Hepatocellular Carcinoma: Epidemiology, Pathogenesis and Treatment

A special issue of Current Oncology (ISSN 1718-7729).

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 17066

Special Issue Editors


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Guest Editor
Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum Università di Bologna, Bologna, Italy
Interests: hepatocellular carcinoma; outcome; diagnosis; immunotherapy; artificial intelligence; lenvatinib; trans-arterial chemoemboilzation; selective internal radiotherapy; microwave ablation; surgery
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Guest Editor
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
Interests: hepatocellular carcinoma; cholangiocellular carcinoma

Special Issue Information

Dear Colleagues, 

The topic of liver cancer is receiving increasing attention. Hepatocellular carcinomas are still the primary liver cancers, with the highest prevalence and death toll worldwide. Intrahepatic cholangiocarcinoma is also on the rise, and an ever-increasing number of rare liver cancers are being reported. Epidemiology, pathogenesis, and response to surgical, locoregional, and systemic treatments are all elements of particular interest which need further elucidation by future studies. This Special Issue will cover all aspects, and welcomes both original research and comprehensive review papers to guide a wide readership toward the most recent and ground-breaking research in this complex field.

Dr. Francesco Tovoli
Dr. Luca Ielasi
Guest Editors

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Keywords

  • hepatocellular carcinoma
  • liver cancer
  • epidemiology
  • pathogenesis
  • treatment

Published Papers (7 papers)

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Research

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11 pages, 1009 KiB  
Article
Comparative Analysis of Subclassification Systems in Patients with Intermediate-Stage Hepatocellular Carcinoma (Barcelona Clinic Liver Classification B) Receiving Systemic Therapy
by Luca Ielasi, Bernardo Stefanini, Fabio Conti, Matteo Tonnini, Raffaella Tortora, Giulia Magini, Rodolfo Sacco, Tiziana Pressiani, Franco Trevisani, Francesco Giuseppe Foschi, Fabio Piscaglia, Alessandro Granito and Francesco Tovoli
Curr. Oncol. 2024, 31(1), 547-557; https://doi.org/10.3390/curroncol31010038 - 19 Jan 2024
Cited by 2 | Viewed by 938
Abstract
Background: Intermediate-stage hepatocellular carcinoma (BCLC B HCC) occurs in a heterogeneous group of patients and can be addressed with a wide spectrum of treatments. Consequently, survival significantly varies among patients. In recent years, several subclassification systems have been proposed to stratify patients’ prognosis. [...] Read more.
Background: Intermediate-stage hepatocellular carcinoma (BCLC B HCC) occurs in a heterogeneous group of patients and can be addressed with a wide spectrum of treatments. Consequently, survival significantly varies among patients. In recent years, several subclassification systems have been proposed to stratify patients’ prognosis. We analyzed and compared these systems (Bolondi, Yamakado, Kinki, Wang, Lee, and Kim criteria) in patients undergoing systemic therapy. Methods: We considered 171 patients with BCLC B HCC treated with sorafenib as first-line systemic therapy in six Italian centers from 2010 to 2021 and retrospectively applied the criteria of six different subclassification systems. Results: Except for the Yamakado criteria, all the subclassification systems showed a statistically significant correlation to overall survival (OS). In the postestimation analysis, the Bolondi criteria (OS of subgroups 22.5, 11.9, and 6.6 mo, respectively; C-index 0.586; AIC 1338; BIC 1344) and the Wang criteria (OS of subgroups 20.6, 11.9, and 7.0, respectively; C-index 0.607; AIC 1337; BIC 1344) presented the best accuracy. Further analyses of these two subclassification systems implemented with the prognostic factor of alpha-fetoprotein (AFP) > 400 ng/mL have shown an increase in accuracy for both systems (C-index 0.599 and 0.624, respectively). Conclusions: Intermediate-stage subclassification systems maintain their predictive value also in the setting of systemic therapy. The Bolondi and Wang criteria showed the highest accuracy. AFP > 400 ng/mL enhances the performance of these systems. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Epidemiology, Pathogenesis and Treatment)
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8 pages, 544 KiB  
Communication
Adjuvant Sorafenib for Postoperative Patients with Hepatocellular Carcinoma and Macrovascular Invasion
by Che-Jui Chang, Wei-Fan Hsu, Long-Bin Jeng, Hsueh-Chou Lai, Shih-Chao Hsu, Te-Hung Chen, Hung-Wei Wang and Cheng-Yuan Peng
Curr. Oncol. 2023, 30(12), 10134-10141; https://doi.org/10.3390/curroncol30120737 - 28 Nov 2023
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Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in Taiwan. Some patients with HCC are diagnosed with macrovascular invasion (MVI), which is associated with a poorer prognosis. In Taiwan, sorafenib is the first-line therapy for patients with advanced HCC. However, the [...] Read more.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in Taiwan. Some patients with HCC are diagnosed with macrovascular invasion (MVI), which is associated with a poorer prognosis. In Taiwan, sorafenib is the first-line therapy for patients with advanced HCC. However, the efficacy of adjuvant sorafenib therapy remains unclear for the subset of patients with HCC and MVI who are eligible for surgery. Therefore, we investigated the potential benefit of adjuvant sorafenib therapy for patients with HCC and MVI after surgery. Our study showed that the lack of improved PFS or OS of adjuvant sorafenib challenged the therapeutic benefit of postoperative sorafenib. Alcohol consumption and an α-fetoprotein level of ≥400 ng/mL were independent predictors of overall survival (OS); however, adjuvant sorafenib therapy was not a predictor of progression-free survival (PFS) or OS. In conclusion, our study indicated that adjuvant sorafenib therapy did not provide PFS or OS benefits in patients with HCC and MVI. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Epidemiology, Pathogenesis and Treatment)
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14 pages, 1806 KiB  
Article
Alcoholic Liver Disease-Related Hepatocellular Carcinoma: Characteristics and Comparison to General Slovak Hepatocellular Cancer Population
by Dominik Šafčák, Sylvia Dražilová, Jakub Gazda, Igor Andrašina, Svetlana Adamcová-Selčanová, Radovan Barila, Michal Mego, Marek Rác, Ľubomír Skladaný, Miroslav Žigrai, Martin Janičko and Peter Jarčuška
Curr. Oncol. 2023, 30(3), 3557-3570; https://doi.org/10.3390/curroncol30030271 - 22 Mar 2023
Cited by 2 | Viewed by 2562
Abstract
Hepatocellular carcinoma (HCC) has multiple molecular classes that are associated with distinct etiologies and, besides particular molecular characteristics, that also differ in clinical aspects. We aim to characterize the clinical aspects of alcoholic liver disease-related HCC by a retrospective observational study that included [...] Read more.
Hepatocellular carcinoma (HCC) has multiple molecular classes that are associated with distinct etiologies and, besides particular molecular characteristics, that also differ in clinical aspects. We aim to characterize the clinical aspects of alcoholic liver disease-related HCC by a retrospective observational study that included all consequent patients diagnosed with MRI or histologically verified HCC in participating centers from 2010 to 2016. A total of 429 patients were included in the analysis, of which 412 patients (96%) had cirrhosis at the time of diagnosis. The most common etiologies were alcoholic liver disease (ALD) (48.3%), chronic hepatitis C (14.9%), NAFLD (12.6%), and chronic hepatitis B (10%). Patients with ALD-related HCC were more commonly males, more commonly had cirrhosis that was in more advanced stages, and had poorer performance status. Despite these results, no differences were observed in the overall (median 8.1 vs. 8.5 months) and progression-free survival (median 4.9 vs. 5.7 months). ALD-HCC patients within BCLC stage 0–A less frequently received potentially curative treatment as compared to the control HCC patients (62.2% vs. 87.5%, p = 0.017); and in patients with ALD-HCC liver function (MELD score) seemed to have a stronger influence on the prognosis compared to the control group HCC. Systemic inflammatory indexes were strongly associated with survival in the whole cohort. In conclusion, alcoholic liver disease is the most common cause of hepatocellular carcinoma in Slovakia, accounting for almost 50% of cases; and patients with ALD-related HCC more commonly had cirrhosis that was in more advanced stages and had poorer performance status, although no difference in survival between ALD-related and other etiology-related HCC was observed. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Epidemiology, Pathogenesis and Treatment)
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13 pages, 953 KiB  
Article
CXCL1 and CXCL6 Are Potential Predictors for HCC Response to TACE
by Maximilian N. Kinzler, Katrin Bankov, Julia Bein, Claudia Döring, Falko Schulze, Henning Reis, Scherwin Mahmoudi, Vitali Koch, Leon D. Grünewald, Angelika Stehle, Dirk Walter, Fabian Finkelmeier, Stefan Zeuzem, Peter J. Wild, Thomas J. Vogl and Simon Bernatz
Curr. Oncol. 2023, 30(3), 3516-3528; https://doi.org/10.3390/curroncol30030267 - 20 Mar 2023
Cited by 2 | Viewed by 1968
Abstract
Distinct immune patterns of hepatocellular carcinoma (HCC) may have prognostic implications in the response to transarterial chemoembolization (TACE). Thus, we aimed to exploratively analyze tumor tissue of HCC patients who do or do not respond to TACE, and to identify novel prognostic biomarkers [...] Read more.
Distinct immune patterns of hepatocellular carcinoma (HCC) may have prognostic implications in the response to transarterial chemoembolization (TACE). Thus, we aimed to exploratively analyze tumor tissue of HCC patients who do or do not respond to TACE, and to identify novel prognostic biomarkers predictive of response to TACE. We retrospectively included 15 HCC patients who had three consecutive TACE between January 2019 and November 2019. Eight patients had a response while seven patients had no response to TACE. All patients had measurable disease according to mRECIST. Corresponding tumor tissue samples were processed for differential expression profiling using NanoString nCounter® PanCancer immune profiling panel. Immune-related pathways were broadly upregulated in TACE responders. The top differentially regulated genes were the upregulated CXCL1 (log2fc 4.98, Benjamini–Hochberg (BH)-p < 0.001), CXCL6 (log2fc 4.43, BH-p = 0.016) and the downregulated MME (log2fc −4.33, BH-p 0.001). CD8/T-regs was highly increased in responders, whereas the relative number of T-regs to tumor-infiltrating lymphocytes (TIL) was highly decreased. We preliminary identified CXCL1 and CXCL6 as candidate genes that might have the potential to serve as therapeutically relevant biomarkers in HCC patients. This might pave the way to improve patient selection for TACE in HCC patients beyond expert consensus. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Epidemiology, Pathogenesis and Treatment)
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Review

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19 pages, 1758 KiB  
Review
The New Era of Systemic Treatment for Hepatocellular Carcinoma: From the First Line to the Optimal Sequence
by Maria Cerreto, Ferdinando Cardone, Lucia Cerrito, Leonardo Stella, Francesco Santopaolo, Maria Pallozzi, Antonio Gasbarrini and Francesca Romana Ponziani
Curr. Oncol. 2023, 30(10), 8774-8792; https://doi.org/10.3390/curroncol30100633 - 26 Sep 2023
Cited by 5 | Viewed by 3925
Abstract
Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and is considered a major global health problem as one of the leading causes of cancer-related death in the world. Due to the increase in life expectancy and the epidemiological growth of specific [...] Read more.
Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and is considered a major global health problem as one of the leading causes of cancer-related death in the world. Due to the increase in life expectancy and the epidemiological growth of specific risk factors, such as metabolic dysfunction-associated steatotic liver disease (MASLD), the incidence of HCC is growing globally, and mortality rates are still high. Moreover, patients frequently present at an intermediate or advanced tumor stage, when curative treatments, such as surgical resection, liver transplantation or ablation are no longer applicable. In these cases, trans-arterial chemoembolization (TACE), trans-arterial radioembolization (TARE), and systemic therapy are the only suitable options to achieve disease control. The multi-kinase inhibitor Sorafenib has been the only systemic treatment available for unresectable advanced HCC for almost a decade, but in the last couple of years new therapeutic options have emerged. Recent advances in understanding the interactions between the tumor and its microenvironment, especially cancer immune escape, led to the advent of immunotherapy. Currently, first-line systemic treatment for HCC is represented by the combination of the immune checkpoint inhibitor (ICI) Atezolizumab plus Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, but many other ICIs have been investigated, such as Nivolumab, Pembrolizumab, Durvalumab and Ipilimumab. However, the problem of second- and third-line therapies, and the correct sequence of treatments remains open and is not addressed in most studies. This explains the urge to find new systemic treatments that can improve the survival and quality of life in patients that can go beyond the first line of treatment. The aim of this paper is to offer a complete overview of the most recent innovations in systemic treatments for unresectable locally advanced and metastatic HCC, including emerging therapies, with a particular focus on treatment sequences. Moreover, we will provide an outlook on possible future approaches to patients who progress beyond first-line therapies. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Epidemiology, Pathogenesis and Treatment)
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13 pages, 1379 KiB  
Review
Current Landscape of Immune Checkpoint Inhibitor Therapy for Hepatocellular Carcinoma
by Samantha M. Ruff, Ashish Manne, Jordan M. Cloyd, Mary Dillhoff, Aslam Ejaz and Timothy M. Pawlik
Curr. Oncol. 2023, 30(6), 5863-5875; https://doi.org/10.3390/curroncol30060439 - 18 Jun 2023
Cited by 7 | Viewed by 3122
Abstract
The liver maintains a balance between immune tolerance and activation in its role as a filtration system. Chronic inflammation disrupts this immune microenvironment, thereby allowing for the rise and progression of cancer. Hepatocellular carcinoma (HCC) is a liver tumor generally diagnosed in the [...] Read more.
The liver maintains a balance between immune tolerance and activation in its role as a filtration system. Chronic inflammation disrupts this immune microenvironment, thereby allowing for the rise and progression of cancer. Hepatocellular carcinoma (HCC) is a liver tumor generally diagnosed in the setting of chronic liver disease. When diagnosed early, the primary treatment is surgical resection, liver transplantation, or liver directed therapies. Unfortunately, patients with HCC often present at an advanced stage or with poor liver function, thereby limiting options. To further complicate matters, most systemic therapies are relatively limited and ineffective among patients with advanced disease. Recently, the IMbrave150 trial demonstrated that the combination of atezolizumab and bevacizumab was associated with better survival compared to sorafenib among patients with advanced HCC. As such, atezolizumab and bevacizumab is now recommended first-line therapy for these patients. Tumor cells work to create an immunotolerant environment by preventing the activation of stimulatory immunoreceptors and upregulating expression of proteins that bind inhibitory immunoreceptors. ICIs work to block these interactions and bolster the anti-tumor function of the immune system. We herein provide an overview of the use of ICIs in the treatment of HCC. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Epidemiology, Pathogenesis and Treatment)
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18 pages, 757 KiB  
Review
Potential Molecular Targeted Therapy for Unresectable Hepatocellular Carcinoma
by Shashank Kumar and Abhay Kumar Pandey
Curr. Oncol. 2023, 30(2), 1363-1380; https://doi.org/10.3390/curroncol30020105 - 18 Jan 2023
Cited by 1 | Viewed by 2612
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers, representing a serious worldwide health concern. The recurrence incidence of hepatocellular carcinoma (HCC) following surgery or ablation is as high as 70%. Thus, the clinical applicability of standard surgery and other [...] Read more.
Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers, representing a serious worldwide health concern. The recurrence incidence of hepatocellular carcinoma (HCC) following surgery or ablation is as high as 70%. Thus, the clinical applicability of standard surgery and other locoregional therapy to improve the outcomes of advanced HCC is restricted and far from ideal. The registered trials did not identify a treatment that prolonged recurrence-free survival, the primary outcome of the majority of research. Several investigator-initiated trials have demonstrated that various treatments extend patients’ recurrence-free or overall survival after curative therapies. In the past decade, targeted therapy has made significant strides in the treatment of advanced HCC. These targeted medicines produce antitumour effects via specific signals, such as anti-angiogenesis or advancement of the cell cycle. As a typical systemic treatment option, it significantly improves the prognosis of this fatal disease. In addition, the combination of targeted therapy with an immune checkpoint inhibitor is redefining the paradigm of advanced HCC treatment. In this review, we focused on the role of approved targeted medicines and potential therapeutic targets in unresectable HCC. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Epidemiology, Pathogenesis and Treatment)
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