Vessels Encapsulating Tumor Clusters (VETC) Is a Powerful Predictor of Aggressive Hepatocellular Carcinoma

Abstract

We investigated the clinical significance of a vascular growth pattern of hepatocellular carcinoma (HCC), the vessels that encapsulate tumor clusters (VETC), previously linked to HCC metastatic dissemination. VETC was assessed in a large multi‐institutional cohort of 541 resected HCCs from Italy, Korea and Japan, and matched against a full spectrum of clinical and pathological variables. The VETC phenotype (defined as ≥ 55% tumor area by CD34 immunostaining) was easily reproducible and reliably detectable in whole sections and small‐sized tissues of tissue microarray. VETC HCCs represented 18.9% of the whole series, the lowest proportion occurring in the cohort with smallest tumors (8.7%, Japanese series). VETC was significantly associated with several clinical and pathological features such as high alfa‐fetoprotein (AFP) level, tumor size greater than 5 cm, poor differentiation, macrotrabecular pattern, less compact pattern, less inflammatory infiltrates, and frequent microvascular invasion. VETC was associated with early recurrence (hazard ratio [HR]: 1.52 [1.06‐2.19], P = 0.023), disease‐free survival (HR: 1.66 [1.21‐2.27], P = 0.002), and overall survival (HR: 2.26 [1.37‐3.72], P = 0.001) at multivariable analysis. VETC affected the survival in HCC patients stratified for etiology (hepatitis C virus/hepatitis B virus), vascular invasion, and specific molecular phenotypes (β‐catenin/GS+). This distinct vascular pattern was enriched in the recently reported macrotrabecular massive HCC subtype, which was seen in 7.8% (42 of 541) of patients and associated with high AFP levels and poor differentiation. Conclusion: The VETC pattern was found to be easily detectable in a consistent fraction of HCC and a powerful pathological finding affecting survival. This study suggests that the heterogeneous pattern of angiogenesis is involved in HCC behavior.

Role of liver biopsy in hepatocellular carcinoma

“…VETC is a peculiar vascular phenotype, originally described by Fang et al[45]. We recently confirmed its strong impact on the prognosis of resectable HCC[46]. Moreover we observed the close correlation of VETC with several ominous prognostic features such as MVI.…”

“…In the first group, HCC presents as well-differentiated tumors with cholestasis and microtrabecular and pseudoglandular patterns of growth; in the second, HCC is mostly poorly differentiated with frequent vascular invasion. Using the corresponding im-munohistochemical markers (p53, β-catenin, and GS) we have recently confirmed the clinical-pathological correlations of these two subclasses in the daily clinical practice[46]; however, none of these categories proved to be of prognostic relevance[31,48]. Interestingly, the subgroup of HCC correlated to β-catenin pathway activation was recently associated with an exhausted immune infiltrate[49].…”

Evaluation of Intra-Tumoral Vascularization in Hepatocellular Carcinomas

“…They suggested that this vascular pattern was an effective mode of HCC metastasis independent of epithelial-to-mesenchymal transition. In 2019, Renne et al demonstrated that it was an independent risk factor for early recurrence and decreased overall survival in a large multi-institutional cohort containing 541 resected HCCs from Italy, South Korea, and Japan (73). Seemingly, it reminds us that the MVD influence the clinical outcomes of HCC, and the heterogeneity of vascular patterns might regulate HCC progression.…”

“…This special microvascular pattern, which ranges from 18.9 to 45.2% in HCC (70,71,73), ordinarily has a lower blood vessel density than ordinary capillary-like pattern and tends to form a large vessel lumen (76). Importantly, it has independent negative effects on OS and DFS (69)(70)(71)(72)(73). Neglecting the possible impacts of microvascular pattern on prognosis will cause unpredictable interference for the judgment of the actual role of MVD.…”

Integrative Concepts for Liver Surgery

“…The main histological determinant for a high recurrence risk is the presence of microvascular invasion (MVI) [6]. In addition, a novel parameter might be the vessel encapsulating tumor cluster, which is also associated with a higher recurrence rate after surgical therapy [7]. Since both features are difficult or even impossible to assess on preoperative biopsies, these biological parameters are not included in the preoperative treatment planning for HCC.…”