Non-cirrhotic Hepatocellular Carcinoma Research Articles

Role of Imaging in Screening for Hepatocellular Carcinoma.

Primary liver cancer is among the most common cancers globally. It is the sixth-most common malignancy encountered and the third-most common cause of cancer-related death. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, accounting for about 90% of primary liver cancers. The majority of HCCs occur in patients with underlying cirrhosis, which results from chronic liver diseases such as fatty liver, hepatitis B and hepatitis C infections, and chronic alcohol use, which are the leading causes. The obesity pandemic has led to an increased prevalence of nonalcoholic fatty liver disease (NAFLD), which leads to nonalcoholic steatohepatitis and could progress to cirrhosis. As HCC is among the most common cancers and occurs in the setting of chronic liver disease in most patients, screening the population at risk could help in early diagnosis and management, leading to improved survival. Screening for HCC is performed using biochemical marker testing such as α-fetoprotein (AFP) and cross-sectional imaging. It is critical to emphasize that HCC could potentially occur in patients without cirrhosis (non-cirrhotic HCC), which can account for almost 20% of all HCCs. The lack of cirrhosis can cause a delay in surveillance, which could potentially lead to diagnosis at a later stage, worsening the prognosis for such patients. In this article, we discuss the diagnosis of cirrhosis in at-risk populations with details on the different modalities available for screening HCC in patients with cirrhosis, emphasizing the role of abdominal ultrasounds, the primary imaging modality in HCC screening.

Changes in Incidence of Cirrhotic and Noncirrhotic Hepatocellular Carcinoma in the United States

IntroductionHepatocellular carcinoma (HCC) occurs most often in a background of cirrhosis. Patients with noncirrhotic HCC represent a distinct population, which has been characterized in single-center studies, but has not been fully evaluated on a population level in the United States. Materials and methodsHCC cases from Surveillance, Epidemiology, and End-Results diagnosed between 2000 and 2020 were categorized as cirrhotic or noncirrhotic. Clinical and pathologic factors, age-adjusted incidence rates (AAIR), and the overall HCC-specific survival were compared between groups. ResultsThere were 18,592 patients with cirrhosis (80.4%) and 4545 without (19.6%). AAIRs for noncirrhotic HCC remained relatively unchanged from 2010 to 2020, with a mean incidence of 0.35 per 100,000. The AAIR for cirrhotic HCC declined from 1.59 to 0.85 per 100,000 during the same period. Patients with cirrhosis were younger (median age 62 versus 65 y, P < 0.001). Patients without cirrhosis, compared to those with cirrhosis, were less likely to have elevated alpha fetoprotein (53.9% versus 62.0%, P < 0.001), had larger tumors (median tumor size 5.0 versus 3.5 cm, P < 0.001), presented more frequently with localized disease (59.9% versus 55.8%, P < 0.001), were more likely to undergo surgery (OR 2.21, 95% CI 2.07-2.36), and had better HCC-specific survival (median 40 versus 27 mo, P < 0.001). ConclusionsThe relative increase in the proportion of noncirrhotic HCC in the Untied States may be due to a decline in the incidence of cirrhotic HCC. Patients with noncirrhotic HCC have larger tumors, are more likely to undergo surgical resection, and have improved cancer-specific survival.

Lower hepatocellular carcinoma surveillance in metabolic dysfunction-associated steatotic liver disease: Impact on treatment eligibility.

This study aimed to compare the determinants and impact of hepatocellular carcinoma (HCC) surveillance rates for people with metabolic dysfunction-associated steatotic liver disease (MASLD) versus other chronic liver diseases. A dataset of HCC patients from a UK hospital (2007-2022) was analyzed. The Mann-Whitney U-test compared continuous variables. The χ2 and two-tailed Fisher exact tests compared categorical data. Regression modeling analyzed the impact of MASLD on the size and number of HCC nodules and curative treatment. The Cox proportional hazards model assessed the influence of MASLD on overall survival. A total of 176 of 687 (25.6%) HCC patients had MASLD. Fewer people with MASLD HCC were enrolled in HCC surveillance compared to non-MASLD HCC (38 [21.6%] vs 215 [42.1%], P<0.001). Patients with MASLD HCC were less likely to have been under secondary care (n=57 [32.4%] vs 259 [50.7%], P<0.001) and less likely to have cirrhosis (n=113 [64.2%] vs 417 [81.6%], P<0.001). MASLD was associated with a 12.3-mm (95% confidence interval [CI] 10.8-14.0mm) greater tumor diameter compared to people without MASLD (P=0.002). Patients with MASLD HCC had 0.62 reduced odds (95% CI 0.43-0.91) of receiving curative treatment compared to non-MASLD HCC (P=0.014). Overall survival was similar for patients with MASLD HCC versus non-MASLD HCC (hazard ratio 1.03, 95% CI 0.85-1.25, P=0.748). Patients with MASLD are less likely to have been enrolled in HCC surveillance due to undiagnosed cirrhosis or presenting with non-cirrhotic HCC. Patients with MASLD HCC present with larger tumors and are less likely to receive curative treatment.

Comparison between patient characteristics, aetiology and outcomes in patients with and without cirrhosis with hepatocellular carcinoma diagnosed in a regional centre

IntroductionHepatocellular carcinoma (HCC) is increasing in incidence across the UK. Most patients have underlying cirrhosis, but a significant minority do not. Progression and outcomes of HCC in patients without cirrhosis...

LncRNA DERCNC in Hepatocellular Carcinoma with Cirrhosis Aggravates Tumor Proliferation by Targeting SOX9.

This study aims to understand the role of cirrhosis in promoting hepatocellular carcinoma (HCC) progression by analyzing the differential expression of long noncoding RNAs (lncRNAs) between cirrhotic hepatocellular carcinoma (CHCC) and noncirrhotic hepatocellular carcinoma (NCHCC). A transcriptional profile array was used to identify differentially expressed lncRNAs. Subsequently, a specific lncRNA was selected to evaluate the clinical significance, potential functions, regulatory targets, and pathways through both in vitro and in vivo experiments. The study identified a lncRNA, which we termed DERCNC, an acronym for Differentially Expressed RNA between Cirrhotic and Non-Cirrhotic HCC. DERCNC was significantly more highly expressed in CHCC than in NCHCC. Clinically, elevated levels of DERCNC expression were positively correlated with both the cirrhotic state and tumor stage and inversely correlated with tumor differentiation. Furthermore, high expression of DERCNC was associated with a poor prognosis for patients. Conditioned medium from the hepatic stellate cell (LX2) was found to enhance DERCNC expression, SOX9 expression, and tumor proliferation. Overexpression of DERCNC similarly promoted tumor proliferation and increased SOX9 levels. Conversely, DERCNC silencing resulted in the opposite effects. Moreover, the pro-proliferative function of DERCNC was reversible through the modulation of SOX9 expression. Further mechanistic studies revealed that DERCNC upregulated SOX9 by increasing the enrichment of H3K27ac modifications near the SOX9 promoter. In conclusion, DERCNC expression in CHCC has significant clinical implications and can aggravate tumor proliferation by targeting SOX9. This represents a novel mechanism by which cirrhosis promotes tumor progression.

The TGF-β1 target WISP1 is highly expressed in liver cirrhosis and cirrhotic HCC microenvironment and involved in pro- and anti-tumorigenic effects

IntroductionWNT1-inducible signalling pathway protein 1 (WISP1) promotes progression of several tumor entities often correlating with worse prognosis. Here its expression regulation and role in the progression of chronic liver diseases (CLD) was investigated. MethodsWISP1 expression was analyzed in human HCC datasets, in biopsies and serum samples and an HCC patient tissue microarray (TMA) including correlation to clinicopathological parameters. Spatial distribution of WISP1 expression was determined using RNAscope analysis. Regulation of WISP1 expression was investigated in cytokine-stimulated primary mouse hepatocytes (PMH) by array analysis and qRT-PCR. Outcome of WISP1 stimulation was analyzed by IncuCyte S3-live cell imaging, qRT-PCR, and immunoblotting in murine AML12 cells. ResultsIn a TMA, high WISP1 expression was positively correlated with early HCC stages and male sex. Highest WISP1 expression levels were detected in patients with cirrhosis as compared to healthy individuals, patients with early fibrosis, and non-cirrhotic HCC in liver biopsies, expression datasets and serum samples. WISP1 transcripts were predominantly detected in hepatocytes of cirrhotic rather than tumorous liver tissue. High WISP1 expression was associated with better survival. In PMH, AML12 and HepaRG, WISP1 was identified as a specific TGF-β1 target gene. Accordingly, expression levels of both cytokines positively correlated in human HCC patient samples. WISP1-stimulation induced the expression of Bcl-xL, PCNA and p21 in AML12 cells. ConclusionsWISP1 expression is induced by TGF-β1 in hepatocytes and is associated with cirrhotic liver disease. We propose a crucial role of WISP1 in balancing pro- and anti-tumorigenic effects during premalignant stages of CLD.

Comparison of Characteristics and Survival of New-Onset Hepatocellular Carcinomas With or Without Cirrhosis in a Tertiary Center.

Although hepatocellular carcinoma (HCC) usually develops in cirrhotic livers, HCCs could also arise in non-cirrhotic livers. We aimed to compare the characteristics and survival of cirrhotic- and non-cirrhotic HCCs. Data of HCC patients between 2011 and 2021 in a single tertiary center was evaluated retrospectively. Demographic, clinical, laboratory, tumoral and pathological features, and survival outcomes of cirrhotic and non-cirrhotic HCCs were compared. The study included 188 HCC patients. Median age was 64 (26-92) years and similar for study groups (P = .208). Both groups had similar male/female ratio. Forty-two patients (22.3%) had HCC in non-cirrhotic liver. Non-cirrhotic HCCs had similar tumor differentiation type, radiological characteristics, Milan, University of California San Francisco, and the Barcelona Clinic Liver Cancer stages, but more unifocal lesion (78.6% vs. 59.6%) and larger tumor size (89.5 (16-240) mm vs. 59.0 (12-290) mm) at presentation compared to non-cirrhotic HCCs. Despite larger tumor size, non-cirrhotic HCC patients had better overall, disease-free and progression-free survival rates than cirrhotic HCCs. Overall survivals for 1 and 3 years were 71.4% and 49.7% for non-cirrhotic and 54% and 28.3% for cirrhotic HCCs, respectively (P = .035). According to Cox analyses, Eastern Cooperative Oncology Group score (P <.001, hazards ratio (HR): 4.05) and curative treatments (P < .001, HR: 0.21) were predictive for overall survival in cirrhotic HCCs. Curative treatment (P = .027, HR: 0.31) was found to be a significant predictor for overall survival in non-cirrhotic HCCs. Vascular invasion was the only independent predictor for disease-free survival (HR: 2.62, 95% CI 1.01-6.93, P = .049) for non-cirrhotic HCCs. Despite larger tumor size and similar tumor stages, compared to cirrhotic HCCs, non-cirrhotic HCCs were associated with better survival outcomes.

Cryptogenic non-cirrhotic HCC: Clinical, prognostic and immunologic aspects of an emerging HCC etiology

The incidence of hepatocellular carcinoma (HCC) in non-cirrhotic livers is rising significantly, but clear risk factors for screening remain elusive. This study sought to characterize non-cirrhotic HCC etiologies. HCC cases from 2009 to 2020 in a Dutch referral center were examined, revealing 371 out of 1654 cases (22%) as non-cirrhotic. Notably, the incidence of non-cirrhotic HCC increased by 61% in the time frame between 2009 and 2020. Interestingly 39% of non-cirrhotic HCC cases had cryptogenic origins. Cryptogenic non-cirrhotic HCC exhibited similarities with non-cirrhotic NAFLD HCC, but displayed advanced tumor stages, lower surgical rates, and a more frequent presence of symptoms, which substantiated in poor survival rates. Advanced cryptogenic non-cirrhotic HCC stages exhibited elevated serum interleukin-6 levels compared to non-cirrhotic HCC with defined etiologies. Comparative analysis encompassing cryptogenic and NAFLD non-cirrhotic HCC cohorts and controls unveiled comparable circulating immune biomarker profiles and PNPLA3 polymorphisms. To conclude, the primary etiology of non-cirrhotic HCC in our cohort has not defined risk factors. This cryptogenic variant exhibits distinct traits, such as advanced tumors and increased symptoms, and most resemble burned-out NAFLD. Understanding this HCC variant is crucial for improving screening and management strategies.

Non-cirrhotic hepatocellular carcinoma has a distinct metabolomic fingerprint in a Sub-Saharan African cohort: are we looking at a different disease?

Non-cirrhotic hepatocellular carcinoma has a distinct metabolomic fingerprint in a Sub-Saharan African cohort: are we looking at a different disease?

Hypermethylation of DNA Methylation Markers in Non-Cirrhotic Hepatocellular Carcinoma.

Aberrant DNA methylation changes have been reported to be associated with carcinogenesis in cirrhotic HCC, but DNA methylation patterns for these non-cirrhotic HCC cases were not examined. Therefore, we sought to investigate DNA methylation changes on non-cirrhotic HCC using reported promising DNA methylation markers (DMMs), including HOXA1, CLEC11A, AK055957, and TSPYL5, on 146 liver tissues using quantitative methylation-specific PCR and methylated DNA sequencing. We observed a high frequency of aberrant methylation changes in the four DMMs through both techniques in non-cirrhotic HCC compared to cirrhosis, hepatitis, and benign lesions (p < 0.05), suggesting that hypermethylation of these DMMs is specific to non-cirrhotic HCC development. Also, the combination of the four DMMs exhibited 78% sensitivity at 80% specificity with an AUC of 0.85 in discriminating non-cirrhotic HCC from hepatitis and benign lesions. In addition, HOXA1 showed a higher aberrant methylation percentage in non-cirrhotic HCC compared to cirrhotic HCC (43.3% versus 13.3%, p = 0.039), which was confirmed using multivariate linear regression (p < 0.05). In summary, we identified aberrant hypermethylation changes in HOXA1, CLEC11A, AK055957, and TSPYL5 in non-cirrhotic HCC tissues compared to cirrhosis, hepatitis, and benign lesions, providing information that could be used as potentially detectable biomarkers for these unusual HCC cases in clinical practice.

Development and Validation of a Novel Prognosis Model Based on a Panel of Three Immunogenic Cell Death-Related Genes for Non-Cirrhotic Hepatocellular Carcinoma.

The accurate prediction of non-cirrhotic hepatocellular carcinoma (NCHCC) risk facilitates improved surveillance strategy and decreases cancer-related mortality. This study aimed to explore the correlation between immunogenic cell death (ICD) and NCHCC prognosis using The Cancer Genome Atlas (TCGA) datasets, and the potential prognostic value of ICD-related genes in NCHCC. Clinical and transcriptomic data of patients with NCHCC patients were retrieved from TCGA database. Weighted gene co-expression network analysis was performed to obtain the NCHCC phenotype-related module genes. Consensus clustering analysis was performed to classify the patients into two clusters based on intersection genes among differentially expressed genes (DEGs) between cancer and adjacent tissues, NCHCC phenotype-related genes, and ICD-related genes. NCHCC-derived tissue microarray was used to evaluate the correlation of the expression levels of key genes with NCHCC prognosis using immunohistochemical staining. Cox regression analyses were performed to construct a prognostic risk score model comprising three genes (TMC7, GRAMD1C, and GNPDA1) based on DEGs between two clusters. The model stratified patients with NCHCC into two risk groups. The overall survival (OS) of the high-risk group was significantly lower than that of the low-risk group. Univariable and multivariable Cox regression analyses revealed that these signature genes are independent predictors of OS. Functional analysis revealed differential immune status between the two risk groups. Next, a nomogram was constructed, which demonstrated the potent distinguishing ability of the developed model based on receiver operating characteristic curves. In vitro functional validation revealed that the migration and invasion abilities of HepG2 and Huh7 cells were upregulated upon GRAMD1C knockdown but downregulated upon TMC7 knockdown. This study developed a prognostic model comprising three genes, which can aid in predicting the survival of patients with NCHCC and guide the selection of drugs and molecular markers for NCHCC.

SEER-based risk stratification system for patients with primary non-cirrhotic liver cancer

BackgroundLittle research has been done on the factors affecting the survival of patients with non-cirrhotic hepatocellular carcinoma (HCC-NCL). Our aim was to develop and validate a nomogram and a new risk stratification system that can evaluate overall survival (OS) in HCC-NCL patients.MethodsWe retrospectively analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2019 to study HCC-NCL patients. The patients were randomly split into training and validation groups at a 7:3 ratio and subjected to single-factor and multi-factor COX regression analysis. We then developed a nomogram and evaluated its accuracy and clinical validity using time-dependent ROC, DCA, and calibration curves. We compared the nomogram with the AJCC staging system by calculating C-index, NRI, and IDI. Finally, we used Kaplan–Meier curves to compare the nomogram and AJCC staging. These analyses were performed without altering the original intended meaning.ResultsAFP levels, surgical intervention, T-stage, tumor size, and M-stage were independent prognostic indicators for overall survival among the HCC-NCL population studied. We developed a nomogram based on these factors, and time-dependent ROC, calibration curves, DCA analyses, and C-index proved its accuracy. Compared to the AJCC staging system, the nomogram showed better prognostic accuracy through time-dependent ROC, DCA analyses, C-index, NRI, IDI, and Kaplan–Meier curves.ConclusionWe have developed and validated a survival nomogram applicable to HCC-NCL patients, with risk stratification. Our nomogram offers personalized treatment and management options superior to those provided by the AJCC staging system.

FRI-291 - Cryptogenic non-cirrhotic HCC: clinical, prognostic and immunologic aspects of an emerging HCC etiology

FRI-291 - Cryptogenic non-cirrhotic HCC: clinical, prognostic and immunologic aspects of an emerging HCC etiology

Abstract 4369: The effects of primary hepatocellular carcinoma surgical resection on five year survival rates among different races

Abstract Background: Hepatic surgical resection is the treatment of choice for noncirrhotic HCC patients. Previous studies indicate that Asian patients were proportionally more likely to be treated surgically. However, studies on the outcome of this preference are very limited. Methods:We examined data from the Surveillance, Epidemiology and End Results (SEER)-Medicare database to identify patients diagnosed with HCC between 2004 and 2017.The disease specific and relative five year survival rates as well as 95% Cl were calculated. Results:Among the total of 6,716 Asian or Pacific Islander (A/P) patients diagnosed with localized HCC, 45.9% of them received surgical resection. The localized HCC surgical resection rates for White (27,360 total cases) and Black (4,546 total cases) were 35.6% and 33.1% respectively. This pattern remained the same for patients with regional and distant site involved HCC: Highest percentage of A/P patients received surgical resections. For patients with localized HCC, five year cause specific survival rate was statistically higher for A/P patients than White and Black (P&amp;lt;0.05) 24 months after the surgery. These trends continued until the end of the study. For patients with regional HCC, surgical resection played no significant role for the five year cause specific survival rate among the different races. However, for patients with distant involved HCC, five year cause specific survival gap between White and A/P gradually increased after surgery and reached a statistically significant level on month 48 (23.9% with 95% CI 18.6% to 29.6% for White and 9.7% with 95% CI 4.4% to 17.5% for A/P). The pattern remained the same between Black and A/P patients without statistical significance, most likely due to the limited sample size for both.. Our research also indicated that surgical resection may play a similar role for the five year relative survival rate. After localized HCC surgical resection, A/P patients had the highest five year relative survival rate compared to White and Black patients (P&amp;lt;0.05). For the patients with regional HCC, surgical resection played no significant role on five year relative survival rate among different races. However, for the patients diagnosed with distant involved HCC, five year relative survival gap between White and A/P gradually increased after surgery and reached a statistically significant level on month 48 (23.7% with 95% CI 18.3% to 29.4% for White and 10.5% with 95% CI 5.2% to 18.0% for A/P). The pattern remained the same between Black and A/P patients without statistical significance due to the limited sample size in both categories. Conclusion: A/P primary HCC patients were more likely to be treated surgically. However, the benefits of surgical resection for A/P patients can only be appreciated for those with localized HCC. For A/P patients diagnosed with distant site node involved HCC, surgical resection may cause more harm than good. Citation Format: Jingwei Song, Eric Song, Daniel Gharavi. The effects of primary hepatocellular carcinoma surgical resection on five year survival rates among different races. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4369.

Prognostication algorithm for non-cirrhotic non-B non-C hepatocellular carcinoma-a multicenter study under the aegis of the French Association of Hepato-Biliary Surgery and liver Transplantation.

Liver resection and local ablation are the only curative treatment for non-cirrhotic hepatocellular carcinoma (HCC). Few data exist concerning the prognosis of patients resected for non-cirrhotic HCC. The objectives of this study were to determine the prognostic factors of recurrence-free survival (RFS) and overall survival (OS) and to develop a prognostication algorithm for non-cirrhotic HCC. French multicenter retrospective study including HCC patients with non-cirrhotic liver without underlying viral hepatitis: F0, F1 or F2 fibrosis. A total of 467 patients were included in 11 centers from 2010 to 2018. Non-cirrhotic liver had a fibrosis score of F0 (n=237, 50.7%), F1 (n=127, 27.2%) or F2 (n=103, 22.1%). OS and RFS at 5 years were 59.2% and 34.5%, respectively. In multivariate analysis, microvascular invasion and HCC differentiation were prognostic factors of OS and RFS and the number and size were prognostic factors of RFS (P<0.005). Stratification based on RFS provided an algorithm based on size (P=0.013) and number (P<0.001): 2 HCC with the largest nodule ≤10 cm (n=271, Group 1); 2 HCC with a nodule >10 cm (n=176, Group 2); >2 HCC regardless of size (n=20, Group 3). The 5-year RFS rates were 52.7% (Group 1), 30.1% (Group 2) and 5% (Group 3). We developed a prognostication algorithm based on the number (≤ or >2) and size (≤ or >10 cm), which could be used as a treatment decision support concerning the need for perioperative therapy. In case of bifocal HCC, surgery should not be a contraindication.

Hepatocellular Carcinoma in Cirrhotic Versus Noncirrhotic Livers: Clinicomorphologic Findings and Prognostic Factors.

Hepatocellular carcinoma mostly develops in a cirrhotic (80%) background. The clinical features of cirrhotic hepatocellular carcinoma and non-cirrhotic hepatocellular carcinoma also differ. We aimed to determine the clinicopathologic features, tumor characteristics, treatment options, and overall survival after diagnosing hepatocellular carcinoma and prognostic factors effective on survival of hepatocellular carcinoma developing in cirrhotic and non-cirrhotic conditions. In our study, 220 patients aged over 18 years who were histologically diagnosed as having hepatocellular carcinoma were included. The patients were divided into 2 groups as cirrhotic and non-cirrhotic. When the tumor morphologies were examined in our study, it was observed that they were mostly solitary in both groups. Cirrhotic hepatocellular carcinomas had significantly higher rates of invasion than the non-cirrhotic group (35.3% vs. 20.3%, respectively) (P <.05). The survival rate was found to be better in the non-cirrhotic group (17.5 months vs. 11.5 months) (P <.05). Age, maximal tumor diameter, and morphologically infiltrative tumor character were found to be independent risk factors affecting survival in patients with cirrhosis. Portal vein invasion, alfa-fetoprotein, and the absence of an underlying risk factor in the etiology were observed as independent risk factors affecting survival in patients with non-cirrhosis. Cirrhotic hepatocellular carcinoma and non-cirrhotic hepatocellular carcinoma had different clinicopathologic features and risk factors. We analyzed that treatment choice trends were different between the 2 groups. We also observed that the factors that affected survival were different between the 2 groups.

Mixed Hepatocellular Cholangiocarcinoma: A Comparison of Survival between Mixed Tumors, Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma from a Single Center.

Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy, followed by intrahepatic cholangiocarcinoma (ICC). In addition, there is a mixed form for which only limited data are available. The aim of this study was to compare recurrence and survival of the mixed form within the cohorts of patients with HCC and ICC from a single center. Between January 2008 and December 2020, all patients who underwent surgical exploration for ICC, HCC, or mixed hepatocellular cholangiocarcinoma (mHC-CC) were included in this retrospective analysis. The data were analyzed, focusing on preoperative and operative details, histological outcome, and tumor recurrence, as well as overall and recurrence-free survival. A total of 673 surgical explorations were performed, resulting in 202 resections for ICC, 344 for HCC (225 non-cirrhotic HCC, ncHCC; 119 cirrhotic HCC, cHCC), and 14 for mHC-CC. In addition, six patients underwent orthotopic liver transplant (OLT) in the belief of dealing with HCC. In 107 patients, tumors were irresectable (resection rate of 84%). Except for the cHCC group, major or even extended liver resections were required. Vascular or visceral extensions were performed regularly. Overall survival (OS) was highly variable, with a median OS of 17.6 months for ICC, 26 months for mHC-CC, 31.8 months for cHCC, and 37.2 months for ncHCC. Tumor recurrence was common, with a rate of 45% for mHC-CC, 48.9% for ncHCC, 60.4% for ICC, and 67.2% for cHCC. The median recurrence-free survival was 7.3 months for ICC, 14.4 months for cHCC, 16 months for mHC-CC, and 17 months for ncHCC. The patients who underwent OLT for mHC-CC showed a median OS of 57.5 and RFS of 56.5 months. mHC-CC has a comparable course and outcome to ICC. The cholangiocarcinoma component seems to be the dominant one and, therefore, may be responsible for the prognosis. 'Accidental' liver transplant for mHC-CC within the Milan criteria offers a good long-term outcome. This might be an option in countries with no or minor organ shortage.

Hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis.

Cirrhosis is an emerging major cause of the development of hepatocellular carcinoma (HCC), but in non-alcoholic fatty liver disease (NAFLD), up to 50% of patients with HCC had no clinical or histological evidence of cirrhosis. It is currently challenging to propose general recommendations for screening patients with NAFLD without cirrhosis, and each patient should be evaluated on a case-by-case basis based on the profile of specific risk factors identified. For HCC screening in NAFLD, a valid precision-based screening is needed. Currently, when evaluating this population of patients, the use of non-invasive methods can guide the selection of those who should undergo a screening and surveillance program. Hence, the objective of the present study is to review the epidemiology, the pathophysiology, the histopathological aspects, the current recommendations, and novel perspectives in the surveillance of non-cirrhotic NAFLD-related HCC.

Non-cirrhotic Hepatocellular Carcinoma Has a Distinct Metabolomic Fingerprint in a Sub-Saharan African Cohort: Are We Looking at a Different Disease?

Non-cirrhotic Hepatocellular Carcinoma Has a Distinct Metabolomic Fingerprint in a Sub-Saharan African Cohort: Are We Looking at a Different Disease?

Inflammation and Fibrosis in Patients with Non-Cirrhotic Hepatitis B Virus-Associated Hepatocellular Carcinoma: Impact on Prognosis after Hepatectomy and Mechanisms Involved.

Background: We investigated whether the degree of inflammation and fibrosis in para-carcinoma tissue can predict prognosis of patients with non-cirrhotic hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) after hepatectomy. We also explored the mechanisms through which inflammation and fibrosis might affect prognosis. Methods: Clinicopathological data were retrospectively analyzed from 293 patients with non-cirrhotic HBV-associated HCC who were treated at our institution by curative resection from 2012 to 2017. Based on the Scheuer score system, patients were classified into those showing mild or moderate-to-severe inflammation and fibrosis. Rates of overall and recurrence-free survival were compared between the groups using Kaplan-Meier curves, and survival predictors were identified using Cox regression. Using tumor and para-tumor tissues from independent samples of patients with non-cirrhotic HBV-associated HCC who were treated at our institution by curative resection from 2018 to 2019, we performed next-generation sequencing and time-of-flight cytometry (CyTOF) to examine the influence of inflammation and fibrosis on gene expression and immune cell infiltration. Results: In the analysis of the 293 patients, those with mild inflammation and fibrosis showed significantly better overall and recurrence-free survival than those with moderate-to-severe inflammation and fibrosis. Multivariate Cox regression confirmed that moderate-to-severe inflammation and fibrosis were independent risk factors for worse survival. RNA sequencing and CyTOF showed that more severe inflammation and fibrosis were associated with stronger invasion and migration by hepatocytes. In cancerous tissues, the biological processes of cell proliferation were upregulated, the signaling pathways promoting tumor growth were activated, the proportion of Th17 cells promoting tumor progression was increased, and CD8+ T cells expressed higher levels of PD-L1. In para-cancerous tissues, biological processes of immune response and cell chemotaxis were downregulated, and the proportion of tumor-killing immune cells was decreased. Conclusion: Worse inflammation and fibrosis in non-cirrhotic HBV-associated HCC is associated with worse prognosis, which may reflect more aggressive tumor behavior and an immunosuppressed, pro-metastatic tumor microenvironment.