Hyungjin Rhee

Differentiation of early hepatocellular carcinoma from benign hepatocellular nodules on gadoxetic acid-enhanced MRI.

OBJECTIVE To test new diagnostic criteria for the discrimination of early hepatocellular carcinoma (HCC) from benign hepatocellular nodules on gadoxetic acid-enhanced MRI (Gd-EOB-MRI). METHODS We retrospectively analysed 34 patients with 29 surgically diagnosed early HCCs and 31 surgically diagnosed benign hepatocellular nodules. Two radiologists reviewed Gd-EOB-MRI, including diffusion-weighted imaging (DWI), and the signal intensity at each sequence, presence of arterial enhancement and washout were recorded. We composed new diagnostic criteria based on the lesion size and MRI findings, and then the diagnostic performance was compared with that of conventional imaging criteria with logistic regression and a generalised estimating equation method. RESULTS A size cut-off value (≥1.5 cm diameter) and MRI findings of T(1) hypointensity, T(2) hyperintensity, DWI hyperintensity on both low and high b-value images (b=50 and 800 s mm(-2), respectively), arterial enhancement, late washout and hepatobiliary hypointensity were selected as the diagnostic criteria. When lesions were considered malignant if they satisfied three or more of the above criteria, the sensitivity was significantly higher than when making a diagnosis based on arterial enhancement and washout alone (58.6% vs 13.8%, respectively; p=0.0002), while the specificity was 100.0% for both criteria. CONCLUSION Our new diagnostic criteria on Gd-EOB-MRI may help to improve the discrimination of early HCC from benign hepatocellular nodules.

Gadoxetic acid-enhanced MRI findings of early hepatocellular carcinoma as defined by new histologic criteria.

To describe the imaging features of early hepatocellular carcinoma (HCC) on gadoxetic acid‐enhanced MRI (Gd‐EOB‐MRI) in comparison with multidetector computed tomography (MDCT) examinations.

Increased expression of CCN2, epithelial membrane antigen, and fibroblast activation protein in hepatocellular carcinoma with fibrous stroma showing aggressive behavior.

Tumor behavior is affected by the tumor microenvironment, composed of cancer-associated fibroblasts (CAFs). Meanwhile, hepatocellular carcinomas (HCC) with fibrous stroma reportedly exhibit aggressive behavior suggestive of tumor-stroma interaction. However, evidence of the crosstalk remains unclear. In this study, CCN2, epithelial membrane antigen (EMA), fibroblast activation protein (FAP), and keratin 19 (K19) expression was studied in 314 HCCs (cohort 1), 42 scirrhous HCCs (cohort 2), and 36 chronic hepatitis/cirrhosis specimens by immunohistochemistry. Clinicopathological parameters were analyzed according to the expressions of these markers. In tumor epithelial cells from cohort 1, CCN2 and EMA were expressed in 15.3% and 17.2%, respectively, and their expressions were more frequent in HCCs with fibrous stroma (≥5% of tumor area) than those without (P<0.05 for all); CCN2 expression was well correlated with K19 and EMA expression. In tumor stromal cells, FAP expression was found in 6.7%. In cohort 2, CCN2, EMA, and FAP expression was noted in 40.5%, 40.5%, and 66.7%, respectively, which was more frequent than that in cohort 1 (P<0.05 for all). Additionally, EMA expression was associated with the expression of K19, CCN2, and FAP (P<0.05 for all); EMA expressing tumor epithelial cells showed a topographic closeness to FAP-expressing CAFs. Analysis of disease-free survival revealed CCN2 expression to be a worse prognostic factor in both cohort 1 (P = 0.005) and cohort 2 (P = 0.023), as well as EMA as a worse prognostic factor in cohort 2 (P = 0.048). In conclusion, expression of CCN2, EMA, and FAP may be involved in the activation of CAFs in HCC, giving rise to aggressive behavior. Significant correlation between EMA-expressing tumor cells and FAP-expressing CAFs and their topographic closeness suggests possible cross-talk between tumor epithelial cells and stromal cells in the tumor microenvironment of HCC.

Single Hepatocellular Carcinoma: Preoperative MR Imaging to Predict Early Recurrence after Curative Resection

PURPOSE To identify magnetic resonance (MR) imaging features that enable prediction of early recurrence (<2 years) after curative resection of hepatocellular carcinoma (HCC) and to derive a preoperative prediction model. MATERIALS AND METHODS This retrospective study was approved by the institutional review board. The requirement to obtain written informed consent was waived. A total of 268 patients who underwent hepatic resection for a single HCC from January 2008 to August 2011 were divided into two cohorts: a training cohort, which was used to derive a prediction model (n = 187), and a validation cohort (n = 81). All MR images from the training cohort were reviewed by two radiologists. A prediction model was constructed by using MR imaging features that were independently associated with early recurrence with use of multiple logistic regression analysis. The performance of the prediction model in the validation cohort was evaluated with respect to discrimination (ie, whether the relative ranking of individual predictions of subsequent early recurrence is in the correct order). RESULTS In the training cohort, four MR imaging features were independently associated with early recurrence: rim enhancement (odds ratio [OR] = 3.83; 95% confidence interval [CI]: 1.39, 10.52), peritumoral parenchymal enhancement in the arterial phase (OR = 2.64; 95% CI: 1.27, 5.46), satellite nodule (OR = 4.07; 95% CI: 1.09, 15.21), and tumor size (OR = 1.66; 95% CI: 1.31, 2.09). A prediction model derived from these variables showed an area under the receiver operating characteristic curve (AUC) of 0.788 in the prediction of the risk of early recurrence in the training cohort. When applied to the validation cohort, this model showed good discrimination (AUC, 0.783). CONCLUSION The prediction model derived from rim enhancement, peritumoral parenchymal enhancement, satellite nodule, and tumor size can be used preoperatively to estimate the risk of early recurrence after resection of a single HCC.

Histological characteristics of small hepatocellular carcinomas showing atypical enhancement patterns on gadoxetic acid-enhanced MR imaging

To define the histological characteristics of hepatocellular carcinomas (HCCs) showing atypical dynamic enhancement patterns on gadoxetic acid‐enhanced dynamic magnetic resonance imaging (EOB‐MRI).

Transarterial Therapies for Hepatocellular Carcinoma

Background: The treatment of hepatocellular carcinoma (HCC) is still a major health issue because of its increasing incidence and because of the complexity of its management. Transarterial embolization (TAE) and transarterial chemoembolization (TACE) are two widely used locoregional therapies in the treatment of HCC, especially for unresectable intermediate and advanced HCCs. Summary: The modern use of TAE and TACE opens new scenarios for the treatment of unresectable HCC and has yielded interesting results. The present work describes the role of transarterial therapies for HCC and focuses on the different Western and Eastern approaches to the study of response predictors. Key Messages: Recent refinements in interventional radiology techniques and in HCC patient selection have facilitated better local control of the disease. The molecular profiling of HCC to predict the response to TACE and TAE will greatly help clinicians identify the optimum therapy.

β-Catenin Activated Hepatocellular Adenoma: A Report of Three Cases in Korea

Hepatocellular adenoma (HCA) is an uncommon benign hepatic tumor, and the use of oral contraceptives is known to contribute to the development of HCA. Recently, a genotype and phenotype classification system for HCA was suggested, and malignant transformation to hepatocellular carcinoma (HCC) was shown to be strongly associated with activating mutations in β-catenin. Here, we report three cases of HCA in Korean patients: 7-cm, inflammatory and β-catenin-activated HCA with HCC transformation in a 46-year-old man; 13-cm, β-catenin-activated HCA with cytological atypia in a 23-year-old woman; and 10-cm, pigmented, inflammatory and β-catenin-activated HCA in a 36-year-old man. All cases exhibited the nuclear expression of β-catenin and diffuse cytoplasmic expression of glutamine synthetase upon immunohistochemical staining. All tumors were completely resected, and the patients were followed for 3 to 6 years with no evidence of local recurrence or metastasis.

Transcriptomic and histopathological analysis of cholangiolocellular differentiation trait in intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is a heterogeneous entity with diverse aetiologies, morphologies and clinical outcomes. Recently, histopathological distinction of cholangiolocellular differentiation (CD) of iCCA has been suggested. However, its genome‐wide molecular features and clinical significance remain unclear.

Tumor stroma with senescence-associated secretory phenotype in steatohepatitic hepatocellular carcinoma

Senescence secretome was recently reported to promote liver cancer in an obese mouse model. Steatohepatitic hepatocellular carcinoma (SH-HCC), a new variant of HCC, has been found in metabolic syndrome patients, and pericellular fibrosis, a characteristic feature of SH-HCC, suggests that alteration of the tumor stroma might play an important role in SH-HCC development. Clinicopathological characteristics and tumor stroma showing senescence and senescence-associated secretory phenotype (SASP) were investigated in 21 SH-HCCs and 34 conventional HCCs (C-HCCs). The expression of α-smooth muscle actin (α-SMA), p21Waf1/Cif1, γ-H2AX, and IL-6 was investigated by immunohistochemistry or immunofluorescence. SH-HCCs were associated with older age, higher body mass index, and a higher incidence of metabolic syndrome, compared to C-HCC (P <0.05, all). The numbers of α-SMA-positive cancer-associated fibroblasts (CAFs) (P = 0.049) and α-SMA-positive CAFs co-expressing p21Waf1/Cif1 (P = 0.038), γ-H2AX (P = 0.065), and IL-6 (P = 0.048) were greater for SH-HCCs than C-HCCs. Additionally, non-tumoral liver from SH-HCCs showed a higher incidence of non-alcoholic fatty liver disease and a higher number of α-SMA-positive stellate cells expressing γ-H2AX and p21Waf1/Cif1 than that from C-HCCs (P <0.05, all). In conclusion, SH-HCCs are considered to occur more frequently in metabolic syndrome patients. Therein, senescent and damaged CAFs, as well as non-tumoral stellate cells, expressing SASP including IL-6 may contribute to the development of SH-HCC.

Progressive enrichment of stemness features and tumor stromal alterations in multistep hepatocarcinogenesis

Cancer stem cells (CSCs), a subset of tumor cells, contribute to an aggressive biological behavior, which is also affected by the tumor stroma. Despite the role of CSCs and the tumor stroma in hepatocellular carcinoma (HCC), features of stemness have not yet been studied in relation to tumor stromal alterations in multistep hepatocarcinogenesis. We investigated the expression status of stemness markers and tumor stromal changes in B viral carcinogenesis, which is the main etiology of HCC in Asia. Stemness features of tumoral hepatocytes (EpCAM, K19, Oct3/4, c-KIT, c-MET, and CD133), and tumor stromal cells expressing α-smooth muscle actin (α-SMA), CD68, CD163, and IL-6 were analyzed in 36 low grade dysplastic nodules (DNs), 48 high grade DNs, 30 early HCCs (eHCCs), and 51 progressed HCCs (pHCCs) by immunohistochemistry or real-time PCR. Stemness features (EpCAM and K19 in particular) were progressively acquired during hepatocarcinogenesis in combination with enrichment of stromal cells (CAFs, TAMs, IL-6+ cells). Stemness features were seen sporadically in DNs, more consistent in eHCCs, and peaked in pHCCs. Likewise, stromal cells were discernable in DNs, showed up as consistent cell densities in eHCCs and peaked in pHCCs. The stemness features and tumor stromal alterations also peaked in less differentiated or larger HCCs. In conclusion, progression of B viral multistep hepatocarcinogenesis is characterized by an enrichment of stemness features of neoplastic hepatocytes and a parallel alteration of the tumor stroma. The modulation of neoplastic hepatocytes and stromal cells was at low levels in precancerous lesions (DNs), consistently increased in incipient cancer (eHCCs) and peaked in pHCCs. Thus, in B viral hepatocarcinogenesis, interactions between CSCs and the tumor stroma, although starting early, seem to play a major role in tumor progression.