Perhilar cholangiocarcinoma late local recurrence-Time to define, treat, and standardize.

Abstract

Perihilar cholangiocarcinoma remains associated with poor long-term survival despite advances in surgical technique and perioperative care, largely due to disease recurrence. Emerging evidence suggests that recurrence follows a bimodal temporal distribution, with a distinct subset of late local recurrences occurring ≥24 months after resection. These late local recurrences appear biologically indolent and are often amenable to aggressive salvage therapy, yet remain under-recognized in current staging and surveillance frameworks. This study aimed to define the biologic and clinical characteristics of perihilar cholangiocarcinoma late local recurrences, propose a standardized diagnostic framework, and evaluate optimal treatment strategies. systematic PubMed search was conducted using terms "perihilar∗ OR Klatskin∗" AND "recurrence" to identify original articles published since 2015. Pooled analyses from large Western and Asian cohorts (n > 3,000) were reviewed to characterize the temporal distribution of recurrence. Whole-exome sequencing data from paired primary and late recurrent tumors were analyzed to assess genomic concordance. Evidence-based recommendations for surveillance imaging, diagnostic workup, and salvage therapeutic strategies were formulated through critical synthesis of published literature. Among 87 identified articles, 68 reported time-to-recurrence analyses with highly variable definitions of "late" recurrence (12-60 months), precluding meaningful comparison. Pooled cohort data demonstrated a marked decrement in recurrence risk after approximately 24 months, with a secondary plateau thereafter. Genomic analyses of paired primary-recurrent tumors revealed low mutational concordance in a substantial proportion of late recurrences, suggesting de novo tumorigenesis rather than clonal relapse. Salvage surgery adhering to primary oncological standards (ipsilateral hemihepatectomy, caudate lobectomy, formal portal lymphadenectomy) achieved 5-year survival rates approaching 30-40%, significantly superior to nonoperative management. Liver transplantation for selected patients demonstrated 3-year survival of 73% in early single-center data. Perihilar cholangiocarcinoma late local recurrence represents a clinically meaningful and potentially curable entity distinct from early metastatic relapse. Adoption of a standardized 24-month definition, rigorous application of oncological principles in salvage surgery, and establishment of a global prospective registry (HILAR-RECURE) are essential to transform late local recurrence from an anecdotal observation into a reproducible therapeutic opportunity.