Editor’s Note:
Hepatocellular carcinoma (HCC) is a highly malignant tumor, and one of its main characteristics is its rich vascular supply. Therefore, anti-angiogenic drugs have become one of the most important choices in the systematic treatment of HCC. In recent years, as research on HCC has deepened, researchers have discovered a unique vascular pattern in HCC tissue. Identified through CD34 immunohistochemical staining, this pattern differs from the classical capillary pattern. In this new pattern, blood vessels encapsulate the tumor in clusters and are termed “Vessels Encapsulating Tumor Clusters” (VETC). Increasing research suggests that the presence of VETC is associated with poor prognosis in HCC patients. From September 7-9, 2023, the 17th International Liver Cancer Association (ILCA) Annual Meeting (ILCA 2023) was grandly held in Amsterdam, the Netherlands. At this conference, Dr. Camilla De Carlo from the Human Research Hospital IRCCS in Rosano, Italy, presented a study (Abstract No: P-15) that found that pathological tissue section evaluation of VETC could predict the clinical benefit of anti-angiogenic treatment in patients with advanced HCC. This research provides guidance for the systematic treatment of patients with advanced HCC and was honored with the ILCA 2023 Excellent Poster Award.
As early as 2015, a study by Professor Shimei Zhuang’s team from the School of Life Sciences of Sun Yat-sen University, China, was published in the journal Hepatology. They were the first to discover a unique, small tumor cell cluster in some HCCs. These cell clusters are encapsulated by endothelial cells, forming many separate, dispersed, spheroid units, termed VETC. These units merge with microvessels to enter the bloodstream, becoming a new vascular pattern promoting HCC metastasis. This conservative organizational structure with endothelial disguise can protect tumor cells from immune attacks (Figure 1).
Figure 1. Diagram illustrating VETC-mediated HCC spread.
After the entire tumor cluster is released into the blood by endothelial cells, it can spread to nearby or distant sites.
In 2020, a multi-center study by Renne S. Lorenzo and others from the Human Research Hospital IRCCS in Rosano, Italy, published in the Hepatology journal, confirmed that VETC is closely related to HCC metastasis caused by different etiologies and can be used as an indicator to predict poor prognosis in HCC patients.
In 2021, Professor Guo Rongping’s team from the Sun Yat-sen University Cancer Prevention Center published a study in the Hepatology International journal. They retrospectively included 498 HCC patients from five clinical centers who underwent radical resection. Based on postoperative pathological evaluation of VETC and microvascular invasion (MVI), patients were divided into four different groups. The results showed that patients who were VETC-negative and MVI-negative had the best prognosis, while those who were VETC-positive and MVI-positive had the worst prognosis (see Figure 2). This research indicates that the results of VETC and MVI evaluations are closely related to the postoperative prognosis of HCC patients after radical resection.
Figure 2. VETC and MVI evaluation results are closely related to the postoperative prognosis of HCC patients after radical resection.
At the ILCA 2023 conference, based on their previous research, Dr. Camilla De Carlo from the Human Research Hospital IRCCS in Rosano, Italy, studied the histological and phenotypic features of tumor biopsies taken before systemic treatment in patients with advanced HCC, particularly focusing on the role of VETC in predicting the efficacy of anti-angiogenic treatment for these patients.
The study included 81 patients who completed tumor biopsies, collecting complete clinical data and follow-up results. H/E, CD34, GS, CD3, and CD79 stains were used on five consecutive sections. According to the World Health Organization standards, H/E staining was used to evaluate HCC grading, tissue type, and lymphocyte aggregation within the tumor; CD34 staining was used to evaluate the presence of VETC, using a 5% threshold to define VETC-positive cases; GS, CD3, and CD79 staining were used as alternative markers for HCC immune classification.
Among all patients, 73% were male, 52% had HBV/HCV infection, and 74% were at BCLC stage C. At the morphological level, 70% were HCC, showing strong diffuse GS staining (45%), and 51% of patients presented a VETC-positive phenotype.
In terms of clinical features, multivariate analysis showed that the Child-Pugh score and alpha-fetoprotein (AFP) levels significantly affected OS. Morphological features, namely HCC tissue type and grade, VETC positivity, high CD3/CD79 count, and strong diffuse GS staining, were not related to patient prognosis. Specifically, the median OS for VETC-positive HCC patients was 14 months, while for VETC-negative cases it was 11 months (P=0.82, Figure 3A).
In contrast, the VETC evaluation result showed a significant correlation with the clinical benefit of systemic treatment for patients. Specifically, compared to patients treated with immunosuppressants (ICI), VETC-positive patients treated with anti-angiogenic drugs (TKIs and/or anti-VEGF antibodies) had significantly extended OS (10 months vs. more than 50% of patients still alive after 36 months and median OS not yet reached, HR=0.3, 95%CI: 0.11-0.65, P=0.0019, see Figure 3B);In VETC-negative patients, this difference was not observed (P=0.69, see Figure 3C). Apart from this, no other morphological features were observed to be related to the benefit of systemic treatment for patients.
Figure 3. VETC evaluation results are closely related to the clinical benefits of systematic treatment in HCC patients
The research team believes that the identification of VETC on pathological tissue sections can serve as an important reference indicator for systemic treatment in patients with advanced HCC. The results of this study suggest that VETC-positive patients benefit significantly from anti-angiogenic treatment.
In an interview with Dr. Camilla De Carlo, she mentioned that “the presence of VETC in the tumor can significantly influence the choice of treatment for HCC patients. In particular, if we can predict the clinical benefit of anti-angiogenic treatment based on VETC evaluation, it will undoubtedly be of great significance to the optimization and personalization of the systemic treatment of HCC.” She also emphasized that the study was based on a limited number of patients, and more extensive clinical trials are needed to further validate these findings.
References:
- Fang JH, Zhou HC, Zhang C, et al. A novel vascular pattern promotes metastasis of hepatocellular carcinoma in an epithelial-mesenchymal transition-independent manner. Hepatology. 2015 Aug;62(2):452-65. doi: 10.1002/hep.27760. Epub 2015 Apr 22. PMID: 25711742.
2. Hanley KL, Feng GS. A new VETC in hepatocellular carcinoma metastasis. Hepatology. 2015 Aug;62(2):343-5. doi: 10.1002/hep.27860. Epub 2015 Jun
3. PMID: 25902918; PMCID: PMC5330284.3. Renne SL, Woo HY, Allegra S, Rudini N, Yano H, Donadon M, Viganò L, Akiba J, Lee HS, Rhee H, Park YN, Roncalli M, Di Tommaso L. Vessels Encapsulating Tumor Clusters (VETC) Is a Powerful Predictor of Aggressive Hepatocellular Carcinoma. Hepatology. 2020 Jan;71(1):183-195. doi: 10.1002/hep.30814. Epub 2019 Aug 9. PMID: 31206715.
4. Lu L, Wei W, Huang C, et al. A new horizon in risk stratification of hepatocellular carcinoma by integrating vessels that encapsulate tumor clusters and microvascular invasion. Hepatol Int. 2021 Jun;15(3):651-662. doi: 10.1007/s12072-021-10183-w. Epub 2021 Apr 9. PMID: 33835379.
TAG: ILCA 2023, Commentary, HCC
