A population-based cohort study of all patients with inflammatory bowel disease diagnosed in Norway and Sweden from 1987 through 2016 was conducted to quantify the risk of small bowel adenocarcinoma and neuroendocrine tumours in patients with ulcerative colitis and Crohn’s disease. Patients with Crohn’s disease experienced an 8-fold increased risk of small bowel adenocarcinomas, while patients with both ulcerative colitis and Crohn’s disease experienced an about 2-fold increased risk of neuroendocrine tumours, and patients with ulcerative colitis experienced 2-fold increased risk of small bowel adenocarcinoma. Because the absolute risk increase is so small, surveillance programmes that aim to detect small bowel cancer in early, asymptomatic stages are unlikely to generate a measurable, cost-effective mortality benefit according to Prof. Hans-Olov Adami of the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet in Stockholm, Sweden and colleagues, who published the results on 8 March 2022 in the Annals of Oncology.
Proper, individualised surveillance of cancer risk in patients with inflammatory bowel disease requires valid risk prediction. However, only few, if any, of published studies were able to accommodate the exceptional methodologic challenges in studies of inflammatory bowel disease and cancer risk. Symptoms of inflammatory bowel disease may be so mild that the diagnosis is not confirmed until a cancer has already become symptomatic. This introduces selection bias because patients with a prevalent cancer are overrepresented at enrollment into any cohort study which is often reflected in the highest excess risk during early follow-up. This bias also precludes any valid quantification of risk and assessment of the temporal relationship between inflammatory bowel disease onset and cancer diagnosis.
Furthermore, many studies have analyzed Crohn’s disease and ulcerative colitis, the two distinct types of inflammatory bowel disease together. Even studies focused on one inflammatory bowel disease entity and small bowel cancer generally fail to distinguish between different histopathologic types (adenocarcinomas, neuroendocrine tumours, lymphomas and sarcomas), with plausibly different aetiologies.
The authors wrote in the background that large, stringently designed, ideally population-based, studies are required to generate valid estimates of risk for the different cancer types in the small bowel, a prerequisite for causal inference and rational surveillance in patients with inflammatory bowel disease. They performed a nation-wide cohort study of inflammatory bowel disease and small bowel cancer by histopathologic type in Norway and Sweden. The large size and complete long-term follow-up allowed analyses by disease characteristics, age at diagnosis, and duration of follow-up.
Patients were followed through linkage to national registers. The study team calculated standardised incidence ratios (SIRs) with 95% confidence intervals (CIs) of small bowel adenocarcinomas and neuroendocrine tumours for patients with Crohn’s disease and ulcerative colitis. They excluded the first year of follow-up to reduce reverse causality.
Among 142,008 patients with inflammatory bowel disease with a median follow-up of 10 years, the study team identified 66 adenocarcinomas and 57 neuroendocrine tumours in the small bowel. The SIR of small bowel adenocarcinoma was 8.3 (95% CI 5.9-11.3) in Crohn’s disease and 2.0 (95% CI 1.2-3.1) in ulcerative colitis. The incidence rates of adenocarcinomas were highest in Crohn’s disease with stricturing disease and extent limited to the small bowel, at 14.7 (95% CI 8.2-24.2) and 15.8 (95% CI 8.4-27.0) per 100,000 person-years, respectively. The SIR of neuroendocrine tumours was 2.5 (95% CI 1.5-3.9) in Crohn’s disease and 2.0 (95% CI 1.4-2.8) in ulcerative colitis.
The authors concluded that in patients with Crohn’s disease a likely causal association exists with an 8-fold increased risk of small bowel adenocarcinoma. Whether the 2-fold increased risk of developing neuroendocrine tumours reflects a causal association or arises due to ascertainment bias is currently uncertain. Patients with ulcerative colitis probably experience a 2-fold increased risk of both small bowel adenocarcinomas and neuroendocrine tumours which may be confined to those with extensive disease. The small absolute excess cancer risk suggests that active surveillance to diagnose small bowel cancer early is unlikely to be cost-effective.
This work was supported by the Swedish Cancer Society, Swedish Research Council, Norwegian Cancer Society, and South-Eastern Norway Regional Health Authority.
Yu J, Refsum E, Perrin V, et al. Inflammatory bowel disease and risk of adenocarcinoma and neuroendocrine tumors in the small bowel. Annals of Oncology; Published online 8 March 2022. DOI: https://doi.org/10.1016/j.annonc.2022.02.226