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.