Hepatocellular Carcinoma Cholangiocarcinoma Research Articles

Is it necessary to distinguish between combined hepatocellular carcinoma-cholangiocarcinoma with less than 10% of cholangiocarcinoma components versus hepatocellular carcinoma?

Is it necessary to distinguish between combined hepatocellular carcinoma-cholangiocarcinoma with less than 10% of cholangiocarcinoma components versus hepatocellular carcinoma?

Context-Dependent Distinct Roles of SOX9 in Combined Hepatocellular Carcinoma-Cholangiocarcinoma.

Combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) is a challenging primary liver cancer subtype with limited treatment options and a devastating prognosis. Recent studies have underscored the context-dependent roles of SOX9 in liver cancer formation in a preventive manner. Here, we revealed that liver-specific developmental Sox9 elimination using Alb-Cre;Sox9(flox/flox) (LKO) and CRISPR/Cas9-based tumor-specific acute Sox9 elimination (CKO) in SB-HDTVI-based Akt-YAP1 (AY) and Akt-NRAS (AN) cHCC-CCA models showed contrasting responses. LKO abrogates the AY CCA region while stimulating poorly differentiated HCC proliferation, whereas CKO prevents AY and AN cHCC-CCA development irrespective of tumor cell fate. Additionally, AN, but not AY, tumor formation partially depends on the Sox9-Dnmt1 cascade. SOX9 is dispensable for AY-mediated, HC-derived, LPC-like immature CCA formation but is required for their maintenance and transformation into mature CCA. Therapeutic Sox9 elimination using the OPN-CreERT2 strain combined with inducible Sox9 iKO specifically reduces AY but not AN cHCC-CCA tumors. This necessitates the careful consideration of genetic liver cancer studies using developmental Cre and somatic mutants, particularly for genes involved in liver development. Our findings suggest that SOX9 elimination may hold promise as a therapeutic approach for a subset of cHCC-CCA and highlight the need for further investigation to translate these preclinical insights into personalized clinical applications.

MR radiomics to predict microvascular invasion status and biological process in combined hepatocellular carcinoma-cholangiocarcinoma

ObjectivesTo establish an MRI-based radiomics model for predicting the microvascular invasion (MVI) status of cHCC-CCA and to investigate biological processes underlying the radiomics model.MethodsThe study consisted of a retrospective dataset (82 in the training set, 36 in the validation set) and a prospective dataset (25 patients in the test set) from two hospitals. Based on the training set, logistic regression analyses were employed to develop the clinical-imaging model, while radiomic features were extracted to construct a radiomics model. The diagnosis performance was further validated in the validation and test sets. Prognostic aspects of the radiomics model were investigated using the Kaplan–Meier method and log-rank test. Differential gene expression analysis and gene ontology (GO) analysis were conducted to explore biological processes underlying the radiomics model based on RNA sequencing data.ResultsOne hundred forty-three patients (mean age, 56.4 ± 10.5; 114 men) were enrolled, in which 73 (51.0%) were confirmed as MVI-positive. The radiomics model exhibited good performance in predicting MVI status, with the area under the curve of 0.935, 0.873, and 0.779 in training, validation, and test sets, respectively. Overall survival (OS) was significantly different between the predicted MVI-negative and MVI-positive groups (median OS: 25 vs 18 months, p = 0.008). Radiogenomic analysis revealed associations between the radiomics model and biological processes involved in regulating the immune response.ConclusionA robust MRI-based radiomics model was established for predicting MVI status in cHCC-CCA, in which potential prognostic value and underlying biological processes that regulate immune response were demonstrated.Critical relevance statementMVI is a significant manifestation of tumor invasiveness, and the MR-based radiomics model established in our study will facilitate risk stratification. Furthermore, underlying biological processes demonstrated in the radiomics model will offer valuable insights for guiding immunotherapy strategies.Key PointsMVI is of prognostic significance in cHCC-CCA, but lacks reliable preoperative assessment.The MRI-based radiomics model predicts MVI status effectively in cHCC-CCA.The MRI-based radiomics model demonstrated prognostic value and underlying biological processes.The radiomics model could guide immunotherapy and risk stratification in cHCC-CCA.Graphical

How to differentiate between combined hepatocellular carcinoma-cholangiocarcinoma and intrahepatic cholangiocarcinoma with rim arterial phase hyperenhancement?

To analyze and compare the differences in MRI features between combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) and intrahepatic cholangiocarcinoma (iCCA) with arterial phase peripheral enhancement, so as to provide valuable references for preoperative differential diagnosis. Seventy cHCC-CCA patients and 74 iCCA patients confirmed by pathology were included in this study. Their contrast-enhanced MRI showed rim arterial phase hyperenhancement (Rim APHE). The differences of clinicopathological data and MRI features between cHCC-CCA and iCCA were compared. Then, the sensitivity, specificity, and area under curve (AUC) were also analyzed and compared. Seventy cHCC-CCA patients (mean age, 55.7 ± 10.6years) and 74 iCCA patients (mean age, 61.1 ± 10.5years) were evaluated. In this study, univariable and multivariable regression analysis showed that AFP > 20ng/ml (OR = 5.824, p = 0.006), enhancing capsule (OR = 7.252, p = 0.001), and mosaic architecture (OR = 32.732, p < 0.001) were independent risk factors of cHCC-CCA with Rim APHE. However, only hepatic capsule retraction (OR = 0.091, p < 0.001) was an independent predictor of iCCA. In addition, combining AFP > 20ng/ml with enhancing capsule (96.7% vs. 79.2%, p < 0.001) and/or mosaic architecture (96.4% vs. 94.7%, p < 0.001) can improve the sensitivity of differentiating cHCC-CCA (vs. iCCA) with Rim APHE. The combination of elevated AFP and MRI features, such as enhancing capsule and mosaic architecture, will help in preoperative differential diagnosis of cHCC-CCA and iCCA with Rim APHE.

Component prediction in combined hepatocellular carcinoma-cholangiocarcinoma: habitat imaging and its biologic underpinnings.

To construct an MRI-based habitat imaging model to help predict component percentage in combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) preoperatively, and investigate the biologic underpinnings of habitat imaging in cHCC-CCA. The study consisted of one retrospective model-building dataset and one prospective validation dataset from two hospitals. All voxels were assigned into different clusters according to the similarity of enhancement pattern by using K-means clustering method, and each habitat's volume fraction in each lesion was calculated. Least absolute shrinkage and selection operator (LASSO) regression analysis was performed to select optimal predictors, and then to establish an MRI-based habitat imaging model. R-squared was calculated to evaluate performance of the prediction models. Model performance was also verified in the prospective dataset with RNA sequencing data, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was then applied to investigate the biologic underpinnings of habitat imaging. A total of 129 patients were enrolled (mean age, 56.1 ± 10.4, 102 man), among which 104 patients were in the retrospective model-building set, while 25 patients in the prospective validation set. Three habitats, habitat1 (HCC-alike habitat), habitat2 (iCCA-alike habitat), and habitat3 (in-between habitat), were identified. Habitat 1's volume fraction, habitat 3's volume fraction, nonrim APHE, nonperipheral washout, and LI-RADS categorization were selected to develop an HCC percentage prediction model with R-squared of 0.611 in the model-building set and 0.541 in the validation set. Habitat 1's volume fraction was correlated with genes involved in regulation of actin cytoskeleton and Rap1 signaling pathway, which regulate cell migration and tumor metastasis. Preoperative prediction of HCC percentage in patients with cHCC-CCA was achieved using an MRI-based habitat imaging model, which may correlate with signaling pathways regulating cell migration and tumor metastasis.

Characterization of outcomes and genomic alterations (GA) in combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA).

458 Background: Hepatobiliary cancers comprise a heterogeneous spectrum of invasive carcinomas involving the liver and bile ducts. Due to its rarity, the prognosis and clinical outcomes data are poorly understood. This study aims to provide insight into the response to therapeutic options and GA in patients (pts) with cHCC-CCA. Methods: We conducted a retrospective analysis of clinical outcomes data and GA at MD Anderson (MDA) from 2009 to 2023 in pts with cHCC-CCA. Pt characteristics were compared using Fisher’s exact test and Mann-Whitney U. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier and the log-rank test. Results: 40 pts with cHCC-CCA were analyzed. Hepatitis B and C were the most common etiologies (Table). 25.0% had portal vein tumor thrombus and 72.0% had advanced disease (M1/N1) at diagnosis. Radiographic washout was seen in 55.9%. Elevation of CA19-9, AFP, and both was in 42.5, 57.5, and 30.0%. Cirrhosis at diagnosis was 35.0%. Pts who underwent surgery (n=10) had significant OS benefit (55.6 vs. 14.1 m, p&lt;0.001). Y90 (n=4)/radiation therapy (n=10) provided significant OS benefit in pts who did not undergo surgery (23.3 vs 10.9 m; p=0.012). 34 pts received 1st line systemic therapy: 10 pts received gemcitabine/cisplatin (GC) combined with immunotherapy (GCI): GC + nivolumab (n=5), durvalumab (n=3), or atezolizumab/bevacizumab (AB, n=2). GCI was compared to other regimens (OR, n=24) including chemotherapy alone (GC, FOLFIRI, FOLFOX), HCC-directed therapy alone (AB, lenvatinib, nivolumab), or chemotherapy plus lenvatinib or bevacizumab with mPFS of 7.0 vs. 2.9 m (p=0.014) showing significant PFS benefit. Pts who received GCI trended to better OS compared to OR (18.9 vs. 12.0 m, p=0.380). 2 pts treated with GC+AB had complete responses to date at 36.0 and 14.0 m. Of 31 pts who underwent GA testing, the 2 most frequent GAs were TP53 (38.7%) and TERT (35.5%) mutations. Neither impacted OS: TP53 15.8 vs. 17.6 m (p=0.746); TERT 9.8 vs. 23.3 m (p=0.355). Conclusions: GCI had survival benefit compared to OR in cHCC-CCA. Pts who present with early stage of disease should be evaluated early for surgical resection or maximize local therapy in the case of nonresectable disease to improve survival. [Table: see text]

Pathology of Combined Hepatocellular Carcinoma-Cholangiocarcinoma: An Update.

Combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer that is composed of both hepatocellular and cholangiocellular differentiated cells. It is slightly more common in men and among Asian and Pacific islanders. Overall, risk factors are similar to classic risk factors of hepatocellular carcinoma (HCC). The classification has significantly evolved over time. The last WHO classification (2019) mainly emphasized diagnosis on morphological basis with routine stainings, discarded previously recognized classifications with carcinomas with stem cell features, introduced intermediate cell carcinoma as a specific subtype and considered cholangiolocarcinoma as a subtype of cholangiocellular carcinoma. Immunohistochemical markers may be applied for further specification but have limited value for diagnosis. Recent discoveries in molecular pathway regulation may pioneer new therapeutic approaches for this poor prognostic and challenging diagnosis.

Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL-6 trans-signaling.

Primary liver cancers include hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCA) and combined HCC-CCA tumors (cHCC-CCA). It has been suggested, but not unequivocally proven, that hepatic progenitor cells (HPCs) can contribute to hepatocarcinogenesis. We aimed to determine whether HPCs contribute to HCC, cHCC-CCA or both types of tumors. To trace progenitor cells during hepatocarcinogenesis, we generated Mdr2-KO mice that harbor a yellow fluorescent protein (YFP) reporter gene driven by the Foxl1 promoter which is expressed specifically in progenitor cells. These mice (Mdr2-KOFoxl1-CRE;RosaYFP) develop chronic inflammation and HCCs by the age of 14-16 months, followed by cHCC-CCA tumors at the age of 18 months. In this Mdr2-KOFoxl1-CRE;RosaYFP mouse model, liver progenitor cells are the source of cHCC-CCA tumors, but not the source of HCC. Ablating the progenitors, caused reduction of cHCC-CCA tumors but did not affect HCCs. RNA-sequencing revealed enrichment of the IL-6 signaling pathway in cHCC-CCA tumors compared to HCC tumors. Single-cell RNA-sequencing (scRNA-seq) analysis revealed that IL-6 is expressed by immune and parenchymal cells during senescence, and that IL-6 is part of the senescence-associated secretory phenotype. Administration of an anti-IL-6 antibody to Mdr2-KOFoxl1-CRE;RosaYFP mice inhibited the development of cHCC-CCA tumors. Blocking IL-6 trans-signaling led to a decrease in the number and size of cHCC-CCA tumors, indicating their dependence on this pathway. Furthermore, the administration of a senolytic agent inhibited IL-6 and the development of cHCC-CCA tumors. Our results demonstrate that cHCC-CCA, but notHCC tumors, originate from HPCs, and that IL-6, which derives in part from cells in senescence, plays an important role in this process via IL-6 trans-signaling. These findings could be applied to develop new therapeutic approaches for cHCC-CCA tumors. Combined hepatocellular carcinoma-cholangiocarcinoma is the third most prevalent type of primary liver cancer (i.e. a cancer that originates in the liver). Herein, we show that this type of cancer originates in stem cells in the liver and that it depends on inflammatory signaling. Specifically, we identify a cytokine called IL-6 that appears to be important in the development of these tumors. Our results could be used for the development of novel treatments for these aggressive tumors.

Alternative lengthening of telomeres in primary hepatic neoplasms

The alternative lengthening of telomeres (ALT) phenotype is characterized by ultra-bright telomeres on fluorescence in situ hybridization (FISH) and is a marker of a unique mechanism of telomere maintenance in tumors. ALT does not occur in normal tissues. ALT has been described in hepatocellular carcinoma (5-10%) and in primary hepatic angiosarcomas (75%). To study the frequency of ALT in other primary hepatic tumors, a wide range of primary hepatic neoplasms were retrieved. The tumors included the following: intrahepatic and hilar cholangiocarcinomas (N=110), hepatic adenomas (N=35), hepatocellular carcinomas (N=30), fibrolamellar carcinomas (n=11), combined cholangiocarcinoma-hepatocellular carcinomas (N=8), carcinosarcoma (N=10), hepatoblastomas (N=5), hemangiomas (N=4), angiosarcomas (N=8), epithelioid hemangioendotheliomas (N=10), calcified nested stromal epithelial tumor (N=2), embryonal sarcoma (N=2), rhabdoid tumor (N=1), bile duct adenoma (N=1), and angiomyolipoma (N=1). For epithelial tumors, ALT-FISH was positive in one carcinosarcoma (10% of cases), one cholangiocarcinoma (1% of cases), and one combined hepatocellular carcinoma-cholangiocarcinoma (13% of cases). In the hepatocellular carcinoma component of both the carcinosarcoma and the combined hepatocellular carcinoma-cholangiocarcinoma, the tumor cells showed patchy marked nuclear pleomorphism akin to that described previously for chromophobe hepatocellular carcinoma, which are typically ALT FISH positive. The ALT-positive cholangiocarcinoma also showed patchy, striking nuclear pleomorphism. For soft tissue tumors, ALT was positive in two angiosarcomas (N=2; 25% of cases). In summary, this study shows that ALT-FISH is positive in rare carcinosarcomas, cholangiocarcinomas, and combined cholangiocarcinoma-hepatocellular carcinoma. ALT is not a significant mechanism of telomere maintenance in hepatocellular adenomas or fibrolamellar carcinomas and was negative in all other tested primary hepatic neoplasms. ALT-FISH is also positive in a subset of primary hepatic angiosarcomas.

Combined hepatocellular carcinoma-cholangiocarcinoma with a predominant HCC component: better survival and MRI-based prediction.

To determine the optimal cutoff value of HCC% for predicting the outcome of patients with combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) and to investigate how preoperative MR features based on the Liver Imaging Reporting and Data System (LI-RADS ver. 2018) are related to the HCC% in cHCC-CCA. The study enrolled 107 patients pathologically confirmed to have single cHCC-CCA according to the 2019 WHO classification. A receiver operating characteristic (ROC) curve was used to find the optimal cutoff value of HCC% based on overall survival (OS). The preoperative MR imaging features and clinicopathological findings were retrospectively evaluated and compared between the high HCC% and low HCC% groups. In total, 107 patients (mean age, males vs. females: 56.6 ± 10.7 years vs. 54.2 ± 12.8 years) were evaluated. Analysis of the relationship between HCC% and OS by ROC curve suggested that the optimal cutoff value was 65%, by which 51 (47.7%) patients were assigned to the high HCC% group. LI-RADS categorization (OR = 3.657, p = 0.006 vs. OR = 4.075, p = 0.004) and serum carcinoembryonic antigen (CEA) >5 ng/mL (OR = 0.348, p = 0.089 vs. OR = 0.298, p = 0.040) were significant predictors for HCC% in cHCC-CCA in both univariate and multivariate analysis. cHCC-CCA patients with HCC components higher than 65% tend to exhibit better overall survival, and MRI-based LI-RADS categorization and serum CEA level are valuable for identifying HCC% in cHCC-CCA preoperatively. • cHCC-CCA patients with HCC components higher than 65% tend to exhibit better overall survival. • MRI-based LI-RADS categorization and serum CEA level were significant predictors for HCC% in cHCC-CCA in both univariate and multivariate analyses and valuable for identifying HCC% in cHCC-CCA preoperatively.

Histopathological components correlated with MRI features and prognosis in combined hepatocellular carcinoma-cholangiocarcinoma.

To distinguish MR features according to different proportions of the histopathological hepatocellular carcinoma (HCC) component and to investigate whether the proportion of the HCC component can predict the prognosis of patients with cHCC-CCA. The study enrolled 106 cHCC-CCA patients confirmed by histopathology. The MR imaging features and clinicopathological findings were retrospectively evaluated and compared between two subgroups with different proportions of the HCC component. The recurrence-free survival (RFS) and overall survival (OS) were evaluated using Kaplan-Meier survival curves and compared using the log-rank test. Moreover, whether the proportion of the HCC component was a predictor of RFS and OS was investigated using Cox regression analyses. The Liver Imaging Reporting and Data System (LI-RADS) category 4/5 was more prevalent in cHCC-CCAs with an HCC component > 50% (odds ratio (OR) = 5.559, p = 0.018), 70% (OR = 4.031, p = 0.008), and 90% (OR = 6.282, p = 0.012) than in those with an HCC component ≤ 50%, 70%, and 90%, respectively. In addition, cHCC-CCAs with an HCC component > 70% (HR: 0.241, p = 0.023) had a better OS prognosis than those with an HCC component ≤ 70%. cHCC-CCAs categorized as LR-4/5 are mainly composed of HCC component, and cHCC-CCAs with an HCC component > 70% are associated with better OS than those with an HCC component ≤ 70%. These findings suggest that the proportion of HCC or CCA component can predict the prognosis of cHCC-CCA patients. • cHCC-CCAs categorized as LR-4/5 are mainly composed of HCC component. • cHCC-CCAs with an HCC component > 70% are associated with better OS than those with an HCC component ≤ 70%.

Interpretation pitfalls in immunohistochemistry of primary liver carcinoma: a retrospective analysis of liver biopsy specimens

Background: The diagnosis of primary liver carcinoma (PLC) primarily relies on routine histopathology with hematoxylin and eosin (H&amp;E) and the supportive evidence of immunohistochemistry (IHC). Inappropriate use of immunostains without either careful histomorphological evaluation or clinical correlation may lead to misdiagnosis and inappropriate patient management. Objective: To retrospectively analyze the interpretation pitfalls in IHC as an adjunct in assessing PLCs in liver biopsy specimens at a tertiary hospital in Thailand. Materials and Methods: The archives of the Division of Pathology, Thammasat University Hospital, were searched between 2015 and 2020 using a search tool from the pathology software system and a combination of codewords, including PLC, hepatocellular carcinoma (HCC), and intrahepatic cholangiocarcinoma (iCCA). Histomorphology of PLCs in liver biopsy specimens and the corresponding immunophenotypes were retrospectively analyzed. Clinical data for each patient was retrieved from the electronic medical record. Results: One hundred fifty-three liver biopsy specimens were retrieved. There were 128 (83.7%) iCCA, 23 (15%) HCC, and 2 (1.3%) combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Six cases (3.9%) with interpretation pitfalls in IHC were analyzed. These pitfalls included incorrect subtyping of PLCs in two cases (1.3%) and PLCs misdiagnosed as metastatic cancers in four cases (2.6%). Conclusion: Interpretation pitfalls in IHC of PLCs were noted in 3.9% of the present study cohorts. Pathologists should be familiar with the histomorphology of PLCs together with their rare variants. Appropriate use of IHC as adjuncts for evaluating PLCs and correlation with clinical details were essential for rendering the correct diagnoses of PLCs. Keywords: Immunohistochemistry; Primary liver carcinoma; Interpretation

Automated machine learning for differentiation of hepatocellular carcinoma from intrahepatic cholangiocarcinoma on multiphasic MRI

With modern management of primary liver cancer shifting towards non-invasive diagnostics, accurate tumor classification on medical imaging is increasingly critical for disease surveillance and appropriate targeting of therapy. Recent advancements in machine learning raise the possibility of automated tools that can accelerate workflow, enhance performance, and increase the accessibility of artificial intelligence to clinical researchers. We explore the use of an automated Tree-Based Optimization Tool that leverages a genetic programming algorithm for differentiation of the two common primary liver cancers on multiphasic MRI. Manual and automated analyses were performed to select an optimal machine learning model, with an accuracy of 73–75% (95% CI 0.59–0.85), sensitivity of 70–75% (95% CI 0.48–0.89), and specificity of 71–79% (95% CI 0.52–0.90) on manual optimization, and an accuracy of 73–75% (95% CI 0.59–0.85), sensitivity of 65–75% (95% CI 0.43–0.89) and specificity of 75–79% (95% CI 0.56–0.90) for automated machine learning. We found that automated machine learning performance was similar to that of manual optimization, and it could classify hepatocellular carcinoma and intrahepatic cholangiocarcinoma with an sensitivity and specificity comparable to that of radiologists. However, automated machine learning performance was poor on a subset of scans that met LI-RADS criteria for LR-M. Exploration of additional feature selection and classifier methods with automated machine learning to improve performance on LR-M cases as well as prospective validation in the clinical setting are needed prior to implementation.

An update on radiomics techniques in primary liver cancers

BackgroundRadiomics is a progressing field of research that deals with the extraction of quantitative metrics from medical images. Radiomic features detention indirectly tissue features such as heterogeneity and shape and can, alone or in combination with demographic, histological, genomic, or proteomic data, be used for decision support system in clinical setting.MethodsThis article is a narrative review on Radiomics in Primary Liver Cancers. Particularly, limitations and future perspectives are discussed.ResultsIn oncology, assessment of tissue heterogeneity is of particular interest: genomic analysis have demonstrated that the degree of tumour heterogeneity is a prognostic determinant of survival and an obstacle to cancer control. Therefore, that Radiomics could support cancer detection, diagnosis, evaluation of prognosis and response to treatment, so as could supervise disease status in hepatocellular carcinoma (HCC) and Intrahepatic Cholangiocarcinoma (ICC) patients. Radiomic analysis is a convenient radiological image analysis technique used to support clinical decisions as it is able to provide prognostic and / or predictive biomarkers that allow a fast, objective and repeatable tool for disease monitoring.ConclusionsAlthough several studies have shown that this analysis is very promising, there is little standardization and generalization of the results, which limits the translation of this method into the clinical context. The limitations are mainly related to the evaluation of data quality, repeatability, reproducibility, overfitting of the model.Trial registration: Not applicable.

Spatial Multiomics Analysis Reveals Only Minor Genetic and Epigenetic Changes in Human Liver Cancer Stem-Like Cells Compared With Other Tumor Parenchymal Cells.

Cancer stem cells (CSCs) usually account for a very small tumor cell population but play pivotal roles in human cancer development and recurrence. A fundamental question in cancer biology is what genetic and epigenetic changes occur in CSCs. Here we show that the in-situ global levels of DNA cytosine modifications, including 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and 5-formylcytosine (5fC), are similar between liver cancer stem-like (LCSL) cells and paratumor liver cells of liver cancer patients. We then developed a robust method combining immunohistochemistry, laser capture microdissection and genome sequencing with ultra-low-input cells (CIL-seq) to study the detailed genetic and DNA methylation changes in human LCSL cells. We first used clinical samples of mixed hepatocellular carcinoma-cholangiocarcinoma (HCC-CCA) with stem cell features to investigate human LCSL cells. The CIL-seq analysis of HCC-CCA and HCC patients showed that LCSL cells had strong spatial genetic and epigenetic heterogeneity. More interestingly, although the LCSL cells had some potential key changes in their genome, they had substantially fewer somatic single nucleotide variants (SNVs), copy number alterations (CNAs) and differentially methylated regions than other tumor parenchymal cells. The cluster analysis of SNVs, CNAs, DNA methylation patterns and spatial transcriptomes all clearly showed that the LCSL cells were clustered with the paratumor liver cells. Thus, spatial multiomics analysis showed that LCSL cells had only minor genetic and epigenetic changes compared with other tumor parenchymal cells. Targeting key changes in CSCs, not just changes in bulk tumor cells, should be more effective for human cancer therapy.

Resection and transplantation for hepatocellular carcinoma and intrahepatic cholangiocarcinoma

Treatment of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) has markedly improved in recent years. Liver resection and, for HCC, liver transplantation are essential components of curative treatment in the nonmetastatic stage. In the current S3guideline, the role of the interdisciplinary tumor board is strengthened for the individual therapy decision. Overall, liver transplantation offers the best long-term results in terms of survival and relapse rate for selected patients. For liver resection, the use of minimally invasive resection techniques can significantly reduce perioperative morbidity and mortality compared to open liver surgery, so that it can be used both as acurative therapeutic approach and as part of bridging strategies for liver transplantation. The 5‑year survival rate after liver transplantation in selected, nonresectable patients who fulfil and also those who do not fulfil the Milan criteria is above 70%, compared with about 30% without liver transplantation under locoregional therapy. The following article reports the status of evidence-based surgical therapy for HCC and iCCA based on the recommendations of the current German S3guideline. The differentiated local therapy of HCC in cirrhosis is based on many patient- and tumor-specific factors. In addition to surgical resection, liver transplantation plays an important role as acurative therapy for patients with irresectable HCCs regardless of whether they meet the Milan criteria. For resectable iCCA or HCC without cirrhosis in the nonmetastatic stage, surgical resection represents the treatment of choice.

Differences in the presentation and treatment of primary liver tumors at a hepatology center and an oncology center.

Primary liver cancer is a public health problem in Mexico and the world. Liver transplantation (LT) is the ideal treatment for early hepatocellular carcinoma (HCC). Our aim was to evaluate the characteristics of patients with HCC and cholangiocarcinoma (CC) at two centers and identify transplantation candidates. A retrospective observational study was conducted at the Hepatology Center (HC) and the University Center Against Cancer (UCAC), within the time frame of 2012-2018. HCC or intrahepatic CC was confirmed in 109 patients. Staging classifications, transplant selection models, and a predictive model for post-LT recurrence were applied to the HCC patients. Of the total population, 93% (n = 102) presented with cirrhosis, 86% (n = 94) had HCC (HC: 58%, UCAC: 42%), and 14% (n = 15) had intrahepatic CC (HC: 40%, UCAC: 60%). Of the HC patients with HCC, Okuda I-II, BCLC A-B, and AFP levels < 100 ng/m predominated, whereas Okuda II-III, BCLC C-D, and AFP levels > 1,000 ng/mL predominated in the UCAC patients. Half of the HC population with HCC met the criteria for LT, in contrast to 23% of the UCAC patients. Fifteen patients were evaluated for LT, and at present, six have undergone transplantation. The most frequent primary liver tumor was HCC. Patients from the HC presented with earlier-stage disease and a high number of them met the criteria for LT. Only patients from the HC underwent transplantation.

Differences in the presentation and treatment of primary liver tumors at a hepatology center and an oncology center

Introduction and aimsPrimary liver cancer is a public health problem in Mexico and the world. Liver transplantation (LT) is the ideal treatment for early hepatocellular carcinoma (HCC). Our aim was to evaluate the characteristics of patients with HCC and cholangiocarcinoma (CC) at two centers and identify transplantation candidates. Materials and methodsA retrospective observational study was conducted at the Hepatology Center (HC) and the University Center Against Cancer (UCAC), within the time frame of 2012–2018. HCC or intrahepatic CC was confirmed in 109 patients. Staging classifications, transplant selection models, and a predictive model for post-LT recurrence were applied to the HCC patients. ResultsOf the total population, 93% (n=102) presented with cirrhosis, 86% (n=94) had HCC (HC: 58%, UCAC: 42%), and 14% (n=15) had intrahepatic CC (HC: 40%, UCAC: 60%). Of the HC patients with HCC, Okuda I–II, BCLC A–B, and AFP levels <100ng/m predominated, whereas Okuda II-III, BCLC C-D, and AFP levels >1000ng/mL predominated in the UCAC patients. Half of the HC population with HCC met the criteria for LT, in contrast to 23% of the UCAC patients. Fifteen patients were evaluated for LT, and at present, six have undergone transplantation. ConclusionsThe most frequent primary liver tumor was HCC. Patients from the HC presented with earlier-stage disease and a high number of them met the criteria for LT. Only patients from the HC underwent transplantation.

MR Features Based on LI-RADS Ver. 2018 Correlated with Cytokeratin 19 Expression in Combined Hepatocellular Carcinoma-Cholangiocarcinoma.

PurposeTo investigate the significance of MR features based on the Liver Imaging Reporting and Data System (LI-RADS ver. 2018) for identifying the expression of cytokeratin 19 (CK-19) in patients with combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) before surgery.Patients and MethodsThe study enrolled 174 patients pathologically confirmed to have cHCC-CCA according to the 2019 WHO classification. The preoperative MR imaging features and clinicopathological findings were retrospectively evaluated and compared between the CK-19-positive and CK-19-negative cHCC-CCA groups.ResultsOne hundred seventy-four patients (mean age, males vs females: 56.6 ± 10.0 years vs 54.7 ± 14.2 years) were evaluated. The presence of mosaic architecture, targetoid appearance, cholangiectasis, hepatic capsule retraction, and corona enhancement was significantly higher in the CK-19-positive group (all p < 0.05), while nonrim arterial phase hyperenhancement (APHE) was more common in the CK-19-negative group (p = 0.04). The univariate analysis showed that hepatitis B virus infection, CEA > 5 ng/mL, tumor size, nonrim APHE, mosaic architecture, targetoid appearance, cholangiectasis, hepatic capsule retraction, and corona enhancement were significant risk factors for CK-19-positive cHCC-CCA (all p < 0.05). Unfortunately, the multivariate analysis revealed that only corona enhancement (OR = 2.359, p = 0.03) was an independent risk factor associated with CK-19-positive cHCC-CCA.ConclusionCorona enhancement is significantly correlated with CK-19 positivity in patients with cHCC-CCA.

Combined hepatocellular carcinoma-cholangiocarcinoma: MRI features correlated with tumor biomarkers and prognosis.

To determine how MRI features are correlated to biomarkers, and to the prognostic factors for recurrence-free survival (RFS) and overall survival (OS) in combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) patients. The study enrolled 160 cHCC-CCA patients pathologically confirmed according to the 2019 WHO classification. The preoperative MRI features and clinical data were retrospectively evaluated and compared between patients grouped by AFP or CA19-9 level and with pathological findings. The RFS and OS of cHCC-CCA patients were estimated using Kaplan-Meier survival curves and compared using the log-rank test. Moreover, predictors of RFS and OS were investigated using Cox regression analyses. One hundred and sixty patients (mean age, males vs. females: 55.7 ± 10.2 years vs. 54.9 ± 14.0 years) were evaluated. The incidence of nodule-in-nodule architecture, mosaic architecture, intratumoral hemorrhage, hepatic capsule retraction, arterial phase peritumoral enhancement, and portal vein thrombus was significantly higher in patients with AFP > 20 ng/ml (all p < 0.05). Multivariate Cox regression analysis indicated that age (HR 1.031, p = 0.03), CA19-9 > 37 U/ml (HR 1.880, p = 0.04), arterial phase peritumoral enhancement (HR 2.287, p = 0.01), and delayed enhancement (HR 0.377, p = 0.02) were independent predictors of poor RFS, while arterial phase peripheral enhancement (HR 2.391, p = 0.04) was an independent predictor of poor OS. cHCC-CCA imaging features are complex and not correlated with AFP or CA19-9. Age, CA19-9 > 37 U/ml, arterial phase peritumoral enhancement, and delayed enhancement are independent predictors of poor RFS. Arterial phase peripheral enhancement is an independent predictor of poor OS. • The imaging features of combined hepatocellular carcinoma-cholangiocarcinoma are complex and are not correlated with the alpha fetoprotein or CA19-9 levels. • Age, CA19-9 > 37 U/ml, arterial phase peritumoral enhancement, and delayed enhancement are independent predictors of poor recurrence-free survival in combined hepatocellular carcinoma-cholangiocarcinoma patients. • Arterial phase peripheral enhancement is an independent predictor of poor overall survival in patients with combined hepatocellular carcinoma-cholangiocarcinoma.