Azusa Kitao

Hepatocellular carcinoma: signal intensity at gadoxetic acid-enhanced MR Imaging--correlation with molecular transporters and histopathologic features.

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.

IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases.

Immunoglobulin G4 (IgG4)-related disorders can occur in the respiratory system. However, the clinicopathologic characteristics have not been well clarified. In this study, we examined clinical and pathologic features of, and follow-up data on, IgG4-related lung and pleural lesions. The patients group consisted of 17 males and 4 females with an average age of 69 years (range: 42 to 76). Pulmonary lesions in 16 patients and pleural lesions in 5 patients were examined. Histologically, all lesions showed diffuse lymphoplasmacytic infiltration. Irregular fibrosis and obliterative vascular changes were more common in solid areas. Nine cases (43%) had eosinophilic infiltration with more than 5 cells per high-power field. Immunostaining revealed numerous IgG4-positive plasma cells in inflamed areas. Sclerosing inflammation was distributed with intrapulmonary connective tissue. Pulmonary lesions showed a variety of morphologic changes according to the predominant area of inflammation. Serum IgG4 concentrations were elevated in 9 of 11 patients tested (average 6.9 g/L; range 0.3 to 18.0 g/L; normal range <1.35 g/L). Extra-pulmonary and extra-pleural IgG4-related lesions were identified in 9 patients (43%), and developed simultaneously or asynchronously during follow up. All patients treated with steroids responded, but some radiologic abnormalities remained in 3 patients. Interestingly, 1 patient was found to have a primary adenocarcinoma against a background of IgG4-related lung disease during follow up. In conclusion, IgG4-related diseases show a greater variety of pulmonary and pleural lesions than previously thought. It is important, therefore, to know the morphologic variety and clinicopathologic characteristics of this disorder.

The uptake transporter OATP8 expression decreases during multistep hepatocarcinogenesis: correlation with gadoxetic acid enhanced MR imaging

ObjectivesTo 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.MethodsIn 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.ResultsThe 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).ConclusionsThe immunohistochemical expression of OATP8 significantly decreases during multistep hepatocarcinogenesis, which may explain the decrease in enhancement ratio on gadoxetic acid-enhanced MR imaging.

Hepatocarcinogenesis: Multistep Changes of Drainage Vessels at CT during Arterial Portography and Hepatic Arteriography—Radiologic-Pathologic Correlation

PURPOSE To clarify the changes that occur in drainage vessels of dysplastic nodules and hepatocellular carcinoma (HCC) during hepatocarcinogenesis by using computed tomography (CT) during arterial portography (CTAP) and CT during hepatic arteriography (CTHA), with histologic findings as the reference standard. MATERIALS AND METHODS Institutional ethics committee approval and informed consent were obtained. According to the findings at CTAP and CTHA, 46 surgically resected hepatocellular nodules were classified into three types: type A (n = 18) (equivalent or decreased portal perfusion compared with background liver at CTAP, decreased arterial perfusion, and no corona enhancement [perinodular contrast material drainage] at CTHA), type B (n = 13) (no portal perfusion, increased arterial perfusion, and thin (< or = 2-mm) corona enhancement), or type C (n = 15) (no portal perfusion, increased arterial perfusion, and thick (> 2-mm) corona enhancement). We compared the histopathologic features and microangioarchitecture between the types. RESULTS Type A nodules histologically consisted of dysplastic nodules and well-differentiated HCC; type B and C nodules were moderately differentiated HCC. Replacing growth was commonly observed in type A nodules, whereas compressing growth was more frequently seen in types B and C. Sixty percent of type C nodules had a fibrous capsule. There were significantly fewer intranodular hepatic veins in types B and C. Serial pathologic slices demonstrated continuity from intranodular capillarized sinusoids to hepatic veins in type A nodules and to surrounding hepatic sinusoids in type B nodules. In type C nodules, intranodular capillarized sinusoids were connected to extranodular portal veins either directly or through portal venules within the fibrous capsule. CONCLUSION Drainage vessels of HCC change from hepatic veins to hepatic sinusoids and then to portal veins during multistep hepatocarcinogenesis.

Hepatocelluar nodules in liver cirrhosis: hemodynamic evaluation (angiography- assisted CT) with special reference to multi-step hepatocarcinogenesis

To understand the hemodynamics of hepatocellular carcinoma (HCC) is important for the precise imaging diagnosis and treatment, because there is an intense correlation between their hemodynamics and pathophysiology. Angiogenesis such as sinusoidal capillarization and unpaired arteries shows gradual increase during multi-step hepatocarcinogenesis from high-grade dysplastic nodule to classic hypervascular HCC. In accordance with this angiogenesis, the intranodular portal supply is decreased, whereas the intranodular arterial supply is first decreased during the early stage of hepatocarcinogenesis and then increased in parallel with increasing grade of malignancy of the nodules. On the other hand, the main drainage vessels of hepatocellular nodules change from hepatic veins to hepatic sinusoids and then to portal veins during multi-step hepatocarcinogenesis, mainly due to disappearance of the hepatic veins from the nodules. Therefore, in early HCC, no perinodular corona enhancement is seen on portal to equilibrium phase CT, but it is definite in hypervascular classical HCC. Corona enhancement is thicker in encapsulated HCC and thin in HCC without pseudocapsule. To understand these hemodynamic changes during multi-step hepatocarcinogenesis is important, especially for early diagnosis and treatment of HCCs.

Hypervascular Hepatocellular Carcinoma: Correlation between Biologic Features and Signal Intensity on Gadoxetic Acid–enhanced MR Images

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.

Endothelial to Mesenchymal Transition via Transforming Growth Factor-β1/Smad Activation Is Associated with Portal Venous Stenosis in Idiopathic Portal Hypertension

Idiopathic portal hypertension (IPH) represents noncirrhotic portal hypertension of unknown etiology, mainly due to stenosis of peripheral portal veins. This study was performed to clarify the mechanism of portal venous stenosis in IPH from the viewpoint of the contribution of the endothelial to mesenchymal transition of the portal vein endothelium via transforming growth factor-beta1 (TGF-beta1)/Smad activation. In vitro experiments using human dermal microvascular endothelial cells demonstrated that TGF-beta1 induced myofibroblastic features in human dermal microvascular endothelial cells, including spindle cell morphology, reduction of CD34 expression, and induction of S100A4, alpha-smooth muscle actin, and COL1A1 expression, as well as the increased nuclear expression of phospho-Smad2. Bone morphogenic protein-7 preserved the endothelial phenotype of human dermal microvascular endothelial cells. Immunohistochemical analysis showed that endothelial cells of the peripheral portal veins in IPH were characterized by the decreased expression of CD34 and the enhanced nuclear expression of phospho-Smad2; these results also confirmed the expression of S100A4 and COL1A1 in the portal vein endothelium. Serum TGF-beta1 levels in patients with IPH were significantly higher than those of healthy volunteers and patients with chronic viral hepatitis/liver cirrhosis, while an elevation of serum bone morphogenic protein-7 levels was not observed. These results suggest that the endothelial to mesenchymal transition of the portal venous endothelium via TGF-beta1/Smad activation is associated with portal venous stenosis in IPH, and bone morphogenic protein-7 may therefore be a suitable therapeutic candidate for IPH.

Gd-EOB-DTPA-enhanced magnetic resonance imaging and alpha-fetoprotein predict prognosis of early-stage hepatocellular carcinoma

The survival of patients with hepatocellular carcinoma (HCC) is often individually different even after surgery for early‐stage tumors. Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd‐EOB‐DTPA)‐enhanced magnetic resonance imaging (MRI) has been introduced recently to evaluate hepatic lesions with regard to vascularity and the activity of the organic anion transporter OATP1B3. Here we report that Gd‐EOB‐DTPA‐enhanced MRI (EOB‐MRI) in combination with serum alpha‐fetoprotein (AFP) status reflects the stem/maturational status of HCC with distinct biology and prognostic information. Gd‐EOB‐DTPA uptake in the hepatobiliary phase was observed in ∼15% of HCCs. This uptake correlated with low serum AFP levels, maintenance of hepatocyte function with the up‐regulation of OATP1B3 and HNF4A expression, and good prognosis. By contrast, HCC showing reduced Gd‐EOB‐DTPA uptake with high serum AFP levels was associated with poor prognosis and the activation of the oncogene FOXM1. Knockdown of HNF4A in HCC cells showing Gd‐EOB‐DTPA uptake resulted in the increased expression of AFP and FOXM1 and the loss of OATP1B3 expression accompanied by morphological changes, enhanced tumorigenesis, and loss of Gd‐EOB‐DTPA uptake in vivo. HCC classification based on EOB‐MRI and serum AFP levels predicted overall survival in a single‐institution cohort (n = 70), and its prognostic utility was validated independently in a multi‐institution cohort of early‐stage HCCs (n = 109). Conclusion: This noninvasive classification system is molecularly based on the stem/maturation status of HCCs and can be incorporated into current staging practices to improve management algorithms, especially in the early stage of disease. (Hepatology 2014;60:1674–1685)

Relationship between signal intensity on hepatobiliary phase of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced MR imaging and prognosis of borderline lesions of hepatocellular carcinoma

PURPOSE To elucidate the incidence of signal intensity patterns of borderline lesions of hepatocellular carcinoma (HCC) on hepatobiliary phase Gd-EOB-DTPA (EOB) enhanced MRI and clarify the natural histories of these lesions. MATERIALS AND METHODS Total 99 borderline lesions of HCC were identified by angiography-assisted CT. The signal intensity of borderline lesions on hepatobiliary phase of EOB-enhanced MRI was analyzed. Progress rate from borderline lesions to hypervascular HCC was calculated with the Kaplan-Meier method among each signal intensity groups of nodules. RESULTS On hepatobiliary phase of EOB-enhanced MRI, 41.4% of the borderline lesions showed hypo-, 42.4% showed iso-, and 16.2% showed hyperintense, compared to background liver. Overall progress rates from borderline lesions to HCC were 10% in 1-year, 14% in 2-year and 20% in 3-year follow-up period. Progress rates to HCC in hypointense borderline lesions were 17% in 1-year, 28% in 2-year and 41% in 3-year follow-up period, and in isointense borderline lesions were 7% in 1-year, 7% in 2-year and 7% in 3-year follow-up period. No hyperintense borderline lesions progressed to HCC in follow-up period. CONCLUSION Although borderline lesions of HCC may show hypo-, iso- and hyperintensity on hepatobiliary phase of EOB-enhanced MRI, hypointense borderline lesions are high risk to progress HCC.

Role of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging in the management of hepatocellular carcinoma: consensus at the Symposium of the 48th Annual Meeting of the Liver Cancer Study Group of Japan.

We summarize here the consensus reached at the Symposium of the 48th Annual Meeting of the Liver Cancer Study Group of Japan held in Kanazawa on July 20th and 21st, 2012, on the role of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) in the management of hepatocellular carcinoma (HCC). Currently, dynamic CT is the first choice of imaging modality when HCC is suspected. EOB-MRI is useful for differentiation and definitive diagnosis of HCC when dynamic CT/MRI does not show conclusive findings for HCC. In addition, contrast- enhanced ultrasound with Sonazoid is useful for making a decision on whether or not to treat a hypovascular lesion <1 cm when the nodules are shown with low intensity in the hepatocyte phase of EOB-MRI. Furthermore, EOB-MRI should be performed in selected cases of HCC ultrahigh-risk groups every 3-4 months, or EOB-MRI should be performed at least once at the first visit in all HCC ultrahigh-risk groups.