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Background: Preoperative locoregional treatment (LRT) for hepatocellular carcinoma (HCC) often induces intratumoral necrosis without affecting the overall tumor size, and residual viable tumor size (VTS) on imaging is an important clinical parameter for assessing post-treatment response. However, for surgical specimens, it is unclear whether the VTS would be more relevant to prognosis compared to total tumor size (TTS).Methods: A total of 142 surgically resected solitary HCC cases were retrospectively reviewed. The TTS and VTS were assessed by applying the modified Response Evaluation Criteria in Solid Tumors method to the resected specimens, and correlated with the clinicopathological features and survival.Results: As applying VTS, 13/142 cases (9.2%) were down-staged to ypT1a. Although the survival analysis results for overall survival according to TTS or VTS were similar, VTS was superior to predict disease-free survival (DFS; p = .023) compared to TTS (p = .08). In addition, multivariate analysis demonstrated VTS > 2 cm to be an independent predictive factor for decreased DFS (p = .001). In the subpopulation of patients with LRT (n = 54), DFS in HCCs with TTS or VTS > 2 cm were significantly shorter than those with TTS or VTS ≤ 2 cm (p = .047 and p = .001, respectively). Interestingly, HCCs with TTS > 2 cm but down-staged to VTS ≤ 2 cm after preoperative LRT had similar survival to those with TTS ≤ 2 cm.Conclusions: Although the prognostic impact of tumor size was similar regardless of whether TTS or VTS was applied, reporting VTS may help to increase the number of candidates for surgery in HCC patients with preoperative LRT.

We report a case of adenocarcinoma originating from the duodenal Brunner glands in a 47-year-old female patient. The lesion was 0.8 cm in extent and located at the posterior wall of the first part of the duodenum. Histologically, the tumor showed transition from non-neoplastic Brunner glands through dysplastic epithelium into adenocarcinoma. The carcinoma cells were strongly positive for MUC6 protein, which is an epithelial marker for the Brunner glands. Tumor protein p53 was overexpressed in the carcinoma cells, but not in the non-neoplastic or dysplastic epithelium. Dystrophic calcification was predominant. This is the first case report of duodenal adenocarcinoma of Brunner gland origin in Korea.

BackgroundHenoch-Schönlein purpura nephritis (HSPN), a small-vessel vasculitis, shares renal pathological features with immunoglobulin A nephropathy. Oxford classification of immunoglobulin A nephropathy pathology has been updated to the MEST-C score, but its application in HSPN remains unresolved.MethodsTwo hundred and thirteen patients with biopsy-proven HSPN were retrieved from the Seoul National University Hospital between 2000 and 2017. Renal outcome risks (i.e., end-stage renal disease or doubling of serum creatinine) were evaluated according to MEST-C scores after stratification by age: 113 children aged ResultsTwenty-one child (19%) and 16 adult (16%) patients reached the renal outcome during the median follow-up periods of 12 years and 13 years, respectively (maximum 19 years). In children, M1 and T1/T2 scores revealed worse renal outcomes than did M0 and T0 scores, respectively, whereas the T score was the only factor related to worse outcomes in adult patients after adjusting for multiple clinical and laboratory variables. The pooled data showed that M1, S1, and T1/T2 in children and E1 and T1/T2 in adults were correlated with poorer renal outcomes than those of their counterpart scores.ConclusionsThe Oxford classification MEST-C scores can predict long-term renal outcomes in patients with HSPN.

We investigated protein profiles specific to vascular lesions mimicking Kaposi sarcoma (KS), based on stepwise morphogenesis progression of KS. We surveyed 26 tumor-associated proteins in 130 cases, comprising 39 benign vascular lesions (BG), 14 hemangioendotheliomas (HE), 37 KS, and 40 angiosarcomas (AS), by immunohistochemistry. The dominant proteins in KS were HHV8, lymphatic markers, Rb, phosphorylated Rb, VEGF, and galectin-3. Aberrant expression of p53, inactivation of cell cycle inhibitors, loss of beta-catenin, and increased VEGFR1 were more frequent in AS. HE had the lowest Ki-67 index, and the inactivation rates of cell cycle inhibitors in HE were between those of AS and BG/KS. Protein expression patterns in BG and KS were similar. Clustering analysis showed that the 130 cases were divided into three clusters: AS-rich, BG-rich, and KS-rich clusters. The AS-rich cluster was characterized by high caveolin-1 positivity, abnormal p53, high Ki-67 index, and inactivated p27. The KS-rich cluster shared the features of KS, and the BG-rich group had high positive expression rates of galectin-3 and low bcl2 expression. In conclusion, although the rate was different, AS and HE tended to have less cell cycle marker expression than KS, and features of BG and activated KS cell signaling were similar.

BACKGROUND Liver transplantation (LT) is the treatment of choice for hepatocellular carcinoma (HCC). The aim of this study was to investigate the recurrence rate of HCC after LT and prognostic factors for recurrence by comparing LT with non-transplanted resection. METHODS The participants were 338 patients who underwent LT between 1996 and 2012 at Seoul National University Hospital (LT group) and 520 HCC patients who underwent partial hepatectomy between 1995 and 2006 (control group, non-LT group). RESULTS In the LT group, 68 of 338 patients (19.8%) showed relapse, and the recurrence rate was lower than that in the non-LT group (64.9%, 357/520, p < .001). Stratification analysis by American Joint Committee on Cancer (AJCC) stage showed that the stage I-II LT group had a lower recurrence rate than the non-LT group. Univariate comparative analysis demonstrated that multiplicity of tumor, tumor size, gross type, Edmondson- Steiner (ES) nuclear grade, extent of tumor, angioinvasion, AJCC stage, Milan criteria, University of California at San Francisco criteria on explant pathology (all p < .001), positive expression of cytokeratin 19 (p = .002), and preoperative α-fetoprotein (AFP) (p < .001) were predictors of tumor recurrence. In multivariate analysis, LT, preoperative AFP, multiplicity of tumor, extent of tumor, size of tumor, and ES nuclear grade were independent prognostic factors. CONCLUSIONS LT might have a protective effect against the late recurrence of stage I-II HCC compared to non-LT, and the prognostic factors for recurrence were similar to previously well-known prognostic factors for HCC.

A bile duct lesion originating from intrahepatic bile ducts is generally regarded as an incidental pathologic finding in liver specimens. However, a recent study on the molecular classification of intrahepatic cholangiocarcinoma has focused on the heterogeneity of this carcinoma and has suggested that the cells of different origins present in the biliary tree may have a major role in the mechanism of oncogenesis. In this review, benign intrahepatic bile duct lesions-regarded in the past as reactive changes or remnant developmental anomalies and now noted to have potential for developing precursor lesions of intrahepatic cholangiocarcinoma-are discussed by focusing on the histopathologic features and its implications in clinical practice.

Undifferentiated embryonal sarcoma of the liver (UESL) is rare primary hepatic sarcoma and is known to occur in pediatric patients. This case is the UESL occurred in a 51-year old male patient. Multilocular cystic lesion was composed of primitive spindle cells without specific differentiation. This rare case would help to review differential diagnosis of primary sarcoma in liver and cystic neoplasm of the liver.

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological spectrum characterized by hepatic steatosis without history of significant alcohol use or other known liver disease. The commonly associated factors include obesity, insulin resistance syndrome, and hyperlipidemia. Other associations include jejuno-ileal bypass/gastroplasty surgery for morbid obesity, parenteral nutrition, forms of malnutrition, bacterial contamination of the small bowel, certain inherited metabolic disorders, and a wide range of drugs and environmental toxins [1]. The natural history and histological spectrum of NAFLD range from stable simple steatosis to progressive or advanced disease, such as steatohepatitis, cirrhosis, and even hepatocellular carcinoma [2-13]. A clinicopathological correlation is needed to diagnose NAFLD, as clinical assessment, laboratory tests, and imaging techniques alone provide limited pertinent information. Liver biopsy is the only reliable diagnostic tool to evaluate a patient with suspected NAFLD. Degree of steatosis, liver injury, and fibrosis associated with NAFLD can be identified and differentiated from simple steatosis and nonalcoholic steatohepatitis (NASH), which is the progressive form of NAFLD [14,15]. A NAFLD histopathological grading system was proposed by Brunt et al. in 1999 [16]. They proposed to classify each of steatosis, inflammation, and ballooning degeneration into three grades and fibrosis into four stages. Since then, Kleiner et al. [17] of the NASH Clinical Research Network have proposed a more relevant classification. Other than steatosis, inflammation, and ballooning degeneration, they proposed the classification of fibrosis around the central area into three more detailed grades. Also, they scored each finding and suggested that a score greater than five indicates NASH. However, until now, classifications for NAFLD or NASH have differed depending on the researcher, and no NAFLD histopathological grading system has been standardized, causing confusion for clinicians and pathologists. Furthermore, the histomorphological criteria for NAFLD pathologic features in liver tissue remain subjective. Thus, in this study, we determined the interobserver agreement of NAFLD pathologic features between pathologists and analyzed the causes of the disagreement in order to define the histopathological features in more detail as the basis for a grading system.

Background: Hepatitis B virus (HBV) plays well-known roles in tumorigenesis of hepatocellular carcinoma (HCC) in infected patients. However, HBV-associated protein status in tumor tissues and the relevance to tumor behavior has not been reported. Our study aimed to examine the expression of HBV-associated proteins in HCC and adjacent nontumorous tissue and their clinicopathologic implication in HCC patients. Methods: HBV surface antigen (HBsAg), HBV core antigen (HBcAg), and HBV X protein (HBx) were assessed in 328 HBV-associated HCCs and in 155 matched nontumorous tissues by immunohistochemistry staining. Results: The positive rates of HBsAg and cytoplasmic HBx staining in tumor tissue were lower than those in nontumorous tissue (7.3% vs. 57.4%, p < .001; 43.4% vs. 81.3%, p < .001). Conversely, nuclear HBx was detected more frequently in tumors than in nontumorous tissue (52.1% vs. 30.3%, p < .001). HCCs expressing HBsAg, HBcAg, or cytoplasmic HBx had smaller size; lower Edmondson-Steiner (ES) nuclear grade, pT stage, and serum alpha-fetoprotein, and less angioinvasion than HCCs not expressing HBV-associated proteins. Exceptionally, nuclear HBx-positive HCCs showed higher ES nuclear grade and more frequent large-vessel invasion than did nuclear HBx-negative HCCs. In survival analysis, only nuclear HBx-positive HCCs had shorter disease-free survival than nuclear HBx-negative HCCs in pT1 and ES nuclear grade 1–2 HCC subgroup (median, 126 months vs. 35 months; p = .015). Conclusions: Our data confirmed that expression of normal HBV-associated proteins generally decreases in tumor cells in comparison to nontumorous hepatocytes, with the exception of nuclear HBx, which suggests that nuclear HBx plays a role in recurrence of well-differentiated and early-stage HCCs.

Tissue adhesives have emerged as an alternative to sutures and staples for wound closure and reconnection of injured tissues after surgery or trauma. Owing to their convenience and effectiveness, these adhesives have received growing attention particularly in minimally invasive procedures. For safe and accurate applications, tissue adhesives should be detectable via clinical imaging modalities and be highly biocompatible for intracorporeal procedures. However, few adhesives meet all these requirements. Herein, we show that biocompatible tantalum oxide/silica core/shell nanoparticles (TSNs) exhibit not only high contrast effects for real-time imaging but also strong adhesive properties. Furthermore, the biocompatible TSNs cause much less cellular toxicity and less inflammation than a clinically used, imageable tissue adhesive (that is, a mixture of cyanoacrylate and Lipiodol). Because of their multifunctional imaging and adhesive property, the TSNs are successfully applied as a hemostatic adhesive for minimally invasive procedures and as an immobilized marker for image-guided procedures., The use of tissue adhesives for the closure of wounds is of growing interest for surgery and trauma management. Here, the authors develop an adhesive that is biocompatible, enables tissue adhesion and also permits real-time imaging due to the presence of contrast agents for multiple modalities.

Cellular schwannoma is an uncommon variant of schwannomas that can occur in a peripheral nerve. Although cellular schwannomas typically do not differ in prognosis from regular schwannomas, they are known to cause local recurrence when not completely resected. Here, we report the case of a patient with cellular schwannoma of the posterior mediastinum, which recurred after 13 years.

OBJECTIVE To evaluate the in vivo technical feasibility, efficiency, and safety of switching bipolar (SB) and switching monopolar (SM) radiofrequency ablation (RFA) as a no-touch ablation technique in the porcine liver. MATERIALS AND METHODS The animal care and use committee approved this animal study and 16 pigs were used in two independent experiments. In the first experiment, RFA was performed on 2-cm tumor mimickers in the liver using a no-touch technique in the SM mode (2 groups, SM1: 10 minutes, n = 10; SM2: 15 minutes, n = 10) and SB-mode (1 group, SB: 10 minutes, n = 10). The technical success with sufficient safety margins, creation of confluent necrosis, ablation size, and distance between the electrode and ablation zone margin (DEM), were compared between groups. In the second experiment, thermal injury to the adjacent anatomic organs was compared between SM-RFA (15 minutes, n = 13) and SB-RFA modes (10 minutes, n = 13). RESULTS The rates of the technical success and the creation of confluent necrosis were higher in the SB group than in the SM1 groups (100% vs. 60% and 90% vs. 40%, both p < 0.05). The ablation volume in the SM2 group was significantly larger than that in the SB group (59.2±18.7 cm3 vs. 39.8±9.7 cm3, p < 0.05), and the DEM in the SM2 group was also larger than that in the SB group (1.39±0.21 cm vs. 1.07±0.10 cm, p < 0.05). In the second experiment, the incidence of thermal injury to the adjacent organs and tissues in the SB group (23.1%, 3/13) was significantly lower than that in the SM group (69.2%, 8/13) (p = 0.021). CONCLUSION SB-RFA was more advantageous for a no-touch technique for liver tumors, showing the potential of a better safety profile than SM-RFA.

Background The Hippo pathway plays a vital role in liver regeneration and development by determining cellular lineage and regulating cell proliferation and apoptosis. In this study, we aimed to assess the role of the Hippo pathway in hepatic carcinogenesis and morphogenesis by examining Yes-associated protein 1 (YAP1) expression in the spectrum of hepatic carcinomas based on cellular lineage. Methods We examined 913 primary hepatic carcinomas, including hepatocellular carcinomas (HCCs), combined hepatocellular and cholangiocarcinomas (cHC-CCAs), intrahepatic cholangiocarcinomas (IHCCAs) and perihilar extrahepatic bile duct carcinomas (EHBCAs). Our study group was categorized into 8 disease groups, based on histological diagnosis and cytokeratin 19 (CK19) expression, and immunohistochemistry was used to detect and compare YAP1 expression levels between the groups. The eight disease groups we identified were: 1) CK19(−) HCC, 2) CK19(−) scirrhous HCC, 3) CK19(+) HCC, 4) stem cell feature of cHC-CCA, 5) classical cHC-CCA, 6) cholangiolocellular IHCCA, 7) non-cholangiolocellular IHCCA, and 8) EHBCA. Results Positive rates of YAP1 were the highest in the EHBCA group (21%). CK19(+) HCC and non-cholangiolocellular IHCCA groups also showed high expression levels (10% -11%), while the CK19 (−) HCC, CK19 (−) scirrhous HCC, cHC-CCA, and cholangiolocellular IHCCA groups showed low expression levels, ranging between 0% and 5%. Survival analysis, restricted to pT1 stage HCCs and IHCCAs, showed poor overall survival for YAP1(+) IHCCA patients (39 ± 17 vs. 109 ± 10 months, mean ± SD, log rank p-value 0.005). For HCCs, a trend of poor progression-free survival for YAP1(+) HCCs was observed (39 ± 18 vs. 81 ± 5 months, mean ± SD, log rank p-value 0.205) Conclusions YAP1 activation was more commonly found in CCAs than in pure HCCs. However, a differing pattern of YAP1 expression between cHC-CCAs and CK19(+) HCCs and the poor prognosis of YAP1 positive hepatic carcinomas suggests that YAP1 may have a preferential role in aggressive tumor behavior, rather than in the determination of cellular lineage in hepatic carcinomas. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3431-1) contains supplementary material, which is available to authorized users.

Hepatitis B virus (HBV) is the most common cause of chronic liver disease in South Korea and is one of the major risk factors of hepatocellular carcinoma (HCC) worldwide. Although various radiologic techniques for early detection and medical or surgical methods have successfully controlled the primary tumor, HCC still shows unsatisfactory long-term prognosis after surgical resection probably due to high recurrence rate.1 Most studies reported greater than 70% recurrence rate within a 5-year period. This recurrence, rather than the underlying cirrhosis, is the major cause of death.2-4 Hence, many investigations have studied risk factors for HCC recurrence after curative resection. Clinicopathologic characteristics of HCC such as micrometastasis, vascular invasion, and positive resection margin are well-known risk factors for tumor recurrence.5 Recently, peritumoral non-neoplastic liver parenchyma (PNLP) has been suggested to be an important predictive marker of HCC recurrence after surgical resection.6-8 PNLP can be defined as hepatic parenchyma without histologic evidence of tumors. However, in patients with chronic liver disease, PNLP has two different levels; the first is adjacent parenchyma that is affected by tumors and the second one is remote parenchyma that is not affected by primary tumors. Adjacent PNLP is claimed to be influenced by mass effect of tumor proper and several tumor-producing factors via paracrine or autocrine manners, indirectly depicting the trait of tumors. Meanwhile, remote PNLP may express the patient's underlying chronic liver disease and indirectly the trait of tumorigenesis, implying new occurrence of HCCs. It is therefore important to determine the exact distance of adjacent PNLP that is directly influenced by the tumor, which differs from remote PNLP, the background liver parenchyma. However, published reports lack consistency on the precise distance that defines adjacent PNLP. Some authors used the farthest non-cancerous liver parenchyma in the entire surgical specimen.9 However, there were some other studies that have limited specimens to a distance of 10 mm from the tumor,10 while others have simply made use of the peritumoral liver tissue that was available at the time of the study.11 In this study, we sought the pathologic characteristics of PNLP of HCCs in chronic HBV patients in order to suggest a reasonable cut-off point between adjacent and remote PNLP from the histologic view point.

In this study, the effects of autologous islet transplantation (ITx) were compared to those of oral antidiabetic drugs (OAD) after distal pancreatectomy (NCT01922492). We enrolled nondiabetic patients who underwent distal pancreatectomy for benign tumors. In the ITx group, islets were isolated from the normal part of the resected pancreas and implanted via the portal vein. Patients who did not receive ITx were regularly monitored and were enrolled in the OAD group if diabetes mellitus developed. The OAD group was treated with metformin with or without vildagliptin. Metabolic parameters were monitored for 12 months postoperatively. Nine patients in the ITx group and 10 in the OAD group were included in the analysis. After 12 months, hemoglobin A1c significantly increased by 5% of the baseline in each group. Area under the curve for blood glucose (AUCglucose) of the 75-g oral glucose tolerance test increased similarly in the immediate postoperative period in both groups but significantly reduced only in the ITx group thereafter. Insulinogenic index (INSindex) significantly decreased from 25.6 ± 18.9 to 4.7 ± 3.7 in the OAD group, while no significant change was observed in the ITx group (from 15.0 ± 4.5 to 11.0 ± 8.2). In the multiple regression analysis, ITx was an independent factor for changes in AUCglucose and INSindex. In addition, changes in INSindex in the ITx group after postoperative 6 months were associated with the efficacy of islet isolation, amount of grafts, and peak serum HMGB1 and VEGF levels after ITx. ITx was superior to OAD in maintaining insulin secretory capacity and glucose tolerance after distal pancreatectomy.

AIM: To identify clinical and pathological differences between serum immunoglobulin G4 (IgG4)-positive (SIP) and IgG4-negative (SIN) type 1 autoimmune pancreatitis (AIP) in South Korea. METHODS: AIP was diagnosed by the international consensus diagnostic criteria. The medical records and pathology were retrospectively reviewed and IgG4-positive cells were counted in a high power field (HPF). Type I AIP was defined as a high serum level of IgG4 or histological finding. SIN type 1 AIP was defined as a histological evidence of type 1 AIP and a normal serum IgG4 level. The clinical and pathological findings were compared between the two groups. The analysis was performed using Student’s t test, Fischer’s exact test and Mann-Whitney’s U test. A P value of < 0.05 was considered statistically significant. As repeated comparison was made, P values of less than 5% (P < 0.05) were considered significant. RESULTS: Twenty five patients with definite type 1 AIP (19 histologically and six serologically diagnosed cases) were enrolled. The mean tissue IgG4 concentrations were significantly higher in SIP than SIN group (40 cells per HPF vs 18 cells per HPF, P = 0.02). Among eight SIN patients, the tissue IgG4 concentrations were less than 15 cells per HPF in most of cases, except one. The sensitivity of serum IgG4 was 68% (17 SIP and eight SIN AIP). Other organ involvement was more frequently associated with SIP than SIN AIP (59% vs 26%, P = 0.016). However, the relapse rate and diffuse swelling of the pancreas were not associated with serum IgG4 level. The concentrations of IgG4-positive cells per HPF were higher in SIP than SIN AIP (40 vs 18, P = 0.02). CONCLUSION: The sensitivity of serum IgG4 was 68% in type 1 AIP. High serum IgG4 level was associated with other organ involvement and tissue IgG4 concentration but did not affect the relapse rate in type 1 AIP.

MicroRNAs (miRNAs) participate in diverse biological functions and carcinogenesis by inhibiting specific gene expression. We previously reported that suppression of adenine nucleotide translocase 2 (ANT2) by using the short hairpin RNA (shRNA) approach has an antitumor effect in several cancer cells. We here examined the influence of ANT2 on expression of miRNAs in hepatocellular carcinoma (HCC) to further elucidate the tumor-suppressive mechanism of ANT2 shRNA. We first carried out screening for miRNAs, whose expression is regulated by ANT2 suppression in the Hep3B HCC cell line using miRNA microarrays. Validation of candidate miRNAs was done by incorporating clinical samples, and their effects on the tumorigenesis of HCC were studied in vitro and in vivo. miR-636 was one of the miRNAs whose expression was highly upregulated by ANT2 suppression in miRNA microarray analysis, as confirmed by real-time reverse transcription-polymerase chain reaction. Notably, miR-636 was markedly downregulated in HCC tissues compared with matched non-neoplastic liver in clinical samples. Restoration of miR-636 in Hep3B cells led to significant reduction of cell proliferation and colony formation. miR-636 restoration resulted in a decreased level of Ras, one of the putative targets of miR-636, and inactivation of its signaling pathway. Moreover, tumorigenesis was efficiently suppressed by miR-636 in an in vivo tumor xenograft model of HCC. The data suggest that miR-636 might function as a tumor suppressor miRNA affecting HCC tumorigenesis via downregulation of Ras, and that ANT2 suppression by shRNA could exert an anticancer effect by restoring miR-636 expression in HCC.