Abstract

Background & Aims Perihilar cholangiocarcinoma is an aggressive malignancy with clinical heterogeneity and poor long-term outcomes after resection. Current prognostic assessment relies mainly on anatomical staging and pathological features, which incompletely capture the entire postoperative risk. We aimed to determine whether integrative analysis of clinical, surgical, pathological and tumor genomic data could improve time-resolved, individualized recurrence-risk prediction after curative-intent resection.

Methods We performed a multicenter retrospective study including patients undergoing curative-intent resection for perihilar cholangiocarcinoma in ten Spanish hospitals (2003-2023). Overall and disease-free survival were analyzed using Cox models. Outcome-agnostic clinical phenotypes were derived by unsupervised clustering of clinical and surgical features. Targeted tumor sequencing of cancer-associated hotspot regions and selected genes was performed. Prognostic models integrating clinical and genomic data were trained and evaluated in independent training/test sets using penalized and latent-component Cox frameworks, with time dependent discrimination.

Results The final cohort comprised 142 patients, with a median follow-up of 26.4 months. Recurrence occurred in 61.3% of patients, and 53.5% died during follow-up. Classical pathological factors were strongly associated with survival and recurrence. Unsupervised outcome-agnostic clustering identified three reproducible clinical phenotypes with markedly different recurrence patterns and survival, only partially explained by anatomical staging. Integrative clinical-genomic modelling further improved recurrence-risk prediction, achieving high discrimination in independent validation (time-dependent AUC ∼0.8). Moreover, the integrative model assigned higher risk over time to patients who relapsed. Patients combining unfavorable clinical phenotype with high genomic-derived risk exhibited a high probability of early recurrence.

Conclusions Integrated clinical phenotyping and targeted genomic profiling substantially refine recurrence-risk stratification after resection of perihilar cholangiocarcinoma beyond anatomical staging alone. This provides a pragmatic framework for risk-adapted postoperative surveillance and therapeutic decision-making.

Impact and Implications This study provides a data-driven framework integrating clinical, surgical and targeted genomic information to refine prognostic stratification after resection of perihilar cholangiocarcinoma, addressing the limitations of anatomy-based staging in capturing biological heterogeneity. The results are particularly relevant for clinicians managing postoperative surveillance and adjuvant strategies, as they identify patient subgroups with markedly different risks of early recurrence despite similar conventional staging. In practical terms, the combination of unsupervised clinical phenotyping and a targeted, biologically informed genomic panel could support risk-adapted follow-up intensity, selection for adjuvant or experimental therapies, and enrolment into clinical trials. While prospective validation is required before routine implementation, this approach offers a feasible and interpretable pathway toward precision postoperative management in a highly aggressive malignancy.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

A.B-M. was funded by Fundación Mutua Madrilena (AP210012025) and Instituto de Salud Carlos III (PI24/00129), co-funded by the European Union. F.L-R. was funded by a Sara Borrell post-doctoral grant from Instituto de Salud Carlos III (CD23/00036), co-funded by the European Union. Funding sources provided financial support but had no involvement in study design, collection, analysis and interpretation of data.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study protocol was approved by the central ethics committee of Hospital Universitario Virgen de la Arrixaca (Murcia, Spain; registry number 2021-4-7-HCUVA) and by the institutional review boards of all participating centers.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Footnotes

↵* These authors share first authorship.

↵† These authors share senior authorship

Data Availability

Variant call data generated in this study have been deposited in the European Variation Archive (EVA) and are accessible under project accession PRJEB107911. The rest of data, analytical methodologies, and research materials that support the findings of this study are available from the corresponding author upon reasonable request.

https://www.ebi.ac.uk/eva/?eva-study=PRJEB107911

AbbreviationsAJCCAmerican Joint Committee on CancerAKT1AKT serine/threonine kinase 1APCAPC regulator of Wnt signaling pathwayARID1AAT-rich interaction domain 1AAUCarea under the curveCA 19-9carbohydrate antigen 19-9CDKNcyclin dependent kinase inhibitorCOXMOSCox MultiBlock SurvivalDIANADIvisive ANAlysisDFSDisease-free survivalEGFRepidermal growth factor receptorERBBErb-B2 receptor tyrosine kinaseFLT3Fms related receptor tyrosine kinase 3IQRinterquartile rangeKITKIT proto-oncogene, receptor tyrosine kinaseKRASKRAS proto-oncogene, GTPaseLPlinear predictorOSOverall survivalpCCAPerihilar cholangiocarcinomaPIK3phosphatidylinositol-4,5-bisphosphate 3-kinasePTCDpercutaneous transhepatic biliary drainagePVEportal vein embolizationRETret proto-oncogeneRTKactivated receptor tyrosine kinaseSMARCB1SWI/SNF related BAF chromatin remodeling complex subunit B1sPLS-DACOXsparse Partial Least Squares Discriminant Analysis CoxsPLS-DRCOXsparse Partial Least Squares Deviance Residuals CoxTP53tumor protein P53t-SNET-distributed Stochastic Neighbour Embedding