Correspondence to editorial on “Molecular classification of hepatocellular carcinoma based on zoned metabolic feature and oncogenic signaling pathway” Tomoko Aoki, Naoshi Nishida, Masatoshi Kudo Clinical and Molecular Hepatology.2026; 32(1): e79. CrossRef
Reply to correspondence on “Molecular classification of hepatocellular carcinoma based on zoned metabolic feature and oncogenic signaling pathway” Eun Ji Jang, Pil Soo Sung Clinical and Molecular Hepatology.2026; 32(1): e115. CrossRef
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Hepatocellular carcinoma (HCC) is a major global burden, ranking as the third leading cause of cancer-related mortality. HCC due to chronic hepatitis B virus (HBV) or C virus (HCV) infection has decreased due to universal vaccination for HBV and effective antiviral therapy for both HBV and HCV, but HCC related to metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease is increasing. Biannual liver ultrasonography and serum α-fetoprotein are the primary surveillance tools for early HCC detection among high-risk patients (e.g., cirrhosis, chronic HBV). Alternative surveillance tools such as blood-based biomarker panels and abbreviated magnetic resonance imaging (MRI) are being investigated. Multiphasic computed tomography or MRI is the standard for HCC diagnosis, but histological confirmation should be considered, especially when inconclusive findings are seen on cross-sectional imaging. Staging and treatment decisions are complex and should be made in multidisciplinary settings, incorporating multiple factors including tumor burden, degree of liver dysfunction, patient performance status, available expertise, and patient preferences. Early-stage HCC is best treated with curative options such as resection, ablation, or transplantation. For intermediate-stage disease, locoregional therapies are primarily recommended although systemic therapies may be preferred for patients with large intrahepatic tumor burden. In advanced-stage disease, immune checkpoint inhibitor-based therapy is the preferred treatment regimen. In this review article, we discuss the recent global epidemiology, risk factors, and HCC care continuum encompassing surveillance, diagnosis, staging, and treatments.
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Seogsong Jeong, Yun Hwan Oh, Joseph C Ahn, Seulggie Choi, Sun Jae Park, Hye Jun Kim, Gyeongsil Lee, Joung Sik Son, Heejoon Jang, Dong Hyeon Lee, Meng Sha, Lei Chen, Won Kim, Sang Min Park
Clin Mol Hepatol 2024;30(3):487-499. Published online May 7, 2024
Background/Aims To determine the association between evolutionary changes in metabolic dysfunction-associated steatotic liver disease (MASLD) status and the risk of hepatocellular carcinoma (HCC) in a nationwide population-based cohort.
Methods Information on study participants was derived from the Korea National Health Insurance Service database. The study population consisted of 5,080,410 participants who underwent two consecutive biennial health screenings between 2009 and 2012. All participants were followed up until HCC, death, or 31 December 2020. The association of evolutionary changes in MASLD status, as assessed by the fatty liver index and cardiometabolic risk factors, including persistent non-MASLD, resolved MASLD, incident MASLD, and persistent MASLD, with HCC risk was evaluated using multivariable-adjusted Cox proportional hazards regression.
Results Among the 5,080,410 participants with 39,910,331 person-years of follow-up, 4,801 participants developed HCC. The incidence of HCC in participants with resolved, incident, and persistent MASLD was approximately 2.2-, 2.3-, and 4.7-fold higher, respectively, than that in those with persistent non-MASLD among the Korean adult population. When stratifying the participants according to the evolutionary change in MASLD status, persistent (adjusted hazard ratio [aHR], 2.94; 95% confidence interval [CI], 2.68–3.21; P<0.001), incident (aHR, 1.85; 95% CI, 1.63–2.10; P<0.001), and resolved MASLD (aHR, 1.33; 95% CI, 1.18–1.50; P<0.001) had an increased risk of HCC compared to persistent non-MASLD.
Conclusions The evolutionary changes in MASLD were associated with the differential risk of HCC independent of metabolic risk factors and concomitant medications, providing additional information on the risk of HCC stratification in patients with MASLD.
Citations
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Background/Aims Primary liver cancer is one of the leading causes of cancer mortality worldwide. However, the causes of death have not been studied in detail in patients with liver cancer.
Methods The causes of death and cause-specific mortality risks in patients with primary liver cancer, diagnosed during 2000–2016, were investigated using the nationwide population-based cancer registry data in South Korea (n=231,388). The cumulative incidence function and Fine-Gray models were used to estimate the cause-specific mortality under the competing risks. Risks of non-cancer deaths relative to the general population were compared by standardized mortality ratios (SMRs).
Results Among 179,921 total deaths, 92.4%, 1.7%, and 6.0% of patients died of primary liver cancer, cancer from other sites, and non-cancer illnesses, respectively. Proportionate mortality from liver cancer remained high. The 5-year competing risks probability of death from liver cancer varied by tumor stage, from 42% to 94%, and it remained high 10 years after the diagnosis (61–95%). Competing mortality from other causes has continuously increased. The most common non-cancer causes of death were underlying liver diseases (SMR, 15.6; 95% confidence interval [CI], 15.1–16.1) and viral hepatitis (SMR, 46.5; 95% CI, 43.9–49.2), which demonstrated higher mortality risks compared to the Korean general population. Higher mortality risks of suicide (SMR, 2.6; 95% CI, 2.4–2.8) was also noted.
Conclusions Patients with liver cancer are most likely to die from liver cancer and related liver disease, even 10 years after the diagnosis, highlighting a need for specialized long-term follow-up care.
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Background/Aims The role of hepatitis B virus (HBV) integration into the host genome in hepatocarcinogenesis following hepatitis B surface antigen (HBsAg) seroclearance remains unknown. Our study aimed to investigate and characterize HBV integration events in chronic hepatitis B (CHB) patients who developed hepatocellular carcinoma (HCC) after HBsAg seroclearance.
Methods Using probe-based HBV capturing followed by next-generation sequencing technology, HBV integration was examined in 10 samples (seven tumors and three non-tumor tissues) from seven chronic carriers who developed HCC after HBsAg loss. Genomic locations and patterns of HBV integration were investigated.
Results HBV integration was observed in six patients (85.7%) and eight (80.0%) of 10 tested samples. HBV integration breakpoints were detected in all of the non-tumor (3/3, 100%) and five of the seven (71.4%) tumor samples, with an average number of breakpoints of 4.00 and 2.43, respectively. Despite the lower total number of tumoral integration breakpoints, HBV integration sites in the tumors were more enriched within the genic area. In contrast, non-tumor tissues more often showed intergenic integration. Regarding functions of the affected genes, tumoral genes with HBV integration were mostly associated with carcinogenesis. At enrollment, patients who did not remain under regular HCC surveillance after HBsAg seroclearance had a large HCC, while those on regular surveillance had a small HCC.
Conclusions The biological functions of HBV integration are almost comparable between HBsAg-positive and HBsAgserocleared HCCs, with continuing pro-oncogenic effects of HBV integration. Thus, ongoing HCC surveillance and clinical management should continue even after HBsAg seroclearance in patients with CHB.
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In patients with unresectable hepatocellular carcinoma (HCC) without both macrovascular invasion and extrahepatic metastasis, the initial treatment choice recommended is transarterial chemoembolization (TACE). Before sorafenib came into wide use, TACE had been pointlessly carried out repeatedly. It was in the early 2010s that the concept of TACE refractory was advocated. Two retrospective studies from Japan indicated that conversion from TACE to sorafenib the day after patients were deemed as TACE refractory improved overall survival compared with continued TACE, according to the definition by the Japan Society of Hepatology. Nowadays, phase 3 trials have shown clinical benefits of several novel molecular target agents. Compared with the era of sorafenib, sequential treatments with these molecular target agents have gradually prolonged patients’ survival and have become major strategies in patients with HCC. Taking these together, conversion from TACE to systemic therapies at the time of TACE refractory, compared with before, may have a greater impact on survival and may be considered deeper in the decisions-making process in patients with unresectable HCC who are candidate for TACE. Up-to-date information on the concept of TACE refractory is summarized in this review. We believe that the survival of patients with unresectable HCC without both macrovascular invasion and extrahepatic metastasis may be dramatically improved by optimal timing of TACE refractory and switching to systemic therapies.
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Haneulsaem Shin, Yeon Woo Jung, Beom Kyung Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Kwang-Hyub Han, Yeun-Yoon Kim, Jin-Young Choi, Seung Up Kim
Clin Mol Hepatol 2019;25(4):390-399. Published online May 31, 2019
Background/Aims A risk prediction model for the development of hepatocellular carcinoma (HCC) from indeterminate nodules detected on computed tomography (CT) (RadCT score) in patients with chronic hepatitis B (CHB)-related cirrhosis was proposed. We validated this model for indeterminate nodules on magnetic resonance imaging (MRI).
Methods Between 2013 and 2016, Liver Imaging Reporting and Data System (LI-RADS) 2/3 nodules on MRI were detected in 99 patients with CHB. The RadCT score was calculated.
Results The median age of the 72 male and 27 female subjects was 58 years. HCC history and liver cirrhosis were found in 47 (47.5%) and 44 (44.4%) patients, respectively. The median RadCT score was 112. The patients with HCC (n=41, 41.4%) showed significantly higher RadCT scores than those without (median, 119 vs. 107; P=0.013); the Chinese university-HCC and risk estimation for HCC in CHB (REACH-B) scores were similar (both P>0.05). Arterial enhancement, T2 hyperintensity, and diffusion restriction on MRI were not significantly different in the univariate analysis (all P>0.05); only the RadCT score significantly predicted HCC (hazard ratio [HR]=1.018; P=0.007). Multivariate analysis showed HCC history was the only independent HCC predictor (HR=2.374; P=0.012). When the subjects were stratified into three risk groups based on the RadCT score (<60, 60–105, and >105), the cumulative HCC incidence was not significantly different among them (all P>0.05, log-rank test).
Conclusions HCC history, but not RadCT score, predicted CHB-related HCC development from LI-RADS 2/3 nodules. New risk models optimized for MRI-defined indeterminate nodules are required.
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Background/Aims Transarterial chemoembolization (TACE) is a standard treatment for intermediate-stage hepatocellular carcinoma (HCC), but there is much controversy about TACE refractoriness. The aim of this study was to identify trends in the actual clinical application of TACE and recognition of TACE refractoriness by Korean experts.
Methods In total, 17 questionnaires on TACE refractoriness were administered to 161 clinicians via an online survey. Multiple answers were allowed for some questions.
Results Most clinicians agreed that there is a need for standardization of TACE application through specific scoring systems (n=124, 77.0%). TACE refractoriness was predominantly expected by participants when recurrences were detected within 1 month (n=70, 43.5%), there were 4 to 6 tumors (n=77, 47.8%), the maximal tumor size was 3–5 cm (n=49, 30.4%), and when there was insufficient tumor necrosis despite TACE being repeated more than three times (n=78, 48.4%). Overall, sorafenib therapy (n=137) and radiotherapy (n=114) were preferred when repeated TACE was considered ineffective.
Conclusions Treatment of HCC is often based on the clinical judgment of clinicians because of the heterogeneity among individuals. Experts need to continue discussions on the standardization and sub-classification of HCC treatment guidelines in Korea.
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The liver is one of the most common sites to which malignancies preferentially metastasize. Although a substantial number of liver malignancies are primary tumors, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma, the metastasis of carcinomas to the liver is relatively common and frequently encountered in clinical settings. Representative carcinomas that frequently metastasize to the liver include colorectal carcinoma, breast carcinoma, neuroendocrine tumors, lung carcinoma, and gastric carcinoma. The diagnostic confirmation of suspected metastatic lesions in the liver is generally achieved through a histopathologic examination of biopsy tissues. Although morphology is the most important feature for a pathologic differential diagnosis of metastatic carcinomas, immunohistochemical studies facilitate the differentiation of metastatic carcinoma origins and subtypes. Useful immunohistochemical markers for the differential diagnosis of metastatic carcinomas in the liver include cytokeratins (CK7, CK19, and CK20), neuroendocrine markers (CD56, synaptophysin, and chromogranin A), and tissue-specific markers (CDX2, SATB2, TTF-1, GCDFP-15, mammaglobin, etc.). Here, we provide a brief review about the pathologic differential diagnosis of major metastatic carcinomas in the liver.
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Backgound/Aims - We compared the accuracy in the diagnosis of hepatic masses such as hepatocellular carcinoma (HCC), metastasis and hemangioma using enhancing pattern alone with using additional findings, and determined whether the additional findings could improve the diagnostic accuracy. M ethods/Materials Triphasic spiral CT images were retro- spectively analyzed in 83 cases of hepatic lesions,' 40 HCC, 21 metastases, and 22 hemangiomas. Three observers made the diagnosis first by the enhancement pattern of the mass alone, and then, by the whole information. The diagnosis of a lesion was considered correct if the lesion was correctly categorized by at least two observers. Diagnostic accuracies of two sessions were compared with McNemar test. Results - Using enhancing patterns alone, 31/40 HCC (78%), 8/21 metastases (38%), 21/22 hemangiomas (95%) were correctly diagnosed. The frequency of correct diagnosis was significantly improved when all images with additional findings were used: 36/40 (90%) HCC, 20/21 (95%) metastases, 22/22 (100%) hemangiomas (P=0.00006). Metastasis showed most prominent and statistically significant improvement in the diagnostic accuracy (P=0.0004). The number of correct diagnoses for HCC increased without statistical significance (P=0.17). However, the images with additional findings did not significantly contribute to the diagnosis of hemangiomas. The additional finidngs those led to correct diagnosis of metastases were multiple mass (7 cases), coexistence of primary malignancy (6 cases), and metastasis to other organ (1 case). The findings of liver cirrhosis were helpful to diagnose HCC correctly in 5 cases. Conclusion- The enhancing pattems of tumors were important in the diagnosis of hepatic masses in spiral CT. However, the additional finidngs were also helpful for the diagnosis of hepatic masses especially for the masses with atypical enhancement pattern. In metastases, the additional findings such as multiple masses or detection of primary malignant focus were useful to diagnose correctly. (Korean J Hepatol 1998;8:23 - 32)
Needle tract implantation of hepatocellular carcinoma (HCC) is a rare complication of percutaneous biopsy,
and it is largely associated with end-cutting needles or aspiration biopsy. The CT findings that have been
reported include oval or round soft tissue nodules with persistent contrast enhancement along the needle tract,
mostly in the subcutaneous tissue or the intercostal muscle layers. In this report, we describe a case of needle
tract implantation of HCC after US-guided percutaneous biopsy with an 18G tru-cut needle. (Korean J
Hepatol 2006;12:439-443)
Background/Aims Positron emission tomography (PET) is an imaging technique reflecting cellular metabolism. However, the feasibility of PET in the diagnosis of hepatocellular carcinoma (HCC) is limited because of vague accuracy and high cost. The aim of this study was to evaluate the diagnostic accuracy of 18F-FDG-PET in detection of HCC. Methods: We retrospectively studied HCC patients who underwent 18F- FDG-PET between June 2001 and February 2005 in Korea National Cancer Center. Thirty-two patients were enrolled and HCC status of these patients were verified by surgical pathology or clinical course using imaging studies (CT, MRI or angiography) within 3 months after PET. PET studies were read by 2 specialists for nuclear medicine and determined as malignant when its standardized uptake value (SUV) was over 2.5. Results: HCC was suspected in 21 out of 32 cases on 18F-FDG-PET. On follow-up, 2 of 21 cases were determined false-positive. In cases of 11 patients without evidence of HCC on 18F-FDG-PET, 10 patients were found to have HCC on follow-up. Thus, the sensitivity and specificity of 18F-FDG-PET were 65.5% and 33.3% respectively. The positive predictive value was 90.5%. The diagnostic accuracy was 62.5%. Conclusion: 18F- FDG-PET showed a low accuracy in diagnosis of HCC. Therefore, 18F-FDG-PET has a limited role in a staging and detection of occult HCC. (Korean J Hepatol 2006;12:546-552)
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