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Cancers
Special Issues
Diagnosis and Treatment for Hepatocellular Tumors
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Diagnosis and Treatment for Hepatocellular Tumors

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 51595

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Prof. Dr. Georgios Germanidis

E-Mail Website
Guest Editor
First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
Interests: NASH; HCC; liver biology; liver immunology; HBV; HCV; clinical liver diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, accounting for >80% of primary liver cancers worldwide, with geographical variations among its prevalence. It is the leading cause of death in patients with cirrhosis, with an annual HCC incidence of 1–6%. The diagnosis of HCC, relying solely on noninvasive criteria, is currently under debate due to the need for molecular information that necessitates tissue biopsies, while therapy is provided in accordance with tumor stages and the anticipated advantages of major interventions, following the Barcelona Clinic Liver Cancer (BCLC) staging system. Principally, resection, transplantation and local ablation are most commonly performed in patients with early-stage HCC tumors, while TACE and systemic therapy are respectively the preferred treatment options for intermediate- and advanced-stage tumors. However, the HCC tumor immune microenvironment (TME) affects response to current anti-PD-1/PD-L1 immunotherapies. Therefore, an enhanced understanding of the immunobiology of TME is essential for the development of predictive biomarkers of patient stratification and strategies of drug combinations to improve therapeutic efficacy, especially for patients with tumors irresponsive to anti-PD-1/PD-L1 therapy. Taking into account the health burden of HCC worldwide, with this Special Issue we aim to enhance our knowledge of innovative diagnostic and prognostic methods, and to discuss experimentation with different novel treatment modalities, believed to be of utmost priority to progress in our seemingly never-ending fight against hepatocellular cancer.

Dr. Georgios Germanidis
Guest Editor

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Keywords

  • HCC
  • hepatocellular tumors
  • diagnosis
  • treatment
  • BCLC-B
  • BCLC-C
  • anti-PD-1/PD-L1 immunotherapy
  • TKIs
  • combinations
  • TME
  • addiction loops
  • interventions
  • established data
  • future perspectives

Published Papers (19 papers)

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Editorial

Jump to: Research, Review

6 pages, 509 KiB  
Editorial
The Liver Cancer Immune Microenvironment: Emerging Concepts for Myeloid Cell Profiling with Diagnostic and Therapeutic Implications
by Konstantinos Arvanitakis, Ioannis Mitroulis, Antonios Chatzigeorgiou, Ioannis Elefsiniotis and Georgios Germanidis
Cancers 2023, 15(5), 1522; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15051522 - 28 Feb 2023
Cited by 11 | Viewed by 1856
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide [...] Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors)
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Research

Jump to: Editorial, Review

16 pages, 4295 KiB  
Article
Causes of Death among Patients with Hepatocellular Carcinoma According to Chronic Liver Disease Etiology
by Yi-Hao Yen, Kwong-Ming Kee, Wei-Feng Li, Yueh-Wei Liu, Chih-Chi Wang, Tsung-Hui Hu, Ming-Chao Tsai, Yuan-Hung Kuo and Chih-Yun Lin
Cancers 2023, 15(6), 1687; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15061687 - 09 Mar 2023
Viewed by 1467
Abstract
This study was conducted to determine whether the causes of death among patients with hepatocellular carcinoma (HCC) differ according to chronic liver disease (CLD) etiology. Between 2011 and 2020, 3977 patients who were newly diagnosed with HCC at our institution were enrolled in [...] Read more.
This study was conducted to determine whether the causes of death among patients with hepatocellular carcinoma (HCC) differ according to chronic liver disease (CLD) etiology. Between 2011 and 2020, 3977 patients who were newly diagnosed with HCC at our institution were enrolled in this study. We determined whether the cause of death was HCC-related and non-HCC-related. For patients with multiple CLD etiologies, etiology was classified using the following hierarchy: hepatitis C virus (HCV) > hepatitis B virus (HBV) > alcohol-related causes > all negative. All negative was defined as negative for HCV, HBV, and alcohol-related causes. Among 3977 patients, 1415 patients were classified as HCV-related, 1691 patients were HBV-related, 145 patients were alcohol-related, and 725 patients were all negative. HCC-related mortality was the leading cause of death, irrespective of etiology. Among patients who underwent curative treatment, HCC-related mortality was the leading cause of death for patients in the HCV, HBV, and all-negative groups, but not for patients in the alcohol-related group. Among patients 75 years and older who underwent curative treatment, HCC-related mortality was the leading cause of death in the HCV but not HBV or all-negative groups. In conclusion, although most patients with HCC die due to HCC-related causes, non-HCC-related mortality represents a competing event in certain patient subgroups. The current study results underscore the importance of assessing and managing underlying comorbidities, particularly among patients with HCC at risk of non-HCC-related mortality. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors)
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11 pages, 1564 KiB  
Article
Stationary Trend in Elevated Serum Alpha-Fetoprotein Level in Hepatocellular Carcinoma Patients
by Yi-Hao Yen, Kwong-Ming Kee, Wei-Feng Li, Yueh-Wei Liu, Chih-Chi Wang, Tsung-Hui Hu, Ming-Chao Tsai and Chih-Yun Lin
Cancers 2023, 15(4), 1222; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15041222 - 15 Feb 2023
Cited by 3 | Viewed by 1836
Abstract
A recent study from the US showed a decreasing trend in the elevated serum alpha-fetoprotein (AFP) level (i.e., ≥20 ng/mL) in hepatocellular carcinoma (HCC) patients at the time of diagnosis. Furthermore, advanced tumor stage and severe underlying liver disease were associated with elevated [...] Read more.
A recent study from the US showed a decreasing trend in the elevated serum alpha-fetoprotein (AFP) level (i.e., ≥20 ng/mL) in hepatocellular carcinoma (HCC) patients at the time of diagnosis. Furthermore, advanced tumor stage and severe underlying liver disease were associated with elevated AFP levels. We aimed to evaluate this issue in an area endemic for hepatitis B virus (HBV). Between 2011 and 2020, 4031 patients were newly diagnosed with HCC at our institution. After excluding 54 patients with unknown AFP data, the remaining 3977 patients were enrolled in this study. Elevated AFP level was defined as ≥20 ng/mL. Overall, 51.2% of HCC patients had elevated AFP levels; this proportion remained stationary between 2011 and 2020 (51.8% vs. 51.1%). Multivariate analysis showed that female gender (odds ratio (OR) = 1.462; p < 0.001), tumor size per 10 mm increase (OR = 1.155; p < 0.001), multiple tumors (OR = 1.406; p < 0.001), Barcelona Clinic Liver Cancer stages B–D (OR = 1.247; p = 0.019), cirrhosis (OR = 1.288; p = 0.02), total bilirubin > 1.4 mg/dL (OR = 1.218; p = 0.030), and HBV- or hepatitis C virus (HCV)-positive status (OR = 1.720; p < 0.001) were associated with elevated AFP levels. In conclusion, a stationary trend in elevated serum AFP level in HCC patients has been noted in the past 10 years. Advanced tumor stage, severe underlying liver disease, viral etiology, and female gender are associated with elevated AFP levels in HCC patients. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors)
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10 pages, 1039 KiB  
Article
Alpha-Fetoprotein Combined with Radiographic Tumor Burden Score to Predict Overall Survival after Liver Resection in Hepatocellular Carcinoma
by Yi-Hao Yen, Yueh-Wei Liu, Wei-Feng Li, Chih-Chi Wang, Chee-Chien Yong, Chih-Che Lin and Chih-Yun Lin
Cancers 2023, 15(4), 1203; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15041203 - 14 Feb 2023
Cited by 7 | Viewed by 1297
Abstract
We evaluated whether combining the radiographic tumor burden score (TBS) and alpha-fetoprotein (AFP) level could be used to stratify overall survival (OS) among hepatocellular carcinoma (HCC) patients after liver resection (LR). Patients who underwent LR for Barcelona Clinic Liver Cancer stage 0, A, [...] Read more.
We evaluated whether combining the radiographic tumor burden score (TBS) and alpha-fetoprotein (AFP) level could be used to stratify overall survival (OS) among hepatocellular carcinoma (HCC) patients after liver resection (LR). Patients who underwent LR for Barcelona Clinic Liver Cancer stage 0, A, or B HCC between 2011 and 2018 were enrolled. TBS scores were calculated using the following equation: TBS2 = (largest tumor size (in cm))2 + (tumor number)2. Among 743 patients, 193 (26.0%) patients had a low TBS (<2.6), 474 (63.8%) had a moderate TBS (2.6–7.9), and 75 (10.1%) had a high TBS (>7.9). Those with a TBS ≤ 7.9 and AFP < 400 ng/mL had a significantly better OS than those with a TBS > 7.9 and an AFP < 400 ng/mL (p = 0.003) or ≥ 400 ng/mL (p < 0.001). A multivariate analysis using TBS ≤ 7.9 and AFP < 400 ng/mL as the reference values showed that a TBS > 7.9 and an AFP < 400 ng/mL (hazard ratio (HR): 2.063; 95% confidence interval [CI]: 1.175–3.623; p = 0.012) or ≥ 400 ng/mL (HR: 6.570; 95% CI: 3.684–11.719; p < 0.001) were independent predictors of OS. In conclusion, combining radiographic TBSs and AFP levels could stratify OS among HCC patients undergoing LR. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors)
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10 pages, 684 KiB  
Article
Changes in ALBI Score and PIVKA-II within Three Months after Commencing Atezolizumab Plus Bevacizumab Treatment Affect Overall Survival in Patients with Unresectable Hepatocellular Carcinoma
by Shinji Unome, Kenji Imai, Koji Takai, Takao Miwa, Tatsunori Hanai, Yoichi Nishigaki, Hideki Hayashi, Takahiro Kochi, Shogo Shimizu, Junji Nagano, Soichi Iritani, Atsushi Suetsugu and Masahito Shimizu
Cancers 2022, 14(24), 6089; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14246089 - 10 Dec 2022
Cited by 7 | Viewed by 1509
Abstract
In this study, we aimed to evaluate the efficacy and safety of atezolizumab plus bevacizumab (Atez/Bev) treatment for unresectable hepatocellular carcinoma (HCC) and to analyze the factors affecting overall survival (OS). A total of 69 patients who received Atez/Bev at our institutions for [...] Read more.
In this study, we aimed to evaluate the efficacy and safety of atezolizumab plus bevacizumab (Atez/Bev) treatment for unresectable hepatocellular carcinoma (HCC) and to analyze the factors affecting overall survival (OS). A total of 69 patients who received Atez/Bev at our institutions for unresectable HCC were enrolled in this study. OS and progression-free survival (PFS) were estimated using the Kaplan–Meier method. Changes in clinical indicators within 3 months were defined as delta (∆) values, and the Cox proportional hazards model was used to identify which ∆ values affected OS. The median OS, PFS, objective response rate, and disease control rate were 12.5 months, 5.4 months, 23.8%, and 71.4%, respectively. During the observational period, 62 patients (92.5%) experienced AEs (hypertension (33.3%) and general fatigue), and 27 patients (47.4%) experienced grade ≥ 3 AEs (hypertension (10.1%) and anemia (7.2%)). There was a significant deterioration in the albumin-bilirubin (ALBI) score (−2.22 to −1.97; p < 0.001), and a reduction in PIVKA-II levels (32,458 to 11,584 mAU/mL; p = 0.040) within 3 months after commencing Atez/Bev. Both the worsening ∆ ALBI score (p = 0.005) and increasing ∆ PIVKA-II (p = 0.049) were significantly associated with the OS of patients. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors)
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12 pages, 1865 KiB  
Article
Baseline Splenic Volume Outweighs Immuno-Modulated Size Changes with Regard to Survival Outcome in Patients with Hepatocellular Carcinoma under Immunotherapy
by Lukas Müller, Simon Johannes Gairing, Roman Kloeckner, Friedrich Foerster, Arndt Weinmann, Jens Mittler, Fabian Stoehr, Tilman Emrich, Christoph Düber, Peter Robert Galle and Felix Hahn
Cancers 2022, 14(15), 3574; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14153574 - 22 Jul 2022
Cited by 4 | Viewed by 1313
Abstract
Background: An association between immunotherapy and an increase in splenic volume (SV) has been described for various types of cancer. SV is also highly predictive of overall survival (OS) in patients with hepatocellular carcinoma (HCC). We evaluated SV and its changes with [...] Read more.
Background: An association between immunotherapy and an increase in splenic volume (SV) has been described for various types of cancer. SV is also highly predictive of overall survival (OS) in patients with hepatocellular carcinoma (HCC). We evaluated SV and its changes with regard to their prognostic influence in patients with HCC undergoing immunotherapy. Methods: All patients with HCC who received immunotherapy in first or subsequent lines at our tertiary care center between 2016 and 2021 were screened for eligibility. SV was assessed at baseline and follow-up using an AI-based tool for spleen segmentation. Patients were dichotomized into high and low SV based on the median value. Results: Fifty patients were included in the analysis. The median SV prior to treatment was 532 mL. The median OS of patients with high and low SV was 5.1 months and 18.1 months, respectively (p = 0.01). An increase in SV between treatment initiation and the first follow-up was observed in 28/37 (75.7%) patients with follow-up imaging available. This increase in itself was not prognostic for median OS (7.0 vs. 8.5 months, p = 0.73). However, patients with high absolute SV at the first follow-up continued to have impaired survival (4.0 months vs. 30.7 months, p = 0.004). Conclusion: High SV prior to and during treatment was a significant prognostic factor for impaired outcome. Although a large proportion of patients showed an SV increase after the initiation of immunotherapy, this additional immuno-modulated SV change was negligible compared to long-standing changes in the splanchnic circulation in patients with HCC. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors)
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11 pages, 2038 KiB  
Article
Cytological Comparison between Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma by Image Analysis Software Using Touch Smear Samples of Surgically Resected Specimens
by Sho Kitamura, Keita Kai, Mitsuo Nakamura, Tomokazu Tanaka, Takao Ide, Hirokazu Noshiro, Eisaburo Sueoka and Shinich Aishima
Cancers 2022, 14(9), 2301; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092301 - 05 May 2022
Viewed by 2968
Abstract
To investigate useful cytological features for differential diagnosis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), this study cytologically compared HCC to ICC using image analysis software. Touch smear specimens of surgically resected specimens were obtained from a total of 61 nodules of [...] Read more.
To investigate useful cytological features for differential diagnosis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), this study cytologically compared HCC to ICC using image analysis software. Touch smear specimens of surgically resected specimens were obtained from a total of 61 nodules of HCC and 16 of ICC. The results indicated that the major/minor axis ratio of ICC is significantly larger than that of HCC (1.67 ± 0.27 vs. 1.32 ± 0.11, p < 0.0001) in Papanicolaou staining. This result means that the nucleus of HCC is close to round and the nucleus of ICC is close to an oval. This significant difference in the major/minor axis ratio between ICC and HCC was consistently observed by the same analyses using clinical samples of cytology (4 cases of HCC and 13 cases of ICC) such a fine-needle aspiration, brushing and ascites (ICC: 1.45 ± 0.13 vs. HCC: 1.18 ± 0.056, p = 0.004). We also confirmed that nuclear position center-positioned nucleus (p < 0.0001) and granular cytoplasm (p < 0.0001) are typical features of HCC tumor cells compared to ICC tumor cells. The research study found a significant difference in the nuclear morphology of HCC (round shape) and ICC (oval shape) in Papanicolaou-stained cytology specimens. This simple and objective finding will be very useful for the differential cytodiagnosis of HCC and ICC. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors)
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14 pages, 1582 KiB  
Article
Determinants of Survival and Post-Progression Outcomes by Sorafenib–Regorafenib Sequencing for Unresectable Hepatocellular Carcinoma
by I-Cheng Lee, Yee Chao, Pei-Chang Lee, San-Chi Chen, Chen-Ta Chi, Chi-Jung Wu, Kuo-Cheng Wu, Ming-Chih Hou and Yi-Hsiang Huang
Cancers 2022, 14(8), 2014; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14082014 - 15 Apr 2022
Cited by 7 | Viewed by 1821
Abstract
The predictors of response and survival in patients with hepatocellular carcinoma (HCC) receiving regorafenib remain unclear. This study aimed to delineate the determinants of response and survival after regorafenib and evaluate post-progression treatment and outcomes. We retrospectively enrolled 108 patients with unresectable HCC [...] Read more.
The predictors of response and survival in patients with hepatocellular carcinoma (HCC) receiving regorafenib remain unclear. This study aimed to delineate the determinants of response and survival after regorafenib and evaluate post-progression treatment and outcomes. We retrospectively enrolled 108 patients with unresectable HCC receiving regorafenib after sorafenib failure. Progression-free survival (PFS), overall survival (OS), post-progression survival (PPS) and post-progression treatments were evaluated. The median PFS, OS and PPS were 3.1, 13.1 and 10.3 months, respectively. Achieving disease control by prior sorafenib, early AFP reduction and hand-foot skin reaction (HFSR) were associated with significantly better radiologic responses. By multivariate analysis, the time to progression on prior sorafenib, HFSR and early AFP reduction were associated with PFS; ALBI grade, portal vein invasion, HFSR and early AFP reduction were associated with OS. ALBI grade at disease progression, main portal vein invasion, high tumor burden and next-line therapy were associated with PPS. The median PPS was 12 months in patients who received next-line therapy, and the PPS was comparable between patients who received next-line targeted agents and immunotherapy. In conclusion, survival outcomes of regorafenib for HCC have improved in the era of multi-line sequential therapy. Preserved liver function and next-line therapy are important prognostic factors after regorafenib failure. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors)
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12 pages, 1487 KiB  
Article
Efficacy and Safety of Atezolizumab and Bevacizumab in the Real-World Treatment of Advanced Hepatocellular Carcinoma: Experience from Four Tertiary Centers
by Vera Himmelsbach, Matthias Pinter, Bernhard Scheiner, Marino Venerito, Friedrich Sinner, Carolin Zimpel, Jens U. Marquardt, Jörg Trojan, Oliver Waidmann and Fabian Finkelmeier
Cancers 2022, 14(7), 1722; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14071722 - 28 Mar 2022
Cited by 28 | Viewed by 3129
Abstract
The combination of atezolizumab and bevacizumab (A + B) is the new standard of care for the systemic first-line treatment of hepatocellular carcinoma (HCC). However, up to now there are only few data on the safety and efficacy of A + B in [...] Read more.
The combination of atezolizumab and bevacizumab (A + B) is the new standard of care for the systemic first-line treatment of hepatocellular carcinoma (HCC). However, up to now there are only few data on the safety and efficacy of A + B in real life. We included patients with advanced HCC treated with A + B as first-line therapy at four cancer centers in Germany and Austria between December 2018 and August 2021. Demographics, overall survival (OS), and adverse events were assessed until 15 September 2021. We included 66 patients. Most patients had compensated cirrhosis (n = 34; 52%), while Child–Pugh class B cirrhosis was observed in 23 patients (35%), and class C cirrhosis in 5 patients (8%). The best responses included a complete response (CR) in 7 patients (11%), a partial response (PR) in 12 patients (18%), stable disease (SD) in 22 patients (33%), and progressive disease in 11 patients (17%). The median progression-free (PFS) survival was 6.5 months, while the median overall survival (OS) was not reached in this cohort (6-month OS: 69%, 12-month OS: 60%, 18-month OS: 58%). Patients with viral hepatitis seemed to have a better prognosis than patients with HCC of non-viral etiology. The real-world PFS and OS were comparable to those of the pivotal IMBRAVE trial, despite including patients with worse liver function in this study. We conclude that A + B is also highly effective in a real-life setting, with manageable toxicity, especially in patients with compensated liver disease. In patients with compromised liver function (Child B and C), the treatment showed low efficacy and, therefore, it should be well considered before administration to these patients. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors)
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Review

Jump to: Editorial, Research

19 pages, 344 KiB  
Review
Management of Hepatocellular Carcinoma in Decompensated Cirrhotic Patients: A Comprehensive Overview
by Maria Tampaki, George V. Papatheodoridis and Evangelos Cholongitas
Cancers 2023, 15(4), 1310; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15041310 - 18 Feb 2023
Cited by 5 | Viewed by 1716
Abstract
Primary liver cancer is the sixth most common cancer and the fourth leading cause of cancer-related death. Hepatocellular carcinoma (HCC) accounts for 75% of primary liver cancer cases, mostly on the basis of cirrhosis. However, the data and therapeutic options for the treatment [...] Read more.
Primary liver cancer is the sixth most common cancer and the fourth leading cause of cancer-related death. Hepatocellular carcinoma (HCC) accounts for 75% of primary liver cancer cases, mostly on the basis of cirrhosis. However, the data and therapeutic options for the treatment of HCC in patients with decompensated cirrhosis are rather limited. This patient category is often considered to be in a terminal stage without the possibility of a specific treatment except liver transplantation, which is restricted by several criteria and liver donor shortages. Systemic treatments may provide a solution for patients with Child Pugh class B or C since they are less invasive. Although most of the existing trials have excluded patients with decompensated cirrhosis, there are increasing data from real-life settings that show acceptable tolerability and satisfying efficacy in terms of response. The data on the administration of locoregional treatments in such patients are also limited, but the overall survival seems to be potentially prolonged when patients are carefully selected, and close adverse event monitoring is applied. The aim of this review is to analyze the existing data regarding the administration of treatments in decompensated patients with HCC, evaluate the effect of therapy on overall survival and highlight the potential risks in terms of tolerability. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors)
16 pages, 3400 KiB  
Review
New Challenges in the Management of Cholangiocarcinoma: The Role of Liver Transplantation, Locoregional Therapies, and Systemic Therapy
by Ezequiel Mauro, Joana Ferrer-Fàbrega, Tamara Sauri, Alexandre Soler, Amparo Cobo, Marta Burrel, Gemma Iserte and Alejandro Forner
Cancers 2023, 15(4), 1244; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15041244 - 15 Feb 2023
Cited by 15 | Viewed by 3187
Abstract
Cholangiocarcinoma (CCA) is a neoplasm with high mortality that represents 15% of all primary liver tumors. Its worldwide incidence is on the rise, and despite important advances in the knowledge of molecular mechanisms, diagnosis, and treatment, overall survival has not substantially improved in [...] Read more.
Cholangiocarcinoma (CCA) is a neoplasm with high mortality that represents 15% of all primary liver tumors. Its worldwide incidence is on the rise, and despite important advances in the knowledge of molecular mechanisms, diagnosis, and treatment, overall survival has not substantially improved in the last decade. Surgical resection remains the cornerstone therapy for CCA. Unfortunately, complete resection is only possible in less than 15–35% of cases, with a risk of recurrence greater than 60%. Liver transplantation (LT) has been postulated as an effective therapeutic strategy in those intrahepatic CCA (iCCA) smaller than 3 cm. However, the low rate of early diagnosis in non-resectable patients justifies the low applicability in clinical practice. The evidence regarding LT in locally advanced iCCA is scarce and based on small, retrospective, and, in most cases, single-center case series. In this setting, the response to neoadjuvant chemotherapy could be useful in identifying a subgroup of patients with biologically less aggressive tumors in whom LT may be successful. The results of LT in pCCA are promising, however, we need a very careful selection of patients and adequate experience in the transplant center. Locoregional therapies may be relevant in unresectable, liver-only CCA. In iCCA smaller than 2 cm, particularly those arising in patients with advanced chronic liver disease in whom resection or LT may not be feasible, thermal ablation may become a reliable alternative. The greatest advances in the management of CCA occur in systemic treatment. Immunotherapy associated with chemotherapy has emerged as the gold standard in the first-line treatment. Likewise, the most encouraging results have been obtained with targeted therapies, where the use of personalized treatments has shown high rates of objective and durable tumor response, with clear signs of survival benefit. In conclusion, the future of CCA treatment seems to be marked by the development of new treatment strategies but high-quality, prospective studies that shed light on their use and applicability are mandatory. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors)
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40 pages, 7282 KiB  
Review
Current Imaging Diagnosis of Hepatocellular Carcinoma
by Evangelos Chartampilas, Vasileios Rafailidis, Vivian Georgopoulou, Georgios Kalarakis, Adam Hatzidakis and Panos Prassopoulos
Cancers 2022, 14(16), 3997; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14163997 - 18 Aug 2022
Cited by 19 | Viewed by 6903
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer related death worldwide. Radiology has traditionally played a central role in HCC management, ranging from screening of high-risk patients to non-invasive diagnosis, as well as the evaluation of treatment response and post-treatment follow-up. [...] Read more.
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer related death worldwide. Radiology has traditionally played a central role in HCC management, ranging from screening of high-risk patients to non-invasive diagnosis, as well as the evaluation of treatment response and post-treatment follow-up. From liver ultrasonography with or without contrast to dynamic multiple phased CT and dynamic MRI with diffusion protocols, great progress has been achieved in the last decade. Throughout the last few years, pathological, biological, genetic, and immune-chemical analyses have revealed several tumoral subtypes with diverse biological behavior, highlighting the need for the re-evaluation of established radiological methods. Considering these changes, novel methods that provide functional and quantitative parameters in addition to morphological information are increasingly incorporated into modern diagnostic protocols for HCC. In this way, differential diagnosis became even more challenging throughout the last few years. Use of liver specific contrast agents, as well as CT/MRI perfusion techniques, seem to not only allow earlier detection and more accurate characterization of HCC lesions, but also make it possible to predict response to treatment and survival. Nevertheless, several limitations and technical considerations still exist. This review will describe and discuss all these imaging modalities and their advances in the imaging of HCC lesions in cirrhotic and non-cirrhotic livers. Sensitivity and specificity rates, method limitations, and technical considerations will be discussed. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors)
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28 pages, 4995 KiB  
Review
Etiology, Pathogenesis, Diagnosis, and Practical Implications of Hepatocellular Neoplasms
by Prodromos Hytiroglou, Paulette Bioulac-Sage, Neil D. Theise and Christine Sempoux
Cancers 2022, 14(15), 3670; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14153670 - 28 Jul 2022
Cited by 7 | Viewed by 2729
Abstract
Hepatocellular carcinoma (HCC), a major global contributor of cancer death, usually arises in a background of chronic liver disease, as a result of molecular changes that deregulate important signal transduction pathways. Recent studies have shown that certain molecular changes of hepatocarcinogenesis are associated [...] Read more.
Hepatocellular carcinoma (HCC), a major global contributor of cancer death, usually arises in a background of chronic liver disease, as a result of molecular changes that deregulate important signal transduction pathways. Recent studies have shown that certain molecular changes of hepatocarcinogenesis are associated with clinicopathologic features and prognosis, suggesting that subclassification of HCC is practically useful. On the other hand, subclassification of hepatocellular adenomas (HCAs), a heterogenous group of neoplasms, has been well established on the basis of genotype–phenotype correlations. Histologic examination, aided by immunohistochemistry, is the gold standard for the diagnosis and subclassification of HCA and HCC, while clinicopathologic correlation is essential for best patient management. Advances in clinico-radio-pathologic correlation have introduced a new approach for the diagnostic assessment of lesions arising in advanced chronic liver disease by imaging (LI-RADS). The rapid expansion of knowledge concerning the molecular pathogenesis of HCC is now starting to produce new therapeutic approaches through precision oncology. This review summarizes the etiology and pathogenesis of HCA and HCC, provides practical information for their histologic diagnosis (including an algorithmic approach), and addresses a variety of frequently asked questions regarding the diagnosis and practical implications of these neoplasms. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors)
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20 pages, 3293 KiB  
Review
Salvage versus Primary Liver Transplantation for Hepatocellular Carcinoma: A Twenty-Year Experience Meta-Analysis
by Gian Piero Guerrini, Giuseppe Esposito, Tiziana Olivieri, Paolo Magistri, Roberto Ballarin, Stefano Di Sandro and Fabrizio Di Benedetto
Cancers 2022, 14(14), 3465; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14143465 - 16 Jul 2022
Cited by 8 | Viewed by 1625
Abstract
(1) Background: Primary liver transplantation (PLT) for HCC represents the ideal treatment. However, since organ shortage increases the risk of drop-out from the waiting list for tumor progression, a new surgical strategy has been developed: Salvage Liver Transplantation (SLT) can be offered as [...] Read more.
(1) Background: Primary liver transplantation (PLT) for HCC represents the ideal treatment. However, since organ shortage increases the risk of drop-out from the waiting list for tumor progression, a new surgical strategy has been developed: Salvage Liver Transplantation (SLT) can be offered as an additional curative strategy for HCC recurrence after liver resection. The aim of this updated meta-analysis is to compare surgical and long-term outcomes of SLT versus PLT for HCC. (2) Materials and Methods: A systematic review and meta-analysis was conducted using the published papers comparing SLT and PLT up to January 2022. (3) Results: 25 studies describing 11,275 patients met the inclusion criteria. The meta-analysis revealed no statistical difference in intraoperative blood loss, overall vascular complications, retransplantation rate, and hospital stay in the SLT group compared with the PLT group. However, the SLT group showed a slightly significant lower 5-year OS rate and 5-year disease-free survival rate. (4) Conclusion: meta-analysis advocates the relative safety and feasibility of both Salvage LT and Primary LT strategies. Specifically, SLT seems to have comparable surgical outcomes but slightly poorer long-term survival than PLT. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors)
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14 pages, 822 KiB  
Review
Could We Predict the Response of Immune Checkpoint Inhibitor Treatment in Hepatocellular Carcinoma?
by Choong-kun Lee, Stephen L. Chan and Hong Jae Chon
Cancers 2022, 14(13), 3213; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14133213 - 30 Jun 2022
Cited by 9 | Viewed by 2744
Abstract
The use of anti-programmed cell-death protein (ligand)-1 (PD-[L]1) is an important strategy for treating hepatocellular carcinoma (HCC). However, the treatment only benefits 10–20% of patients when used as a monotherapy. Therefore, the selection of patients for anti-PD-1/PD-L1 treatment is crucial for both patients [...] Read more.
The use of anti-programmed cell-death protein (ligand)-1 (PD-[L]1) is an important strategy for treating hepatocellular carcinoma (HCC). However, the treatment only benefits 10–20% of patients when used as a monotherapy. Therefore, the selection of patients for anti-PD-1/PD-L1 treatment is crucial for both patients and clinicians. This review aimed to explore the existing literature on tissue or circulating markers for the identification of responders or non-responders to anti-PD-1/PD-L1 in HCC. For the clinically available markers, both etiological factors (viral versus non-viral) and disease extent (intra-hepatic vs. extrahepatic) impact the responses to anti-PD-1/PD-L1, warranting further studies. Preliminary data suggested that inflammatory indices (e.g., neutrophil-lymphocyte ratio) may be associated with clinical outcomes of HCC during the anti-PD-1/PD-L1 treatment. Finally, although PD-L1 expression in tumor tissues is a predictive marker for multiple cancer types, its clinical application is less clear in HCC due to the lack of a clear-cut association with responders to anti-PD-1/PD-L1 treatment. Although all translational markers are not routinely measured in HCC, recent data suggest their potential roles in selecting patients for anti-PD-1/PD-L1 treatment. Such markers, including the immune classification of HCC, selected signaling pathways, tumor-infiltrating lymphocytes, and auto-antibodies, were discussed in this review. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors)
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14 pages, 811 KiB  
Review
The Role of the NLRP3 Inflammasome in HCC Carcinogenesis and Treatment: Harnessing Innate Immunity
by Stavros P. Papadakos, Nikolaos Dedes, Elias Kouroumalis and Stamatios Theocharis
Cancers 2022, 14(13), 3150; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14133150 - 27 Jun 2022
Cited by 14 | Viewed by 2562
Abstract
The HCC constitutes one of the most frequent cancers, with a non-decreasing trend in disease mortality despite advances in systemic therapy and surgery. This trend is fueled by the rise of an obesity wave which is prominent the Western populations and has reshaped [...] Read more.
The HCC constitutes one of the most frequent cancers, with a non-decreasing trend in disease mortality despite advances in systemic therapy and surgery. This trend is fueled by the rise of an obesity wave which is prominent the Western populations and has reshaped the etiologic landscape of HCC. Interest in the nucleotide-binding domain leucine-rich repeat containing (NLR) family member NLRP3 has recently been revived since it would appear that, by generating inflammasomes, it participates in several physiologic processes and its dysfunction leads to disease. The NLRP3 inflammasome has been studied in depth, and its influence in HCC pathogenesis has been extensively documented during the past quinquennial. Since inflammation comprises a major regulator of carcinogenesis, it is of paramount importance an attempt to evaluate the contribution of the NLRP3 inflammasome to the generation and management of HCC. The aim of this review was to examine the literature in order to determine the impact of the NLRP3 inflammasome on, and present a hypothesis about its input in, HCC. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors)
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25 pages, 421 KiB  
Review
Local and Regional Therapies for Hepatocellular Carcinoma and Future Combinations
by Adam Hatzidakis, Lukas Müller, Miltiadis Krokidis and Roman Kloeckner
Cancers 2022, 14(10), 2469; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14102469 - 17 May 2022
Cited by 10 | Viewed by 2633
Abstract
Background: Hepatocellular carcinoma (HCC) can be treated by local and regional methods of percutaneous interventional radiological techniques. Indications depend on tumor size, type and stage, as well as patient’s condition, liver function and co-morbidities. According to international classification systems such as Barcelona Clinic [...] Read more.
Background: Hepatocellular carcinoma (HCC) can be treated by local and regional methods of percutaneous interventional radiological techniques. Indications depend on tumor size, type and stage, as well as patient’s condition, liver function and co-morbidities. According to international classification systems such as Barcelona Clinic Liver Cancer (BCLC) classification, very early, early or intermediate staged tumors can be treated either with ablative methods or with transarterial chemoembolization (TACE), depending on tumor characteristics. The combination of both allows for individualized forms of treatment with the ultimate goal of improving response and survival. In recent years, a lot of research has been carried out in combining locoregional approaches with immune therapy. Although recent developments in systemic treatment, especially immunotherapy, seem quite promising and have expanded possible combined treatment options, there is still not enough evidence in their favor. The aim of this review is to provide a comprehensive up-to-date overview of all these techniques, explaining indications, contraindications, technical problems, outcomes, results and complications. Moreover, combinations of percutaneous treatment with each other or with immunotherapy and future options will be discussed. Use of all those methods as down-staging or bridging solutions until surgery or transplantation are taken into consideration will also be reviewed. Conclusion: Local and regional therapies remain a mainstay of curative and palliative treatment of patients with HCC. Currently, evidence on potential combination of the local and regional treatment options with each other as well as with other treatment modalities is growing and has the potential to further individualize HCC therapy. To identify the most suitable treatment option out of these new various options, a repeated interdisciplinary discussion of each case by the tumor board is of utmost importance. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors)
22 pages, 1033 KiB  
Review
Tumor-Associated Macrophages in Hepatocellular Carcinoma Pathogenesis, Prognosis and Therapy
by Konstantinos Arvanitakis, Triantafyllia Koletsa, Ioannis Mitroulis and Georgios Germanidis
Cancers 2022, 14(1), 226; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010226 - 04 Jan 2022
Cited by 58 | Viewed by 4976
Abstract
Hepatocellular carcinoma (HCC) constitutes a major health burden globally, and it is caused by intrinsic genetic mutations acting in concert with a multitude of epigenetic and extrinsic risk factors. Cancer induces myelopoiesis in the bone marrow, as well as the mobilization of hematopoietic [...] Read more.
Hepatocellular carcinoma (HCC) constitutes a major health burden globally, and it is caused by intrinsic genetic mutations acting in concert with a multitude of epigenetic and extrinsic risk factors. Cancer induces myelopoiesis in the bone marrow, as well as the mobilization of hematopoietic stem and progenitor cells, which reside in the spleen. Monocytes produced in the bone marrow and the spleen further infiltrate tumors, where they differentiate into tumor-associated macrophages (TAMs). The relationship between chronic inflammation and hepatocarcinogenesis has been thoroughly investigated over the past decade; however, several aspects of the role of TAMs in HCC development are yet to be determined. In response to certain stimuli and signaling, monocytes differentiate into macrophages with antitumor properties, which are classified as M1-like. On the other hand, under different stimuli and signaling, the polarization of macrophages shifts towards an M2-like phenotype with a tumor promoting capacity. M2-like macrophages drive tumor growth both directly and indirectly, via the suppression of cytotoxic cell populations, including CD8+ T cells and NK cells. The tumor microenvironment affects the response to immunotherapies. Therefore, an enhanced understanding of its immunobiology is essential for the development of next-generation immunotherapies. The utilization of various monocyte-centered anticancer treatment modalities has been under clinical investigation, selectively targeting and modulating the processes of monocyte recruitment, activation and migration. This review summarizes the current evidence on the role of TAMs in HCC pathogenesis and progression, as well as in their potential involvement in tumor therapy, shedding light on emerging anticancer treatment methods targeting monocytes. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors)
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15 pages, 735 KiB  
Review
Is There Still a Place for Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma at the Time of Immunotherapies? A Focus on Lenvatinib
by Marie Decraecker, Caroline Toulouse and Jean-Frédéric Blanc
Cancers 2021, 13(24), 6310; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13246310 - 16 Dec 2021
Cited by 7 | Viewed by 2551
Abstract
The systemic treatment of hepatocellular carcinoma is changing rapidly. Three main classes of treatment are now available. Historically, multi-targeted tyrosine kinase inhibitors (TKIs) (sorafenib and lenvatinib as first-line; regorafenib and cabozantinib as second-line) were the first to show an improvement in overall survival [...] Read more.
The systemic treatment of hepatocellular carcinoma is changing rapidly. Three main classes of treatment are now available. Historically, multi-targeted tyrosine kinase inhibitors (TKIs) (sorafenib and lenvatinib as first-line; regorafenib and cabozantinib as second-line) were the first to show an improvement in overall survival (OS). Anti-vascular endothelial growth factor (anti-VEGF) antibodies can be used in first-line (bevacizumab) or second-line (ramucirumab) combination therapy. More recently, immuno-oncology (IO) has profoundly changed therapeutic algorithms, and the combination of atezolizumab-bevacizumab is now the first-line standard of care. Therefore, the place of TKIs needs to be redefined. The objective of this review was to define the place of TKIs in the therapeutic algorithm at the time of IO treatment in first-line therapy, with a special focus on lenvatinib that exhibits one of the higher anti-tumoral activity among TKI in HCC. We will discuss the place of lenvatinib in first line (especially if there is a contra-indication to IO) but also after failure of atezolizumab and bevacizumab. New opportunities for lenvatinib will also be presented, including the use at an earlier stage of the disease and combination with IOs. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors)
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