Epidemiology, clinical, molecular features, and prognosis of early-onset biliary tract cancer: A systematic review and meta-analysis

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Background & Aims Early-onset gastrointestinal cancers represent a growing global health concern. Among these, early-onset biliary tract cancer (EO-BTC) remains relatively understudied. In this systematic review, we synthesize current evidence for EO-BTC. Methods A comprehensive systematic literature search was performed across multiple databases. Original studies investigating epidemiology, risk factors, clinical presentation, pathological and/or molecular features, treatment, and prognosis of EO-BTC were included and synthesized. Meta-analyses were performed using the Mantel–Haenszel and generic inverse variance methods with random-effects models. Results In total, 32 studies were included. EO-BTC incidence varied by anatomical subtype, with a notable increase in early-onset intrahepatic cholangiocarcinoma. Disparities in ethnicity and socioeconomic status were apparent between younger and older patients. Clinically, the disease was often diagnosed at a more advanced stage in younger patients (for stage IV, odds ratio [OR], 1.31; 95% CI, 1.19–1.43; p <0.001; I 2 , 62%) and was associated with a higher prevalence of intrahepatic cholangiocarcinoma (OR, 1.41; 95% CI, 1.23–1.61; p <0.001; I 2 , 49%). FGFR2 fusions were significantly more common in early-onset cases (OR, 2.81; 95% CI, 2.31–3.64; p <0.001; I 2 , 0%). Younger patients had fewer comorbidities and more frequently received curative-intent local and systemic therapies (surgery: OR, 1.38; 95% CI, 1.22–1.57; p <0.001; I 2 , 85%). Prognostic data were heterogeneous; however, pooled analysis suggested a trend to improved OS in patients with early-onset disease (unadjusted hazard ratio [HR], 0.84; 95% CI, 0.75–0.93; p = 0.001; I 2 , 81%); adjusted HR, 0.78; 95% CI, 0.66–0.94; p = 0.007; I 2 , 91%). Conclusions EO-BTC represents a clinically and molecularly distinct subset within biliary tract cancers, with emerging epidemiological patterns, a higher prevalence of actionable molecular alterations, and differences in treatment allocation. Further prospective and age-stratified studies are needed to guide age-adapted detection and therapeutic strategies. PROSPERO ID CRD420251039039. Impact and implications This systematic review highlights that EO-BTC exhibits different epidemiological and molecular patterns compared with later-onset disease, including a higher prevalence of intrahepatic subtypes and greater frequency of targetable alterations, such as FGFR2 fusions. These findings underscore the importance of incorporating routine molecular profiling and the integration of stratified management pathways into clinical practice. From a public health perspective, the rising incidence of EO-BTC, especially among individuals without traditional risk factors, highlights the urgent need for increased awareness and the development of risk-adapted early detection strategies. Interestingly, younger patients were more likely to undergo surgical resection, even those with advanced-stage disease. This trend might reflect a greater clinical willingness to pursue aggressive approaches in this population, likely influenced by better performance status and fewer comorbidities. However, it also reinforces the need for careful patient selection to avoid unnecessary surgical morbidity when the anticipated oncological benefit is limited. Overall, these findings emphasize the need for prospective, age-stratified studies to better define prognostic models and guide personalized therapeutic approaches for this distinct patient population.

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