Primary sclerosing cholangitis (PSC) remains a challenging liver condition in modern day medicine due to its enigmatic pathophysiology, the lack of effective disease-modifying medical therapy, and a complex gut-liver relationship. As a pre-malignant disease, the morbidity and mortality burden from hepatobiliary (HB) and colorectal cancer (CRC) amongst individuals with PSC and co-occurring inflammatory bowel disease (IBD) (PSC-IBD) is well established 1, 2, with current screening guidelines recommending annual colonoscopy surveillance and hepatobiliary imaging. In a contemporary, multi-centre study, Alsakameh et al. 3 highlight a 3–4 fold elevated CRC risk in PSC without IBD individuals, compared to a propensity-matched general population cohort. This is on a background of individuals with PSC-IBD facing a 6-fold higher risk of CRC. An increased CRC risk in PSC without IBD has also been reported in a smaller, single-centre retrospective study 4. The risk of HB and other gastrointestinal (GI) cancers was also increased in PSC without IBD compared to the general population. The increased risk of CRC amongst PSC without IBD suggests that aberrant gut-liver interactions may still impact cancer development despite lack of overt colonic inflammation. Amongst PSC without IBD patients, immune cell infiltration and increased cytokine expression (e.g., IL17A, IFNG) in the colon have been noted, along with dysbiosis 5 that may have downstream effects on colonic bile-acid metabolism. Even amongst PSC-IBD individuals, increased histological activity does not portend elevated risk of dysplasia 6. It is prudent to note that although most individuals are diagnosed with IBD before PSC, a proportion of patients are diagnosed with IBD years after their PSC diagnosis 2. Subclinical inflammation may also be present for years prior to overt clinical presentation with IBD amongst PSC individuals 7, which could lead to a delayed diagnosis and misclassification bias in such population-based studies. The authors suggest their findings could guide tailored CRC surveillance for isolated PSC. Based on expert opinion, current international guidelines recommend regular colonoscopies at 5-year intervals for PSC without IBD 8, 9. The current recommendations may also help in detecting subclinical IBD. Notably, CRC risk in PSC without IBD mirrors that of having a first-degree relative diagnosed before age 50, for which a similar surveillance interval of 5-year colonoscopy is routinely recommended 10. Standardised mortality ratios (e.g., for all-cause and CRC-related mortality) to demonstrate benefit from such surveillance programmes would be helpful, while accounting for surveillance bias and disparities in healthcare access. However, evaluating this in PSC comes with challenges due to disease chronicity, heterogeneity and outcome rarity. In conclusion, this study highlights increased CRC and GI cancer risk in PSC without IBD, emphasising the need for personalised counselling and surveillance. Further validation in diverse cohorts is needed to refine risk stratification and assess outcomes under current surveillance practices. Natassia Tan: writing – original draft, writing – review and editing. Kristel Leung: conceptualization, writing – review and editing. This article is linked to Alsakarneh et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70303. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
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