Perineural invasion as a prognostic determinant in combined hepatocellular-cholangiocarcinoma: a multicenter pathological study.

Background: The prognostic role of perineural invasion (PNI) in combined hepatocellular-cholangiocarcinoma (cHCC-CCA) remains undefined. This multicenter study assessed the incidence, patterns, and clinical significance of PNI in cHCC-CCA.

Methods: This study included 307 patients with cHCC-CCA undergoing hepatectomy with curative intent. Three independent pathologists conducted histopathological assessments of the frequency (single/multiple), involved tumor components (HCC/CCA/intermediate cell carcinoma), and spatial distribution (intratumoral/intratumoral + peritumoral/peritumoral) of PNI. The impact of postoperative adjuvant transarterial chemoembolization (PA-TACE) on the prognosis was further evaluated. Survival outcomes (recurrence-free survival [RFS], overall survival [OS], and early [≤2 years] and late [>2 years] RFS) were analyzed using Kaplan-Meier and Cox regression. Logistic regression identified the predictors of PNI.

Results: Among 307 patients (median age, 52.7 years; 87.6% male), the prevalence of PNI was 16.0% (49 of 307). PNI-positive patients had significantly worse median RFS (0.21 vs 0.54 years; hazard ratio [HR], 2.003; P <.001) and OS (1.18 vs 2.56 years; HR, 2.213; P <.001) than PNI-negative patients. Early RFS differed significantly (P <.001), but late RFS did not (P =.443). Subgroup analysis showed that the worst RFS and early RFS were noted in patients with HCC-component PNI (P =.025; P =.024) and purely intratumoral PNI (P =.025; P =.024). PA-TACE improved the early RFS only in PNI-negative patients (P =.031). Elevated alkaline phosphatase (odds ratio [OR], 1.005; P =.029), macrovascular invasion (OR, 2.873; P =.003), microvascular invasion (OR, 2.291; P =.033), and absent tumor capsule (OR, 2.539; P =.014) independently predicted PNI. Multivariable analysis confirmed PNI as an independent risk factor for RFS (HR, 1.700; P =.002), OS (HR, 1.760; P =.001), and early RFS (HR, 1.749; P =.001).

Conclusion: PNI is a noteworthy pathological feature in cHCC-CCA, independently associated with early recurrence, inferior survival, and increased therapeutic challenge. Standardized pathological reporting of PNI status may improve prognostic stratification for patients with cHCC-CCA.