Density and Maturity of Tertiary Lymphoid Structures Predict Clinical Outcome in Invasive Lung Adenocarcinoma

IntroductionTertiary lymphoid structures (TLSs) have been associated with the prognosis of various solid tumors. However, the association between TLSs and the prognosis of invasive lung adenocarcinoma (IAC) remains unclear in terms of location, density, and maturity.MethodsWe retrospectively reviewed the clinicopathological characteristics of 750 patients with IAC. The density of TLSs in various tumor regions, as well as their maturation status, was examined by pathologists. The X-tile software was employed to determine the optimal cut-off values for the intratumoral and peritumoral TLS density based on overall survival. A threshold of 1.33 TLSs/cm² was used to distinguish between low- and high-density intratumoral TLSs, while a threshold of 1.39 TLSs/cm² was applied for peritumoral TLSs. Tissue slides exhibiting no or early TLSs demonstrated low maturation levels, while those with at least one lymphoid follicle indicated high maturation. We analyzed the correlation between TLS characteristics and clinicopathological parameters and assessed the impact of multiple clinicopathological factors on patient prognosis using Cox regression and Kaplan-Meier analyses. A multivariate logistic regression analysis model was used to explore predictive factors for the density of intratumoral TLSs and TLS maturity in patients with IAC.ResultsLower intratumoral TLS density, increased TLS maturation, lymph node metastasis, and the presence of solid (≥30%) and micropapillary (≥5%) pathological subtypes were identified as poor independent prognostic factors for overall survival in patients with IAC. Solid (≥30%) and micropapillary (≥5%) pathological subtypes were predictive factors for lower intratumoral TLS density (hazard ratio [HR] = 0.434, 95% confidence interval [CI] = 0.267-0.706, P = 0.001), while higher TLSs maturity was associated with a smoking history or pleural invasion (HR = 1.655, 95% CI = 1.048-2.613, P = 0.031; HR = 1.933, 95% CI = 1.054-3.546, P = 0.033).ConclusionsBoth intratumoral TLS density and TLS maturation are independent prognostic factors for IAC. Additionally, higher TLS density predicted better prognosis, whereas greater TLS maturity predicted worse prognosis.