Ma Lidi, Liao Shuting, Yuan Shasha, Li Xueyan, Zhang Cheng, Zhou Fan, Geng Zhijun, Xie Chuanmiao, Lu Lianghe, Xing Kaili
Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, P. R. China.
Department of Radiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China.
Int J Surg. 2025 Jul 17. doi: 10.1097/JS9.0000000000003045.
The pattern of tertiary lymphoid structures (TLS) differs from that of microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC). This multicenter study aimed to evaluate the prognostic value of integrating TLS and MVI and assess their interaction with adjuvant hepatic arterial infusion chemotherapy (aHAIC).
From January 2013 to December 2021, this study enrolled 923 HCC patients (cohort A: 437; cohort B: 275; cohort C: 211) who underwent curative resection and stratified them into different groups based on their TLS and MVI status. The cohort C (the aHAIC group vs. the control group) enrolled patients confirmed HCC with MVI+. Recurrence-free survival (RFS) and overall survival (OS) were evaluated. RNA-seq analysis was performed on 79 patients fresh-frozen tissues of the cohort C.
The patients were divided into four subgroups based on TLS and MVI status: 21.05% TLS-/MVI-, 15.10% TLS-/MVI+, 46.91% TLS+/MVI-, and 16.93% TLS+/MVI+ in the cohort A, and 25.82% TLS-/MVI-, 11.27% TLS-/MVI+, 47.27% TLS+/MVI-, and 15.64% TLS+/MVI+ in the cohort B. Patients in the TLS+/MVI- group exhibited the best prognosis, while those in the TLS-/MVI+ group had the worst prognosis. The outcomes for the TLS-/MVI- and TLS+/MVI+ patients were comparable (RFS: p = 0.528, 0.354; OS: p = 0.931, 0.805, respectively for the A and B cohorts). In the cohort C, TLS+ patients had better RFS than TLS- patients both in the control (TLS+ vs TLS-: 19.57 [95% CI: 13.17, NA] vs 8.53 [95% CI: 5.33, 13.33] months) and adjuvant HAIC groups (TLS+ vs TLS-: NA vs 14.80 [95% CI: 10.30, NA] months). RFS was improved, however, no significant difference in OS was observed between TLS- and TLS+ groups in the cohort C. RNA-seq data analysis revealed that the differentially expressed genes between TLS+ and TLS- were predominantly associated with T-cell-inflamed tumor microenvironment and anti-tumor immune response.
Our findings establish TLS as a complementary biomarker to MVI, refining postoperative risk stratification. TLS status further stratifies MVI+ patients for HAIC responsiveness, identifying those more likely to benefit from adjuvant HAIC, highlighting its potential to guide personalized therapeutic strategies.
肝细胞癌（HCC）患者的三级淋巴结构（TLS）模式与微血管侵犯（MVI）模式不同。这项多中心研究旨在评估整合TLS和MVI的预后价值，并评估它们与辅助性肝动脉灌注化疗（aHAIC）的相互作用。
2013年1月至2021年12月，本研究纳入了923例行根治性切除术的HCC患者（队列A：437例；队列B：275例；队列C：211例），并根据其TLS和MVI状态将他们分为不同组。队列C（aHAIC组与对照组）纳入确诊为MVI+的HCC患者。评估无复发生存期（RFS）和总生存期（OS）。对队列C的79例患者的新鲜冷冻组织进行了RNA测序分析。
根据TLS和MVI状态，患者被分为四个亚组：队列A中，21.05%为TLS-/MVI-，15.10%为TLS-/MVI+，46.91%为TLS+/MVI-，16.93%为TLS+/MVI+；队列B中，25.82%为TLS-/MVI-，11.27%为TLS-/MVI+，47.27%为TLS+/MVI-，15.64%为TLS+/MVI+。TLS+/MVI-组患者的预后最佳，而TLS-/MVI+组患者的预后最差。TLS-/MVI-和TLS+/MVI+患者的预后结果相当（队列A和队列B的RFS：p分别为0.528和0.354；OS：p分别为0.931和0.805）。在队列C中，无论是在对照组（TLS+组与TLS-组：19.57 [95% CI：13.17，NA]个月 vs 8.53 [95% CI：5.33，13.33]个月）还是辅助性HAIC组（TLS+组与TLS-组：NA个月 vs 14.80 [95% CI：10.30，NA]个月），TLS+患者的RFS均优于TLS-患者。然而，队列C中TLS-组和TLS+组之间的OS无显著差异。RNA测序数据分析显示，TLS+和TLS-之间的差异表达基因主要与T细胞炎症性肿瘤微环境和抗肿瘤免疫反应相关。
我们的研究结果确立了TLS作为MVI的补充生物标志物，完善了术后风险分层。TLS状态进一步对MVI+患者进行HAIC反应性分层，识别出更可能从辅助性HAIC中获益的患者，突出了其指导个性化治疗策略的潜力。
