To evaluate the predictive value of vessels encapsulating tumor clusters (VETC) in the survival and prognosis of hepatocellular carcinoma (HCC) patients treated with lenvatinib.

Clinicopathological data of 101 patients with HCC treated with lenvatinib alone in Sun Yat-sen University Cancer Center from July 2018 to January 2020 were retrospectively analyzed. Among them, 88 patients were male and 13 female, aged from 19 to 78 years, with a median age of 51 years. Exemption from the informed consents of all patients was obtained and the local ethical committee approval was received. The status of VETC was evaluated by CD34 immunohistochemical staining. All patients were divided into the VETC positive and negative groups. Baseline characteristics between two groups were balanced by 1:2 propensity score matching (PSM). The primary endpoint was progression-free survival (PFS), and the secondary endpoints included overall survival (OS), extrahepatic and intrahepatic PFS. Survival analysis was performed by Kaplan-Meier method and Log-rank test. The influencing factors of survival and prognosis were identified by Cox proportional hazards regression model.

Before PSM, there were 33 patients in the VETC positive group and 68 in the VETC negative group. The incidence of portal vein tumor thrombus in the VETC positive group was 21%(7/33), significantly lower than 50%(34/68) in the VETC negative group (χ²=7.635, P=0.006). After PSM, there were 33 patients in the VETC positive group and 48 in the VETC negative group. The median PFS in the VETC positive and negative groups was 5.0 and 7.6 months, and the difference was statistically significant (HR=0.60, P=0.037). However, no statistical difference was observed in OS between two groups (HR=1.00, P=0.990). The extrahepatic PFS in the VETC positive group was significantly shorter than that in the VETC negative group (HR=0.46, P=0.004), but no significant difference was found in intrahepatic PFS between two groups (HR=0.81, P=0.475). Multivariate Cox regression analysis showed that receiving systematic therapy after the progression post-lenvatinib treatment alone was the independent protective factor of OS (HR=0.50, 95%CI: 0.30-0.84; P=0.009). However, VETC positivity (HR=1.74, 95%CI: 1.09-2.80), distant metastasis (HR=1.83, 95%CI: 1.09-3.09) and AFP≥400 μg/L (HR=2.07, 95%CI: 1.30-3.31) were the independent protective factors of PFS (all P<0.05). VETC positivity (HR=2.47, 95%CI: 1.40-4.35), distant metastasis (HR=2.03, 95%CI: 1.09-3.81) and AFP≥400 μg/L (HR=2.10, 95%CI: 1.21-3.64) were the independent risk factors of extrahepatic PFS (all P<0.05).

VETC positivity is the independent risk factor of PFS and extrahepatic PFS in HCC patients treated with lenvatinib. VETC positivity indicates a higher risk of extrahepatic progression and shorter PFS.