Immature Peritumoral Tertiary Lymphoid Structures Indicate Poor Prognosis in Pancreatic Ductal Adenocarcinoma After NAC

Background/Aim: Tertiary lymphoid structures (TLSs) have prognostic relevance in various cancers; however, the relationship is complex and depends on TLS properties. In this study, we evaluated the prognostic significance of TLS spatial distribution and maturation in patients with pancreatic ductal adenocarcinoma (PDAC) undergoing neoadjuvant chemotherapy (NAC). Patients and Methods: We retrospectively analyzed data for 131 patients with PDAC, including 64 who underwent upfront surgery (UpS) and 67 who underwent NAC followed by surgery. TLSs were evaluated using hematoxylin–eosin staining and immunohistochemistry. TLSs were categorized as intratumoral or peritumoral (periTLS) and by maturation status using immunohistochemical markers. Survival outcomes were evaluated using Kaplan–Meier curves and Cox proportional hazards models. Results: TLSs were identified in 81.3% of patients in the UpS group and 83.6% in the NAC group. The prevalence of periTLS was significantly lower in the NAC group than in the UpS group (50.7% vs. 73.4%, p<0.05). Among NAC-treated patients, those with immature periTLS showed significantly higher rates of early distant recurrence within 12 months after surgery (53.8% vs. 14.3%, p<0.05). In a multivariate analysis, the presence of immature periTLS was the only independent poor prognostic factor for recurrence-free survival [hazard ratio (HR)=2.89, 95% confidence interval (CI)=1.20-6.91, p<0.05], only in the NAC group. Serum CA19-9 levels decreased following NAC treatment in 47.4% of PDACs with mature periTLS and 10% of those with immature periTLS (p<0.05). Among 22 patients with post-NAC CA19-9 <100 U/ml, immature periTLS remained the only factor significantly associated with shorter recurrence-free survival (RFS) (HR=2.97, 95%CI=1.05-8.36, p<0.05). Conclusion: Immature periTLS could serve as a novel histological biomarker for poor RFS in patients with PDAC treated with NAC.