The prognostic value of peritumoural and intratumoural tertiary lymphoid structures in hepatocellular carcinoma

The prognostic relevance of peritumoural tertiary lymphoid structure (pTLSs) in hepatocellular carcinoma (HCC) remains uncertain. We used three methods to analyse pTLSs and performed a combined analysis incorporating intratumoural TLSs (iTLSs). Of 99 resected HCC cases, 74 evaluable samples were retrospectively analysed. We quantified pTLSs using three methods: (1) pTLS density; (2) pTLS maximum length; and (3) pTLS hotspot count. They were then further classified into three grades based on pTLS measurements and the presence of iTLSs: Grade 1 - low pTLS and iTLS-negative (iTLS-); Grade 2 - low pTLS and iTLS-positive (iTLS +) or high pTLS and iTLS-; and Grade 3 - high pTLS and iTLS + . A high pTLS density (HR 0.32, 95% CI, 0.11-0.99, p = 0.048), maximum length (HR 0.33, 95% CI, 0.13-0.86, p = 0.023) and hotspot count (HR 0.30, 95% CI, 0.11-0.81, p = 0.018) were independent predictors of improved 5-year overall survival in multivariable analysis. A high pTLS density (HR 0.23, 95% CI, 0.06-0.91, p = 0.036) and hotspot count (HR 0.14, 95% CI, 0.04-0.56, p = 0.005) were linked with improved 5-year disease-specific survival. In the combined analysis, having grade 3 compared to grade 1 was associated with better overall and disease-specific survival in multivariable analysis across all evaluation methods. Higher pTLS density and hotspot count are independent predictors of improved survival in resected HCC. Furthermore, integrating pTLS measurements with iTLS presence provides enhanced prognostic stratification.