Vessels encapsulating tumor clusters in hepatocellular carcinoma: a unique and valuable pathological imaging.

HepatoBiliary Surg Nutr 2020;9(4):484-487 | http://dx.doi. org/10.21037/hbsn.2019. 11.16 We read with great interest a paper recently published in Hepatology entitled “VETC (vessels encapsulating tumor clusters) is a powerful predictor of aggressive hepatocellular carcinoma (HCC)” written by Renne et al., a multi-center study from Italy, Korea, and Japan (1). VETC is characterized by the presence of CD34+ vessels completely encapsulating tumor clusters in pathological imaging. The paper reports that VETC is independently associated with early recurrence within 2 years (HR: 1.52, P=0.023), disease-free survival (DFS) [HR: 1.66, P=0.002), and overall survivals (OS)] (HR: 2.26, P=0.001) in a large cohort of 541 resected HCCs. The term “VETC” first appeared in 2015, in a paper by Fang et al. in Hepatology (2). This earlier study also showed that VETC could predict higher metastasis and recurrence rates of HCC, and that VETC + HCC clusters were released into the bloodstream in an epithel ia l-mesenchymal transi t ion (EMT)independent manner using a PDX mouse model. The basic characteristics of VETC in HCC were already described in the preceding paper; however, the novelty of this paper is its detailed comparisons of the relationship between VETC and many clinicopathological variables using a large international multi-institutional cohort of resected HCCs with tissue microarray analyses. The concept of VETC-mediated cancer metastasis is unique. In the classical metastasis model, cancer cells need to invade through the vascular wall and escape anoikis and immune attack. The EMT endows cancer cells with these abilities. In VETC-mediated metastasis, the tissue organization and the encapsulating endothelium protect cancer cells from anoikis and immune assaults. Although the term “VETC” only appeared in 2015, the concept of VETC-mediated metastasis has long attracted attention under a different name. This unique metastasis pattern was first reported in the murine mammary carcinoma model as early as 1993 by Sugino et al. (3,4), who described it as “an invasion-independent pathway of blood-borne metastasis”; they also focused on “tumor nests” surrounded by sinusoidal blood vessels. This pathway is initiated by intravasation of tumor nests enveloped by endothelial cells of sinusoidal vasculature within the tumor. In clinical samples of 10 common human cancers, Sugino et al. also noted the presence of sinusoidal vasculature enveloping tumor nests and of subsequently generated endothelial-covered tumor emboli in efferent veins, especially in HCC, renal cell carcinoma, and follicular thyroid carcinoma (5). We usually consider these three cancers to have similar clinical and molecular characteristics, so their results matched our clinical impressions. In a further study of 80 HCC autopsy specimens, Sugino et al. documented the presence of tumor emboli in liver, lung, and lymphatic routes, consisting of CD31+/laminin+ sinusoidal tumor vasculature with basement membrane surrounding HCC nests (6). They named this process “sinusoidal tumor angiogenesis”. They did not use the term “VETC”; however, the basic concept of the non-EMT metastasis of VETC + HCC was Editorial