High-grade Dysplastic Nodules Research Articles

Feeding artery: a valuable feature for differentiation of regenerative nodule, dysplastic nodules and small hepatocellular carcinoma in CEUS LI-RADS.

To investigate whether the feeding artery (FA) feature can aid in discriminating small hepatocellular carcinoma (HCC) using the contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) from precancerous lesions. Between June 2017 and May 2021, a total of 347 patients with 351 precancerous liver lesions or small HCCs who underwent CEUS were enrolled. Two independent radiologists assigned LI-RADS categories to all lesions and assessed the presence of the FA feature, which was used as an ancillary feature to either upgrade or downgrade the LI-RADS category. The diagnostic performance of CEUS LI-RADS, both with and without the FA feature, was evaluated based on accuracy, sensitivity, specificity, positive predictive value, and negative predictive value. The FA feature was found to be more prevalent in HCC (85.54%, p < 0.001) than in regenerative nodules (RNs, 29.73%), low-grade dysplastic nodules (LGDNs, 33.33%), and high-grade dysplastic nodules (HGDNs, 55.26%). Furthermore, the presence of arterial phase hyperenhancement (APHE), washout (WO), and FA in liver nodules was associated with a higher expression of GPC-3 and Ki-67 compared to the group without these features (p < 0.001). After adjusting, the sensitivity and accuracy of LR-5 for HCC improved from 68.67% (95%CI: 62.46%, 74.30%) to 77.51% (95%CI: 71.72%, 82.44%) and from 69.23% (95%CI: 64.11%, 74.02%) to 73.79% (95%CI: 68.86%, 78.31%), respectively. The FA feature is a valuable feature for distinguishing small HCC and precancerous lesions and could be added as a possible ancillary feature in CEUS LI-RADS which was backed up by biomarkers. The presence of a feeding artery is a valuable imaging feature in the differentiation of HCC and precancerous lesions. Incorporating this characteristic in the CEUS LI-RADS can enhance the diagnostic ability. • Feeding artery is more frequent in HCC than in regenerative nodules, low-grade dysplastic nodules, and high-grade dysplastic nodules. • Feeding artery feature is a valuable ancillary feature for CEUS LI-RADS to differentiate regenerative nodules, low-grade dysplastic nodules, high-grade dysplastic nodules, and HCC. • The existence of feeding artery, arterial phase hyperenhancement, and washout is associated with more GPC-3 positive expression and higher Ki-67 expression than the group without these features.

Current Concepts of Precancerous Lesions of Hepatocellular Carcinoma: Recent Progress in Diagnosis

The most common cause of hepatocellular carcinoma (HCC) is chronic hepatitis and cirrhosis. It is proposed that precancerous lesions of HCC include all stages of the disease, from dysplastic foci (DF), and dysplastic nodule (DN), to early HCC (eHCC) and progressed HCC (pHCC), which is a complex multi-step process. Accurately identifying precancerous hepatocellular lesions can significantly impact the early detection and treatment of HCC. The changes in high-grade dysplastic nodules (HGDN) were similar to those seen in HCC, and the risk of malignant transformation significantly increased. Nevertheless, it is challenging to diagnose precancerous lesions of HCC. We integrated the literature and combined imaging, pathology, laboratory, and other relevant examinations to improve the accuracy of the diagnosis of precancerous lesions.

State-of-the-art review on the correlations between pathological and magnetic resonance features of cirrhotic nodules.

Hepatocellular carcinoma (HCC) has become the second greatest cause of cancer-related mortality worldwide and the newest advancements in liver imaging have improved the diagnosis of both overt malignancies and premalignant lesions, such as cirrhotic or dysplastic nodules, which is crucial to improve overall patient survival rate and to choose the best treatment options. The role of Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) has grown in the last 20 years. In particular, the introduction of hepatospecific contrast agents has strongly increased the definition of precursor nodules and detection of high-grade dysplastic nodules and early HCCs. Nevertheless, the diagnosis of liver tumours in cirrhotic patients sometimes remains challenging for radiologists, thus, in doubtful cases, biopsy and histological analysis become critical in clinical practice. This current review briefly summarizes the history of imaging and histology for HCC, covering the newest techniques and their limits. Then, the article discusses the links between radiological and pathological characteristics of liver lesions in cirrhotic patients, by describing the multistep process of hepatocarcinogenesis. Explaining the evolution of pathologic change from cirrhotic nodules to malignancy, the list of analyzed lesions provides regenerative nodules, low-grade and high-grade dysplastic nodules, small HCC and progressed HCC, including common subtypes (steatohepatitic HCC, scirrhous HCC, macrotrabecular massive HCC) and more rare forms (clear cell HCC, chromophobe HCC, neutrophil-rich HCC, lymphocyte-rich HCC, fibrolamellar HCC). The last chapter covers the importance of the new integrated morphological-molecular classification and its association with radiological features.

The dual role of transforming growth factor-beta signatures in human B viral multistep hepatocarcinogenesis: early and late responsive genes.

Transforming growth factor-beta (TGF-β) has a dichotomous role, functioning as a tumor suppressor and tumor promoter. TGF-β signatures, explored in mouse hepatocytes, have been reported to predict the clinical outcomes of hepatocellular carcinoma (HCC) patients; HCCs exhibiting early TGF-β signatures showed a better prognosis than those with late TGF-β signatures. The expression status of early and late TGF-β signatures remains unclear in defined lesions of human B-viral multistep hepatocarcinogenesis. The expression of TGF-β signatures, early and late responsive signatures of TGF-β were investigated and analyzed for their correlation in cirrhosis, low-grade dysplastic nodules (DNs), high-grade DNs, early HCCs and progressed HCCs (pHCCs) by real-time PCR and immunohistochemistry. The expression levels of TGF-β signaling genes (TGFB1, TGFBR1, TGFBR2 and SMAD4) gradually increased with the progression of hepatocarcinogenesis, peaking in pHCCs. The expression of early responsive genes of TGF-β (GADD45B, FBP1, CYP1A2 and CYP3A4) gradually decreased, and that of the late TGF-β signatures (TWIST and SNAI1) significantly increased according to the progression of multistep hepatocarcinogenesis. Furthermore, mRNA levels of TWIST and SNAI1 were well correlated with those of stemness markers, with upregulation of TGF-β signaling, whereas FBP1 expression was inversely correlated with that of stemness markers. The enrichment of the late responsive signatures of TGF-β with induction of stemness is considered to be involved in the progression of the late stage of multistep hepatocarcinogenesis, whereas the early responsive signatures of TGF-β are suggested to have tumor-suppressive roles in precancerous lesions of the early stage of multistep hepatocarcinogenesis.

Deep Learning-Based Classification of Hepatocellular Nodular Lesions on Whole-Slide Histopathologic Images

Hepatocellular nodular lesions (HNLs) constitute a heterogeneous group of disorders. Differential diagnosis among these lesions, especially high-grade dysplastic nodules (HGDNs) and well-differentiated hepatocellular carcinoma (WD-HCC), can be challenging, letalone biopsy specimens. We aimed to develop a deep learning system to solve these puzzles, improving the histopathologic diagnosis of HNLs (WD-HCC, HGDN, low-grade DN, focal nodular hyperplasia, hepatocellular adenoma), and background tissues (nodular cirrhosis, normal liver tissue). The samples consisting of surgical and biopsy specimens were collected from 6 hospitals. Each specimen was reviewed by 2 to 3 subspecialists. Four deep neural networks (ResNet50, InceptionV3, Xception, and the Ensemble) were used. Their performances were evaluated by confusion matrix, receiver operating characteristic curve, classification map, and heat map. The predictive efficiency of the optimal model was further verified by comparing with that of 9 pathologists. We obtained 213,280 patches from 1115 whole-slide images of 738 patients. An optimal model was finally chosen based on F1 score and area under the curve value, named hepatocellular-nodular artificial intelligence model (HnAIM), with the overall 7-category area under the curve of 0.935 in the independent external validation cohort. For biopsy specimens, the agreement rate with subspecialists' majority opinion was higher for HnAIM than 9 pathologists on both patch level and whole-slide images level. We first developed a deep learning diagnostic model for HNLs, which performed well and contributed to enhancing the diagnosis rate of early HCC and risk stratification of patients with HNLs. Furthermore, HnAIM had significant advantages in patch-level recognition, with important diagnostic implications for fragmentary or scarce biopsy specimens.

Preneoplastic lesions in the liver: Molecular insights and relevance for clinical practice.

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the most frequent primary liver cancers, accounting for approximately 80% and 15%, respectively. HCC carcinogenesis occurs mostly in cirrhosis and is a complex multi-step process, from precancerous lesions (low-grade and high-grade dysplastic nodules) to progressed HCC. During the different stages of liver carcinogenesis, there is an accumulation of pathological, genetic and epigenetic changes leading to initiation, malignant transformation and finally tumour progression. In contrast, a small subset of HCC occurs in normal liver from the transformation of hepatocellular adenoma (HCA), a benign hepatocellular tumour. The recent molecular classification enables to stratify HCAs according to their risk of complication, in particular malignant transformation, associated with mutations in exon 3 of the catenin beta 1 (CTNNB1) gene. Cholangiocarcinoma (CCA) derives from the multistep malignant transformation of preneoplastic lesions, like biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB), for which a pre-operative diagnosis remains difficult. Different genetic alterations are involved in BilIN and IPNB progression, leading to the development of tubular or intestinal adenocarcinoma. The aims of this review are to describe the main clinical and molecular features of preneoplastic lesions leading to the development of HCC and CCA, their implications in clinical practice and the perspectives for future research.

High Grade Dysplastic Nodule in a Non-Cirrhotic Liver in the Young

Patients with high grade dysplastic nodule (HGDN) have an increased risk for development of hepatocellular carcinoma. Hepatocellular carcinoma (HCC) in a young patient with no cirrhosis or fibrosis is a relatively rare condition. HCC develops in patients in the setting of liver cirrhosis with established risk factors related to various etiologies including hepatitis virus infection, high alcohol intake or metabolic diseases. This was a case of a 29-year-old male with a 7-month history of intermittent right upper quadrant pain with CT scan findings of caudate lobe mass with malignant features. The patient underwent extended left hepatectomy with caudate lobectomy. Patient was discharged on fifth postoperative day, and was advised for follow-up surveillance on an outpatient basis. Liver cirrhosis is the main risk factor for developing HGDN, although rare cases of HGDN in a non-cirrhotic young patient should not be disregarded. Even though, it difficult to differentiate HGDN from early HCC based on radiologic imaging and histopathological criteria. Early diagnosis accompanied with proper surgical intervention such as anatomic resection and regular surveillance should be considered in the course and management of these patients, despite its rarity

Evaluation of nuclear PGAM2 value in hepatocellular carcinoma prognosis.

Phosphoglycerate mutase (PGAM) is a critical enzyme in glycolysis. PGAM2 is abundant in several types of tissues and malignant tumours. However, there is limited information regarding their clinicopathological significance in dysplastic nodules and hepatocellular carcinoma (HCC). This study aims to investigate the prognostic value of PGAM2 as a new biomarker for HCC. The PGAM2 expression level was evaluated by immunohistochemistry in liver cirrhosis (n = 10), low-grade dysplastic nodules (n = 15), high-grade dysplastic nodules (n = 15) and HCCs (n = 20) and 178 pairs of HCC and adjacent peritumoral liver tissues. We selected X-tile software for counting cut-point based on the outcomes for prognosis analysis, and used Kaplan-Meier analysis and Cox regression analysis can assess the prognosis of clinicopathologic parameters. Nuclear PGAM2 was significantly overexpressed in peritumoral liver tissues compared with HCC tissues (P = 0.0010). Kaplan-Meier analyses of 178 HCC samples revealed that nuclear PGAM2's high expression level, but not cytoplasmic PGAM2, was significantly related to good overall survival rate (OS). In addition, univariate and multivariate Cox analyses indicated nuclear PGAM2 expression could be regarded as valuable predictors for OS in HCC. PGAM2 was highly expressed in HCC tissues than liver cirrhosis tissues, and nuclear PGAM2's high expression might demonstrate HCC patients have poor postoperative results. Thus, nuclear PGAM2 can be regarded as valuable predictors for OS in HCC patients after surgery.

Characterisation of dysplastic liver nodules using low-pass DNA sequencing and detection of chromosome arm-level abnormalities in blood-derived cell-free DNA.

High-grade dysplasia carries significant risk of transformation to hepatocellular carcinoma (HCC). Despite this, at the current standard of care, all non-malignant hepatic nodules including high-grade dysplastic nodules are managed similarly. This is partly related to difficulties in distinguishing high-risk pathology in the liver. We aimed to identify chromosome arm-level somatic copy number alterations (SCNAs) that characterise the transition of liver nodules along the cirrhosis-dysplasia-carcinoma axis. We validated our findings on an independent cohort using blood-derived cell-free DNA. A repository of non-cancer DNA sequences obtained from patients with HCC (n = 389) was analysed to generate cut-off thresholds aiming to minimise false-positive SCNAs. Tissue samples representing stages from the multistep process of hepatocarcinogenesis (n = 184) were subjected to low-pass whole genome sequencing. Chromosome arm-level SCNAs were identified in liver cirrhosis, dysplastic nodules, and HCC to assess their discriminative capacity. Samples positive for 1q+ or 8q+ arm-level duplications were likely to be either HCC or high-grade dysplastic nodules as opposed to low-grade dysplastic nodules or cirrhotic tissue with an odds ratio (OR) of 35.5 (95% CI 11.5-110) and 16 (95% CI 6.4-40.2), respectively (p < 0.0001). In an independent cohort of patients recruited from Nottingham, UK, at least two out of four alterations (1q+, 4q-, 8p-, and 8q+) were detectable in blood-derived cell-free DNA of patients with HCC (n = 22) but none of the control patients with liver cirrhosis (n = 9). Arm-level SCNAs on 1q+ or 8q+ are associated with high-risk liver pathology. These can be detected using low-pass sequencing of cell-free DNA isolated from blood, which may be a future early cancer screening tool for patients with liver cirrhosis. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

RESULTS OF IMMUNOHISTOCHEMISTRY IN THE DIFFERENTIAL DIAGNOSIS OF EARLY HEPATOCELLULAR CARCINOMA AND NODULES WITH HIGH-GRADE DYSPLASIA IN PATIENTS WITH CIRRHOSIS.

Hepatocellular carcinoma (HCC) is the most frequent primary cancer of the liver and cirrhosis is considered a pre-malignant disease. In this context, the evolutionary sequence from low grade dysplastic nodule and high grade dysplastic nodule (HGDN) to early HCC and advanced HCC has been studied. The differential diagnosis between HGDN and early HCC is still a challenge, especially in needle biopsies. To evaluate an immunohistochemistry panel to differentiate dysplastic nodules and HCC. Patients with cirrhosis who underwent surgical resection or liver transplantation were included. The sensitivity, specificity and accuracy for the diagnosis of neoplasia were analyzed by evaluating five markers: heat shock protein 70, glypican 3, glutamine synthetase, clathrin heavy chain and beta-catenin. P≤0.05 was considered statistically significant. One hundred and fifty-six nodules were included; of these, 57 were HCC, 14 HGDN, 18 low grade dysplastic nodules and 67 regenerative macronodules. Sensitivity of HCC diagnosis was 64.9% for glypican 3 and 77.2% for glutamine syntetase, while specificity was 96.0% and 96.0% respectively. When the panel of four markers was considered (excluding beta catenin), the specificity ranged from 87.9% for one positive marker to 100% for at least three markers. The best accuracy for HCC diagnosis was obtained with at least two positive markers, which was associated with a sensitivity of 82.5% and specificity of 99%. Differential diagnosis of dysplastic nodules and HCC by morphological criteria can be challenging. Immunomarkers are useful and should be used for the differential diagnosis between HCC and HGDN.

Abnormal expression of HNRNPA3 in multistep hepatocarcinogenesis.

Hepatocarcinogenesis is a multistep process involving progression from cirrhosis, to low-grade dysplastic nodule, to high-grade dysplastic nodule (HGDN) and, eventually, to hepatocellular carcinoma (HCC). Early detection of HCC is challenging as the differential diagnosis between HGDN and early HCC (eHCC) is difficult. The aim of the present study was to identify a novel biomarker to specifically differentiate between HGDN and eHCC, which may facilitate early diagnosis of HCC. Immunohistochemistry was performed to determine the expression of heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3) in cirrhosis, dysplastic nodules (DNs), well-differentiated HCC and progressed HCC. The staining was evaluated by assigning a staining intensity score of 0–3 and a percentage of positively stained cells score of 0–4. Receiver operator characteristic (ROC) curve analysis was used to assess the ability of HNRNPA3 expression to differentiate between DNs and HCC. HNRNPA3 expression increased in a stepwise trend in non-tumor hepatic tissue, DNs, eHCC and progressed HCC. ROC curves revealed that HNRNPA3 expression could be used to differentiate between HGDN and eHCC, particularly in combination with glypican 3 (GPC3), with a specificity of 100%. Moreover, HNRNPA3 expression was associated with HCC differentiation. In addition, high expression of HNRNPA3 was found to be associated with poor survival rates in patients with HCC. These findings demonstrated that HNRNPA3 combined with GPC3 is a helpful diagnostic biomarker in the differential diagnosis during the multistep process of hepatocarcinogenesis, particularly in the differential diagnosis between HGDN and eHCC. To the best of our knowledge, this is the first study to report the significance of HNRNPA3 in hepatocarcinogenesis and its potential role in carcinogenesis.

Radiologic-Pathologic Correlation of Hepatobiliary Phase Hypointense Nodules without Arterial Phase Hyperenhancement at Gadoxetic Acid-enhanced MRI: A Multicenter Study.

Background Hepatobiliary phase (HBP) hypointense nodules without arterial phase hyperenhancement (APHE) at gadoxetic acid-enhanced MRI may indicate hepatocellular carcinoma (HCC) or nonmalignant cirrhosis-associated nodules. Purpose To assess the distribution of pathologic diagnoses of HBP hypointense nodules without APHE at gadoxetic acid-enhanced MRI and to evaluate clinical and imaging features in differentiating their histologic grades. Materials and Methods This retrospective multicenter study included pathologic analysis-confirmed HBP hypointense nodules without APHE (≤30 mm) in patients with chronic liver disease or cirrhosis screened between January 2008 and June 2016. Central pathologic review by 10 pathologists determined final histologic grades as progressed HCC, early HCC, high-grade dysplastic nodule (DN), and low-grade DN or regenerative nodule. Gadoxetic acid-enhanced MRI features were analyzed by three radiologists. Multivariable logistic regression analyses with elastic net regularization were performed to identify clinical and imaging features for differentiating histologic grades. Results There were 298 patients (mean age, 59 years ± 10; 226 men) with 334 nodules evaluated, and progressed HCCs were diagnosed in 44.0% (147 of 334), early HCCs in 20.4% (68 of 334), high-grade DNs in 27.5% (92 of 334), and low-grade DNs or regenerative nodules in 8.1% (27 of 334). Serum α-fetoprotein level 100 ng/mL or greater (odds ratio, 2.7; P = .01) and MRI features including well-defined margin (odds ratio, 5.5; P = .003), hypointensity at precontrast T1-weighted imaging (odds ratio, 3.2; P < .001), intermediate hyperintensity at T2-weighted imaging (odds ratio, 3.4; P < .001), and restricted diffusion (odds ratio, 1.9; P = .04) were independent predictors for progressed HCC at multivariable analysis. Conclusion In patients at high risk for hepatocellular carcinoma (HCC), hepatobiliary phase hypointense nodules without arterial phase hyperenhancement at gadoxetic acid-enhanced MRI corresponded mainly to progressed HCCs, early HCCs, and high-grade dysplastic nodules. High α-fetoprotein level and some imaging features at MRI helped to differentiate progressed HCC from lower grade nodules. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Motosugi in this issue.

Characterization of Early Hepatocellular Carcinoma and High-Grade Dysplastic Nodules on Contrast-Enhanced Ultrasound: Correlation With Histopathologic Findings.

To explore the enhancement features of early hepatocellular carcinoma (HCC, including well-differentiated HCC and high-grade dysplastic nodules with a focus of HCC) and high-grade dysplastic nodules (HGDNs) on contrast-enhanced ultrasound (CEUS), correlated with the histopathologic findings. This retrospective study enrolled 81 patients with 85 pathologically confirmed hepatic lesions (69 early HCCs and 16 HGDNs). All of the hepatic lesions were examined by CEUS with SonoVue (Bracco SpA, Milan, Italy) before surgery or biopsy. The enhancement features of early HCCs and HGDNs were evaluated and compared with histopathologic findings. Thirty-eight (55.1%) early HCCs showed arterial-phase hyperenhancement (APHE). The major enhancement pattern of early HCCs was APHE without portal venous/late-phase wash-out (20 of 69 [29.0%]). Eight (11.6%) early HCCs manifested APHE. Wash-out was observed in 30 (43.5%) early HCCs. Sixteen (23.2%) early HCCs showed very-late wash-out (>120 seconds). Wash-out was not observed in all HGDNs. Of the 16 HGDNs, arterial-phase isoenhancement without portal venous/late-phase wash-out was the major enhancement pattern (n = 7 [43.8%]). The degree of CD34 expression of sinusoidal endothelial cells was more diffuse in early HCCs than in HGDNs (56.5% versus 12.5%; P = .001). Arterial-phase enhancement patterns of early HCCs on CEUS were correlated with the degree of CD34 expression (P = .039). Enhancement patterns were significantly different between early HCCs and HGDNs on CEUS. Diffuse CD34 expression of sinusoidal endothelial cells in early HCC was correlated with APHE on CEUS.

MRI in the differential diagnosis between well-differentiated hepatocellular carcinomas and high-grade dysplastic nodules in cirrhotic liver

ObjectiveTo assess the diagnostic efficacy of magnetic resonance imaging (MRI) in the differential diagnosis between well-differentiated hepatocellular carcinomas (WD-HCCs) and high-grade dysplastic nodules (HGDNs) in cirrhotic liver. MethodsFrom January 2012 to April 2018, we retrospectively analyzed 91 cirrhotic nodules (HGDN, n = 31, WD-HCC, n = 60) which were confirmed by surgery or pathology. Each patient underwent gadobenate dimeglumine-enhanced hepatic MRI. The MRI characteristics and enhancement effects were calculated and analyzed. ResultsHyperintensity on diffusion-weighted imaging (DWI), the typical enhancement pattern and hypo-intensity on T1-Weighted imaging (T1WI)were showed with statistically significant difference between WD-HCCs and HGDNs in cirrhotic live (P = 0.002, 0.008, 0.002, respectively). And high signal intensity (SI) on DWI (sensitivity, 66.7%, specificity, 67.7%) was the most specific feature to differentiated WD-HCCs from HGDNs. The combination of DWI and the dynamic enhancement pattern improved the differentiation of WD-HCCs from HGDNs(specificity 83.9%). ConclusionDWI is the most specific technique to differentiate WD-HCCs from HGDNs. The combination of DWI and the typical dynamic enhancement pattern can improve the differentiation of WD-HCCs from HGDNs. Pre-enhanced T1WI, as well as a capsule, provides additional diagnostic values.

Risk analysis for hypervascular transformation of precancerous lesion of hepatocellular carcinoma

Objective: To investigate the risk factors for diagnosis of transformation of high-grade dysplastic nodules (HGDN) to hypervascular hepatocellular carcinoma (HCC) in patients with chronic liver disease with gadoxetate disodium-enhanced magnetic resonance imaging (MRI). Methods: 2 037 cases that underwent gadoxetate disodium-enhanced magnetic resonance imaging from January 2012 to December 2014 were retrospectively analyzed. 51 cases of HGDN with a background of chronic liver disease were screened and followed-up for at least 2 times with gadoxetate disodium-enhanced MRI scans and contrast enhanced CT scans was performed within 1 month before and after the first MRI. The endpoint of study was transformation of HGDN to hypervascular hepatocellular carcinoma, with a deadline of April 2019. Transformation was divided into transformed (group A) and untransformed (group B) group according to the presence or absence of hypervascularization. Linear regression was used to analyze the possible risk factors for hypervascular transformation. Results: There were 36 nodules in group A and 79 nodules in group B, and hypervascular transformation rate was 31.3% (36/115). On univariate analysis, the length and diameter of nodule was > 10.2 mm (P = 0.034), with annual growth rate > 2% (P < 0.001), and lipid content (P = 0.007) was related to the occurrence of hypervascularity. On multivariate analysis, the annual growth rate of nodules was an independent risk factor for the occurrence of hypervascularity (P < 0.000 1). Conclusion: The annual growth rate of HGDN in patients with chronic liver disease diagnosed with gadoxetate disodium-enhanced MRI imaging can be used as a potential predictor of hypervascularization.

[Expert consensus on multidisciplinary diagnosis and treatment of precancerous lesions of hepatocellular carcinoma (2020 edition)].

Hepatocellular carcinoma (HCC) currently holds the second position for cause of cancer-related deaths in China. Most of the pathogenic characteristics of HCC in China follow the tri-step model of hepatitis B-cirrhosis-liver cancer. The screening of precancerous lesions of stomach cancer, colorectal cancer and cervical cancer has achieved remarkable results for the diagnosis and treatment of malignant tumors. Dysplastic nodules in the state of cirrhosis have strong potential for malignant changes, especially high-grade dysplastic nodules, have extremely high canceration rate. This expert consensus is based on the research results and clinical experience of foreign and native experts of this field. Furthermore, this consensus summarizes and defines high-grade dysplastic nodules of the liver as precancerous lesions of HCC through multidisciplinary collaboration in terms of conception, screening, diagnosis, treatment and follow-up, with the aim to reduce the HCC incidence and improve the overall therapeutic effect of HCC in China.

[Research progress in imaging characteristics of precancerous nodules in hepatocellular carcinoma cells].

Hepatocarcinogenesis is a multi-step process in which detection of precancerous lesions and advanced hepatocellular carcinoma in its progressive stage is crucially important for predicting tumor behavior, estimating the extent of lesions, implementing the optimal treatment strategy, and improving the survival of patients. The rapid development and wide application of liver imaging technology, especially the application of hepatocyte-specific gadoxetate disodium MRI contrast agent (Gd-EOB-DTPA MRI), not only provide information on vascular changes of liver nodules and hepatocyte function, but also has become a precise diagnostic method for differentiating cirrhotic regenerative nodule (RN), low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN), early hepatocellular carcinoma and HCC. Hence, the risk for malignant progression is stratified. This review summarizes the value of Gd-EOB-DTPA MRI for early HCC diagnosis and analyzes the key concepts in the multi-step process of HCC development as well as the imaging manifestations of precancerous lesions that may eventually be transformed into typical HCC.

663 Hepatic Adenoma Masquerading as a Hepatocellular Carcinoma in a Patient With a Fontan Procedure on the Oral Contraceptive Pill

The oral contraceptive pill (OCP) has traditionally been contraindicated in the Fontan circulation due to its thromboembolic profile [[1]Gordon-Walker T.T. Bove K. Veldtman G. Fontan-associated liver disease: A review.Journal of cardiology. 2019; 74: 223-232Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar]; though our centre uses it with caution with concomitant anticoagulation. Our case suggests that the OCP may be a potential confounder in Fontan patients with liver lesions and this possibility should be discussed with patients. A 21-year-old female was found to have an incidental liver nodule on routine hepatocellular carcinoma (HCC) screening on a background of an extra-cardiac conduit Fontan procedure for tricuspid atresia and pulmonary stenosis and Crohn’s disease. Medications included the OCP, Warfarin and Sulfasalazine. Liver ultrasound with acoustic radiation force impulse elastography suggested cirrhosis. Subsequent magnetic resonance imaging demonstrated a 25mm liver lesion consistent with a HCC. Percutaneous biopsy and microwave ablation was performed. Histology was initially described as HCC or a high-grade dysplastic nodule. Further opinion with immunohistochemistry however revealed an inflammatory subtype hepatic adenoma(HA). Cirrhosis and HCC are well described in patients with Fontan palliation postulated due to increased central venous pressure and reduced cardiac output [[2]Kuwabara M. Niwa K. Toyoda T. Shirai T. Tateno S. Ohuchi H. et al.Liver Cirrhosis and/or Hepatocellular Carcinoma Occurring Late After the Fontan Procedure- A Nationwide Survey in Japan.Circulation journal : official journal of the Japanese Circulation Society. 2018; 82: 1155-1160Crossref PubMed Scopus (21) Google Scholar]. Fontan patients often have benign liver lesions confirmed via imaging. Unlike HCC that is often associated with a poor prognosis [[3]Oh C. Youn J.K. Han J.W. Kim G.B. Kim H.Y. Jung S.E. Hepatocellular carcinoma after the Fontan procedure in a 16-year-old girl: A case report.Medicine (Baltimore). 2016; 95: e4823Crossref PubMed Scopus (30) Google Scholar], HAs are rare benign liver tumours [[4]Babaoglu K. Binnetoglu F.K. Aydogan A. Altun G. Gurbuz Y. Inan N. et al.Hepatic adenomatosis in a 7-year-old child treated earlier with a Fontan procedure.Pediatric cardiology. 2010; 31: 861-864Crossref PubMed Scopus (20) Google Scholar] that are rarely associated with cardiac hepatopathy [[5]Ponnatapura J. Kielar A. Burke L.M.B. Lockhart M.E. Abualruz A.R. Tappouni R. et al.Hepatic complications of oral contraceptive pills and estrogen on MRI: Controversies and update - Adenoma and beyond.Magnetic resonance imaging. 2019; 60: 110-121Crossref PubMed Scopus (6) Google Scholar]. However, HAs are strongly associated with the OCP, anabolic steroids and conditions that cause impaired glycogenolysis [[6]Abarbanell G. Tepper N.K. Farr S.L. Safety of contraceptive use among women with congenital heart disease: A systematic review.Congenital heart disease. 2019; 14: 331-340Crossref PubMed Scopus (11) Google Scholar]. We highlight need for care by expert centres and for specialised opinion in interpretation of investigations. We reinforce need for on-going HCC surveillance in Fontan patients and careful consideration of the OCP.

Dynamics of Genomic, Epigenomic, and Transcriptomic Aberrations during Stepwise Hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) undergoes a stepwise progression from liver cirrhosis to low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN), early HCC (eHCC), and progressed HCC (pHCC). Here, we profiled multilayered genomic, epigenomic, and transcriptomic aberrations in the stepwise hepatocarcinogenesis. Initial DNA methylation was observed in eHCC (e.g., DKK3, SALL3, and SOX1) while more extensive methylation was observed in pHCC. In addition, eHCCs showed an initial loss of DNA copy numbers of tumor suppressor genes in the 4q and 13q regions, thereby conferring survival benefits to cancer cells. Transcriptome analysis revealed that HGDNs expressed endoplasmic reticulum (ER) stress-related genes, while eHCC started to express oncogenes. Furthermore, integrative analysis indicated that expression of the serine peptidase inhibitor, Kazal type 1 (SPINK1), played a pivotal role in eHCC development. Significant demethylation of SPINK1 was observed in eHCC compared to HGDN. The study also demonstrated that ER stress may induce SPINK1 demethylation and expression in liver cancer cells. In conclusion, these results reveal the dynamics of multiomic aberrations during malignant conversion of liver cancer, thus providing novel pathobiological insights into hepatocarcinogenesis. SIGNIFICANCE: Multiomics profiling and integrative analyses of stepwise hepatocarcinogenesis reveal novel mechanistic and clinical insights into hepatocarcinogenesis.

Comparison of pulsed and oscillating gradient diffusion-weighted MRI for characterizing hepatocellular nodules in liver cirrhosis: ex vivo study in a rat model.

In contrast to classical pulsed gradient diffusion-weighted MRI, oscillating gradient diffusion-weighted MR imaging (DWI) is sensitive to short distance diffusion changes at the intracellular level. To compare the diagnostic performance of pulsed and oscillating DWI for characterizing hepatocellular nodules in a rat model of hepatic cirrhosis. Prospective, experimental study. Cirrhosis was induced by weekly intraperitoneal injection of diethylnitrosamine in Wistar rats. Ex vivo liver MRI was performed at 7T with T1 -weighted, T2 -weighted, pulsed, and oscillating gradient diffusion-weighted sequences. Apparent diffusion coefficient from pulsed (ADCpulsed ) and oscillating gradient (ADCoscillating ) sequences was calculated in 82 nodules identified on the T1 /T2 -weighted images and on pathological examination. Two pathologists classified the nodules in three categories: benign (regenerative and low-grade dysplastic nodules), with intermediate malignancy (high-grade dysplastic nodules and early hepatocellular carcinomas) and overtly malignant (progressed hepatocellular carcinomas). Differences between groups were assessed with Kruskal-Wallis and Mann-Whitney tests. ADC, mainly ADCoscillating , increased in the group of nodules with intermediate malignancy (ADCpulsed : 0.75 ± 0.25 × 10-3 mm2 /s vs. 0.64 ± 0.07 × 10-3 mm2 /s in benign nodules, P = 0.025; ADCoscillating : 0.81 ± 0.20 × 10-3 mm2 /s vs. 0.65 ± 0.13 × 10-3 mm2 /s, P = 0.0008) and ADCpulsed decreased in the group of progressed hepatocellular carcinomas (ADCpulsed : 0.60 ± 0.08 × 10-3 mm2 /s, P = 0.042; ADCoscillating : 0.68 ± 0.08 × 10-3 mm2 /s, P = 0.1). ADC during hepatocarcinogenesis in rats increased in nodules with intermediate malignancy and decreased in progressed hepatocellular carcinomas. Our results suggest that oscillating gradient DWI is more sensitive to the early steps of hepatocarcinogenesis and might be useful for differentiating between high-grade dysplastic nodules / early hepatocellular carcinomas and regenerating nodules / low-grade dysplastic nodules. 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:1065-1074.