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Background Imaging markers of hepatocellular carcinoma (HCC) on the basis of molecular classification are important for predicting malignancy grade and prognosis. P53-mutated HCC is a major aggressive subtype; however, its imaging characteristics have not been clarified. Purpose To clarify the imaging characteristics of P53-mutated HCC at dynamic CT and gadoxetic acid-enhanced MRI that are correlated with its clinical features, pathologic findings, and prognosis. Materials and Methods In this retrospective single-center study, patients with surgically resected HCC between January 2015 and May 2018 in a university hospital were evaluated. HCC was classified into P53-mutated HCC and non-P53-mutated HCC using immunostaining. Dynamic CT and gadoxetic acid-enhanced MRI findings, clinical features, pathologic findings, and prognosis were compared using Mann-Whitney test, χ 2 test, multivariable regression analysis, receiver operating characteristic analysis, Kaplan-Meier method, and log-rank test. Immunohistochemical expression of P53, organic anion transporting polypeptide 1B3 (OATP1B3), and CD34 were evaluated, and the correlations were analyzed using the Pearson correlation test. Results In total, 149 patients (mean age, 67 years ± 9 [SD]; 103 men) with 173 HCCs were evaluated. P53-mutated HCC ( n = 28) demonstrated higher serum α-fetoprotein (median, 127.5 ng/mL vs 5.5 ng/mL; P < .001), larger size (40.4 mm ± 29.7 vs 26.4 mm ± 20.5; P = .001), and higher rates of poorly differentiated HCC (22 of 28 [79%] vs 24 of 145 [17%]; P < .001). Dilated vasculature in the arterial phase of dynamic CT (odds ratio, 14; 95% CI: 3, 80; P = .002) and a lower relative enhancement ratio in the hepatobiliary phase (odds ratio, 0.05; 95% CI: 0.01, 0.34; cutoff value, 0.69; P = .002) independently predicted P53-mutated HCC. OATP1B3 expression and P53 expression were inversely correlated ( P = .002; R = -0.24). Five-year overall survival was worse for P53-mutated HCC (50.0% vs 72.6%; P = .02). Conclusion Dilated vasculature at the arterial phase of dynamic CT and a lower relative enhancement ratio at the hepatobiliary phase of gadoxetic acid-enhanced MRI were useful markers for P53-mutated hepatocellular carcinoma with poor prognosis. © RSNA, 2022 Online supplemental material is available for this article.

We report a rare case of intrahepatic cholangiocarcinoma (iCCA) that arose from a simple hepatic cyst. A 72-year-old man was transferred to our hospital for treatment of a liver tumor. Dynamic contrast-enhanced computed tomography (CT) detected a small tumor surrounding a hepatic cyst in segment 8 that showed low attenuation on a pre-contrast CT, rim-like enhancement in the arterial dominant phase, and delayed enhancement in the delayed phase. On gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced dynamic magnetic resonance imaging (MRI), the hepatic tumor had hypointensity on T1-weighted images, hyperintensity on T2-weighted images, hyperintensity on diffusion-weighted images, and hypointensity on the hepatobiliary phase. The tumor increased in size after 6 months, and partial hepatectomy was performed. Histopathologically, the tumor was consistent with moderately to poorly differentiated adenocarcinoma with the microscopic lymphatic, portal, and hepatic venous invasion. The epithelium of the cystic region largely comprised carcinoma in situ, with dysplastic biliary epithelial cells and a small portion of normal biliary epithelial cells. The transition from carcinoma in situ to invasive carcinoma was confirmed, and the patient was diagnosed with iCCA arising from a hepatic cyst via dysplasia and carcinomatous transformation., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Gadoxetic acid-enhanced magnetic resonance imaging (MRI) plays important roles in diagnosis of hepatic lesions because of its superiority in the detectability of small lesions, its differentiation ability, and its utility for the early diagnosis of hepatocellular carcinoma (HCC). In HCC, expression of organic anion transporting polypeptide (OATP) 1B3 correlates with the enhancement ratio in the hepatobiliary phase. Gadoxetic acid-enhanced MRI, an indirect molecular imaging method, reflects OATP1B3 expression in HCC. OATP1B3 expression gradually decreases from the dysplastic nodule stage to advanced HCC. Decreased expression is a sensitive marker of multistep hepatocarcinogenesis, especially in the early stages. Hypervascular HCCs commonly show hypointensity in the hepatobiliary phase corresponding to a decrease in OATP1B3; however, approximately 10% of HCCs show hyperintensity due to OATP1B3 overexpression. This hyperintense HCC shows less aggressive biological features and has a better prognosis than hypointense HCC. Hyperintense HCC can be classified into a genetic subtype of HCC with a mature hepatocyte-like molecular expression. OATP1B3 expression and the less aggressive nature of hyperintense HCC are regulated by the molecular interaction of β-catenin signaling and hepatocyte nuclear factor 4α, a tumor suppressor factor. Gadoxetic acid-enhanced MR imaging has the potential to be an imaging biomarker for HCC. KEY POINTS: • The hepatobiliary phase is a sensitive indirect indicator of organic anion transporting polypeptide1B3 (OATP1B3) expression in hepatocellular carcinoma (HCC). • The OATP1B3 expression, namely, enhancement in the hepatobiliary phase, decreases from the very early stage of hepatocarcinogenesis, contributing to early diagnosis of HCC. • HCC showing hyperintensity on the hepatobiliary phase is a peculiar genetic subtype of HCC with OATP1B3 overexpression, a less aggressive nature, and mature hepatocyte-like molecular/genetic features.

Hepatocellular adenomas (HCAs) are benign hepatic tumors that can be complicated by bleeding and/or malignant transformation. The epidemiology of HCAs has changed over recent decades, primarily influenced by an increased incidence of obesity in both men and women. Currently, at least eight distinct pathomolecular subtypes of HCAs have been identified, several of which have distinguishing and pertinent imaging features on MRI. Emerging evidence suggests that hepatobiliary phase appearance may provide diagnostic and prognostic information. The purpose of this article is to review the current pathomolecular lexicon and imaging features with emphasis on hepatobiliary phase appearance. Level of Evidence: 5 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:1630-1640., (© 2019 International Society for Magnetic Resonance in Medicine.)

Objectives: To determine the imaging and clinicopathological features of MRI doughnut-like nodules (HBP-doughnut nodules), hyperintense at the hepatobiliary phase (HBP) after injection of gadoxetic acid (EOB) and without arterial-phase hyperenhancement (APHE) in cirrhotic liver., Methods: The Institutional Review Board approved this retrospective study and informed consent was waived. We enrolled 309 consecutive patients with liver cirrhosis who were examined by EOB-MRI, dynamic CT, and angiography-assisted CT between 2008 and 2012 and searched for HBP-doughnut nodules. We evaluated imaging characteristics including haemodynamics and signal intensity of MRI, pathological findings, and frequency of malignant transformation., Results: One hundred and one HBP-doughnut nodules without APHE were identified in 18 patients (6%), including seven of 59 (12%) patients with hepatitis-B-virus-related, nine of 230 (3.9%) with hepatitis-C-virus-related, and two of 33 (6.1%) with alcoholic cirrhosis. All nodules showed enhancement peaks in the portal phase, the same or increased intranodular portal supply on CT during arterial portography, and the same or decreased intranodular arterial supply on CT during hepatic arteriography. On T2-weighted and diffusion-weighted images, 37 (36%) and 24 (24%) nodules, respectively, showed hyperintensity predominantly in the central area. Three nodules were diagnosed by fine needle biopsy as non-neoplastic hepatic nodules. Ninety-three of 101 (92%) nodules in 16 patients were followed up during an observation period of 1163 ± 902 days (range 57-2920 days), and none showed malignant transformation., Conclusion: HBP-doughnut nodules without APHE in cirrhotic liver were not infrequent. None became malignant. We propose calling them 'multiacinar cirrhotic nodules' based on the classification by an International Working Party., Key Points: • HBP-doughnut nodules without APHE were seen in 6% of patients with liver cirrhosis. • The enhancement peak of HBP-doughnut nodules without APHE was in the portal phase, which reflected the fact that they were supplied predominantly by the portal vein, based on angiography-assisted CT findings. • None of the HBP-doughnut nodules without APHE in cirrhotic liver became malignant, and in conjunction with limited pathological features, they may be corresponding to multiacinar cirrhotic nodules in the International Working Party classification.

Hepatocellular carcinoma (HCC) is heterogeneous in terms of its biological nature. Various factors related to its biological nature, including size, multifocality, macroscopic morphology, grade of differentiation, macro/microvascular invasion, bile duct invasion, intra-tumoral fat and molecular factors, and their value as prognostic imaging biomarkers have been reported. And recently, genome-based molecular HCC classification correlated with clinical outcome has been elucidated. The imaging biomarkers suggesting a less aggressive nature of HCC are smaller size, solitary tumor, smooth margin suggesting small nodular type with indistinct margin and simple nodular type with distinct margin, capsule, imaging biomarkers predicting early or well-differentiated grade, intra-tumoral fat detection, and low fluorodeoxyglucose (FDG) accumulation. The imaging biomarkers suggesting an aggressive HCC nature are larger size, multifocality, non-smooth margin suggesting simple nodular type with extranodular growth, confluent multinodular, and infiltrative type, imaging biomarkers predicting poor differentiation, macrovascular tumor thrombus, predicting microvascular invasion imaging biomarkers, bile duct dilatation or tumor thrombus, and high FDG accumulation. In the genome-based molecular classification, CTNNB-1 mutated HCC shows a less aggressive nature, while CK19/EpCAM positive HCC and macrotrabecular massive HCC show an aggressive one. Better understanding of these imaging biomarkers can contribute to devising more appropriate treatment plans for HCC.

Objective: The purpose of this study is to identify points useful in the imaging differentiation of hepatocellular carcinoma (HCC) showing hyperintensity on the hepatobiliary phase of gadoxetic acid-enhanced MRI and focal nodular hyperplasia (FNH) and FNH-like nodules., Materials and Methods: We enrolled consecutive 51 pathologically diagnosed HCCs that were hyperintense on hepatobiliary phase imaging (47 patients, including 44 with cirrhosis) and 10 FNHs and eight FNH-like nodules (16 patients, including five with cirrhosis). Imaging findings of dynamic CT and gadoxetic acid-enhanced MRI were assessed by two radiologists and compared between HCC and FNH., Results: The apparent diffusion coefficient (ADC) was lower in hyperintense HCC than in FNH (p = 0.004). The enhancement patterns of hyperintense HCC and FNH at dynamic CT were significantly different (p < 0.0001), with 95.9% of HCCs and 22.2% of FNHs showing arterial phase enhancement with a washout pattern, and 4.1% of HCCs and 77.8% of FNHs showing arterial phase enhancement without a washout pattern. The frequency of coronalike enhancement was 84.3% in hyperintense HCCs versus 11.1% in FNHs (p < 0.0001). The signal distribution on the hepatobiliary phase was significantly different between hyperintense HCCs and FNHs (p = 0.0002). The frequency of a capsulelike rim was 88.2% versus 22.2%, that of a mosaic appearance was 72.5% versus 11.1%, and that of a central scar was 0% versus 55.6% in hyperintense HCCs versus FNHs (all p < 0.0001). Multivariate logistic regression analysis showed that ADC ratio (p = 0.03; odds ratio, 0.12) and enhancement pattern at dynamic CT (p = 0.04; odds ratio, 16.21) were the independent factors for differentiation between hyperintense HCC and FNH., Conclusion: For the diagnosis of hyperintense HCC differentiated from FNH and FNH-like nodule, arterial phase enhancement and washout pattern at dynamic CT and decrease of ADC ratio would be important findings.

Purpose: Peri-tumoral hyperintensity (P-hyperintensity) is occasionally seen in hepatocellular carcinoma (HCC) on the hepatobiliary (HB) phase of gadoxetic acid-enhanced MRI (EOB-MRI). A recent study reported peri-tumoral hyperplasia (P-hyperplasia) associated with over-expression of glutamine synthetase (GS) in HCC or metastatic carcinoma. The aim of this study was to analyze the correlation between P-hyperintensity on the HB phase and GS expression indicating P-hyperplasia and reveal its pathological features., Methods: Seventy-seven surgically resected HCCs from 68 patients were analyzed. The grade of P-hyperintensity on HB phase was divided according to the degree of the peri-tumoral hyperintense signal: grade 0 (no P-hyperintensity), grade 1 (less than 50% of the tumor border), grade 2 (50%-80%), grade 3 (80%-100%). Immunohistochemical staining for GS and organic anion transporter polypeptides (OATP)1B3 was performed. The relationships among P-hyperplasia (peri-tumoral GS expression) and OATP1B3 expression, P-hyperintensity, and pathological features of the tumor were analyzed., Results: Thirty-four HCCs were classified as P-hyperintensity grade 0, 29 HCCs as grade 1,10 nodules as grade 2, and 4 HCCs as grade 3. P-hyperplasia was observed in 3/34 (8.8%) P-hyperintensity grade 0, 16/29 (55.2%) grade 1, 9/10 (90%) grade 2, and 4/4 (100%) grade 3. The incidence of P-hyperplasia was significantly increased in P-hyperintensity grades 1-3 compared with grade 0 (p < 0.0001). Hepatocytes in all P-hyperplasia sites demonstrated definite OATP1B3 expression. Microscopic hepatic venous invasion was significantly increased in P-hyperintensity-positive HCCs compared with negative HCCs (p = 0.0017)., Conclusions: P-hyperintensity on HB phase in HCC may indicate p-hyperplasia with GS and OATP1B3 expression and a higher incidence of microscopic hepatic venous invasion.

Recent advances in highly conformal radiotherapies greatly extend the indications for radiotherapy of liver tumors. However, because of poor tolerance to hepatic radiation, estimation of the intensity of irradiation of the liver is important, particularly for a cirrhotic liver. Knowledge of radiation-induced hepatitis is important for understanding how to optimize hepatic radiation therapy. Pathological changes of the irradiated liver, which include perivenular fibrosis, sinusoidal obstruction, and damage to Kupffer cells and hepatocytes, can be visualized using clinical imaging techniques. This review article discusses and illustrates the pathological and radiological changes of hepatic tumors and the surrounding parenchyma of the irradiated liver.

Gadoxetic acid is a contrast agent for magnetic resonance (MR) imaging with hepatocyte-specific properties and is becoming increasingly important in detection and characterization of hepatocellular carcinoma and benign hepatocellular nodules, including focal nodular hyperplasia (FNH), nodular regenerative hyperplasia (NRH), hepatocellular adenoma (HCA), and dysplastic nodule. In these hepatocellular nodules, a positive correlation between the grade of membranous uptake transporter organic anion-transporting polypeptide (OATP) 1B3 expression and signal intensity in the hepatobiliary (HB) phase has been verified. In addition, it has been clarified that OATP1B3 expression is regulated by activation of β-catenin and/or hepatocyte nuclear factor 4α. On the other hand, recent studies have also revealed some of the background molecular mechanisms of benign hepatocellular nodules. FNH commonly shows iso- or hyperintensity in the HB phase with equal or stronger OATP1B3 expression, with map-like distribution of glutamine synthetase (a target of Wnt/β-catenin signaling) and OATP1B3 expression. NRH shows doughnut-like enhancement with hypointensity in the central portion in the HB phase with OATP1B3 expression. The majority of HCAs show hypointensity in the HB phase, but β-catenin-activated HCA exclusively demonstrates iso- or hyperintensity with increased expression of nuclear β-catenin, glutamine synthetase, and OATP1B3. Dysplastic nodule commonly shows iso- or hyperintensity in the HB phase with similar to increased OATP1B3 expression, but one-third of high-grade dysplastic nodules can be demonstrated as a hypointense nodule with decreased OATP1B3 expression. Knowledge of these background molecular mechanisms of gadoxetic acid-enhanced MR imaging is important not only for precise imaging diagnosis but also understanding of the pathogenesis of benign hepatocellular nodules. © RSNA, 2016.

We report a female case of sinusoidal obstruction syndrome (SOS) diagnosed pathologically after chemotherapy (Pmab+m-FOLFOX6) for ascending colon cancer with multiple liver metastases, focusing on the findings of gadoxetic acid-enhanced MRI (EOB-MRI) and the organic anion transporting polypeptide 1B3 (OATP1B3) expression of in the liver. The patient was a 75-year-old female. She had received chemotherapy (Pmab+m-FOLFOX6) as six cycles for preoperative chemotherapy. After the preoperative chemotherapy, tumor sizes of hepatic metastases were reduced and hepatobiliary phase of EOB-MRI clearly depicted diffuse reticular hypointensity in the background liver. On the other hand, dynamic CT and/or other sequences of EOB-MRI did not show definite abnormality in the background liver. After the operation, this patient was pathologically confirmed as SOS demonstrating centrilobular congestion, sinusoidal dilatation, and perisinusoidal fibrosis. In normal liver parenchyma, OATP1B3 (uptake transporter of the EOB-MRI) expression is observed predominantly in centrilobular hepatocytes (zone 3). On the other hand, OATP1B3 expression was remarkably reduced because of the damages in the centrilobular (zone 3) hepatocytes in this SOS case. This indicated that EOB-MRI might be extremely sensitive in diagnosing SOS in its early stage.

Purpose: To identify the imaging features of hepatocellular carcinoma (HCC) associated with β-catenin mutation and their relationship to pathologic findings., Materials and Methods: Institutional ethics committee approval and informed consent were obtained. One hundred thirty-eight surgically resected HCCs were analyzed in this study. Immunohistochemical expression of β-catenin and its transcriptional product, glutamine synthetase (GS), were graded and classified into three groups: the β-catenin positive and GS positive group (HCC with β-catenin mutation), the β-catenin negative and GS positive group (intermediate HCC), and the β-catenin negative and GS negative group (HCC without β-catenin mutation). Clinical, pathologic, and imaging findings from dynamic computed tomography (CT) and gadoxetic acid-enhanced magnetic resonance (MR) imaging (T1-weighted, T2-weighted, diffusion-weighted, and hepatobiliary phase imaging) were evaluated. Correlations among immunohistochemical expression of β-catenin, GS, and organic anion transporting polypeptide 1B3 (uptake transporter of gadoxetic acid) were evaluated. The χ(2), Kruskal-Wallis, and Spearman correlation tests were used., Results: HCCs with β-catenin mutation (n = 27) showed a lower median contrast-to-noise ratio at diffusion-weighted imaging than did intermediate HCCs (n = 23) and HCCs without β-catenin mutation (n = 84) (13.2, 24.4, and 27.0, respectively; P = .02), higher apparent diffusion coefficient (1.33, 1.13, and 1.12, respectively; P < .0001), higher contrast-to-noise ratio (0.58, -28.7, and -45.0, respectively; P < .0001) and higher enhancement ratio during the hepatobiliary phase (0.90, 0.50, and 0.42, respectively; P < .0001). At pathologic examination, HCCs with β-catenin mutation showed pseudoglandular proliferation and bile production with a higher grade of differentiation (P = .04, .001, and .005, respectively). There were significant positive correlations among expression of β-catenin, GS, and organic anion transporting polypeptide 1B3 (P < .0001)., Conclusion: HCCs with β-catenin mutation showed a higher grade of differentiation with frequent pseudoglandular patterns and bile production, and characteristic imaging findings included a high enhancement ratio at gadoxetic acid-enhanced MR imaging and a high apparent diffusion coefficient at diffusion-weighted imaging. Online supplemental material is available for this article., (RSNA, 2015)

Aims: To characterize serum amyloid A (SAA)-positive hepatocellular neoplasms/nodules arising in alcoholic cirrhosis, which are detected as hypervascular hepatocellular nodules resembling hepatocellular carcinoma on imaging., Methods and Results: Fifty-three hepatocellular nodules were examined with immunostaining for SAA, glutamine synthetase and glypican-3 in 23 patients (four women and 19 men) with alcoholic cirrhosis. Sixteen nodules were examined with magnetic resonance imaging with gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid enhancement (EOB-MRI). Somatic mutations in IL6ST, GNAS and STAT3 were examined in 19 nodules. Thirty-six nodules in 18 patients were diagnosed as SAA-positive hepatocellular neoplasms/nodules, and the remaining 17 nodules in eight patients were SAA-negative focal nodular hyperplasia (FNH)-like nodules. SAA-positive hepatocellular neoplasms/nodules showed significantly more extensive sinusoidal dilatation, inflammatory reaction, abnormally thick arteries and cellular atypia than FNH-like nodules (P < 0.05). Eight SAA-positive hepatocellular neoplasms/nodules (67%) showed slight hypointensity in the hepatobiliary phase on EOB-MRI, whereas all four FNH-like nodules showed iso-intensity (P < 0.05). STAT3 mutations were detected in two of 17 SAA-positive hepatocellular neoplasms/nodules., Conclusions: This study showed that approximately two-thirds of hypervascular hepatocellular nodules arising in alcoholic cirrhosis were SAA-positive hepatocellular neoplasms/nodules, which show different findings on the EOB-MRI. STAT3 mutations were detected in 11.8% of SAA-positive hepatocellular neoplasms/nodules, supporting a neoplastic nature., (© 2014 John Wiley & Sons Ltd.)

Purpose: To investigate the hemodynamics and progression of a hypervascular focus (HF) in a borderline lesion by dual-phase CT during hepatic arteriography (CTHA) and reveal the process of the transformation to hypervascular overt hepatocellular carcinoma (HCC)., Materials and Methods: This study was performed with the approval of our institutional ethics committee, and informed consent for the retrospective usage of clinical materials was obtained from all the patients. The 121 nodules in 76 consecutive patients with liver cirrhosis and chronic hepatitis showing an HF in a borderline lesion on angiography-assisted CT were analyzed. Hemodynamic changes were observed in 24 patients who underwent repeated angiography-assisted CT. Histopathological analysis was conducted in eight nodules., Results: HF was classifiable into type A (stain disappeared), B (stain prolonged), C (stain was washed out and corona-like drainage into the outer nodule was seen) and D (stain was washed out and corona-like drainage into the whole outer nodule was seen) on the late phase of CTHA and was seen to progress in this order on follow-up observation. Histopathologically, de-differentiated foci showed significantly higher expression of sinusoidal capillarization and unpaired arteries than background nodules and showed pseudocapsule, compressive and replacing growth at the border of the background nodule., Conclusion: HF showed multi-step progression and transformation to hypervascular overt HCC.

Objectives: To examine the clinicopathologic features of combined hepatocellular-cholangiocarcinoma (HC-CC), which the World Health Organization (WHO) proposed classifying into 2 types, and the expression of delta-like 1 homolog (DLK1), as well as putative stem cell markers, such as NCAM/CD56 and CD133., Methods: In this study we examined the expression of stem cell markers using immunohistochemistry., Results: Thirty-six cases of combined HC-CC were subclassified into 24 cases, with more than 5% stem cell features (group B) and 12 cases with less than 5% stem cell areas (group A). The postoperative overall survival rate was worse for group B than for group A. DLK1 was frequently expressed in group B cases compared with group A, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma cases., Conclusions: The 2010 WHO classification seems important for elucidating the pathogenesis of stem cell-related liver cancers.

Purpose: We evaluated molecular features of hypervascular hepatocellular carcinoma (HCC) that shows iso- or hyperintensity (hyperintense HCC) in the hepatobiliary phase (HB phase) of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI)., Materials and Methods: We investigated 89 surgically resected cases. Patients were divided into two groups according to the signal intensity in the HB phase of EOB-MRI: hyperintense HCCs (n = 18) and hypointense HCCs (n = 71). We performed immunohistochemical staining for uptake transporter of gadoxetic acid: organic anion transporter polypeptides (OATP8); tumor markers: alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist II (PIVKA-II); hepatic stem cell markers: epithelial cell adhesion molecule (EpCAM), cytokeratin 19 (CK19), and neural cell adhesion molecule (NCAM); biliary marker: CK7; hepatocyte marker: hepatocyte paraffin 1 (HepPar1); markers of HCC differentiation: glypican-3; signaling: beta-catenin, and the respective grade was semiquantitatively determined., Results: Histopathologically, hyperintense HCCs showed significantly weaker expression of AFP (p < 0.05), PIVKA-II (p < 0.01), EpCAM (p < 0.005), glypican-3 (p < 0.005) relative to the hypointense HCCs, whereas OATP8 (p < 0.0001), HepPar1 (p < 0.05), and beta-catenin (p < 0.001) were overexpressed in hyperintense HCCs compared with hypointense HCCs., Conclusion: Hyperintense HCC expressed OATP8 and showed a feature of mature hepatocytes with a weak expression of stem cell characteristics immunohistochemically. In addition, this type of HCC demonstrated a weaker expression of the poorer prognosis markers including, AFP, PIVKA-II, EpCAM, CK19, and glypican-3.

Hepatocellular adenoma usually arises in the absence of significant fibrosis. Herein, we report seven patients with serum amyloid A-positive hepatocellular neoplasm, which shares features with inflammatory hepatocellular adenoma arising in alcoholic cirrhosis. Seven patients (two women and five men, age range 41-67 years) with hypervascular hepatocellular nodules associated with alcoholic cirrhosis were retrieved from our pathological files (1997-2011). The hepatocellular nodules were multiple (>3) in all patients and 17 nodules were histologically examined. We surveyed the immunoreactivity for serum amyloid A, glutamine synthetase, and glypican-3 in the hepatocellular nodules and control lesions, including 5 focal nodular hyperplasia, 18 dysplastic nodules, and 54 hepatocellular carcinomas in various background diseases. In all, 15 of 17 nodules showed strong and distinct immunoreactivity for serum amyloid A, sharing features with inflammatory hepatocellular adenoma. The serum amyloid A-positive hepatocellular neoplasms showed increased cellular density, inflammatory infiltrate, sinusoidal dilatation, and ductular reaction to various degrees. Although about a half of dysplastic nodules and hepatocellular carcinomas showed focal immunoreactivity for serum amyloid A, the extent of serum amyloid A expression was significantly higher in serum amyloid A-positive hepatocellular neoplasms, than in control nodules. The serum amyloid A-positive hepatocellular neoplasms did not show the overexpression of glutamine synthetase or immunoreactivity for glypican-3. In contrast, most hepatocellular carcinomas showed the overexpression of glutamine synthetase and immunoreactivity for glypican-3, irrespective of background diseases. In conclusion, this study highlights a characteristic group of hepatocellular neoplasms arising in alcoholic cirrhosis, which share features with inflammatory hepatocellular adenomas. These serum amyloid A-positive hepatocellular neoplasms may be a new type of inflammatory hepatocellular tumors in alcoholic patients.

Purpose: To analyze the correlation among biologic features, tumor marker production, and signal intensity at gadoxetic acid-enhanced MR imaging in hepatocellular carcinomas (HCCs)., Materials and Methods: Institutional ethics committee approval and informed consent were obtained for this retrospective study. From April 2008 to September 2011, 180 surgically resected HCCs in 180 patients (age, 65.0 years ± 10.3 [range, 34-83 years]; 138 men, 42 women) were classified as either hypointense (n = 158) or hyperintense (n = 22) compared with the signal intensity of the background liver on hepatobiliary phase gadoxetic acid-enhanced MR images. Pathologic features were analyzed and a fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) production were compared by means of serum analysis and immunohistochemical staining. Recurrence and survival rates were also evaluated. The Mann-Whitney and Pearson correlation tests were used for statistical analysis., Results: The grade of differentiation was higher (P = .028) and portal vein invasion was less frequent in hyperintense HCCs (13.6%) than in hypointense HCCs (36.7%) (P = .039). The serum levels of AFP, Lens culinaris agglutinin reactive fraction of AFP, and PIVKA-II were lower in hyperintense than in hypointense HCCs (P = .003, .004, and .026, respectively). Immunohistochemical AFP and PIVKA-II expression were lower in hyperintense than in hypointense HCCs (both P < .001). The recurrence rate was lower in hyperintense than in hypointense HCCs (P = .039)., Conclusion: The results suggest that hyperintense HCCs on gadoxetic acid-enhanced MR images are less aggressive than hypointense HCCs., Supplemental Material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120226/-/DC1., (© RSNA, 2012.)

α-Fetoprotein is expressed in hepatocellular carcinoma, yolk sac tumor, and some gastric carcinomas. The α-fetoprotein-producing gastric carcinoma composed of hepatoid and common adenocarcinoma shows morphological similarities to combined hepatocellular and cholangiocarcinoma. In this study, the expression of putative hepatic stem/progenitor markers (EpCAM, OV-6, DLK-1, and NCAM/CD56), hepatocyte markers (HepParI, α-fetoprotein, glypican 3), and the germ cell marker SALL4 was examined in α-fetoprotein-producing gastric carcinoma (20 cases) and combined hepatocellular and cholangiocarcinoma (20 cases) for evaluation of pathologic differentiation and also the histogenesis of both tumors. The SALL4 protein was expressed in 95% of α-fetoprotein-producing gastric carcinoma, including the hepatoid component (hepatoid gastric carcinoma), but was absent in combined hepatocellular and cholangiocarcinoma. Glypican 3 and α-fetoprotein were detected in all hepatoid-type α-fetoprotein-producing gastric carcinoma but variably in combined hepatocellular and cholangiocarcinoma. NCAM/CD56 was expressed focally in combined hepatocellular and cholangiocarcinoma but was rare in hepatoid gastric carcinoma. EpCAM, DLK-1, and OV6 were variably expressed in hepatoid gastric carcinoma and combined hepatocellular and cholangiocarcinoma. SALL4 was a useful differential marker for combined hepatocellular and cholangiocarcinoma and hepatoid gastric carcinoma. The histogenesis of hepatoid gastric carcinoma expressing SALL4 seems to reflect fetal gut differentiation or involve the germ cell lineage and may be different from that of combined hepatocellular and cholangiocarcinoma involving the hepatic stem cell or progenitor cell lineages. In conclusion, hepatoid gastric carcinoma and combined hepatocellular and cholangiocarcinoma shared morphologies, whereas the distinction of hepatoid gastric carcinoma from combined hepatocellular and cholangiocarcinoma is possible by immunostaining for SALL4. These 2 tumors seem to differ in their histogenesis with respect to SALL4 expression.1., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We report a male case of beta-catenin-activated hepatocellular adenoma (HCA) focusing on findings of gadoxetic-acid-enhanced magnetic resonance imaging (EOB-MRI) and discussing the molecular background and possible clinical significance. The patient was a 31-year-old man in whom computed tomography (CT) showed a large nodule of 14 cm in diameter in the right liver lobe. On dynamic contrast-enhanced CT, heterogeneous and slight to moderate enhancement was observed during the early phase, with washout in the late phase. Focal fat deposits and a scar-like portion in the lesion were also seen. Most of the lesion was slightly hyperintense compared with the background liver on the hepatobiliary phase of EOB-MRI. After operation, this patient was confirmed pathologically as having beta-catenin-activated HCA with a portion suggestive of malignant transformation. In addition, intense organic anion transporter polypeptide 8 expression was observed throughout the tumor by immunohistochemical staining.

Background and Aims: Intrahepatic cholangiocarcinomas (ICCs) are usually adenocarcinomas with fibrotic and hypovascular stroma. Intrahepatic cholangiocarcinomas in cirrhosis and precirrhotic liver (ICC-cirrhosis) are increasingly being diagnosed, and can display hypervascular enhancement resembling a hepatocellular carcinoma on dynamic imaging., Methods: In this study using ICC-cirrhosis (71 cases), ICC with non-specific reactive changes (ICC-reactive) (72 cases) and the cholangiocarcinoma component of combined hepatocellular cholangiocarcinoma (HCC-ICC) (30 cases), we tried to compare the tumour vasculature., Results: It was found that ICC-cirrhosis and the cholangiocarcinoma component of HCC-ICC showed a higher density of arteries and microvessels (1.59 ± 0.58/mm(2) (mean ± SD) and 140 ± 43/mm(2) in ICC-cirrhosis and 1.74 ± 0.67/mm(2) and 131 ± 46/mm(2) in the cholangiocarcinoma component of HCC-ICC) than in ICC-reactive (1.26 ± 0.61/mm(2) and 103 ± 45/mm(2) ). Dynamic computed tomography (CT) and magnetic resonance imaging (MRI) showed that a majority of ICC-cirrhosis displayed strong hypervascular enhancement, whereas one-third of ICC-reactive each showed strong, weak and no or minimal enhancement respectively. The increased vascular density was positively correlated with enhanced arterial phase of dynamic CT and MRI., Conclusion: The density of arteries and microvessels of ICC-cirrhosis was higher than that in ICC-reactive and comparable to that in the cholangiocarcinoma component of HCC-ICC, and the higher density of arteries and microvessels in ICC may be responsible for the hypervascular enhancement of ICC-cirrhosis., (© 2012 John Wiley & Sons A/S.)

Objectives: To clarify the changes in organic anion-transporting polypeptide 8 (OATP8) expression and enhancement ratio on gadoxetic acid-enhanced MR imaging in hepatocellular nodules during multistep hepatocarcinogenesis., Methods: In imaging analysis, we focused on 71 surgically resected hepatocellular carcinomas (well, moderately and poorly differentiated HCCs) and 1 dysplastic nodule (DN). We examined the enhancement ratio in the hepatobiliary phase of gadoxetic acid enhanced MR imaging [(1/postcontrast T1 value-1/precontrast T1 value)/(1/precontrast T1 value)], then analysed the correlation among the enhancement ratio, tumour differentiation grade and intensity of immunohistochemical OATP8 expression. In pathological analysis, we focused on surgically resected 190 hepatocellular nodules: low-grade DNs, high-grade DNs, early HCCs, well-differentiated, moderately differentiated and poorly differentiated HCCs, including cases without gadoxetic acid-enhanced MR imaging. We evaluated the correlation between the immunohistochemical OATP8 expression and the tumour differentiation grade., Results: The enhancement ratio of HCCs decreased in accordance with the decline in tumour differentiation (P < 0.0001, R = 0.28) and with the decline of OATP8 expression (P < 0.0001, R = 0.81). The immunohistochemical OATP8 expression decreased from low-grade DNs to poorly differentiated HCCs (P < 0.0001, R = 0.15)., Conclusions: The immunohistochemical expression of OATP8 significantly decreases during multistep hepatocarcinogenesis, which may explain the decrease in enhancement ratio on gadoxetic acid-enhanced MR imaging.

Cytokeratin (CK) 19-positive hepatocellular carcinoma (HCC) has been reported to have a poor prognosis. The mechanism of the development of CK19-positive HCC remains to be studied. To clarify this, in vitro experiments were performed using human HCC cell lines (PLC-5, HepG2), and the phenotypic changes after stimulation with several growth factors were examined using quantitative reverse transcriptase PCR, western blotting, and immunofluorescence staining. In vivo experiments using human HCC specimens obtained from a total of 78 patients and clinicopathological analysis were also performed. Among the growth factors tested, epidermal growth factor (EGF) had prominent effects on inducing CK19 expression in PLC-5 and HepG2, which was accompanied by the reduced expression of α-fetoprotein in PLC-5. The induction of CK19 expression after EGF stimulation was accompanied by the phosphorylation of c-Jun-N-terminal kinase (JNK)/stress-activated protein kinase, which was blocked by the addition of JNK inhibitors. EGF also increased proliferative abilities and invasive properties of the HCC cell lines. In vivo, 9 (12%) of 78 HCC cases showed positive immunohistochemical staining of CK19. The extent of positive immunohistochemical signals of EGF, EGF receptor (EGFR), and JNK expression was significantly intense in CK-19-positive HCC than those of CK19-negative HCC. Clinicopathological analysis showed that CK19-positive HCC had a high incidence of portal vein invasion, extrahepatic metastasis and an early relapse, which was associated with the worsened 2-year disease free survival. These results indicate that the activation of the EGF-EGFR signaling pathway is associated with the development of CK19-positive HCC, and the EGF-induced increase in growth abilities of HCC may account for the poor prognosis of the patients.

Purpose: To analyze the correlation between signal intensity in the hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance (MR) imaging and the expression of hepatocyte transporters with histopathologic features in hepatocellular carcinoma (HCC)., Materials and Methods: Institutional ethics committee approval and informed consent were obtained. Forty surgically resected HCCs were classified as hypointense (n = 32) or iso- or hyperintense (n = 8) on the basis of findings in the hepatobiliary phase of gadoxetic acid-enhanced MR imaging. The following were compared between hypointense and iso- or hyperintense HCCs: the time-signal intensity curves at gadoxetic acid-enhanced MR imaging, the expression levels of seven transporters (four organic anion-transporting polypeptides [OATPs] and three multidrug-resistant proteins [MRPs]) at polymerase chain reaction (PCR) (for 22 nodules), results of immunostaining of OATP8, and histologic features. Statistical analysis (unpaired t test, Mann-Whitney test, chi(2) test, and Fisher exact test) was performed for each result., Results: On the time-signal intensity curves, hypointense HCCs showed a decreasing pattern, whereas iso- or hyperintense HCCs showed an increasing pattern after the dynamic phase. PCR revealed that expression of OATP8 (an uptake transporter) in hypointense HCCs was lower and that in iso- or hyperintense HCCs was higher than in background liver (P < .001). The expression level of MRP3 (a sinusoidal export transporter) showed a similar trend to that of OATP8 (P < .001). Immunostaining revealed that OATP8 expression was weak in hypointense HCCs, whereas it was sustained in iso- or hyperintense HCCs (P < .001). At histologic examination, a pseudoglandular proliferation pattern with bile plugs was more commonly observed in iso- or hyperintense HCCs than in hypointense HCCs (P = .01 for proliferation patterns and P = .006 for bile plugs)., Conclusion: The enhancement ratio of HCCs in the hepatobiliary phase of gadoxetic acid-enhanced MR imaging positively correlated with expression levels of OATP8 and MRP3, indicating that gadoxetic acid is taken up by OATP8 and excreted by MRP3., ((c) RSNA, 2010.)

Objectives: To retrospectively describe imaging analyses of benign hypervascular hyperplastic liver nodules (HHN) that resulted from alcoholic liver cirrhosis and to examine the possibility of imaging differentiation between these nodules and hypervascular hepatocellular carcinoma (HCC)., Methods: Ten histopathologically confirmed HHN arise in alcoholic liver cirrhosis, and 9 HCC were examined. Magnetic resonance imaging (MRI) (10 HHN and 9 HCC), superparamagnetic iron oxide-enhanced T2-weighted MRI (6 HHN and 4 HCC), and dual-phase computed tomography hepatic arteriography (5 HHN and 6 HCC) were performed, respectively., Results: On T1-weighted magnetic resonance images, 7 HHNs showed hyperintensity and 3 showed iso- to hypointensity, and all HCCs showed hypointensity compared with surrounding liver. On T2-weighted magnetic resonance images, 2 HHNs showed hyperintensity and 8 showed iso- to hypointensity. In contrast, 1 HCC showed hypointensity and 8 showed hyperintensity. On superparamagnetic iron oxide-enhanced T2 MRI, all HHNs showed iso- to hypointensity, and all HCCs showed hyperintensity. All HHN and HCCs subjected to dual-phase computed tomography hepatic arteriography showed enhancement on early-phase images and coronalike enhancement on late-phase images., Conclusions: Imaging findings of highly-well differentiated HCCs possibly overlap with HHN. So, for correct diagnosis of HHN, at first, we should suspect HHN based on clinical findings and MRI findings, and then perform core needle biopsy to verify the radiological diagnosis.

Purpose: To retrospectively evaluate the relationship between local tumor recurrence and iodized oil deposition in the portal vein by using ultraselective transcatheter arterial chemoembolization (TACE) for small hepatocellular carcinoma., Materials and Methods: One-hundred twenty-three tumors smaller than 5 cm in diameter (mean diameter, 1.9 cm; median diameter, 1.6 cm) were treated with TACE by using a 2-F tip microcatheter at a distal portion of the subsegmental artery of the liver. Portal vein visualization at spot radiography during TACE was divided into three grades, as follows: 0 = not visualized, 1 = limited near the tumor, and 2 = whole or extended to the embolized area. Local recurrence rates of each grade group were compared. The recurrent pattern was divided into intratumoral and peritumoral recurrence. Complications were also analyzed., Results: Of the 123 tumors, 53 (43.1%) were classified as grade 2, 52 (42.3%) were classified as grade 1, and 18 (14.6%) tumors were classified as grade 0. Overall local recurrence rates at 12, 24, and 36 months were 25.6%, 34.7%, and 34.7%, respectively. The local recurrence rates for the grades 2, 1, and 0 groups were 7.9%, 24.8%, and 85.7%, respectively, at 12 months and 17.7%, 38.9%, and 85.7% at 24 months. Recurrence rates in the grade 2 group were significantly lower than those in the grades 1 and 0 groups (P = .0485 and P < .0001, respectively). Intratumoral recurrence was observed in 21 tumors, most of which were in the grade 0 group. Peritumoral recurrence was noted in 16 tumors, most of which were in the grade 2 group. There were no major complications., Conclusion: Ultraselective TACE was safe and effective in a significant number of tumors. In particular, local recurrence was significantly lower when a greater degree of portal vein visualization was demonstrated during TACE.