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

Abstract


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][2][3][4][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 classi cation 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 classi cation has been validated, it tends to underestimate the importance of ampullary lesions and does not closely correlate with the risk of duodenal cancer [8][9][10][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][13][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 insu cient 15 16 .However, the threshold for duodenal resection is not clearly de ned 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 bene t 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.

De nitions
FAP patients were de ned 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 veri ed 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 identi cation number 19 .We submitted the identi cation 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 de ned 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 ndings, 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 de ned 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 rst.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 signi cant.R version 4.2.1 (R Foundation for Statistical Computing, Vienna, Austria) was used to perform all statistical analyses.

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 identi ed 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.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 identi ed 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 con rmed 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 identi ed 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 rm genotype-phenotype correlation.

Endoscopic ndings 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

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 nal 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 signi cant 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 signi cant proportion of patients 13 20 21 .However, challenges remain.While EMR is e cient in removing larger lesions, duodenal EMR has its own set of adverse events such as bleeding, perforation, and postpolypectomy 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][23][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 de nitively determine if some surgeries could have been avoided, the data strongly suggest that most patients did not receive the full bene t 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 re ecting 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 in uenced 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 identi ed 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][29][30] .Nevertheless, the number of families/patients were too few for us to conclude there is a rm phenotype-genotype correlation; hence, endoscopic surveillance and treatment cannot be strati ed according to speci c 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 signi cant 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 classi cation 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 ndings emphasize the importance of future studies evaluating the potential bene t 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 con icts of interest to declare.
Grant Support: The Misse and Valdemar Risom Foundation

Table 1
Danish nationwide cohort of familial adenomatous polyposis cohort characteristicsIn 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 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 EndoscopyDuring 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).
*Fisher's exact test1Three patients undergoing duodenal surgery had adenocarcinoma in the surgical specimen and high-grade dysplasia in the endoscopic biopsies