Junhan Pan,1,* Cong Zhang,1– 3,* Huizhen Huang,1 Yanyan Zhu,1 Yuhao Zhang,4 Shuzhen Wu,1 Yan-Ci Zhao,1 Feng Chen1 

1Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Feng Chen, Email chenfenghz@zju.edu.cn

Background: Macrotrabecular-massive (MTM) and vessels encapsulating tumor clusters (VETC)-hepatocellular carcinoma (HCC) are aggressive histopathological phenotypes with significant prognostic implications. However, the molecular markers associated with MTM-HCC and VETC-HCC and their implications for clinical outcomes and therapeutic strategies remain unclear.
Methods: Utilizing the TCGA-LIHC cohort, we employed machine learning techniques to develop a prognostic risk score based on MTM and VETC-related genes. The performance of the risk score was assessed by investigating various aspects including clinical outcomes, biological pathways, treatment responses, drug sensitivities, tumor microenvironment, and molecular subclasses. To validate the risk score, additional data from the ICGC-JP, GSE14520, GSE104580, GSE109211, and an in-house cohort were collected and analyzed.
Results: The machine learning algorithm established a 4-gene-based risk score. High-risk patients had significantly worse prognosis compared to low-risk patients, with the risk score being associated with malignant progression of HCC. Functionally, the high-risk group exhibited enrichment in tumor proliferation pathways. Additionally, patients in the low-risk group exhibited improved response to TACE and sorafenib treatments compared to the high-risk group. In contrast, the high-risk group exhibited reduced sensitivity to immunotherapy and increased sensitivity to paclitaxel. In the in-house cohort, high-risk patients displayed higher rates of early recurrence, along with an increased frequency of elevated alpha-fetoprotein, microvascular invasion, and aggressive MRI features associated with HCC.
Conclusion: This study has successfully developed a risk score based on MTM and VETC-related genes, providing a promising tool for prognosis prediction and personalized treatment strategies in HCC patients.

Keywords: hepatocellular carcinoma, prognosis, macrotrabecular-massive, vessels encapsulating tumor clusters