Dynamic CT and Gadoxetic Acid-enhanced MRI Characteristics of P53-mutated Hepatocellular Carcinoma.

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, χ2 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.

CT-diagnosed extra-pancreatic extension of pancreatic ductal adenocarcinoma is a more reliable prognostic factor for survival than pathology-diagnosed extension.

OBJECTIVES: To determine the correlation between CT-diagnosed extra-pancreatic extension of pancreatic ductal adenocarcinoma (PDAC), pathology-diagnosed extra-pancreatic extension, and survival in patients with PDAC. METHODS: This retrospective study included 87 patients with resected PDAC. Two radiologists evaluated negative ((i) tumours surrounded by the pancreatic parenchyma and (ii) tumours contacting the pancreatic surface) or positive ((iii) tumours with peri-pancreatic strand appearances and/or with expansive growth) CT-diagnosed extra-pancreatic extension. Clinical, pathological, and CT imaging characteristics predicting disease-free survival (DFS) and overall survival (OS) were assessed using Cox proportional-hazards models. Diagnostic accuracy for pathology-diagnosed extra-pancreatic extension was also assessed. RESULTS: CT-diagnosed extra-pancreatic extension (42/87 tumours, 48.3%; κ = 0.82) had a higher hazard ratio (HR) for the DFS (HR, 5.30; p < 0.01) and OS (HR, 5.31; p < 0.01) rates than pathology-diagnosed extension in univariable analyses. It was also an independent prognostic factor for the DFS (HR, 4.22; p < 0.01) and OS (HR, 4.38; p < 0.01) rates in multivariable analyses. Of 45 tumours without CT-diagnosed extra-pancreatic extension, pathology-diagnosed extra-pancreatic extension was observed in 2/8 (25.0%) and 32/37 (86.5%) tumours with CT categories (i) and (ii), respectively. However, the differences in the survival rates between patients with CT categories (i) and (ii) were insignificant, although those in the latter category had significantly better survival rates than those with CT-diagnosed extra-pancreatic extension (category (iii)). CONCLUSIONS: CT-diagnosed extra-pancreatic extension was a better prognostic factor than pathology-diagnosed extension and considered an independent factor for the postoperative DFS and OS rates with reasonable frequency and high reproducibility, despite the low diagnostic accuracy for predicting pathology-diagnosed extra-pancreatic extension. KEY POINTS: • A CT-diagnosed extra-pancreatic extension had a higher hazard ratio for both disease-free survival and overall survival compared to pathology-diagnosed extension in univariable survival analyses. • A CT-diagnosed extra-pancreatic extension was a significant independent predictor of both disease-free survival and overall survival, as observed in multivariable survival analyses. • Patients with tumours contacting with the pancreatic surface on CT images (CT category (ii)) showed similar survival rates to those whose tumours were surrounded by the pancreatic parenchyma (CT category (i)), although many tumours with CT category (ii) extended pathologically beyond the pancreas.

Imaging Features of Premalignant Biliary Lesions and Predisposing Conditions with Pathologic Correlation.

Biliary malignancies include those arising from the intrahepatic and extrahepatic bile ducts as well as the gallbladder and hepatopancreatic ampulla of Vater. The majority of intrahepatic and extrahepatic malignancies are cholangiocarcinomas (CCAs). They arise owing to a complex interplay between the patient-specific genetic background and multiple risk factors and may occur in the liver (intrahepatic CCA), hilum (perihilar CCA), or extrahepatic bile ducts (distal CCA). Biliary-type adenocarcinoma constitutes the most common histologic type of ampullary and gallbladder malignancies. Its prognosis is poor and surgical resection is considered curative, so early detection is key, with multimodality imaging playing a central role in making the diagnosis. There are several risk factors for biliary malignancy as well as predisposing conditions that increase the risk; this review highlights the pertinent imaging features of these entities with histopathologic correlation. The predisposing factors are broken down into three major categories: (a) congenital malformations such as choledochal cyst and pancreaticobiliary maljunction; (b) infectious or inflammatory conditions such as parasitic infections, hepatolithiasis, primary sclerosing cholangitis, and porcelain gallbladder; and (c) preinvasive epithelial neoplasms such as biliary intraepithelial neoplasm, intraductal papillary neoplasm of the bile duct, intra-ampullary papillary tubular neoplasm, and intracholecystic papillary neoplasm of the gallbladder. Recognizing the baseline features of these premalignant biliary entities and changes in their appearance over time that indicate the advent of malignancy in high-risk patients can lead to early diagnosis and potentially curative management. An invited commentary by Volpacchio is available online. Online supplemental material is available for this article. ©RSNA, 2022.

Transcatheter arterial embolization of iatrogenic massive arterioportal fistula in the liver.

BACKGROUND: Massive arterioportal fistula (APF) is naturally irreversible and can induce portal hypertension and portal vein thrombosis (PVT), worsening survival outcomes. PURPOSE: To evaluate the clinical course and details of transarterial embolization (TAE) procedures for massive APF. MATERIAL AND METHODS: This retrospective single-center observational study evaluated the time until embolization after puncture, imaging, embolization methods, and laboratory data of 10 consecutive patients who were diagnosed with massive APF after puncture and underwent TAE at our hospital from 1 April 2012 to 30 September 2019. RESULTS: Out of 10 cases, eight demonstrated a simple type and the other two cases a complex network type on the digital subtraction angiography pattern of massive APF. In two simple-type cases for which re-embolization was required, other subsegmental branches were embolized. The two cases showing a complex network type had been embolized via not only the subsegmental branch, but also the extrahepatic and multiple subsegmental branches. Child-Pugh scores were improved in eight of the ten cases. PVT was seen in six cases before embolization, but disappeared after embolization in all cases, despite the fact that three cases had not received anticoagulant therapy. Six cases had digestive varices before embolization, suggesting portal hypertension, and two of the six cases with esophageal varices and one with gastric varices decreased after embolization. CONCLUSION: TAE for massive APF contributed to the improvement of hepatic reserve, the disappearance of PVT, and the improvement of portal hypertension; however, embolization of multiple branches may still be required in some cases.

Ultrasonography of IgG4-related dacryoadenitis and sialadenitis: Imaging features and clinical usefulness.

OBJECTIVES: To clarify the ultrasonographic features of immunoglobulin G4 (IgG4)-related dacryoadenitis and sialadenitis (IgG4-DS) and their usefulness in clinical diagnostic sessions. METHODS: By re-evaluating 96 consecutive patients with IgG4-related disease, we identified 54 patients (male:female = 37:17; median age, 69.5 years) who underwent lacrimal or submandibular gland (LG or SG, respectively) ultrasonography and computed tomography (CT). Their clinical and ultrasonographic features were retrospectively analysed. Radio-pathological correlations were also examined in LG (23 cases) and SG lesions (20 cases). Additionally, the diagnostic accuracy of CT for LG/SG lesions was evaluated. RESULTS: Abnormal ultrasonographic findings were detected in 33 (LGs) and 38 (SGs) patients, and most of them were observed bilaterally. All lesions were well demarcated and demonstrated diffuse low-echoic areas (rocky pattern) or multiple low-echoic nodules surrounded by high-echoic linear shadows (cobblestone pattern) corresponding to intra-lobular inflammation and inter-lobular fibrosis. Moreover, 42% (LGs; 14/33) and 42% (SGs; 16/38) patients had glandular lesions without clinical symptoms associated with the affected glands. The diagnostic accuracy of CT was ∼80% for LG and 55% for SG. CONCLUSIONS: Ultrasonographic findings in IgG4-DS included diffuse or nodular low-echoic areas with linear high-echoic structures corresponding to inflamed lobules and inter-lobular fibrosis. These findings can help detect IgG4-DS.

CT Abnormalities of the Pancreas Associated With the Subsequent Diagnosis of Clinical Stage I Pancreatic Ductal Adenocarcinoma More Than 1 Year Later: A Case-Control Study.

BACKGROUND. Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, partly because of challenges in early diagnosis. However, the prognosis for earlier stages (carcinoma in situ or category T1a invasive carcinoma) is relatively favorable. OBJECTIVE. The purpose of this study was to investigate findings of an earlier diagnosis of PDAC on CT examinations performed at least 1 year before the diagnosis of clinical stage I PDAC. METHODS. This retrospective study included 103 patients with clinical stage I PDAC and a CT examination performed at least 1 year before the CT examination that detected PDAC, as well as 103 control patients without PDAC on CT examinations separated by at least 10 years. The frequency and temporal characteristics of focal pancreatic abnormalities (pancreatic mass, main pancreatic duct [MPD] change, parenchymal atrophy, faint parenchymal enhancement, cyst, and parenchymal calcification) seen on CT examinations conducted before diagnosis (prediagnostic CT) were determined. RESULTS. A focal pancreatic abnormality was present on the most recent prediagnostic CT examination in 55/103 (53.4%) patients with PDAC versus 21/103 (20.4%) control patients (p < .001). In patients with PDAC, the most common focal abnormalities on prediagnostic CT were atrophy (39/103, 37.9%), faint enhancement (17/65, 26.2%), and MPD change (14/103, 13.6%), which were all more frequent in patients with PDAC than in control patients (p < .05). In 54/55 (98.2%) patients with PDAC, the PDAC corresponded to the site of a focal abnormality (exact location or the abnormality's upstream or downstream edge) on prediagnostic CT. Frequency of focal abnormalities decreased with increasing time before CT that detected PDAC (> 1 to ≤ 2 years before diagnosis, 64.9%; > 2 to ≤ 3 years, 49.2%; > 3 to ≤ 5 years, 41.8%; > 5 to ≤ 7 years, 29.7%; > 7 to ≤ 10 years, 18.5%; more than 10 years, 0%). Mean duration from the finding's initial appearance to diagnosis of PDAC was 4.6 years for atrophy, 3.3 years for faint enhancement, and 1.1 years for MPD change. CONCLUSION. Most patients with clinical stage I PDAC showed focal pancreatic abnormalities on CT performed at least 1 year before diagnosis. Focal MPD change exhibited the shortest duration from its development to subsequent diagnosis, whereas atrophy and faint enhancement exhibited a relatively prolonged course. CLINICAL IMPACT. These findings could facilitate earlier PDAC diagnosis and thus improve prognosis.

Hepatocellular adenomas: Understanding the pathomolecular lexicon, MRI features, terminology, and pitfalls to inform a standardized approach.

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.

Gadoxetic acid-enhanced MR imaging for hepatocellular carcinoma: molecular and genetic background.

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 ß-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.

Doughnut-like hyperintense nodules on hepatobiliary phase without arterial-phase hyperenhancement in cirrhotic liver: imaging and clinicopathological features.

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.

CT imaging comparison between intraductal papillary neoplasms of the bile duct and papillary cholangiocarcinomas.

OBJECTIVES: To identify imaging features that assist in discriminating intraductal papillary neoplasms of the bile duct (IPNBs) from papillary cholangiocarcinomas (PCCs). METHODS: This study was approved by the institutional review board. Using the recently proposed histological diagnostic criteria for biliary papillary neoplasms, IPNBs and PCCs were selected from 537 biliary neoplasms consecutively resected in a 12.5-year period. Clinical and imaging features were compared between the two groups. RESULTS: The histology review identified 19 IPNBs and 48 PCCs, representing an estimated prevalence of IPNBs among biliary neoplasms of 4%. Approximately one half of IPNBs were incidentally found on imaging conducted for other purposes. In terms of tumor location, 15/19 IPNBs (79%) developed in intrahepatic bile ducts, and 41/48 PCCs (85%) in the distal bile duct. Cystic appearance was highly suggestive for IPNBs (p < 0.001). Using these two parameters, 78% of papillary bile duct neoplasms could be classified into IPNBs or PCCs. Other imaging findings favoring IPNBs included frond-like mural nodule, downstream bile duct dilatation, and the lack of abnormal enhancement in the adjacent bile duct. Interestingly, two patients with non-invasive or microinvasive IPNB had undergone abdominal imaging studies > 3 years before, and a retrospective review of the previous images identified small nodular or cystic lesions, suggesting a less progressive nature of IPNBs than currently thought. CONCLUSIONS: Imaging findings useful for discriminating IPNBs from PCCs appear to be tumor location, shape of tumor, appearance of mural nodules, duct dilatation at unaffected duct, and abnormal enhancement of the adjacent bile duct. KEY POINTS: • Intrahepatic location and cystic dilatation of the affected bile duct are the strong discriminators between IPNBs and PCCs. • The shape of the mural nodule and appearance of the neighboring bile duct are helpful for distinguishing IPNBs and PCCs. • The less aggressive behavior of IPNBs compared with PCCs may facilitate less invasive management in patients with IPNB.

CT Findings of Thoracic Paravertebral Lesions in IgG4-Related Disease.

OBJECTIVE. The objective of our study was to characterize the CT findings of IgG4-related paravertebral lesions. MATERIALS AND METHODS. We selected cases of IgG4-related paravertebral lesions that satisfied two inclusion criteria: first, lesions in patients with IgG4-related disease diagnosed by a multidisciplinary approach between April 2007 and June 2018; and, second, patients who had soft-tissue lesions in paravertebral regions on CT images. We added one case of an IgG4-related paravertebral lesion diagnosed pathologically in 2003. Finally, the study consisted of 30 patients (25 men and five women; median age, 69.5 years). We retrospectively evaluated the CT findings of the paravertebral lesions. RESULTS. A total of 31 paravertebral lesions were identified in 30 patients. All lesions were located around thoracic vertebrae, particularly the lower thoracic regions (n = 30). Twenty-six lesions (84%) involved two or more vertebrae in a row. The right side of vertebrae was predominantly affected in all cases except one (30/31 lesions). Radiologically, the paravertebral lesions were characterized as a bandlike, demarcated soft-tissue mass (mean maximum thickness, 8.7 mm) with homogeneous enhancement on late phase images of contrast-enhanced CT. All patients had IgG4-related lesions at other sites. Histologically, paravertebral lesions showed sclerosing inflammation consisting of diffuse lymphoplasmacytic infiltrations with many IgG4-positive plasma cells and irregular fibrosis. CONCLUSION. IgG4-related paravertebral lesions occur mainly in the right side of the lower thoracic vertebrae and present as a homogeneously enhanced bandlike mass corresponding to plasma cell-rich sclerosing inflammation.

Imaging and pathological features of gastric lesion of immunoglobulin G4-related disease: A case report and review of the recent literature.

We describe a 67-year-old man with immunoglobulin G4-related disease (IgG4-RD) presenting with optic neuropathy, dacryoadenitis, periaortitis, retroperitoneal fibrosis, and a gastric mass-like lesion. A mass-like lesion measuring 52 × 40 mm in the antrum of the stomach was found incidentally through whole-body screening for other organ involvement of IgG4-RD using contrast-enhanced computed tomography (CT). Histology of the stomach revealed that the lesion was also IgG4-related and was located in the submucosal layer extending to the subserosal region. This case suggests that the stomach can also be a site of involvement of IgG4-RD.

Isolated Arteries Originating from the Intrahepatic Arteries: Anatomy, Function, and Importance in Intervention.

Isolated hepatic arteries are defined as hepatic terminal arterioles that are not accompanied by portal venules or bile ductules and penetrate the liver parenchyma and distribute to the hepatic capsule and intrahepatic hepatic veins. Abundant communications exist between intra- and extrahepatic arteries through isolated arteries and capsular arterial plexus. They play a principal role in the development of subcapsular hemorrhage and arterial collateral formation following transcatheter arterial chemoembolization for liver cancers. The anatomy, function, and clinical importance of isolated hepatic arteries in interventional radiology, especially regarding subcapsular hemorrhage and arterial collateral formation, are highlighted in this article.

Differentiation Between Hepatocellular Carcinoma Showing Hyperintensity on the Hepatobiliary Phase of Gadoxetic Acid-Enhanced MRI and Focal Nodular Hyperplasia by CT and MRI.

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.

Gadoxetic acid-enhanced magnetic resonance imaging reflects co-activation of ß-catenin and hepatocyte nuclear factor 4α in hepatocellular carcinoma.

AIM: The aim of this study is to clarify the correlation of the co-activation of ß-catenin and hepatocyte nuclear factor (HNF)4α with the findings of gadoxetic acid-enhanced magnetic resonance imaging (MRI), organic anion transporting polypeptide (OATP)1B3 expression, and histological findings in hepatocellular carcinoma (HCC). METHODS: One hundred and ninety-six HCCs surgically resected from 174 patients were enrolled in this study. The HCCs were classified into four groups by immunohistochemical expression of ß-catenin, glutamine synthetase (GS), and HNF4α: (i) ß-catenin/GS (positive [+]) HNF4α (+); (ii) ß-catenin/GS (+) HNF4α (negative [-]); (iii) ß-catenin/GS (-) HNF4α (+); and (iv) ß-catenin/GS (-) HNF4α (-). We compared the four groups in terms of the enhancement ratio on the hepatobiliary phase of gadoxetic acid-enhanced MRI, immunohistochemical organic anion transporter polypeptide (OATP)1B3 (a main uptake transporter of gadoxetic acid) expression and histological features, overall survival, and no recurrence survival. The Kruskal-Wallis test, Steel-Dwass multiple comparisons test, Fisher's exact test, and log-rank (Mantel-Cox) test were used for statistical analyses. RESULTS: Enhancement ratio on gadoxetic acid-enhanced MRI in HCC with ß-catenin/GS (+) HNF4α (+) was significantly higher than those of the other three groups (P < 0.001). The OATP1B3 grade was also significantly higher in HCC with ß-catenin/GS (+) HNF4α (+) (P < 0.001). Hepatocellular carcinoma with ß-catenin/GS (+) HNF4α (+) showed the highest differentiation grade as compared to the other groups (P < 0.004). There were no significant differences in portal vein invasion, macroscopic growth pattern, or prognosis analyses between the four groups. CONCLUSION: Co-activation of ß-catenin and HNF4α would promote OATP1B3 expression, and consequently higher enhancement ratio on gadoxetic acid-enhanced MRI and higher differentiation grade in HCC.

Benign Hepatocellular Nodules: Hepatobiliary Phase of Gadoxetic Acid-enhanced MR Imaging Based on Molecular Background.

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 ß-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/ß-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 ß-catenin-activated HCA exclusively demonstrates iso- or hyperintensity with increased expression of nuclear ß-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.

Hepatocellular Carcinoma with ß-Catenin Mutation: Imaging and Pathologic Characteristics.

PURPOSE: To identify the imaging features of hepatocellular carcinoma (HCC) associated with ß-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 ß-catenin and its transcriptional product, glutamine synthetase (GS), were graded and classified into three groups: the ß-catenin positive and GS positive group (HCC with ß-catenin mutation), the ß-catenin negative and GS positive group (intermediate HCC), and the ß-catenin negative and GS negative group (HCC without ß-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 ß-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 ß-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 ß-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 ß-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 ß-catenin, GS, and organic anion transporting polypeptide 1B3 (P < .0001). CONCLUSION: HCCs with ß-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.

Clinicopathological characteristics of serum amyloid A-positive hepatocellular neoplasms/nodules arising in alcoholic cirrhosis.

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.

Correlation between Gd-EOB-DTPA-enhanced MR imaging findings and OATP1B3 expression in chemotherapy-associated sinusoidal obstruction syndrome.

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.

Imaged periductal infiltration: Diagnostic and prognostic role in intrahepatic mass-forming cholangiocarcinoma.

Purpose: This study examines periductal infiltration in intrahepatic mass-forming cholangiocarcinoma (IMCC), focusing on its importance for differentiating hepatic tumors and its influence on post-surgical survival in IMCC patients. Methods: Eighty-three consecutive patients with IMCC (n = 43) and liver cancer whose preoperative images showed intrahepatic bile duct dilatation adjacent to the tumor for differential diagnosis from hepatocellular carcinoma (HCC) [n = 21], metastatic liver cancer (MLC) [n = 16] and combined hepatocellular-cholangiocarcinoma (cHCC-CC) [n = 3] were enrolled. CT and MRI findings of simple bile duct compression, imaged periductal infiltration, and imaged intrabiliary growth adjacent to the main tumor were reviewed. Clinicopathological and imaging features were compared in each group. The sensitivity, specificity, and odds ratio were calculated for each imaging finding of IMCC versus the other tumor groups. Overall survival was compared between cases of IMCC with and without imaged periductal infiltration. Results: Simple bile duct compression and imaged intrabiliary growth were more frequently observed in HCC than in the others (p < 0.0001 and 0.040, respectively). Imaged periductal infiltration was observed more often in histopathologically confirmed large-duct type IMCC than in the small-duct type IMCC (p = 0.034). Multivariable analysis demonstrated that only imaged periductal infiltration (odds ratio, 50.67) was independently correlated with IMCC. Patients with IMCC who had imaged periductal infiltration experienced a poorer prognosis than those without imaged periductal infiltration (p = 0.0034). Conclusion: Imaged periductal infiltration may serve as a significant marker for differentiating IMCC from other liver cancers. It may also have the potential to predict post-surgical outcomes in patients with IMCC.