Vessels that encapsulate tumour clusters vascular pattern in hepatocellular carcinoma

Abstract

Vessels that encapsulate tumour clusters (VETC) is a distinct histologic vascular pattern associated with a novel mechanism of metastasis. First described in human cancers in 2004, its prevalence and prognostic significance in hepatocellular carcinoma (HCC) has only been appreciated in the past decade with a rapidly increasing body of literature. A robust biomarker of aggressive disease, the VETC pattern is easy to recognise but relies on histologic examination of tumour tissue for its diagnosis. Radiological recognition of the VETC pattern is an area of active research and is becoming increasingly accurate. As a prognostic marker, VETC has consistently proven to be an independent predictor of disease recurrence and overall survival in patients with HCC undergoing resection and liver transplantation. It can also guide treatment by predicting response to other therapies such as transarterial chemoembolisation and sorafenib. Without prospective randomised-controlled trials or routine evaluation of VETC in clinical practice, there are currently no firm treatment recommendations for VETC-positive tumours, although some perspectives are provided in this review based on the latest knowledge of their pathogenesis - a complex interplay between tumour angiogenesis and the immune microenvironment. Nevertheless, VETC has great potential as a future biomarker that could take us one step closer to precision medicine for HCC.

Keywords: Vessels that encapsulate tumour clusters (VETC); angiogenesis; biomarker; epithelial mesenchymal transition (EMT); liver transplantation; metastasis.

Fig. 1

Different vascular patterns in HCC. (A) H&E and (B) CD34 immunostaining of HCC tissue sections from explants of patients who have undergone liver transplantation showing a VETC-negative HCC with CD34 staining of capillaries only and no cluster formation; (C) Routine H&E section of a macrotrabecular massive, VETC-positive HCC with black arrows in the inset pointing to endothelial cells; (D) The same macrotrabecular massive, VETC-positive HCC after CD34 immunostaining highlighting a distinct, continuous CD34 endothelial lining around individual tumour clusters; (E) A mixed HCC with an area of VETC (right of image) transitioning to an adjacent area of HCC consisting of capillary staining (left of image); (F) An example of an HCC with marginal VETC pattern where the main locus of VETC is located at the tumour margins (black arrowheads). A-D: 100x magnification; E: 200x magnification; F: 20x magnification.

Fig. 2

Pathogenesis of VETC-positive HCCs. VETC formation is particularly dependent on angiopoietin 2 which is influenced by miR-100, miR-125b, and the androgen receptor. Instead of the traditional EMT pathway for metastasis, VETC-positive HCCs can metastasise in an invasion-independent manner via embolisation of tumour clusters. Ang, angiopoietins; EMT, epithelial mesenchymal transition; FGF, fibroblast growth factor; HCC, hepatocellular carcinoma; mTOR, mammalian target of rapamycin; MVI, microvascular invasion; MTM, macrotrabecular massive; PDGF, platelet-derived growth factor; PD-L1, programmed death-ligand 1; PlGF, placental growth factor; VEGF, vascular endothelial growth factor; VETC, vessels that encapsulate tumour clusters.

Fig. 3

Radiological features of VETC-positive HCCs. (A) An axial arterial phase image of two HCCs on Gd-EOB-DTPA-enhanced MRI: one with peripheral irregular rim-like enhancement which has been associated with VETC positivity (white arrowhead) next to one with a more homogeneous enhancement associated with VETC negativity (white arrow). The patient subsequently received a liver transplant and explant pathology confirmed the respective VETC statuses associated with these two HCCs. (B) An axial arterial and (C) portal venous phase image of an 8 cm HCC on a contrast-enhanced CT scan with radiological features associated with the VETC pattern: size >5 cm, intratumoural necrosis (asterisk) and well-defined capsule (white arrowheads). The HCC was subsequently resected with histology demonstrating a VETC-positive HCC.