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Management of Hepatocellular Carcinoma in Liver Disease

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

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 20454

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Dr. Adriaan J. van der Meer

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Guest Editor

Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
Interests: viral hepatitis; cirrhosis; clinical research; outcome; surveillance; auto-immune and cholestatic liver diseases

Dr. Dave Sprengers

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Guest Editor

Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
Interests: hepatocellular carcinoma; immunotherapies; basic and translational research; biomarkers; viral hepatitis; immunology

Special Issue Information

Dear Colleagues,

Each year, over 900,000 patients are diagnosed with hepatocellular carcinoma (HCC) worldwide. It is the 3rd most common cause of cancer-related death, which highlights the poor prognosis of HCC and the importance of early diagnosis with the possibility of curative locoregional therapy or liver transplantation. Improving the efficacy of HCC surveillance is therefore an ongoing focus of the field. As there is a clear relation between HCC and pre-existing liver disease, with HCC predominantly developing in those who progressed to cirrhosis, many tumors can be prevented by adequate suppression of the aetiolofical factor driving hepatic inflammation and fibrogenesis. With viral hepatitis as the main global cause of HCC, the new effective antiviral therapies may thus substantially reduce the burden of HCC. Yet, non-alcoholic fatty liver disease is now increasingly identified as an important risk factor for HCC, even prior to the stage of cirrhosis. This poses new challenges due to the rising incidence of steatosis with a negative impact on the diagnostic sensitivity for HCC. Although immune-oncologic systemic approaches have recently improved treatment outcomes for a subgroup of patients, HCC will remain a global health problem for many years.

An upcoming special edition of Cancers aims to adress the questions associated with diagnosis and management of HCC in patients with liver disease from a broad perspective. We kindly invite and motivate all to submit their work related to this topic.

Dr. Adriaan J. van der Meer
Dr. Dave Sprengers
Guest Editors

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Keywords

hepatocellular carcinoma
epidemiology
surveillance
biomarkers
treatment
liver transplantation
liver disease
cirrhosis
non-cirrhosis
outcome

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Published Papers (7 papers)

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Research

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14 pages, 5527 KiB

Open AccessArticle

Potential of a Non-Contrast-Enhanced Abbreviated MRI Screening Protocol (NC-AMRI) in High-Risk Patients under Surveillance for HCC

by François Willemssen, Quido de Lussanet de la Sablonière, Daniel Bos, Jan IJzermans, Robert De Man and Roy Dwarkasing

Cancers 2022, 14(16), 3961; https://doi.org/10.3390/cancers14163961 - 17 Aug 2022

Cited by 4 | Viewed by 1621

Abstract

Purpose: To evaluate NC-AMRI for the detection of HCC in high-risk patients. Methods: Patients who underwent yearly contrast-enhanced MRI (i.e., full MRI protocol) of the liver were included retrospectively. For all patients, the sequences that constitute the NC-AMRI protocol, namely diffusion-weighted imaging (DWI), T2-weighted (T2W) imaging with fat saturation, and T1-weighted (T1W) in-phase and opposed-phase imaging, were extracted, anonymized, and uploaded to a separate research server and reviewed independently by three radiologists with different levels of experience. Reader I and III held a mutual training session. Levels of suspicion of HCC per patient were compared and the sensitivity, specificity, and area under the curve (AUC) using the Mann–Whitney U test were calculated. The reference standard was a final diagnosis based on full liver MRI and clinical follow-up information. Results: Two-hundred-and-fifteen patients were included, 36 (16.7%) had HCC and 179 (83.3%) did not. The level of agreement between readers was reasonable to good and concordant with the level of expertise and participation in a mutual training session. Receiver operating characteristics (ROC) analysis showed relatively high AUC values (range 0.89–0.94). Double reading showed increased sensitivity of 97.2% and specificity of 87.2% compared with individual results (sensitivity 80.1%–91.7%–97.2%; specificity 91.1%–72.1%–82.1%). Only one HCC (2.8%) was missed by all readers. Conclusion: NC-AMRI presents a good potential surveillance imaging tool for the detection of HCC in high-risk patients. The best results are achieved with two observers after a mutual training session. Full article

(This article belongs to the Special Issue Management of Hepatocellular Carcinoma in Liver Disease)

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17 pages, 1209 KiB

Open AccessArticle

A Novel Predictive Scoring System for 90-Day Mortality among Patients with Hepatocellular Cell Carcinoma Receiving Major Hepatectomy

by Ruey-Shyang Soong, Yi-Chan Chen, Ta-Chun Chou, Po-Hsing Chiang, Wan-Ming Chen, Ming-Feng Chiang, Ben-Chang Shia and Szu-Yuan Wu

Cancers 2022, 14(6), 1398; https://doi.org/10.3390/cancers14061398 - 9 Mar 2022

Cited by 2 | Viewed by 2087

Abstract

Purpose: Hepatocellular carcinoma (HCC) is a major malignancy and the common cause of cancer-related deaths. Surgical intervention provides superior long-term survival outcomes; however, perioperative mortality is a major concern for clinicians while making treatment decisions, especially for major hepatectomy. Scoring systems for predicting 90-day mortality in patients with HCC undergoing major hepatectomy are not available. Methods: This study used the Taiwan Cancer Registry Database that is linked to the National Health Insurance Research Database to analyze data of 60,250 patients with HCC who underwent major hepatectomy and determine risk factors to establish a novel predictive scoring system. By using the stepwise selection of the multivariate Cox proportional hazards model, we divided the patients with HCC undergoing major hepatectomy into four risk groups. Results: The Chang Gung-PohAi predictive scoring system exhibited significant differences in the 90-day mortality rate among the four risk groups (very low risk: 2.42%, low risk: 4.09%, intermittent risk: 17.1%, and high risk: 43.6%). Conclusion: The Chang Gung-PohAi predictive scoring system is a promising tool for predicting 90-day perioperative mortality in patients with HCC undergoing major hepatectomy. Full article

(This article belongs to the Special Issue Management of Hepatocellular Carcinoma in Liver Disease)

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11 pages, 2207 KiB

Open AccessArticle

Long-Term Hepatocellular Carcinoma Development and Predictive Ability of Non-Invasive Scoring Systems in Patients with HCV-Related Cirrhosis Treated with Direct-Acting Antivirals

by Gian Paolo Caviglia, Giulia Troshina, Umberto Santaniello, Giulia Rosati, Francesco Bombaci, Giovanni Birolo, Aurora Nicolosi, Giorgio Maria Saracco and Alessia Ciancio

Cancers 2022, 14(3), 828; https://doi.org/10.3390/cancers14030828 - 6 Feb 2022

Cited by 18 | Viewed by 2099

Abstract

Patients with hepatitis C virus (HCV)-related cirrhosis treated with direct-acting antivirals (DAA) are still at risk of developing hepatocellular carcinoma (HCC). We investigated the accuracy of non-invasive scoring systems (NSS) for the prediction of de novo HCC development in patients treated with DAA on long-term follow-up (FU). We analyzed data from 575 consecutive patients with cirrhosis and no history of HCC who achieved a sustained virologic response (SVR) to DAA therapy. NSS (i.e., Forns index, APRI, FIB-4, ALBI, and aMAP) were calculated at 3 months after the end of therapy. Performance for de novo HCC prediction was evaluated in terms of area under the curve (AUC) and Harrell’s C-index. During a median FU of 44.9 (27.8–58.6) months, 57 (9.9%) patients developed de novo HCC. All five NSS were associated with the risk of de novo HCC. At multivariate analysis, only the ALBI score resulted in being significantly and independently associated with de novo HCC development (adjusted hazard ratio = 4.91, 95% CI 2.91–8.28, p < 0.001). ALBI showed the highest diagnostic accuracy for the detection of de novo HCC at 1-, 3-, and 5-years of FU, with AUC values of 0.81 (95% CI 0.78–0.85), 0.71 (95% CI 0.66–0.75), and 0.68 (95% CI 0.59–0.76), respectively. Consistently, the best predictive performance assessed by Harrell’s C-statistic was observed for ALBI (C-index = 0.70, 95% CI 0.62–0.77). ALBI score may represent a valuable and inexpensive tool for risk stratification and the personalization of an HCC surveillance strategy for patients with cirrhosis and previous history of HCV infection treated with DAA. Full article

(This article belongs to the Special Issue Management of Hepatocellular Carcinoma in Liver Disease)

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14 pages, 1119 KiB

Open AccessArticle

The Role of Sarcopenia and Myosteatosis in Short- and Long-Term Outcomes Following Curative-Intent Surgery for Hepatocellular Carcinoma in a European Cohort

by Franziska Alexandra Meister, Georg Lurje, Suekran Verhoeven, Georg Wiltberger, Lara Heij, Wen-Jia Liu, Decan Jiang, Philipp Bruners, Sven Arke Lang, Tom Florian Ulmer, Ulf Peter Neumann, Jan Bednarsch and Zoltan Czigany

Cancers 2022, 14(3), 720; https://doi.org/10.3390/cancers14030720 - 30 Jan 2022

Cited by 26 | Viewed by 3191

Abstract

Alterations of body composition, especially decreased muscle mass (sarcopenia) and impaired muscle quality (myosteatosis), are associated with inferior outcomes in various clinical conditions. The data of 100 consecutive patients who underwent partial hepatectomy for hepatocellular carcinoma (HCC) at a German university medical centre were retrospectively analysed (May 2008–December 2019). Myosteatosis and sarcopenia were evaluated using preoperative computed-tomography-based segmentation. We investigated the predictive role of alterations in body composition on perioperative morbidity, mortality and long-term oncological outcome. Myosteatotic patients were significantly inferior in terms of major postoperative complications (Clavien–Dindo ≥ 3b; 25% vs. 5%, p = 0.007), and myosteatosis could be confirmed as an independent risk factor for perioperative morbidity in multivariate analysis (odds ratio: 6.184, confidence interval: 1.184–32.305, p = 0.031). Both sarcopenic and myosteatotic patients received more intraoperative blood transfusions (1.6 ± 22 vs. 0.3 ± 1 units, p = 0.000; 1.4 ± 2.1 vs. 0.3 ± 0.8 units, respectively, p = 0.002). In terms of long-term overall and recurrence-free survival, no statistically significant differences could be found between the groups, although survival was tendentially worse in patients with reduced muscle density (median survival: 41 vs. 60 months, p = 0.223). This study confirms the prognostic role of myosteatosis in patients suffering from HCC with a particularly strong value in the perioperative phase and supports the role of muscle quality over quantity in this setting. Further studies are warranted to validate these findings. Full article

(This article belongs to the Special Issue Management of Hepatocellular Carcinoma in Liver Disease)

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9 pages, 1127 KiB

Open AccessArticle

External Validation of the RETREAT Score for Prediction of Hepatocellular Carcinoma Recurrence after Liver Transplantation

by Maria C. van Hooff, Milan J. Sonneveld, Jan N. Ijzermans, Michail Doukas, Dave Sprengers, Herold J. Metselaar, Caroline M. den Hoed and Robert A. de Man

Cancers 2022, 14(3), 630; https://doi.org/10.3390/cancers14030630 - 27 Jan 2022

Cited by 8 | Viewed by 2515

Abstract

Background. We aimed to externally validate the performance of the RETREAT score in a European population. Methods. This single center retrospective cohort study enrolled all consecutive patients with HCC who underwent LT between 1989 and 2019. The performance of RETREAT was assessed in the overall population and after stratification between being within or beyond the Milan criteria based on the explant pathology report. Recurrence probabilities were estimated by using the Kaplan–Meier method and compared by log-rank test. Results. We studied 203 patients; 42 patients were beyond the Milan criteria based on explant pathology. The median follow-up was 26.8 months (IQR 7.2–60.7). Overall cumulative HCC recurrence rates were 10.6%, 21.3%, and 23.0% at 2, 5, and 10 years, with the majority of recurrences extrahepatic and at multiple sites. Higher RETREAT scores were associated with higher recurrence rates, with a 10-year recurrence rate of 60.5% in patients with RETREAT ≥ 3 (n = 65), compared to 6.2% in those with RETREAT ≤2 (n = 138; p < 0.001). HCC recurrence rates were even lower in patients within the Milan criteria who also had a low RETREAT score (n = 122; 2.7% at 10 years). Conclusion. Low RETREAT scores identify patients at low risk of HCC recurrence after LT in patients within the Milan criteria based on explant pathology. Full article

(This article belongs to the Special Issue Management of Hepatocellular Carcinoma in Liver Disease)

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14 pages, 1968 KiB

Open AccessArticle

Liver Decompensation as Late Complication in HCC Patients with Long-Term Response following Selective Internal Radiation Therapy

by Diederick J. van Doorn, Pim Hendriks, Mark C. Burgmans, Daphne D. D. Rietbergen, Minneke J. Coenraad, Otto M. van Delden, Roel J. Bennink, Tim A. Labeur, Heinz-Josef Klümpen, Ferry A. L. M. Eskens, Adriaan Moelker, Erik Vegt, Dave Sprengers, Nahid Mostafavi, Jan Ijzermans and R. Bart Takkenberg

Cancers 2021, 13(21), 5427; https://doi.org/10.3390/cancers13215427 - 29 Oct 2021

Cited by 5 | Viewed by 2229

Abstract

Selective internal radiation therapy (SIRT) is used as a treatment for hepatocellular carcinoma (HCC). The aim of this study was to assess long-term liver-related complications of SIRT in patients who had not developed radioembolization-induced liver disease (REILD). The primary outcome was the percentage of patients without REILD that developed Child-Pugh (CP) ≥ B7 liver decompensation after SIRT. The secondary outcomes were overall survival (OS) and tumor response. These data were compared with a matched cohort of patients treated with sorafenib. Eighty-five patients were included, of whom 16 developed REILD. Of the remaining 69 patients, 38 developed liver decompensation CP ≥ B7. The median OS was 18 months. In patients without REILD, the median OS in patients with CP ≥ B7 was significantly shorter compared to those without CP ≥ B7; 16 vs. 31 months. In the case-matched analysis, the median OS was significantly longer in SIRT-treated patients; 16 vs. 8 months in sorafenib. Liver decompensation CP ≥ B7 occurred significantly more in SIRT when compared to sorafenib; 62% vs. 27%. The ALBI score was an independent predictor of liver decompensation (OR 0.07) and OS (HR 2.83). After SIRT, liver decompensation CP ≥ B7 often developed as a late complication in HCC patients and was associated with a shorter OS. The ALBI score was predictive of CP ≥ B7 liver decompensation and the OS, and this may be a valuable marker for patient selection for SIRT. Full article

(This article belongs to the Special Issue Management of Hepatocellular Carcinoma in Liver Disease)

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Review

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17 pages, 890 KiB

Open AccessReview

The Role of Cytokines in the Different Stages of Hepatocellular Carcinoma

by Noe Rico Montanari, Chimaobi M. Anugwom, Andre Boonstra and Jose D. Debes

Cancers 2021, 13(19), 4876; https://doi.org/10.3390/cancers13194876 - 29 Sep 2021

Cited by 31 | Viewed by 5320

Abstract

Hepatocellular carcinoma (HCC) is the primary form of liver cancer and a leading cause of cancer-related death worldwide. Early detection remains the most effective strategy in HCC management. However, the spectrum of underlying liver diseases preceding HCC, its genetic complexity, and the lack of symptomatology in early stages challenge early detection. Regardless of underlying etiology, unresolved chronic inflammation is a common denominator in HCC. Hence, many inflammatory molecules, including cytokines, have been investigated as potential biomarkers to predict different stages of HCC. Soluble cytokines carry cell-signaling functions and are easy to detect in the bloodstream. However, its biomarkers’ role remains limited due to the dysregulation of immune parameters related to the primary liver process and their ability to differentiate carcinogenesis from the underlying disease. In this review, we discuss and provide insight on cytokines with clinical relevance for HCC differentiating those implicated in tumor formation, early detection, advanced disease, and response to therapy. Full article

(This article belongs to the Special Issue Management of Hepatocellular Carcinoma in Liver Disease)

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