Article structure
1. Highlights
2. Background and clinical importance
3. Study design and methods
4. Key results
5. Clinical interpretation
6. Strengths and limitations
7. Practice implications and future directions
8. Conclusion
9. Funding and trial registration
10. References
Highlights
In this nationwide Dutch cohort of 1230 patients with familial adenomatous polyposis (FAP), nearly one-third developed cancer, underscoring that malignant risk remains substantial despite modern preventive care.
The highest excess risks were concentrated in the gastrointestinal tract, including very large increases in duodenal, ampullary, small-bowel, gastric, and colorectal cancers compared with the general population.
Since 2020, gastric cancer has become the most commonly diagnosed cancer in this FAP cohort, an epidemiologic shift with immediate implications for upper gastrointestinal surveillance.
Extraintestinal cancer risk was also significantly increased, notably for thyroid, gynecologic, central nervous system, and pediatric liver tumors, reinforcing the systemic nature of APC-associated disease.
Background and clinical importance
Familial adenomatous polyposis is a hereditary cancer predisposition syndrome caused predominantly by pathogenic variants in the APC gene. The phenotype is classically defined by the development of numerous colorectal adenomas, often beginning in adolescence or early adulthood, with near-certain progression to colorectal cancer (CRC) if prophylactic colectomy is not performed. Over the past several decades, structured registries, cascade testing, endoscopic surveillance, and prophylactic colorectal surgery have transformed the natural history of FAP by reducing CRC incidence and mortality.
That success, however, has shifted the clinical problem rather than eliminated it. As patients live longer after colorectal risk reduction, other gastrointestinal and extraintestinal malignancies assume greater importance. Duodenal and ampullary neoplasia are well recognized in FAP, and current practice already emphasizes upper gastrointestinal surveillance, often guided by the Spigelman staging system for duodenal polyposis. Yet the absolute and relative burdens of other cancers, including gastric cancer, thyroid cancer, gynecologic malignancies, and hepatobiliary tumors, remain less precisely quantified in many populations. This uncertainty affects surveillance recommendations, counseling, and prioritization of research.
The present nationwide cohort study from the Netherlands addresses that gap by providing long-term, population-level cancer incidence data in FAP over nearly five decades. For clinicians, the study is especially notable because it suggests a contemporary rise in gastric cancer, a finding that may signal changing risk patterns, improved ascertainment, or both, and may prompt reconsideration of surveillance intensity and endoscopic technique in the upper gastrointestinal tract.
Study design and methods
Bouchiba and colleagues conducted a nationwide cohort study using the Netherlands Foundation for Detection of Hereditary Tumors national registry, linked with the Dutch Pathology Registry. The design is a major strength because both sources are well suited to capture hereditary cancer syndromes and pathology-confirmed outcomes at scale.
The cohort included 1230 patients with FAP between 1975 and 2024. Women comprised 48% of the cohort. A pathogenic APC variant was identified in 1138 patients, representing 93% of the study population. This high molecular confirmation rate supports diagnostic validity, while also indicating that a minority were classified on clinical grounds, reflecting real-world hereditary cancer practice across decades.
The main analytic approach was estimation of cumulative cancer incidence using the Fine and Gray competing risk method. This is an appropriate choice because death and other events can preclude observation of cancer, and standard Kaplan-Meier methods may overestimate cumulative incidence when competing risks are important. The investigators also calculated standardized incidence ratios (SIRs) for all cancer types relative to the general Dutch population. SIRs quantify relative risk at the population level by comparing observed with expected cancer counts after accounting for background incidence.
The study was observational and descriptive rather than interventional. There was no comparator treatment group; instead, risk was contextualized against population cancer rates. While the abstract does not provide detailed age-stratified analyses, surgery-specific analyses, or genotype-phenotype correlations, the national scope and long follow-up make the data highly relevant to surveillance policy.
Key results
Among 1230 patients with FAP, 388 individuals, or 32%, developed cancer, with a total of 461 cancers recorded. This means that multiple primary cancers occurred in a meaningful subset, which is clinically consistent with lifelong inherited susceptibility.
The most frequently observed cancers overall were colon cancer (n = 129), rectal cancer (n = 77), duodenal cancer (n = 31), and gastric cancer (n = 28). Although CRC remained numerically prominent across the full study period, the most striking contemporary observation was temporal: since 2020, gastric cancer has become the most commonly diagnosed cancer in this cohort. Even without full temporal incidence curves in the abstract, this single finding has major clinical resonance. It suggests that as colorectal risk is increasingly controlled, the stomach may now represent a more visible frontier of cancer burden in FAP, at least in this national setting.
The SIR analyses showed markedly increased risks for several gastrointestinal malignancies. Gastric cancer occurred at roughly 12-fold the population rate (SIR, 12.02; P < .01). Duodenal cancer showed an approximately 277-fold excess (SIR, 277.28; P < .01), and ampullary cancer an approximately 114-fold excess (SIR, 113.85; P < .01). CRC remained highly elevated despite prophylactic surgery strategies, with an SIR of 14.22 (P < .01). Small-bowel cancer was also strongly increased (SIR, 122.03; P < .01). These estimates reinforce that upper gastrointestinal and small-bowel neoplasia are not secondary concerns in FAP; they are central components of the syndrome’s cancer phenotype.
Liver-related cancers also showed increased incidence. Hepatoblastoma, a rare pediatric liver tumor classically associated with APC mutations, had the largest relative excess, with an SIR of 747.52 (P < .01). Although based on small absolute numbers, this finding is biologically coherent and clinically important for pediatric counseling in affected families. Hepatocellular carcinoma was also increased (SIR, 5.43; P = .01), an association that is less commonly emphasized in routine FAP discussions and may merit closer scrutiny in future work.
Among extraintestinal cancers, thyroid cancer risk was substantially elevated (SIR, 17.30; P < .01), consistent with longstanding observations that thyroid carcinoma, particularly papillary histology, is overrepresented in FAP. Gynecologic cancers were modestly but significantly increased (SIR, 2.27; P < .01), and central nervous system cancers were also elevated (SIR, 3.79; P < .01). The CNS signal aligns with the broader APC-associated spectrum that includes medulloblastoma in the context historically described as Turcot syndrome.
Although the abstract does not report confidence intervals, age-specific cumulative incidences, or mortality outcomes, the pattern is clear: FAP confers persistent and anatomically wide-ranging cancer risk, and that risk profile appears to be evolving over time. In practical terms, the data imply that a surveillance model built predominantly around the colorectum is no longer sufficient.
Clinical interpretation
The most important clinical message is not simply that cancer risk in FAP remains elevated, which is already known, but that the distribution of cancer burden may be changing. The emergence of gastric cancer as the most frequently diagnosed malignancy since 2020 is particularly consequential. Western FAP practice has traditionally focused more strongly on duodenal and ampullary disease than on gastric adenocarcinoma, partly because gastric cancer has been considered less common in many European populations than in East Asia. This Dutch study suggests that assumption may need updating.
Several explanations are possible. First, true risk may be rising as patients survive longer after effective colorectal prevention and remain under surveillance long enough to develop upper gastrointestinal cancers. Second, more intensive endoscopic follow-up may be increasing detection. Third, changing gastric mucosal phenotypes, environmental exposures, microbiologic factors, or pathology classification could be contributing. The current abstract does not resolve these mechanisms, but it does justify renewed attention to careful gastric inspection during surveillance esophagogastroduodenoscopy, with high-quality visualization, adequate insufflation, and low threshold for targeted biopsy of suspicious lesions.
The very high SIRs for duodenal, ampullary, and small-bowel cancers support continued emphasis on structured upper gastrointestinal surveillance in FAP. Current guideline frameworks already recommend regular upper endoscopy with side-viewing or cap-assisted assessment of the ampullary region, with interval determined in part by duodenal adenoma burden and histology. These Dutch data strengthen the rationale for adherence and may support research into whether surveillance algorithms should incorporate gastric phenotype more explicitly, rather than focusing predominantly on Spigelman staging.
The colorectal findings are also instructive. Even in the era of prophylactic colectomy and vigilant surveillance, CRC risk remained 14-fold higher than in the general population. This likely reflects residual rectal risk after ileorectal anastomosis, pouch or cuff neoplasia after proctocolectomy, delayed diagnosis in some patients, and the inclusion of historical decades when preventive practice was less mature. Clinicians should therefore avoid assuming that colorectal surgery fully neutralizes cancer risk; lifelong lower gastrointestinal surveillance remains necessary.
The extraintestinal signals should not be overlooked. Thyroid cancer is one of the more actionable associations because thyroid ultrasound is noninvasive, although guideline intensity varies internationally. The observed increase in gynecologic cancers is intriguing, as gynecologic malignancy is not usually considered a dominant FAP feature in routine counseling. This signal may reflect a mixture of tumor types and warrants more granular investigation before practice changes are made. Similarly, the increased CNS cancer risk confirms a broader APC-related phenotype, although routine brain imaging in asymptomatic patients is not currently standard and would require stronger evidence of benefit.
For pediatric and family medicine settings, the dramatic hepatoblastoma SIR matters despite the rarity of the tumor. Families with APC pathogenic variants should receive age-appropriate counseling about pediatric cancer risk, and clinicians should remain familiar with pediatric surveillance approaches used in some hereditary cancer programs.
Strengths and limitations
This study has several important strengths. It is nationwide, large for a rare hereditary syndrome, and spans almost 50 years. Linkage of a hereditary tumor registry with a national pathology database likely improved outcome ascertainment and reduced reliance on self-report. The high rate of APC variant confirmation strengthens internal validity. Use of competing-risk methods for cumulative incidence is methodologically appropriate and preferable to simpler approaches in long-term observational cohorts.
There are also limitations that should temper interpretation. First, the abstract does not provide detailed age distributions, person-years, confidence intervals, cumulative incidence percentages for individual cancers, or subgroup analyses by sex, genotype, surgical history, or calendar era. These details are essential for translating relative risk into surveillance intervals. Second, SIRs can appear very large for rare cancers even when absolute case numbers are small; hepatoblastoma and some other rare tumors should therefore be interpreted with an understanding of absolute burden. Third, ascertainment and management likely changed over the long study period, introducing secular effects. Improvements in endoscopy, genetics, pathology, and prophylactic surgery may have altered both detection and incidence. Fourth, the cohort is Dutch, and generalizability to populations with different gastric cancer background rates, endoscopic practices, or APC variant distributions may be incomplete.
Another key limitation is that observational registry data cannot determine whether more intensive surveillance would reduce mortality from the cancers identified. The finding of increased incidence does not automatically define the optimal screening test, starting age, or interval. These questions require prospective risk-stratified studies, ideally incorporating tumor stage, treatment, and survival.
Practice implications and future directions
For practicing gastroenterologists and hereditary cancer specialists, the study supports several immediate conclusions. First, surveillance in FAP should remain multidisciplinary and lifelong. Second, upper gastrointestinal surveillance deserves at least equal prominence with lower gastrointestinal follow-up in adult patients. Third, careful gastric examination should be treated as a core part of FAP endoscopy rather than a secondary task, especially in light of the reported rise in gastric cancer.
At the policy level, these data may prompt reassessment of surveillance guidelines to determine whether gastric neoplasia should be more explicitly incorporated into risk stratification. Existing approaches focused on duodenal polyposis may not fully capture contemporary upper gastrointestinal cancer risk. Research priorities include defining gastric precursor lesions in FAP, clarifying the natural history of gastric adenomas and fundic gland polyps with dysplasia, and identifying clinical or molecular predictors of gastric cancer.
There is also a strong case for genotype-informed analyses. APC variant location has long been associated with phenotype severity in FAP, and future work should test whether specific variant clusters correlate with gastric, duodenal, thyroid, or CNS cancer risk. Such information could eventually personalize surveillance beyond the current one-size-fits-most model.
Finally, survivorship care in FAP should extend beyond procedural surveillance. Patients need coordinated counseling on symptom awareness, family screening, reproductive issues, psychosocial burden, and transitions from pediatric to adult hereditary cancer services. As colorectal mortality falls, quality of long-term comprehensive care becomes increasingly important.
Conclusion
This nationwide Dutch cohort confirms that familial adenomatous polyposis remains a multisystem cancer predisposition syndrome despite major advances in prophylactic colorectal management. The data reaffirm extreme excess risks for duodenal, ampullary, small-bowel, colorectal, and hepatoblastoma-related cancers, while also highlighting significant elevations in thyroid, gynecologic, and CNS malignancies. Most importantly, gastric cancer has emerged since 2020 as the most commonly diagnosed cancer in this cohort, signaling a potentially important shift in the modern burden of disease.
For clinicians, the study’s practical message is clear: successful colorectal prevention does not end cancer surveillance in FAP; it changes its center of gravity. Upper gastrointestinal surveillance, especially rigorous gastric and duodenal assessment, now appears increasingly central to long-term care. The next step for the field is to translate these epidemiologic findings into sharper, evidence-based, risk-adapted surveillance strategies that improve not only detection, but also survival and quality of life.
Funding and trial registration
The abstract provided does not specify funding information. No ClinicalTrials.gov registration number is reported, which is typical for a nationwide observational registry-based cohort study rather than a prospective interventional trial.
References
1. Bouchiba H, Aelvoet AS, van Kouwen MCA, Bastiaansen BAJ, Bisseling TM, Langers AMJ, Bossuyt PMM, van Leerdam ME, Dekker E, Netherlands Foundation for Detection of Hereditary Tumors Collaborative Investigators. Incidence of Cancer in Patients With Familial Adenomatous Polyposis in the Netherlands: A Nationwide Cohort Study. Gastroenterology. 2026-02-25;170(5):942-952. PMID: 41739006.
2. Syngal S, Brand RE, Church JM, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. American Journal of Gastroenterology. 2015;110(2):223-262.
3. Vasen HFA, Möslein G, Alonso A, et al. Guidelines for the clinical management of familial adenomatous polyposis. Gut. 2008;57(5):704-713.
4. NCCN Clinical Practice Guidelines in Oncology. Genetic/Familial High-Risk Assessment: Colorectal. Current publicly available guideline updates should be consulted for contemporary surveillance recommendations.