Well-differentiated Hepatocellular Carcinoma Research Articles

Pathology and diagnostic approaches to well-differentiated hepatocellular lesions: a narrative review.

Well-differentiated hepatocellular lesions (WDHLs) are liver tumors or nonneoplastic lesions in which the cells closely resemble normal hepatocytes. These lesions often include focal nodular hyperplasia, hepatocellular adenoma, macroregenerative nodule, dysplastic nodule, and well-differentiated hepatocellular carcinoma. The diagnosis of these lesions remains challenging because of their morphological similarities, particularly when examined using needle biopsy. The accurate diagnosis of WDHLs is crucial for patient management and prognosis. This review addresses the histopathological characteristics and diagnostic approaches of WDHLs.

Immunohistochemical Glutamine Synthetase As a Surrogate Marker for Beta Catenin (Exon 3 Deletion) in a Rare Case of Hepatic Adenomatosis with Early Malignant Transformation to Well Differentiated Hepatocellular Carcinoma

Abstract Introduction/Objective Hepatic adenomatosis (HA) is a rare entity defined by ≥ 10 hepatocellular adenomas (HCAs). About half of HA cases are asymptomatic and incidentally found. Compared to individual HCAs, HA carries a higher risk of complications including: tumor rupture, bleeding, and an approximate 4.2% overall frequency of malignant transformation. Methods/Case Report A 29-year-old woman presented to the emergency department (ED) requesting a CT scan. She was seen by a gastroenterologist days prior to her ED visit for ongoing sharp rectal pain for 2-3 months. After a recent rectal exam, she was recommended to have a CT abdomen/pelvis to rule out a potential abscess. CT did not show a perianal or perirectal abscess but instead identified a 9.1 cm right hepatic lobe mass. A liver MRI showed a 6.4 x 8.5 cm mass with arterial enhancement. The patient had a prior history of OCP use. She underwent robotic wedge resection of liver segment 6 with cholecystectomy. Gross examination showed a 6 cm tumor with many smaller nodules ranging in size from 0.5-2.2 cm. Our case was submitted entirely for histologic examination. Microscopy demonstrated well differentiated hepatocellular carcinoma (WDHCC) confirmed with positive immunohistochemical (IHC) staining for HepPar1 and Arginase. Tumor cells showed mild patchy cytological atypia, occasional pseudoglands, and architectural atypia with “nodule in nodule growth.” There was reticulin loss in multiple areas and CD34 showed strong diffuse sinusoidal staining. Glypican 3, CRP, and HAA were negative. Low Ki-67, LFABP retention, and absent nuclear staining of beta catenin (BC) were noted. Glutamine synthetase (GS) was diffuse and homogeneous. The gallbladder was unremarkable. Results (if a Case Study enter NA) NA Conclusion This case emphasizes that, despite negative nuclear BC staining, diffuse homogenous staining of GS is a quality surrogate marker for BC mutations (ex. exon 3 deletions). Thorough gross, microscopic, and molecular examination in HA cases is essential for identifying transformation to WDHCC.

A combined model based on radiomics features of Sonazoid contrast-enhanced ultrasound in the Kupffer phase for the diagnosis of well-differentiated hepatocellular carcinoma and atypical focal liver lesions: a prospective, multicenter study.

The objective of this study was to develop a combined model based on radiomics features of Sonazoid contrast-enhanced ultrasound (CEUS) during the Kupffer phase and to evaluate its value in differentiating well-differentiated hepatocellular carcinoma (w-HCC) from atypical benign focal liver lesions (FLLs). A total of 116 patients with preoperatively Sonazoid-CEUS confirmed w-HCC or benign FLL were selected from a prospective multiple study on the clinical application of Sonazoid in FLLs conducted from August 2020 to March 2021. According to the randomization principle, the patients were divided into a training cohort and a test cohort in a 7:3 ratio. Seventy-nine patients were used for establishing and training the radiomics model and combined model. In comparison, 37 patients were used for validating and comparing the performance of the models. The diagnostic efficacy of the models for w-HCC and atypical benign FLLs was evaluated using ROCs curves and decision curves. A combined model nomogram was created to assess its value in reducing unnecessary biopsies. Among the patients, there were 55 cases of w-HCC and 61 cases of atypical benign FLLs, including 28 cases of early liver abscess, 16 cases of atypical hepatic hemangioma, 8 cases of hepatocellular dysplastic nodules (DN), and 9 cases of focal nodular hyperplasia (FNH). The radiomics model and combined model we established had AUCs of 0.905 and 0.951, respectively, in the training cohort, and the AUCs of the two models in the test cohort were 0.826 and 0.912, respectively. The combined model outperformed the radiomics feature model significantly. Decision curve analysis demonstrated that the combined model achieved a higher net benefit within a specific threshold probability range (0.25 to 1.00). A nomogram of the combined model was developed. The combined model based on the radiomics features of Sonazoid-CEUS in the Kupffer phase showed satisfactory performance in diagnosing w-HCC and atypical benign FLLs. It can assist clinicians in timely detecting malignant FLLs and reducing unnecessary biopsies for benign diseases.

The Combination of Gd-EOB-DTPA Enhanced T1 Mapping with Apparent Diffusion Coefficient could Improve the Diagnostic Efficacy of Hepatocellular Carcinoma Grading.

Accurately predicting the hepatocellular carcinoma (HCC) grade may facilitate the rational selection of treatment strategies. The diagnostic efficacy of the combination of Gadolinium ethoxybenzy diethylenetriamine pentaacetic (Gd-EOB-DTPA) enhancement T1 mapping and apparent diffusion coefficient (ADC) values in predicting HCC grade needs further validation. This study aimed to assess the capacity of Gd-EOB-DTPA-enhanced T1 mapping and ADC values, both individually and in combination, to discriminate between different grades of HCC. From July 2017 to February 2020, 96 patients (male, 83; mean age, 53.67 years; age range, 29-71 years) clinically diagnosed with HCC were included in the present study. All patients underwent Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI, including T1 mapping sequence) before surgery or biopsy. All the patients were categorized into 3 groups according to the pathological results (including 24 cases of well-differentiated HCCs, 59 cases of moderately differentiated HCCs, 13 cases of and poorly differentiated HCCs). The mean Gd-EOB-DTPA enhanced T1 values (&#916;T1=[(T1pre-T1post)/T1pre]×100%) and ADC values between different grading groups of HCC were calculated and compared. The area under the characteristics curve (AUC), the diagnostic threshold, sensitivity, and specificity of &#916;T1 and ADC for differential diagnosis were analyzed. Mean &#916;T1 was 58% for well-differentiated HCCs, 50% for moderately-differentiated HCCs, and 43% for poorly-differentiated HCCs. &#916;T1 showed statistical differences between the groups (P<0.001). The mean ADC values of the 3 groups were 1.11×10-3 mm2/s, 0.91×10-3 mm2/s, and 0.80×10-3mm2/s, respectively. ADC showed statistical differences between the groups (P<0.001). In discriminating well- differentiated group from the moderately differentiated group, the AUC of &#916;T1 was 0.751 (95% CI: 0.642, 0.859), the AUC of ADC was 0.782 (95% CI: 0.671, 0.894), the AUC of combined model was 0.811 (95% CI: 0.709, 0.914). In discriminating the poorly differentiated group from the moderately differentiated group, the AUC of &#916;T1 was 0.768 (95% CI: 0.634, 0.902), the AUC of ADC was 0.754 (95% CI: 0.603, 0.904), and the AUC of the combined model was 0.841 (95% CI: 0.729, 0.953). Gd-EOB-DTPA enhanced T1 mapping, and ADC values have complementary effects on the sensitivity and specificity for identifying different HCC grades. A combined model of Gd-EOB-DTPA-enhanced MRI T1 mapping and ADC values could improve diagnostic performance for predicting HCC grades.</p>.

Nodule-in-nodule architecture of hepatocellular carcinomas: enhancement patterns in the hepatobiliary phase and pathological features.

This study aimed to evaluate the enhancement patterns in the hepatobiliary phase (HBP) and pathological features of nodule-in-nodule-type hepatocellular carcinoma (NIN-HCC) patients. In this single-institution retrospective study, 27 consecutive cirrhosis patients with 29 histologically confirmed NIN-HCCs who underwent preoperative examination via Gd-EOB-DTPA-enhanced MRI were enrolled from January 2016 to September 2023. Two blinded radiologists assessed the imaging features of both the inner and outer nodules in NIN-HCCs to reach a consensus on the Liver Imaging Reporting & Data System (LI-RADS) categories of the lesions. Based on the different enhancement patterns of the inner and outer nodules in the HBP, NIN-HCCs were classified into different groups and further divided into different types. Imaging features and LI-RADS categories were subsequently compared among the groups. Pathological findings for NIN-HCCs were also evaluated. Among 29 NIN-HCCs, all inner nodules showed hypervascularity, with a maximum diameter of 13.2 ± 5.5mm; 51.7% (15/29) showed "wash-in with washout" enhancement; and 48.3% (14/29) showed "wash-in without washout" enhancement. All outer nodules showed hypovascularity, with a maximum diameter of 25.6 ± 7.3mm, and 51.9% (14/29) showed a washout appearance on PVP. Among all the lesions, the maximum diameter was 27.5 ± 6.8mm; 12 (41.4%) lesions were LR-4, and 17 (58.6%) lesions were LR-5. NIN-HCCs were classified into hypointense (62.1%, 18/29) and isointense (37.9%, 11/29) groups based on the signal intensity of the outer nodules in the HBP. In the hypointense group, 2 (6.9%) of the inner nodules were hypointense (type A), 11 (37.9%) were isointense (type B), and 5 (17.2%) were hyperintense (type C) compared to the background hypointense outer nodules. In the isointense group, 9 (31.0%) of the inner nodules were hypointense (type D), 2 (6.9%) were isointense (type E), and no (0%) was hyperintense (type F) compared to the background isointense outer nodules. There were no significant differences in the diameter, dynamic enhancement patterns of the inner or outer nodules, or LI-RADS scores of the lesions between the hypointense group and the isointense group (all P > 0.05). Histologically, the inner nodules of NIN-HCCs were mainly composed of moderately differentiated HCC (75.9% 22/29), whereas the outer nodules consisted of either well-differentiated HCC or high-grade dysplastic nodules (HGDNs). NIN-HCCs exhibit specific MRI findings closely associated with their pathological features. The spectrum of HBP enhancement patterns provides valuable insights into the underlying cell biological mechanisms of these lesions. NIN-HCC subtypes may be used as a morphologic marker in the early stage of multistep hepatocarcinogenesis.

Correlation between CEUS LI-RADS categorization of HCC < 20 mm and clinic-pathological features

ObjectiveTo retrospectively evaluate the diagnostic performance of contrast-enhanced ultrasound (CEUS) LI-RADS in liver nodules < 20 mm at high risk of hepatocellular carcinoma (HCC) and their correlation with clinic-pathological features.MethodsA total of 432 pathologically proved liver nodules < 20 mm were included from January 2019 to June 2022. Each nodule was categorized as LI-RADS grade (LR)-1 to LR-5 through LR-M according to CEUS LI-RADS. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) of CEUS LI-RADS were evaluated using pathological reference standard. Correlations between clinic-pathological features and CEUS LI-RADS categorization, together with major CEUS features, were further explored.ResultsWith LR-5 to diagnose HCC, the sensitivity, specificity, PPV, NPV, and AUC were 50.3%, 70.0%, 91.2%, 18.5%, and 0.601, respectively. The proportion of LR-5 in primary HCCs was significantly higher than that in recurrent ones (p = 0.014). HCC 10–19 mm showed significantly more frequent arterial phase hyper-enhancement (APHE) and late washout (p < 0.05) and less no-washout (p = 0.003) compared with those in HCC < 10 mm. Well-differentiated HCCs showed more frequent non-APHE and no-washout than moderate- and poor-differentiated HCCs (p < 0.05). Upgrading “APHE without washout” LR-4 nodules 10–19 mm with HCC history and “APHE with late mild washout” LR-4 nodules < 10 mm to LR-5 could improve the diagnostic performance of LR-5. The corresponding sensitivity, specificity, PPV, NPV, and AUC are 60.2%, 70.0%, 92.6%, 22.1%, and 0.651, respectively.ConclusionsCEUS LI-RADS is valuable in the diagnosis of HCC < 20 mm and performance can be improved with the combination of clinic-pathological features.Critical relevance statementCEUS LI-RADS was valuable in the diagnosis of HCC < 20 mm and its diagnostic performance can be improved by combining clinic-pathological features. Further research is needed to define its value in this set of lesions.Key PointsContrast-enhanced ultrasound can detect small liver lesions where LI-RADS accuracy is uncertain.Many LI-RADS Grade-4 nodules were upgraded to Grade-5 by combining imaging with clinic-pathological factors.The reclassification of LI-RADS Grade-5 can improve sensitivity without decreasing positive predictive value.Graphical

Expression of Fascin-1 and its diagnostic value in liver cancer

Although some studies have reported on the expression and clinical significance of Fascin-1 (FSCN1) in liver cancer, the clinical application and differential diagnosis value of FSCN1 in liver cancer are still unclear. The aim of this study was to analyze the expression level of FSCN1 protein in liver cancer tissues and explore its diagnostic and application value in differentiating between hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The immunehistochemical analysis was used to detect the expression of FSCN1 in 108 cases of HCC, 26 cases of ICC, 23 cases of liver cirrhosis, and 11 cases of normal liver tissues. The differences in the positive expression rate and strong positive expression rate of FSCN1 among different groups were analyzed. The positive rate of FSCN1 in normal liver tissues, liver cirrhosis, HCC, and ICC tissues was 0.0% (0/11), 0.0% (0/23), 13.9% (15/108), and 92.3% (24/26), respectively, while the strong positive rate was 0.0% (0/11), 0.0% (0/23), 0.9% (1/108), and 69.2% (18/26), respectively. Both the positive rate and strong positive rate of FSCN1 in ICC tissues were significantly higher than those in HCC, liver cirrhosis, and normal liver tissues. Additionally, the positive rate of FSCN1 in moderately to poorly differentiated HCC tissues was 18.8% (15/80), significantly higher than in well-differentiated HCC (0.0%, 0/28) (P = 0.031). In liver cancer, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FSCN1 positive prediction for ICC were 92.3%, 86.1%, 61.5%, and 97.9%, respectively, whereas the sensitivity, specificity, PPV, and NPV of FSCN1 strong positive prediction for ICC were 69.2%, 99.1%, 94.7%, and 93.0%, respectively. These results suggest that FSCN1 may play an important role in the occurrence and progression of liver cancer, and it can be used as a novel diagnostic marker for ICC.

Induction of Hepatocellular Carcinoma in Conventional Domestic Swine Using N-Diethylnitrosamine and Phenobarbital.

Large animal models are still used in many studies because of their likeness to humans. It has not been documented that regular-sized conventional farm-breed pigs, generally bred for meat production, can be used to generate hepatocellular carcinoma (HCC) animal models. The goal of this study was to investigate how N-diethylnitrosamine (DENA) and phenobarbital (PB) together can generate HCC in ordinary farmed pigs. Conventional domestic swine (Sus scrofa domesticus) were used. DENA 15 mg/kg was intraperitoneally injected weekly for 12 weeks, while PB tablets (4 mg/kg) were also administered through food for 16 weeks. Blood testing and ultrasonography evaluation were performed to monitor the progress. Subsequently, computed tomography was conducted in cases with suspected nodules, followed by histopathological examination to confirm the diagnosis. Ten swine (seven males, three females; age: 2 months; weight: 9-15 kg) were included in the study and followed up for 25 months; nine were experimental, and one was control for ethical considerations. The maximum weight of animals during this study reached 162-228 kg. The weight gain seen in the intervention swine was predominantly lower than that documented in the control. The laboratory analysis revealed no notable abnormalities in liver function markers but did demonstrate statistically significant changes in urea (p = 0.028) and creatinine (p = 0.003) levels. Ultrasonography and computed tomography showed multiple liver nodules with characteristics resembling HCC. Serial imaging screening and more extended observations revealed that all animals eventually developed tumors. Histopathological confirmation at 15-22 weeks post-induction revealed that all intervened swine developed multiple nodules of well-differentiated HCC and some with hepatic angiosarcoma. This study successfully generated HCC in conventional domestic swine with a DENA and PB combination. This investigation required at least 15 months to develop tumors. This model will be beneficial for future investigations of HCC in large animals.

Abstract No. 164 ▪ Featured Abstract Natural Killer Cell-Based Immunotherapy Maintains Cytotoxicity After Temperature-Controlled Ablation in Poorly and Well-Differentiated Hepatocellular Carcinoma

Abstract No. 164 ▪ Featured Abstract Natural Killer Cell-Based Immunotherapy Maintains Cytotoxicity After Temperature-Controlled Ablation in Poorly and Well-Differentiated Hepatocellular Carcinoma

A rare case of liver regenerative and non-neoplastic lesion resembling a well-differentiated hepatocellular carcinoma

BackgroundNodular regenerative hyperplasia (NRH) is a rare disease that presents pathologically as diffuse hepatic nodules without fibrous septa. It is believed to be caused by vasculopathy against a background of various systemic diseases, such as hematologic, autoimmune, and drug-induced diseases, with various symptoms. In spite of the recent imaging advances, various atypical cases of nodular lesions are observed in daily clinical practice. Cases that do not completely meet these criteria are referred to as -like or -similar lesions in clinical situations, making it difficult to understand their pathogenesis. We present a case in which two hepatic nodular lesions were noted and difficult to differentiate from malignancy preoperatively. The lesions were laparoscopically resected and a pathological diagnosis with non-neoplastic liver regenerative nodules resembling NRH was made.Case presentationA 49-year-old man with no alcohol or drug intake and no past medical history was identified as having liver tumors on screening examination without any symptoms. Contrast-enhanced computed tomography (CT) showed two hepatic tumors; approximately 2-cm tumors at S7 and S8. Gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) revealed fat inclusions in their contents. Ethoxybenzyl (EOB) uptake was also observed during the hepatobiliary phase. Based on preoperative examinations, we suspected well-differentiated hepatocellular carcinoma (HCC) and performed laparoscopic S7/8 partial resection for these lesions. Macroscopically, the resected specimens showed a non-cirrhotic yellowish-cut surface containing brownish, ill-defined lesions with irregular borders. Microscopically, these lesions showed zonal necrosis, congestion, and aggregation of hemosiderin-laden macrophages around the central vein. In these areas, the fatty deposition of hepatocytes was lower than that in the surrounding background hepatocytes. Histopathologically, neither neoplastic nor hyperplastic lesions were observed, and he was diagnosed as regenerative hepatic change with centrilobular necrosis.ConclusionsConsidering the pathological results, these lesions were thought to be a type of NRH-like lesion with possible hepatic vessel disorder. However, the lesion’s cause and classification was difficult to determine. The accumulation of these regenerative changes accompanying fatty liver is needed to clarify the mechanism and its clinical significance.

Mean ADC values and arterial phase hyperintensity discriminate small (≤ 3cm) well-differentiated hepatocellular carcinoma from dysplastic nodule.

This research endeavor sought to distinguish small (≤ 3cm) well-differentiated hepatocellular carcinoma (WD-HCC) from dysplastic nodules (DN) by employing traditional imaging features and mean apparent diffusion coefficient (mADC) values derived from diffusion-weighted imaging (DWI). In this retrospective analysis, we assessed a cohort of ninety patients with confirmed dysplastic nodules (DNs) (n = 71) or well-differentiated hepatocellular carcinoma (WD-HCC) (n = 41) who had undergone dynamic contrast-enhanced magnetic resonance imaging between March 2018 and June 2021. Multivariable logistic regression analyses were executed to pinpoint characteristics that can effectively differentiate histologic grades. A region-of-interest (ROI) encompassing all lesion voxels was delineated on each slice containing the mass in the ADC map. Subsequently, the whole-lesion mean ADC (mADC) were computed from these delineations. A receiver operating characteristic (ROC) curve was generated to assess the discriminatory efficacy of the mADC values in distinguishing between WD-HCC and DN. Among the histopathological types from benign to malignant, mADC showed a significant decrease (P < 0.001). The mADCs were effective in distinguishing WD-HCC from DN [AUC, 0.903 (95% CI 0.849-0.958)]. The best cutoffs for theYoudenindexwere 0.0012mm2/s for mADC, with moderate sensitivity (70.7%) and high specificity (94.4%). MRI features including hyperintensity at arterial phase (odds ratio, 21.2; P = 0.009), mADC < 0.0012mm2/s (odds ratio, 52.2; P < 0.001) were independent predictors for WD-HCC at multivariable analysis. The AUC value of hyperintensity at arterial phase was 0.857 (95% CI 0.786-0.928). The composite diagnostic criterion of arterial hyperintensity + mADC < 0.0012mm2/s showed good performance [AUC, 0.926 (95% CI 0.878-0.975)], displaying increased sensitivity compared to individual assessments involving arterial hyperintensity (P = 0.013), mADC < 0.0012mm2/s (P = 0.004), or LR-5 (P < 0.001), with similar specificity compared to LR-5 (P = 0.193). DN and WD-HCC displayed contrasting diffusion characteristics, attainable to distinguish with satisfactory accuracy. The utilization of arterial phase hyperintensity and mADC < 0.0012 on MRI facilitated the differentiation of WD-HCC from DN.

Significance of p53, cyclooxygenase-2, and epithelial cell adhesion molecule expression in hepatocellular carcinoma: an immunohistochemical study

Background Hepatocellular carcinoma (HCC) is a significant global health concern with a high mortality rate. To date, the most effective therapy for HCC is resection at an early tumor stage. However, tumor recurrence is common, and identifying key molecules facilitates the understanding of the pathogenesis of HCC and the prediction of prognosis to provide novel targets for anticancer therapy. Aim This study evaluated the expression of p53, cyclooxygenase-2 (COX-2), and epithelial cell adhesion molecule (EpCAM) in HCC and investigated their correlation with clinicopathological features and prognosis. Methods An Immunohistochemical analysis of p53, COX-2, and EpCAM was conducted on selected 51 HCC cases and adjacent noncancerous hepatic tissue. Results In the current study, p53, COX-2, and EpCAM expression were significantly higher in HCC cases than in the adjacent nontumor tissue (P=0.05, P=0.03, and P=0.041, respectively). P53, COX-2, and EpCAM were significantly overexpressed among patients with advanced stage (P=0.039, P=0.000, and P=0.016, respectively), large tumor size (P=0.004 and P=0.001) and poor disease-free survival (P=0.036, P=0.001, and P=0.000, respectively). P53 and EpCAM were significantly correlated with vascular invasion (P=0.045 and P=0.032) and higher grade (P=0.019 and P=0.033). While COX-2 was associated with well-differentiated HCC cases. There was no statistically significant correlation between p53 and COX-2 or, EpCAM, while COX-2 was directly correlated with EpCAM (r=0.001). Conclusion p53, COX-2, and EpCAM might have an important role in early carcinogenesis, progression of HCC, and poor prognosis, suggesting that the inhibition of these proteins may hold potential as a multitarget therapeutic approach in HCC patients.

Development and Comparison of Prediction Models Based on Sonovue- and Sonazoid-Enhanced Ultrasound for Pathologic Grade and Microvascular Invasion in Hepatocellular Carcinoma

ObjectiveThis study aimed to develop and compare the prediction model based on Sonovue and Sonazoid contrast enhanced ultrasound (CEUS) for pathologic grade and microvascular invasion (MVI) of hepatocellular carcinoma (HCC). And to investigate whether Kupffer phase images have additional predictive value for the above pathological features. Methods90 patients diagnosed as primary HCC and received curative hepatectomy were prospectively enrolled. All patients underwent conventional ultrasound (CUS), Sonovue and Sonazoid-CEUS examination preoperatively. Clinical, radiological and pathological features including pathologic grade, MVI and CD68 expression were collected. We developed prediction models composing of clinical, CUS and CEUS (Sonovue and Sonazoid, respectively) features for pathologic grade and MVI with both logistic regression and machine learning (ML) method. Results41 (45.6%) patients were poorly differentiated HCC (p-HCC) and 37(41.1%) were MVI positive. For pathologic grade, logistic model based on Sonazoid-CEUS had significant better performance than which based on Sonovue-CEUS (area under curve (AUC), 0.929 versus 0.848, P=0.035). While for MVI, these two models had similar accuracy (AUC, 0.810 versus 0.786, P=0.068). Meanwhile, we found well-differentiated HCC tends to have higher enhancement ratio in 6-12 minutes during Kupffer phase of Sonazoid-CEUS, as well as higher CD68 expression compared with p-HCC. Besides, all of these models can effectively predict the risk of recurrence (P < 0.05). ConclusionSonovue-CEUS and Sonazoid-CEUS showed comparable excellence in predicting MVI, while Sonazoid-CEUS was superior to Sonovue-CEUS in predicting pathologic grade due to the Kupffer phase. Enhancement ratio in Kupffer phase have additional predictive value for pathologic grade prediction.

Characterizing hepatocellular carcinoma stem markers and their corresponding susceptibility to NK-cell based immunotherapy.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the fourth-leading cause of all cancer-related deaths around the world. Liver transplantation, surgery, and local ablation are curative therapies for early-stage HCC. However, post-treatment outcomes can vary based on histopathologic stage. Poorly-differentiated HCC are associated with higher rates of tumor progression and lower overall survival compared to well-differentiated HCC after therapy. In this study, we aimed to characterize the cancer stem cell (CSC) profile of histopathologically-proven well and poorly-differentiated HCCs in an in-vitro environment. We characterized the stem-like profile of each type of HCC based on their surface markers and susceptibility to NK cell-mediated cytotoxicity. Flow cytometry was used to quantify differential expression of MHC-class I, CD54, and CD44 between well- and poorly-differentiated HCCs. Primary untreated NK cells, IL-2 stimulated primary NK cells, and supercharged (sNK) cell-mediated cytotoxicity was assessed against well- and poorly-differentiated HCCs. IFN-γ supernatant from each respective NK cell experimental arm was also used to induce differentiation of HCCs. Finally, we characterized the temporal NK effector cell cytotoxicity using real-time quantitative analysis of imaging and impedance (eSight study). Poorly-differentiated HCCs demonstrated low surface expression of MHC-class I and CD54, and high expression of CD44. Treatment of NK cells secreted IFN-γ or IFN-γ cytokine induced differentiation in HCCs. Poorly-differentiated HCCs in comparison to well-differentiated HCC were more susceptible to NK cell-mediated cytotoxicity in primary NK cells, IL-2 stimulated primary NK cells, and sNK cells. sNK cells induced significantly higher cytotoxicity against well-differentiated HCCs in comparison to untreated or IL-2-stimulated primary NK cells. These findings were recapitulated with real-time quantitative imaging analysis. Poorly-differentiated HCCs were found to have surface marker patterns of CSCs, making them highly susceptible to NK cell-based immunotherapy. NK-cell based therapy can potentially be leveraged as a neoadjuvant or adjuvant therapy in poorly-differentiated HCCs. Supercharged NK cells, which can be rapidly expanded to therapeutic levels, are uniquely capable of lysing both poorly- and well-differentiated HCCs. This finding suggests that sNK cells not only exhibit enhanced features against NK cells' targets but also are capable of activating T cells to induce cytotoxicity against well-differentiated HCCs with high expression of MHC class I.

A case of well-differentiated hepatocellular carcinoma detected with 18F-PSMA-1007 positron emission tomography-computed tomography.

A case of well-differentiated hepatocellular carcinoma detected with 18F-PSMA-1007 positron emission tomography-computed tomography.

P53 expression is associated with tumor stage, grade and subtype in patients with hepatocellular carcinoma.

The present study aimed to determine the expression levels of p53 in patients with hepatocellular carcinoma (HCC) and to evaluate its association with several HCC-related prognostic factors and in particular, with tumor stage, grade and subtype. Therefore, a cross-sectional study, involving 41 patients with HCC, who underwent surgical resection between January, 2013 and December, 2020 was conducted. To assess the expression levels of p53 in all patients with HCC, immunohistochemical staining was performed. In addition, the association between p53 expression and the clinicopathological characteristics of patients with HCC, including prognostic factors, was evaluated by applying the appropriate statistical analysis methods. The results revealed that among the 41 patients enrolled, 35 patients (85.4%) were positive for p53 expression. A higher percentage of positive p53 expression was observed in male patients >60 years old, with single HCC nodules >5 cm in diameter and vascular invasion, compared with their counterparts. A positive p53 expression was associated with well- and poorly differentiated HCC, but not with tumor stage and subtype. No differences in p53 expression were observed across different tumor stages and subtypes. Additionally, patients with moderately and poorly differentiated HCC exhibited significantly higher p53 expression levels compared with those suffering from well-differentiated HCC. Overall, the results demonstrated that the rate of p53 immuno-positive cells was increased in patients with HCC. In addition, p53 expression was associated with well- and poorly differentiated HCC, thus suggesting its association with a poorer prognosis.

Correlation Between Indocyanine Green Fluorescence Patterns and Grade of Differentiation of Hepatocellular Carcinoma: A Western Prospective Cohort Study.

Background. Most of the available evidence on the use of indocyanine green (ICG) fluorescence in clinical practice consists of articles published by surgeons of the Asian-Pacific area. We performed a prospective cohort study to assess the patterns of ICG fluorescence in Western hepatocellular carcinoma (HCC) counterparts.Methods. From April 2019 to January 2022, a total of 31 consecutive patients who underwent laparoscopic liver resection (LLR) for superficial HCC were enrolled in this prospective study. All patients underwent laparoscopic staging with both laparoscopic ultrasound (LUS) and ICG fluorescence imaging.Results. A total of 38 hepatocellular carcinomas (HCCs) were enrolled: 23 superficial (surfacing at the liver's Glissonian capsule), 5 exophytic, 5 shallow (<8mm from the hepatic surface) and 5 deep (>10mm from the hepatic surface). The detection rate with preoperative imaging (abdominal CT/MRI), LUS, ICG fluorescence and combined modalities (ICG and LUS) was 97.4%, 94.9%, 89.7% and 100%, respectively. The five deep seated lesions underwent ultrasound-guided laparoscopic thermal ablation. The other 33 HCCs were treated with minimally invasive liver resection. Intraoperative ultrasound patterns were registered for each single nodule resected. The ICG fluorescence pattern was classified in two types: total fluorescence (all the tumoral tissue showed strong and homogeneous fluorescence), n = 9/33 (27.3%), and non-total fluorescence (partial and rim fluorescence), n = 24/33 (72.7%). There was a statistical correlation between ICG patterns and grade of differentiation. Almost all lesions with uniform fluorescence pattern were well-differentiated HCCs (G1-G2), while partial and rim-type fluorescence pattern were more common among moderately and poorly differentiated HCCs (G3-G4) (88.9% vs 11.1%, 37.5% vs 62.5%, P = .025, respectively).Conclusions. ICG fluorescence imaging could be used to identify early the grade of HCC, ie intraoperatively, thus influencing the intraoperative treatment.

Histopathologic findings and survival outcomes of dogs undergoing liver lobectomy as treatment for spontaneous hemoabdomen secondary to a ruptured liver mass: retrospective analysis of 200 cases (2012-2020).

To describe the distribution of histopathologic diagnoses in a large population of dogs undergoing surgical treatment for spontaneous hemoperitoneum secondary to a ruptured liver mass. Additionally, to describe survival outcomes and assess for prognostic factors for overall survival time in this population. 200 client-owned dogs with spontaneous hemoperitoneum resulting from a liver mass. Medical records from 19 veterinary referral hospitals were reviewed. Data collected included signalment, clinical signs, blood work, radiographic and ultrasonographic findings, surgical methods, intraoperative and postoperative complications, outcomes, and histopathologic findings. Follow-up information was obtained by contacting the referring veterinarian or owner. Well-differentiated hepatocellular carcinoma, benign masses, hemangiosarcoma, and other malignant tumors accounted for 36% (72/200), 27.5% (55/200), 25.5% (51/200), and 11% (22/200) of cases, respectively. Overall survival time for all dogs was 356 days and for the above categories was 897 days, 905 days, 45 days, and 109 days, respectively. Prognostic factors for survival included diagnosis, increased ALT, anemia, and whether a transfusion was received. Overall survival time in dogs with increased ALT was 644 versus 63 days with normal values. The majority of dogs (63.5%) were diagnosed with well-differentiated hepatocellular carcinoma or a benign process, resulting in favorable long-term survival. The distribution of histopathology for ruptured liver masses resulting in hemoperitoneum has not been previously reported and may be useful for client discussions prior to surgery.

Nickel chloride induces anticancer biological responses in hepatocellular carcinoma cell lines.

Nickel has long been known to have a toxic effect in humans and has been defined as a human carcinogen. However, recent studies have suggested that nickel chloride (NiCl2) may also possess anticancer properties. The liver is one of the target organs for nickel, and thus, the present study aims to evaluate the effect of NiCl2 on anticancer biological responses in hepatocellular carcinoma (HCC) cell lines. Both HuH-7, a well-differentiated HCC cell line, and Mahlavu cell line, a poorly differentiated HCC cell line, were exposed to NiCl2. It was determined that NiCl2 decreased cell viability in both cell lines in a dose- and time-dependent manner. Nickel chloride exposure at IC50 doses were observed to suppress the ability of HCC cells to produce colonies and also induce apoptosis of HCC cells by increasing Cleaved Caspase-3 protein levels. It was found that NiCl2 exposure affected cellular morphology, increased the LC3-II protein levels, and induced autophagy in parallel to increased apoptosis in HCC cells. It was also observed that NiCl2 suppressed cell migration, decreased the size and viability of HCC tumor spheroids generated in 3D cell cultures, and disrupted the spheroid structure of the tumor cells depending on E-cadherin expression levels. Furthermore, it was observed that all anticancer biological responses induced by NiCl2 occurred independently of the AKT signaling pathway. In conclusion, our results suggested that NiCl2 induced anticancer biological responses in HCC cell lines. Moreover, this study provided important new molecular and cellular biological basic data about the action mechanisms of NiCl2 in HCC.

Dual segmentation models for poorly and well-differentiated hepatocellular carcinoma using two-step transfer deep learning on dynamic contrast-enhanced CT images.

The aim of this study was to develop dual segmentation models for poorly and well-differentiated hepatocellular carcinoma (HCC), using two-step transfer learning (TSTL) based on dynamic contrast-enhanced (DCE) computed tomography (CT) images. From 2013 to 2019, DCE-CT images of 128 patients with 80 poorly differentiated and 48 well-differentiated HCCs were selected at our hospital. In the first transfer learning (TL) step, a pre-trained segmentation model with 192 CT images of lung cancer patients was retrained as a poorly differentiated HCC model. In the second TL step, a well-differentiated HCC model was built from a poorly differentiated HCC model. The average three-dimensional Dice's similarity coefficient (3D-DSC) and 95th-percentile of the Hausdorff distance (95% HD) were mainly employed to evaluate the segmentation accuracy, based on a nested fourfold cross-validation test. The DSC denotes the degree of regional similarity between the HCC reference regions and the regions estimated using the proposed models. The 95% HD is defined as the 95th-percentile of the maximum measures of how far two subsets of a metric space are from each other. The average 3D-DSC and 95% HD were 0.849 ± 0.078 and 1.98 ± 0.71mm, respectively, for poorly differentiated HCC regions, and 0.811 ± 0.089 and 2.01 ± 0.84mm, respectively, for well-differentiated HCC regions. The average 3D-DSC for both regions was 1.2 times superior to that calculated without the TSTL. The proposed model using TSTL from the lung cancer dataset showed the potential to segment poorly and well-differentiated HCC regions on DCE-CT images.