15:43:29","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1104248,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of the most severe morphologies and dysplasia in familial adenomatous polyposis patients with endoscopic biopsies prior to potential surgery. *FAP: familial adenomatous polyposis\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4363426/v1/b35ef48589dfd21a0360f618.png"},{"id":56396209,"identity":"49cf4975-593d-49bf-94d4-9973b8e06ba7","added_by":"auto","created_at":"2024-05-13 15:43:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":624578,"visible":true,"origin":"","legend":"\u003cp\u003eLollipop plot showing the \u003cem\u003eAPC\u003c/em\u003e(NM_000038.6) single nucleotide variants described in this study in relation to attenuated FAP (AFAP) (light blue) and classical FAP (CFAP) (light brown) regions of the \u003cem\u003eAPC\u003c/em\u003e gene. The variants include 10 frameshift variants (red), eight nonsense variants (green) and one splice variant (blue). Only one variant (p.(Gln161*)) is located in the AFAP region. Exons are indicated with dashed lines starting with the first coding exon (exon 2)\u003c/p\u003e","description":"","filename":"Figur3.png","url":"https://assets-eu.researchsquare.com/files/rs-4363426/v1/2b5f3b93d270b27d7d75caa4.png"},{"id":61596513,"identity":"8ac0f6b7-062d-419b-b100-0a213d906ab0","added_by":"auto","created_at":"2024-08-01 17:28:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2915464,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4363426/v1/8d10a71b-d768-4f0d-aac9-5fcb6c1d001c.pdf"},{"id":56396210,"identity":"5c363844-d2db-4fcd-914a-3ba6168647fc","added_by":"auto","created_at":"2024-05-13 15:43:29","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":17440,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-4363426/v1/fb9daae734327178a5673e3e.docx"}],"financialInterests":"Competing interest reported. JGK is a consultant for SNIPR BIOME. The other authors have no conflicts of interest to declare.","formattedTitle":"Endoscopic indicators in patients with familial adenomatous polyposis undergoing duodenal resections – a nationwide Danish cohort study with long-term follow-up","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFamilial adenomatous polyposis (FAP) is an autosomal dominantly inherited disorder, which in addition to colorectal polyposis predisposes individuals to duodenal adenomatosis and cancer \u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. In the twentieth century, prophylactic colectomy was introduced for FAP patients and it decreased the risk of colorectal cancer and resulted in prolonged life expectancy \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Consequently, the importance of duodenal manifestations has increased. To prevent the development of duodenal cancer, it is essential to identify high-risk cases early on and refer them for surgical intervention before they undergo malignant transformation. Presently, the Spigelman classification system offers a comprehensive approach for endoscopic staging of duodenal adenomatosis and for assessing the risk of duodenal cancer. This system integrates factors such as the number and size of the adenomas, along with their morphology and the extent of dysplasia \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Although the Spigelman classification has been validated, it tends to underestimate the importance of ampullary lesions and does not closely correlate with the risk of duodenal cancer \u003csup\u003e\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Additionally, it requires obtaining biopsies from duodenal lesions that many endoscopists would prefer to remove completely, either by simple polypectomy or endoscopic mucosal resection (EMR) \u003csup\u003e\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDuodenal resection is indicated in the event of a localized duodenal cancer, as well as prophylactically in cases with severe polyposis and/or an assumed high risk of cancer where endoscopic surveillance and treatment is considered insufficient \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. However, the threshold for duodenal resection is not clearly defined and the need for prophylactic surgical resection might be reduced with increased use of invasive endoscopic techniques.\u003c/p\u003e \u003cp\u003eIn Denmark, all known patients with FAP have been meticulously registered in the Danish Polyposis Register for the last 40 years, which includes data about endoscopic and surgical procedures, as well as genetic reports \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. The register is free of referral and selection bias, which helps to ensure reliable estimations for the risk of needing duodenal surgery, as well as preoperative endoscopic interventions and other risk factors.\u003c/p\u003e \u003cp\u003eWe evaluated the histopathological severity of duodenal polyposis in the surgical specimens and compared it with previous endoscopic examinations, as well as genotypes. Furthermore, we examined whether the need for duodenal resections has been reduced in recent decades, possibly as a benefit of endoscopic interventions.\u003c/p\u003e \u003cp\u003eMethods\u003c/p\u003e \u003cp\u003eThe Danish Polyposis Register was established in 1971 and became nationwide in 1974 \u003csup\u003e17\u003c/sup\u003e. It comprises all Danish FAP patients. Endoscopic, surgical, and histopathological reports are all included, together with pedigrees and genetic test results. We conducted a cohort study of all known patients with FAP. No ethics approval or informed written consent were needed as this was a cohort study.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eDefinitions\u003c/strong\u003e \u003cp\u003eFAP patients were defined as having 100 cumulative colorectal adenomas or more and/or having a known germline pathogenic variant in the \u003cem\u003eAPC\u003c/em\u003e gene (pathogenic or likely pathogenic, according to the American Society of Genetics) \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Patients with more than 100 colorectal adenomas and a known non-\u003cem\u003eAPC-\u003c/em\u003erelated genetic etiology were excluded from the register and this study.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eFAP cohort\u003c/p\u003e \u003cp\u003eThe cohort consisted of all verified FAP patients registered in the Danish Polyposis Register up until April 22nd, 2021. Patients needed to have been alive on January 1st 1990 and should not have undergone duodenal surgery or developed duodenal cancer before initiation of the study. Patients with a duodenal resection (Whipple procedure or total pancreatectomy) due to pancreatic premalignant lesions or cancer were excluded. Since 1968, all Danish individuals have had a unique, 10-digit personal identification number \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. We submitted the identification numbers of the FAP patients to Statistics Denmark, which enabled us to extract a complete list of endoscopic and surgical procedures from the National Patient Register (Supplementary Material 1), alongside the histopathological results from the Danish Pathology Register (Supplementary Material 2). Additionally, genotypes and indications for surgery were provided by the Polyposis Register.\u003c/p\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003cp\u003eThe primary outcome was duodenal resection due to duodenal adenomatosis or cancer defined as risk per 1,000 person-years. Pancreatic indications were excluded. Secondary outcomes included the risk of developing duodenal adenomas and their morphology and grade of dysplasia. Additionally, the associations between surgical and endoscopic findings, in terms of adenoma morphology, grade of dysplasia, and adenocarcinoma, were analyzed, together with the risk of duodenal surgery. The most severe morphology and grade of dysplasia in each patient were counted. The most severe morphology was defined as villous, followed by tubulovillous, then tubular. Surgical and endoscopic modalities for the treatment of duodenal adenomas were assessed. Finally, the genotypes for all patients with duodenal resections were noted. According to the regulations of Statistics Denmark, absolute numbers of groups smaller than three were omitted.\u003c/p\u003e"},{"header":"Statistical methods","content":"\u003cp\u003eFollow-up of patients started on the date of their FAP diagnosis or on January 1st, 1990, whichever was most recent. Follow-up ended on the date of duodenal resection, death, loss to follow-up, or the end of the study, whichever occurred first. Baseline characteristics of the cohort were described using medians and interquartile ranges (IQR) for numerical variables and counts and proportions for categorical variables. A two-sided \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;.05 was considered significant. \u003cem\u003eR\u003c/em\u003e version 4.2.1 (R Foundation for Statistical Computing, Vienna, Austria) was used to perform all statistical analyses.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eCharacteristics of patients with familial adenomatous polyposis\u003c/p\u003e \u003cp\u003eThe cohort comprised 500 eligible FAP patients; 235 were female (47%) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The genotype was known in 439 (87.8%) patients, and 176 were probands (35%). Of the 500 patients, 17 (3.4%) developed duodenal cancer (adenocarcinoma), 14 of which were identified in biopsies taken during an esophagogastroduodenoscopy (EGD). The remaining three cases of adenocarcinomas were found in the resected specimens in patients with high-grade dysplasia (HGD) in the endoscopic biopsies prior to surgery.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDanish nationwide cohort of familial adenomatous polyposis cohort characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCohort characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFAP patients, N\u0026thinsp;=\u0026thinsp;324\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e235 (47%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYear of birth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1920\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (0.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1920\u0026ndash;1930\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (3.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1930\u0026ndash;1940\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (7.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1940\u0026ndash;1950\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54 (10.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1950\u0026ndash;1960\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e71 (14.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1960\u0026ndash;1970\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e89 (17.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1970\u0026ndash;1980\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70 (14.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1980\u0026ndash;1990\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60 (12.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1990\u0026ndash;2000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60 (12.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;2000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (8.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProbands\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e176 (35.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenotype\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e439 (87.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61 (12.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of patients with duodenal surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (6.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian (IQR) time to duodenal surgery (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52 (40, 59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFAP, familial adenomatous polyposis; IQR, inter quartile range\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eEndoscopy\u003c/p\u003e \u003cp\u003eDuring the follow-up period, 60.8% (304/500) of patients received at least one EGD, 53.0% (265/500) an EGD with biopsies of duodenal polyps, and 70.6% (353/500) either at least one EGD or an EGD with biopsies. Of those who did not receive an EDG, two out of three were either below the age where duodenal surveillance is initiated or died due to CRC before initiating duodenal surveillance. Duodenal polypectomy was performed in 9.4% of the FAP patients (47/500), while 4.8% (24/500) underwent endoscopic mucosal resection (EMR)/endoscopic submucosal dissection (ESD)/argon plasma coagulation of duodenal lesions (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn 59.2% (209/353) of patients who underwent at least one EGD, the histopathology from either an endoscopic biopsy or a resection showed adenoma. The most severe morphology in these patients included 62.7% (131/209) with tubular adenomas, 25.4% (53/209) with tubulovillous adenomas, and 12.0% (25/209) with villous adenomas (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). There was low-grade dysplasia (LGD) in 67.5% (141/209) and HGD in 25.4% (53/209) of patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The histopathological diagnosis was adenocarcinoma in 3.9% of FAP patients who received at least one EGD (14/353), corresponding to 6.7% of patients with known duodenal adenomatosis (14/209). Of the 14 patients with malignant histopathology, 57.1% (8/14) did not undergo surgery due to disseminated disease.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDuodenal surgery\u003c/p\u003e \u003cp\u003eDuring the follow-up period, 6.2% (31/500) of FAP patients underwent duodenal resection, corresponding to a risk of 1.31 per 1,000 person-years. The median age at surgery was 53 years (IQR\u0026thinsp;=\u0026thinsp;41\u0026ndash;62 years) and 39% (12/31) of patients were female. A Whipple procedure was performed in 67.7% (21/31), while the remaining patients underwent a pancreas-preserving duodenectomy. The histopathology in the resected specimens included adenocarcinoma in 29% (9/31) of the cases and benign histology in the remaining 22 cases (71%). In three of the nine patients diagnosed with adenocarcinoma, the endoscopic biopsies prior to surgery showed HGD as the most severe morphology. However, upon surgical resection, adenocarcinoma was identified in the specimens. In all benign cases, the histopathology showed adenomas with HGD in 86.3% (19/22) of cases and LGD in 13.6% (3/22) of cases.\u003c/p\u003e \u003cp\u003eIndication for duodenal surgery\u003c/p\u003e \u003cp\u003eThe indication for duodenal resection was extensive duodenal adenomatosis prohibiting safe endoscopic surveillance or treatment in 67.7% (21/31) of patients. In the remaining cases, there was an endoscopic suspicion of either an ampullary (22.6%) or luminal (6.5%) cancer. Of these cases, the suspicion of malignancy was confirmed in 88.9% by histopathological examination of the surgical specimen. The indication was not clear in 3.2% of cases. For patients receiving surgery with the indication of extensive polyposis, 9.5% were operated upon between 1990\u0026ndash;1999, 38.1% between 2000\u0026ndash;2009, and 52.3% between 2010\u0026ndash;2019.\u003c/p\u003e \u003cp\u003eGenetics\u003c/p\u003e \u003cp\u003ePatients undergoing duodenal resection or developing unresectable duodenal cancer comprised 28 families; the pathogenic variant was known in 89.7% (35/39) of patients. Three variants (p.(Glu1309Aspfs*4), p.(Glu1156Glyfs*8) and p.(Gln161*)) were detected in more than one family, but otherwise each family carried a different variant. All pathogenic variants were frameshift, nonsense, or splice variants, including single nucleotide variants, smaller or larger deletions or duplications, or large rearrangements (including whole \u003cem\u003eAPC\u003c/em\u003e gene deletion in one family) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). A need for duodenal resection or unresectable duodenal cancer was identified in six patients from one family who were carrying the c.2626C\u0026thinsp;\u0026gt;\u0026thinsp;T, p.(Arg876*) variant. Two families had a variant that was located 5\u0026rsquo; of codon 168 in an area associated with A-FAP, while no variants were detected in other A-FAP regions in the \u003cem\u003eAPC\u003c/em\u003e gene, including codon 312\u0026ndash;412 (alternative part of exon 9) and 3\u0026rsquo; of codon 1580 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Additionally, one family had a variant in the codon 976\u0026ndash;1067 region. Most pathogenic variants were localized in exon 16. We failed to identify any firm genotype-phenotype correlation.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eEndoscopic findings prior to surgery\u003c/p\u003e \u003cp\u003ePrior to the surgical procedure, all patients had received at least one EGD. Of the nine patients with adenocarcinoma in their surgical specimen, 66.7% (6/9) had endoscopic biopsies with adenocarcinoma, while 33.3% (3/9) had HGD in the endoscopic biopsies prior to surgery. In cases with a benign surgical pathology, endoscopic biopsies or polypectomy/EMR specimens before surgery included LGD in 27.3% (6/22) of cases and HGD in 72.7% (16/22) of cases (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). A median of six (IQR: 4\u0026ndash;8) EGDs were performed within the five years prior to surgery and 35.5% (11/31) had villous adenomas (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In 67.6% (21/31) of cases, the patient never underwent a duodenal polypectomy and EMR/ESD/APC were not carried out in 83.9% (26/31) of patients.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMost severe endoscopic morphology and dysplasia of duodenal adenomas in familial adenomatous polyposis patients prior to potential surgery.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpecific pathology\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFAP patients \u003c/p\u003e \u003cp\u003ewithout duodenal surgery\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;469\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFAP patients \u003c/p\u003e \u003cp\u003ewith duodenal surgery\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;31\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e*\u003cem\u003ep\u003c/em\u003e-values\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMorphology\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTubular adenoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(26.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(19.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTubulovillous adenoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(45.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVillous adenoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(3.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(35.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDysplasia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow-grade dysplasia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e135\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(28.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(19.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh-grade dysplasia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(7.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(61.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(19.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eFAP: familial adenomatous polyposis\u003c/p\u003e \u003cp\u003e*Fisher\u0026rsquo;s exact test \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003eThree patients undergoing duodenal surgery had adenocarcinoma in the surgical specimen and high-grade dysplasia in the endoscopic biopsies\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this nationwide cohort study of all known Danish FAP patients, we found that during a 30-year period the risk of duodenal surgery was 1.31 per 1,000 person-years with a median age at surgery of 53, and an increasing number of resections being carried out during this period. In 71.0% of FAP patients undergoing duodenal surgery, the indications, as well as the final histopathology, were benign. However, two-out-of-three patients never underwent a duodenal polypectomy before surgery, and only 16% had a duodenal EMR, thus emphasizing that the full potential of endoscopic interventions might not have been thoroughly explored.\u003c/p\u003e \u003cp\u003eStudies have reported a lifetime risk of duodenal adenomatosis in up to 90% of individuals with FAP \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. The progression from adenoma to adenocarcinoma in the duodenum, albeit slower than in the colon and rectum, remains a significant cause of morbidity and mortality \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. A recent study demonstrated that FAP patients had a 14-fold higher risk of developing duodenal/small bowel cancer compared to the general population \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Thus, regular surveillance for duodenal lesions is paramount. In addition to surveillance, a growing body of evidence suggests that endoscopic techniques can obviate the need for surgery in a significant proportion of patients \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. However, challenges remain. While EMR is efficient in removing larger lesions, duodenal EMR has its own set of adverse events such as bleeding, perforation, and post-polypectomy syndrome. Nevertheless, recent studies evaluating the use of cold snares for EMR have shown promising results, with fewer adverse events and few recurrent lesions \u003csup\u003e\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Likewise, duodenal polypectomy, either with hot or cold snares, seems very safe and might remove duodenal lesions before they advance \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. In our study, we found that only a minority of patients had undergone endoscopic removal of duodenal lesions before surgery. While our study\u0026rsquo;s analyses cannot definitively determine if some surgeries could have been avoided, the data strongly suggest that most patients did not receive the full benefit of currently available endoscopic therapies.\u003c/p\u003e \u003cp\u003eEndoscopic techniques, while reducing the need for surgery, cannot always replace it, especially for ampullary lesions extending into the pancreatic or common bile duct. In FAP patients with duodenal lesions, choices often oscillate between the Whipple procedure, known for its comprehensive resection and associated complications, and the less invasive pancreas-preserving duodenectomy. The latter, while preserving pancreatic function, can raise the risk of recurrence and limit lymph node clearance in cases of malignancy \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Our study showed that two-thirds of patients underwent a Whipple procedure, probably reflecting the presence or suspicion of a malignant lesion. Notably, while the number of Whipple procedures seems to be on the rise, there is a declining trend in pancreas-preserving duodenectomies. This may complicate post-operative endoscopic management, as deep small bowel enteroscopy is needed to inspect the Roux-en-Y limb because of the Whipple operation. The cause of this trend remains undetermined. It might be influenced by surgical preferences, or the future risk of requiring a Whipple procedure due to ampullary adenomatosis \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe FAP patients who received a duodenal resection, together with those who developed disseminated duodenal cancer, represent the most severe phenotype. We analyzed the pathogenic \u003cem\u003eAPC\u003c/em\u003e variants in all these patients and found that only one family had a variant in the codon 976\u0026ndash;1067, which has previously been associated with a 3-4-fold risk of developing duodenal adenomatosis \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Furthermore, one variant identified in two families was somewhat surprisingly located in an area of the gene which has previously been associated with a less severe phenotype (attenuated FAP) \u003csup\u003e\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Nevertheless, the number of families/patients were too few for us to conclude there is a firm phenotype-genotype correlation; hence, endoscopic surveillance and treatment cannot be stratified according to specific pathogenic variants in the \u003cem\u003eAPC\u003c/em\u003e gene based on the present data.\u003c/p\u003e \u003cp\u003eThe evolving role of endoscopic interventions, particularly polypectomy, EMR and endoscopic papillectomy in managing duodenal lesions in FAP cannot be understated \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. While they offer significant advantages over surgical modalities, a comprehensive, individualized approach is crucial to ensure optimal patient outcomes \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Further studies, preferably comparative, that focus on long-term outcomes and newer endoscopic techniques, are eagerly awaited. Of note, in our study the number of endoscopic resection was limited, hence, the FAP cohort may be considered representing the long-term natural course of duodenal adenomatosis under endoscopic surveillance.\u003c/p\u003e \u003cp\u003eThis study is limited by the small number of patients undergoing duodenal resection. Furthermore, our knowledge of the endoscopic surveillance before referral for surgery is limited to procedural codes and details such as Spigelman classification and possible reasons for omitting duodenal surveillance are not available. However, the study\u0026rsquo;s strengths include a national database free of referral and selection bias, as well as access to pathology reports after both endoscopy and surgery for comparison. Finally, endoscopic technology has been improved considerably during the study period, which might have improved the optical diagnoses.\u003c/p\u003e \u003cp\u003eOur nationwide cohort study encompassing the entire Danish FAP population revealed a risk of duodenal surgery of 1.31 per 1,000 person-years, with patients undergoing surgery at a median age of 53 years. Strikingly, two-thirds of the patients referred for surgical intervention had not previously received a duodenal polypectomy, and even fewer an EMR. Furthermore, most patients were found to have a benign histopathology in their surgical specimen. These findings emphasize the importance of future studies evaluating the potential benefit of endoscopic interventions and their role in the management of duodenal lesions in FAP patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eDisclosures: JGK is a consultant for SNIPR BIOME. The other authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003eGrant Support: The Misse and Valdemar Risom Foundation\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKarstensen JG, Bulow S, Hojen H, et al. Cancer in Patients With Familial Adenomatous Polyposis: A Nationwide Danish Cohort Study With Matched Controls. Gastroenterology 2023 doi: 10.1053/j.gastro.2023.05.010 [published Online First: 2023/05/19]\u003c/li\u003e\n\u003cli\u003eBulow S, Christensen IJ, Hojen H, et al. Duodenal surveillance improves the prognosis after duodenal cancer in familial adenomatous polyposis. 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Gastrointest Endosc 2014;80(5):817-25. doi: 10.1016/j.gie.2014.03.012 [published Online First: 2014/05/13]\u003c/li\u003e\n\u003cli\u003eIwata K, Kato M, Sasaki M, et al. Intensive endoscopic resection strategy for multiple duodenal polyposis associated with familial adenomatous polyposis. J Gastroenterol Hepatol 2023 doi: 10.1111/jgh.16281 [published Online First: 2023/07/10]\u003c/li\u003e\n\u003cli\u003eRepici A, Capogreco A, Spadaccini M, et al. Cold versus hot EMR for large duodenal adenomas. Gut 2022;71(9):1763-65. doi: 10.1136/gutjnl-2022-327171 [published Online First: 2022/07/06]\u003c/li\u003e\n\u003cli\u003eWang H, Sidhu M, Gupta S, et al. Cold snare EMR for the removal of large duodenal adenomas. Gastrointest Endosc 2023;97(6):1100-08. doi: 10.1016/j.gie.2023.01.040 [published Online First: 2023/02/01]\u003c/li\u003e\n\u003cli\u003eDang DT, Suresh S, Vance RB, et al. 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Multiple approach to the exploration of genotype-phenotype correlations in familial adenomatous polyposis. J Clin Oncol 2003;21(9):1698-707. doi: 10.1200/JCO.2003.09.118 [published Online First: 2003/05/02]\u003c/li\u003e\n\u003cli\u003eAnele CC, Martin I, McGinty Duggan PM, et al. Attenuated Familial Adenomatous Polyposis: A Phenotypic Diagnosis but Obsolete Term? Dis Colon Rectum 2022;65(4):529-35. doi: 10.1097/DCR.0000000000002217 [published Online First: 2021/11/15]\u003c/li\u003e\n\u003cli\u003eSieber OM, Segditsas S, Knudsen AL, et al. Disease severity and genetic pathways in attenuated familial adenomatous polyposis vary greatly but depend on the site of the germline mutation. Gut 2006;55(10):1440-8. doi: 10.1136/gut.2005.087106 [published Online First: 2006/02/08]\u003c/li\u003e\n\u003cli\u003eSpier I, Yin X, Richardson M, et al. Gene-specific ACMG/AMP classification criteria for germline APC variants: recommendations from the ClinGen InSiGHT Hereditary Colorectal Cancer / Polyposis Variant Curation Expert Panel. Genet Med 2023:100992. doi: 10.1016/j.gim.2023.100992 [published Online First: 2023/10/06]\u003c/li\u003e\n\u003cli\u003eAngsuwatcharakon P, Ahmed O, Lynch PM, et al. Management of ampullary adenomas in familial adenomatous polyposis syndrome: 16 years of experience from a tertiary cancer center. Gastrointest Endosc 2020;92(2):323-30. doi: 10.1016/j.gie.2020.02.040 [published Online First: 2020/03/08]\u003c/li\u003e\n\u003cli\u003eVu Trung K, Abou-Ali E, Caillol F, et al. Endoscopic papillectomy for ampullary lesions in patients with familial adenomatous polyposis compared with sporadic lesions: a propensity score-matched cohort. Endoscopy 2023;55(8):709-18. doi: 10.1055/a-2029-2935 [published Online First: 2023/02/07]\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"familial-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"fame","sideBox":"Learn more about [Familial Cancer](http://link.springer.com/journal/10689)","snPcode":"10689","submissionUrl":"https://submission.nature.com/new-submission/10689/3","title":"Familial Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Familial adenomatous polyposis, endoscopy, duodenal adenomatosis, adenocarcinoma, genetic variants","lastPublishedDoi":"10.21203/rs.3.rs-4363426/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4363426/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eFamilial adenomatous polyposis (FAP) predisposes individuals to duodenal adenomas. This study describes the histopathological features of endoscopic and surgical specimens from the duodenum, as well as genotype-phenotype associations.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eAll known FAP patients were included from the Danish Polyposis Register. FAP patients were defined as having more than 100 cumulative colorectal adenomas and/or having a known germline pathogenic variant in the \u003cem\u003eAPC\u003c/em\u003e gene. Endoscopic procedures, histopathology, and genetics were evaluated.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOf 500 FAP patients, 70.6% underwent esophagogastroduodenoscopy (EGD) at least once. Of these, 59.2% presented with detectable duodenal adenomas. The most severe morphology was tubular in 62.7% patients, tubulovillous in 25.4%, and villous in 12.0%, while the most severe dysplasia was low-grade in 67.5% patients, high-grade in 25.4%, and 6.7% had adenocarcinoma. Seventeen of 500 patients (3.4%) developed duodenal adenocarcinoma, of which 47% were advanced at diagnosis. In 6.2% of FAP patients, duodenal resection was recommended, including 29% with duodenal adenocarcinoma. The risk of duodenal surgery was 1.31 per 1,000 person-years (median age: 53 years). The predominant reason for surgery was extensive polyposis (67.7%). Of the patients who underwent duodenal resection, a median of six (IQR: 4\u0026ndash;8) EGDs were performed within five years prior to surgery, but 67.6% and 83.9% never underwent a duodenal polypectomy or endoscopic mucosa resection, respectively. Genetic evaluations revealed various pathogenic variants in the \u003cem\u003eAPC\u003c/em\u003e gene, with no strong genotype-phenotype association.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe prevalence of duodenal adenomas and cancer in FAP warrants vigilant endoscopic surveillance. Nevertheless, the need for duodenal surgery persists. Future studies should evaluate whether invasive endoscopy can reduce the need for duodenal resections.\u003c/p\u003e","manuscriptTitle":"Endoscopic indicators in patients with familial adenomatous polyposis undergoing duodenal resections – a nationwide Danish cohort study with long-term follow-up","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-13 15:43:24","doi":"10.21203/rs.3.rs-4363426/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-06-14T13:15:52+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-13T16:25:12+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-29T10:26:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"285282785704110930741946747626740211690","date":"2024-05-24T15:47:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"271185144104798778756808038463552384169","date":"2024-05-15T06:12:25+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-05T10:56:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-04T05:37:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-04T05:37:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"Familial Cancer","date":"2024-05-03T10:10:41+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"familial-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"fame","sideBox":"Learn more about [Familial Cancer](http://link.springer.com/journal/10689)","snPcode":"10689","submissionUrl":"https://submission.nature.com/new-submission/10689/3","title":"Familial Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f9075fba-6eb4-4cb5-b65e-1eaca894fccb","owner":[],"postedDate":"May 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-01T17:10:31+00:00","versionOfRecord":{"articleIdentity":"rs-4363426","link":"https://doi.org/10.1007/s10689-024-00415-x","journal":{"identity":"familial-cancer","isVorOnly":false,"title":"Familial Cancer"},"publishedOn":"2024-07-24 16:16:01","publishedOnDateReadable":"July 24th, 2024"},"versionCreatedAt":"2024-05-13 15:43:24","video":"","vorDoi":"10.1007/s10689-024-00415-x","vorDoiUrl":"https://doi.org/10.1007/s10689-024-00415-x","workflowStages":[]},"version":"v1","identity":"rs-4363426","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4363426","identity":"rs-4363426","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}