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1.  Expression of heat shock proteins (HSP27, HSP60, HSP70, HSP90, GRP78, GRP94) in hepatitis B virus-related hepatocellular carcinomas and dysplastic nodules 
AIM: Expression of heat shock proteins (HSPs) is frequently up-regulated in hepatocellular carcinoma (HCC), which evolves from dysplastic nodule (DN) and early HCC to advanced HCC. However, little is known about the differential expression of HSPs in multistep hepatocarcinogenesis. It was the purpose of this study to monitor the expression of HSPs in multistep hepatocarcinogenesis and to evaluate their prognostic significance in hepatitis B virus (HBV)-related HCC.
METHODS: Thirty-eight HCC and 19 DN samples were obtained from 52 hepatitis B surface antigen-positive Korean patients. Immunohistochemical and dot immunoblot analyses of HSP27, HSP60, HSP70, HSP90, glucose regulated protein (GRP)78, and GRP94 were performed and their expression at different stages of HCC development was statistically analyzed.
RESULTS: Expression of HSP27, HSP70, HSP90, GRP78, and GRP94 increased along with the stepwise progression of hepatocarcinogenesis. Strong correlation was found only in GRP78 (Spearman’s r = 0.802). There was a positive correlation between the expressions of GRP78, GRP94, HSP90, or HSP70 and prognostic factors of HCC. Specifically, the expression of GRP78, GRP94, or HSP90 was associated significantly with vascular invasion and intrahepatic metastasis.
CONCLUSION: The expressions of HSPs are commonly up-regulated in HBV-related HCCs and GRP78 might play an important role in the stepwise progression of HBV-related hepatocarcinogenesis. GRP78, GRP94, and HSP90 may be important prognostic markers of HBV-related HCC, strongly suggesting vascular invasion and intrahepatic metastasis.
doi:10.3748/wjg.v11.i14.2072
PMCID: PMC4305774  PMID: 15810071
Heat shock protein; Hepatocellular carcinoma; Dysplastic nodule; Hepatocarcinogenesis; Immunohisto-chemistry; Dot immunoblot analysis
2.  Loss of Tuberous Sclerosis Complex 2 (TSC2) as a Predictive Biomarker of Response to mTOR Inhibitor Treatment in Patients with Hepatocellular Carcinoma1 
Translational Oncology  2016;9(5):466-471.
BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death globally. Mechanistic target of rapamycin (mTOR) is frequently up-regulated in HCC and plays an important role in HCC tumorigenesis. Tumors with loss of tuberous sclerosis complex 2 (TSC2), a negative regulator of mTOR signaling, tend to respond well to mTOR inhibitors. We analyzed TSC2 expression status in Korean patients with HCC and evaluated the correlation between TSC2 loss and response to the mTOR inhibitor, everolimus. METHODS: We retrospectively assessed 36 patients with advanced HCC who had received sorafenib at a single center in Korea between 2008 and 2014, and for whom tumor specimens were available for TSC2 immunohistochemical analysis (IHC). Three patient-derived tumor cell lines (PDCs) were analyzed by western blotting to determine TSC2 expression and drug sensitivity to mTOR. RESULTS: Twelve of 36 patients (33.3%) showed low to undetectable levels of TSC2 expression. No significant differences were observed in progression-free survival (PFS) or overall survival with sorafenib treatment based on TSC2 expression status. Two patients were treated with everolimus after sorafenib failure; one patient, with moderate TSC2 expression, experienced stable disease with a PFS of 5.8 months; the other, with high TSC2 expression, experienced rapid progression. PDC models demonstrated that the TSC2-low HCC PDC line was significantly more sensitive to everolimus than the TSC2-high HCC PDC lines. CONCLUSION: Loss of TSC2 may predict improved response to everolimus in HCC patients, but further studies are needed to confirm the predictive role of TSC2 expression for everolimus treatment.
doi:10.1016/j.tranon.2016.08.009
PMCID: PMC5067924  PMID: 27751352
3.  NADPH Oxidase 1 and NADPH Oxidase 4 Have Opposite Prognostic Effects for Patients with Hepatocellular Carcinoma after Hepatectomy 
Gut and Liver  2016;10(5):826-835.
Background/Aims
Nicotinamide adenine dinucleotide phosphate oxidase (NOX)-mediated reactive oxygen species contribute to various liver diseases, including hepatocellular carcinoma (HCC). Uncertainties remain regarding the prognostic relevance of NOX1 and NOX4 protein expression in HCC.
Methods
NOX1 and NOX4 protein expression was examined by using immunohistochemistry in tumor tissue from 227 HCC patients who underwent hepatectomy.
Results
High immunoreactivity for NOX1 was observed in 197 (86.8%) of the 227 HCC cases and low immunoreactivity for NOX4 in 112 (49.3%). NOX1 and NOX4 proteins had opposite prognostic effects. High NOX1 expression was an independent predictor of both shorter recurrence-free survival (RFS) (p<0.01) and shorter overall survival (OS) (p=0.01). Low NOX4 expression was an independent predictor of both shorter RFS (p<0.01) and shorter OS (p=0.01). Subgroup analysis showed that, among patients with normal α-fetoprotein levels, patients with tumor size ≤5.0 cm and patients in Barcelona Clinic Liver Cancer stage A, high NOX1 expression had unfavorable effects on RFS, whereas low NOX4 expression had unfavorable effects on both RFS and OS.
Conclusions
These findings demonstrated that NOX1 and NOX4 protein expression had opposite prognostic effects for HCC patients. Moreover, both proteins had prognostic value in HCC patients with normal α-fetoprotein levels or with early-stage HCC.
doi:10.5009/gnl15543
PMCID: PMC5003208  PMID: 27282266
NOX1; NOX4; Carcinoma; hepatocellular; Prognosis
4.  The Overexpression of CCAR1 in Hepatocellular Carcinoma Associates with Poor Prognosis 
Purpose
Cell division cycle and apoptosis regulator 1 (CCAR1) plays a dynamic role in regulation of cell growth and apoptosis by serving as a cofactor of steroid/thyroid nuclear receptors, β-catenin, and p53 in a variety of cell types including different cancer cells. However, whether CCAR1 protein is overexpressed in hepatocellular carcinoma (HCC) and the prognostic significance of CCAR1 protein expression in HCC have not been reported.
Materials and Methods
In 167 HCC patients with long-term follow-up, CCAR1 protein expression was examined by immunohistochemistry.
Results
High CCAR1 protein expression was observed in 149 of the 167 HCC cases (89.2%) and showed significant correlation with microvascular invasion, intrahepatic metastasis, higher American Joint Committee on Cancer (AJCC) T stage, and early recurrence. High CCAR1 expression showed an unfavorable effect on recurrence-free survival (RFS) (p=0.002). In subgroup analysis, among patients with α-fetoprotein ≤ 20 ng/mL (n=54) and patients with AJCC T stage 1 (n=62), significant differences in RFS were observed between high CCAR1 expression groups and low CCAR1 expression groups (p=0.015 and p=0.004, respectively). High CCAR1 expression tended to be an independent predictor of shorter RFS (p=0.054) and showed an unfavorable effect on overall survival (OS) (p=0.015). In subgroup analysis, among patients with α-fetoprotein ≤ 20 ng/mL (n=54), significant difference in OS was observed between high CCAR1 expression group and low CCAR1 expression group (p=0.046).
Conclusion
CCAR1 protein could be a potential biomarker predicting RFS in HCC patients after curative hepatectomy. In addition, CCAR1 had prognostic values in HCC patients with normal serum α-fetoprotein levels or early stage HCC.
doi:10.4143/crt.2015.302
PMCID: PMC4946359  PMID: 26511806
CCAR1; Hepatocellular carcinoma; Prognosis
5.  The Prognostic Role of Mitotic Index in Hepatocellular Carcinoma Patients after Curative Hepatectomy 
Purpose
High proliferation rate is a hallmark of cancer. The mitotic index is a useful and simple method for analysis of cell proliferation. However, the practical utility of mitotic index as a predictor of prognosis in patients with hepatocellular carcinoma (HCC) has not been determined. Therefore, we examined mitotic index as a prognostic marker in HCC patients.
Materials and Methods
We counted the number of mitotic cells in 10 high-power fields of the tumor area on hematoxylin and eosin–stained slides representing 282 surgically resected HCCs. The highest number of mitotic cells was defined as the mitotic index.
Results
High mitotic index was observed in 127 of 282 HCCs. High mitotic index showed significant association with younger age, larger tumor size, higher Edmondson grade, microvascular invasion, major portal vein invasion, intrahepatic metastasis, higher American Joint Committee on Cancer (AJCC) T-stage, higher Barcelona Clinic Liver Cancer (BCLC) stage, higher alpha-fetoprotein level, hepatitis B virus etiology, and liver cirrhosis. Patients with high mitotic index had shorter disease-specific survival (DSS) (p < 0.001) and tended to have shorter recurrence-free survival (p=0.112). In subgroup analysis among patients with a larger tumor size, microvascular invasion, intrahepatic metastasis, higher AJCC T-stage, and higher BLCL stage, high mitotic index showed unfavorable influences on DSS (p=0.001, p=0.008, p=0.003, p=0.012, and p < 0.001, respectively). In addition, high mitotic index was an independent predictor of shorter DSS (p=0.004).
Conclusion
High mitotic index may be a novel predictor of DSS in patients with HCC and may have utility as an auxiliary prognostic factor in HCC.
doi:10.4143/crt.2014.321
PMCID: PMC4720078  PMID: 25797572
Mitotic index; Prognostic factor; Survival; Hepatocellular carcinoma
6.  ATAD2 as a Poor Prognostic Marker for Hepatocellular Carcinoma after Curative Resection 
Purpose
Cancer cells frequently express genes that are specifically or preferentially expressed in male germ cells under normal conditions. The ATPase family AAA domain-containing 2 (ATAD2) is one such and works as an important cofactor for MYC-dependent transcription. In hepatocellular carcinoma (HCC), ATAD2 has been identified as a candidate driver gene located within the amplified 8q24 locus. However, the prognostic significance of ATAD2 protein expression in HCC remains uncertain.
Materials and Methods
We investigated ATAD2 protein expression by immunohistochemistry in tumor tissue from 182 HCC patients who underwent curative resection. Associations of ATAD2 expression with clinicopathologic variables or prognosis of HCC patients were analyzed.
Results
ATAD2 expression was observed in 119 (65.4%) of the 182 HCCs and tended to be independent predictor of early recurrence (p=0.059). ATAD2 expression showed an unfavorable influence on recurrence-free survival (RFS) (p < 0.001). Subgroup analysis among patients with tumor size ≤ 5.0 cm (n=109), patients at Barcelona Clinic Liver Cancer stage 0 or A (n=92), and patients with α-fetoprotein ≤ 20 ng/mL (n=61), the ATAD2-positive groups unfavorably influenced RFS (p=0.008, p=0.009, and p=0.013, respectively). In addition, ATAD2 expression was an independent predictor of shorter RFS (p=0.002). ATAD2 expression showed an unfavorable influence on disease-specific survival (p=0.001), but was not an independent predictor of shorter disease-specific survival (p=0.109).
Conclusion
ATAD2 protein expression may be a potential predictor of RFS in HCC patients after curative resection and ATAD2 may have prognostic value in patients with early stage HCC or normal serum α-fetoprotein level.
doi:10.4143/crt.2014.177
PMCID: PMC4614186  PMID: 25687855
ATAD2; Hepatocellular carcinoma; Prognosis
7.  Expression of PEG10 Is Associated with Poor Survival and Tumor Recurrence in Hepatocellular Carcinoma 
Purpose
Paternally expressed gene 10 (PEG10), first identified as an imprinted gene, is paternally expressed and maternally silenced. In hepatocellular carcinoma (HCC), PEG10 has been identified as a potential target gene located within the amplified 7q21 locus. The purpose of this study was to investigate the expression of PEG10 protein in HCC and evaluate its prognostic significance.
Materials and Methods
PEG10 protein expression was examined by immunohistochemistry in tumor tissues from 218 HCC patients undergoing curative resection. Furthermore, the relationships between PEG10 expression and clinicopathologic features or postoperative survival of HCC patients were evaluated. The median follow-up period was 119.8 months for survivors.
Results
PEG10 expression was observed in 148 of the 218 HCCs (67.9%) and was significantly correlated with younger age, female, higher Edmondson grade, microvascular invasion, intrahepatic metastasis, higher American Joint Committee on Cancer T-stage, and higher α-fetoprotein level. PEG10 expression was an independent predictor of early recurrence (p=0.013), and it showed an unfavorable influence on recurrence-free survival (p < 0.001). A subgroup analysis showed that among patients with α-fetoprotein ≤ 20 ng/mL (80 patients), the PEG10-positive group also showed an unfavorable influence on recurrence-free survival (p=0.002). Moreover, a multivariate survival analysis identified PEG10 as an independent predictor of shorter recurrence-free survival (p=0.005). PEG10 expression showed an unfavorable influence on overall survival (p=0.007) but was not an independent predictor of shorter overall survival (p=0.128).
Conclusion
PEG10 protein could be a potential biomarker predicting early recurrence and recurrence-free survival in HCC patients after curative resection, even in those with normal serum α-fetoprotein levels.
doi:10.4143/crt.2014.124
PMCID: PMC4614193  PMID: 25687862
PEG10; Hepatocellular carcinoma; Recurrence
8.  Gastroenteropancreatic Neuroendocrine Tumors with Liver Metastases in Korea: A Clinicopathological Analysis of 72 Cases in a Single Institute 
Purpose
Management of gastroenteropancreatic (GEP) neuroendocrine tumors with liver metastases (NETLM) presents many clinical challenges. Assessment of the extent of disease and primary tumor site is crucial for management. In this study, we investigated the primary tumor sites and prognostic factors in GEP NETLM among Korean patients.
Materials and Methods
We reviewed the medical records of 72 Korean patients diagnosed with GEP NETLM between January 1999 and May 2013, focusing on their clinical and pathologic characteristics.
Results
The most frequently encountered primary tumor sites were the pancreas (n=25, 35%), stomach (n=8, 11%), gall bladder (n=4, 6%) and rectum (n=3, 4%). Twenty-five patients (35%) had occult primary tumor. Twelve patients (17%) had histological grade G1 tumors, 30 patients (42%) had G2 tumors, and 30 patients (42%) had G3 tumors. The mean follow-up period after histological confirmation of hepatic metastases was 11.30±2.44 months for G3 tumors, 19.67±4.09 months for G2 tumors, and 30.67±6.51 months for G1 tumors. Multivariate analyses revealed that an unknown primary tumor site (p=0.001) and higher histological grade (p < 0.001) were independent prognostic indicators for shorter overall survival (OS). Most long-term survivors (OS > 24 months) had received antitumor treatment.
Conclusion
The primary tumor site most frequently associated with GEP NETLM was the pancreas. Unknown primary tumor and higher histological grade were independent prognostic indicators for shorter OS. Patients identified as being at a risk of shorter OS should be followed up closely.
doi:10.4143/crt.2014.224
PMCID: PMC4614220  PMID: 25687852
Liver; Metastasis; Neuroendocrine tumor; Pathology; Prognosis
9.  The prognosis of hepatocellular carcinoma after curative hepatectomy in young patients 
Oncotarget  2015;6(21):18664-18673.
Age at diagnosis is a reported prognostic factor in a variety of solid cancers. In hepatocellular carcinomas (HCCs), several previous studies focused on patient age, but demonstrated inconclusive results on prognosis of young patients. Clinical outcome may differ according to the balance between tumor's own biologic behavior and underlying liver function thus explaining the inconclusive results in previous studies. In this study, we enrolled 282 patients who underwent curative hepatectomy for primary HCCs and had Child Pugh Class A, representing good liver function. Clinicopathologic features were compared between patients aged ≤40 years (young age group) and those aged >40 years (old age group). Thirty-five patients (12.4%) were classified as the young age group and showed larger tumor size (>5cm), higher Edmondson grade, more frequent intrahepatic metastasis and higher alpha-fetoprotein level (>200ng/mL) than old age group. Young age group showed shorter disease specific survival than the old age group. Symptomatic presentation without surveillance was more frequent in the young age group than old age group (45.7% vs. 23.9%). In gene expression profiling analysis, 69 differentially expressed genes between young and old age groups were generated and these genes were mostly associated with cell cycle or cell division. Mitotic rate was significantly higher in HCCs of young patients than those of old patients. In conclusion, HCCs in young patients have distinct clinicopathologic features. Poor prognosis in the young age group could be explained by late detection as well as their own aggressive tumor biology.
PMCID: PMC4621918  PMID: 26093092
oncology; carcinogenesis; age; cell cycle; liver
10.  HULC and H19 Played Different Roles in Overall and Disease-Free Survival from Hepatocellular Carcinoma after Curative Hepatectomy: A Preliminary Analysis from Gene Expression Omnibus 
Disease Markers  2015;2015:191029.
Objective. This study aimed to evaluate the relationships between long noncoding RNAs (lncRNAs) in tumor tissues and hepatocellular carcinoma (HCC) aggressiveness and survival. Methods. We correlated the lncRNAs in tumor tissues with HCC survival and clinicopathological features based on Gene Expression Omnibus expression profile GSE36376. Results. Eight lncRNAs and 240 HCC patients were included. Cox regression analysis indicated that HULC was a positive factor for HCC overall survival (HR = 0.885, 95% CI = 0.797–0.983, and P = 0.023) and disease-free survival time (HR = 0.913, 95% CI = 0.835–0.998, and P = 0.045). H19 and UCA1 were both demonstrated to be risk factors of HCC disease-free survival in multivariate Cox model (HR = 1.071, 95% CI = 1.01–1.137, and P = 0.022 and HR = 2.4, 95% CI = 1.092–5.273, and P = 0.029, resp.). But Kaplan-Meier method showed no significant association between UCA1 and HCC disease-free survival (log rank P = 0.616). Logistic regression demonstrated that H19 was overexpressed in HBV-infected patients (OR = 1.14, 95% CI = 1.008–1.29, and P = 0.037). HULC had a significant association with vascular invasion (OR = 0.648, 95% CI = 0.523–0.803, and P < 0.001). H19 and MEG3 were both considered to be risk factors for high AFP level (OR = 1.45, 95% CI = 1.277–1.646, and P < 0.001 and OR = 1.613, 95% CI = 1.1–2.365, and P = 0.014, resp.). Conclusions. Contributing to decreased susceptibility to vascular invasion, upregulation of HULC in tumor tissues was positively associated with HCC survival. In contrast, H19 overexpression might be risk factor for HCC aggressiveness and poor outcomes.
doi:10.1155/2015/191029
PMCID: PMC4475561  PMID: 26136615
11.  High Expression of Aldo-Keto Reductase 1B10 Is an Independent Predictor of Favorable Prognosis in Patients with Hepatocellular Carcinoma 
Gut and Liver  2014;8(6):648-654.
Background/Aims
Upregulation of aldo-keto reductase 1B10 (AKR1B10) through the mitogenic activator protein-1 signaling pathway might promote hepatocarcinogenesis and tumor progression. The goal of this study was to evaluate the prognostic significance of AKR1B10 protein expression in patients with hepatocellular carcinoma after surgery.
Methods
A tissue microarray was used to detect the expression level of AKR1B10 protein in tumors from 255 patients with hepatocellular carcinoma who underwent curative hepatectomy. The impact of AKR1B10 expression on the survival of patients was analyzed. The median follow-up period was 119.8 months.
Results
High AKR1B10 protein expression was observed in 125 of the 255 patients with hepatocellular carcinoma (49.0%). High AKR1B10 expression was significantly associated with a lack of invasion of the major portal vein (p=0.022), a lack of intrahepatic metastasis (p=0.010), lower the American Joint Committee on Cancer T stage (p=0.016), lower the Barcelona Clinic Liver Cancer stage (p=0.006), and lower α-fetoprotein levels (p=0.020). High AKR1B10 expression was also correlated with a lack of early recurrence (p=0.022). Multivariate analyses of survival revealed that intrahepatic metastases and lower albumin levels were independent predictors of both shorter recurrence-free survival and shorter disease-specific survival. High AKR1B10 expression was an independent predictor of both longer recurrence-free survival (p=0.024) and longer disease-specific survival (p=0.046).
Conclusions
High AKR1B10 protein expression might be useful as a marker of a favorable prognosis in patients with hepatocellular carcinoma after curative hepatectomy.
doi:10.5009/gnl13406
PMCID: PMC4215452  PMID: 25287169
AKR1B10; Carcinoma; hepatocellular; Survival
12.  High Expression of Ribonucleotide Reductase Subunit M2 Correlates with Poor Prognosis of Hepatocellular Carcinoma 
Gut and Liver  2014;8(6):662-668.
Background/Aims
Ribonucleotide reductase subunit M2 (RRM2) catalyzes the production of deoxynucleotide triphosphates, which are necessary for DNA synthesis. RRM2 has been reported to play an active role in tumor progression, and elevated RRM2 levels have been correlated with poor prognosis for colorectal cancer patients. This study aimed to elucidate the prognostic significance of RRM2 protein expression in hepatocellular carcinoma after surgery.
Methods
RRM2 protein expression was evaluated using immunohistochemistry in tumor tissues from 259 hepatocellular carcinoma patients who underwent curative hepatectomy.
Results
High RRM2 expression was observed in 210 of 259 patients (81.1%) with hepatocellular carcinomas. High RRM2 expression was significantly associated with viral etiology (p=0.035) and liver cirrhosis (p=0.036). High RRM2 expression was correlated with early recurrence (p=0.004) but not with late recurrence (p=0.144). Logistic regression analysis revealed that high RRM2 expression (p=0.040) and intrahepatic metastasis (p<0.001) were independent predictors of early recurrence. High RRM2 expression unfavorably influenced both shorter recurrence-free survival (p=0.011) and shorter disease-specific survival (p=0.002) and was an independent predictor of shorter disease-specific survival (p=0.008).
Conclusions
High RRM2 protein expression might be a useful marker for predicting early recurrence and may be a marker for poor prognosis of hepatocellular carcinoma after curative hepatectomy.
doi:10.5009/gnl13392
PMCID: PMC4215454  PMID: 25368754
Ribonucleotide reductase subunit M2; Hepatocellular carcinoma; Survival
13.  Prognostic Significance of BCL9 Expression in Hepatocellular Carcinoma 
Korean Journal of Pathology  2013;47(2):130-136.
Background
BCL9 enhances β-catenin-mediated transcriptional activity regardless of the mutational status of the Wnt signaling components and increases the cell proliferation, migration, invasion, and metastatic potential of tumor cells. The goal of this study was to elucidate the prognostic significance of BCL9 protein expression in hepatocellular carcinoma (HCC) patients.
Methods
We evaluated BCL9 protein expression by immunohistochemistry in tumor tissue from 288 primary HCC patients who underwent curative hepatectomy. The impact of BCL9 expression on the survival of the patients was analyzed. The median follow-up period was 97.1 months.
Results
Nuclear BCL9 protein expression was observed in 74 (25.7%) of the 288 HCCs. BCL9 expression was significantly associated with younger age (p=0.038), higher Edmondson grade (p=0.001), microvascular invasion (p=0.013), and intrahepatic metastasis (p=0.017). Based on univariate analyses, BCL9 expression showed an unfavorable influence on both disease-free survival (DFS, p=0.012) and disease-specific survival (DSS, p=0.032). Multivariate analyses revealed that higher Barcelona Clinic Liver Cancer stage was an independent predictor of both shorter DFS (p<0.001) and shorter DSS (p<0.001). BCL9 expression tended to be an independent predictor of shorter DFS (p=0.078).
Conclusions
BCL9 protein expression might be a marker of shorter DFS in HCC patients after curative hepatectomy.
doi:10.4132/KoreanJPathol.2013.47.2.130
PMCID: PMC3647125  PMID: 23667372
BCL9; Carcinoma, hepatocellular; Recurrence; Survival
14.  Metadherin Is a Prognostic Predictor of Hepatocellular Carcinoma after Curative Hepatectomy 
Gut and Liver  2013;7(2):206-212.
Background/Aims
The prognosis after surgical resection of hepatocellular carcinoma (HCC) remains poor because of a high rate of recurrence. Thus, it is crucial to identify patients with a high risk of recurrence after curative hepatectomy and to develop more effective and targeted treatment strategies to improve disease outcomes. In this study, we investigated the roles of metadherin (MTDH) in the prognosis of HCC.
Methods
We investigated MTDH expression using immunohistochemistry in tumor tissue microarrays of 288 primary HCC patients who underwent curative surgical resection.
Results
High MTDH expression was observed in 138 of the 288 HCC cases (47.9%). High MTDH expression was associated with a younger age (p<0.001), higher Edmondson grade (p<0.001), microvascular invasion (p<0.001), higher American Joint Committee on Cancer T stage (p=0.001), and higher α-fetoprotein level (p=0.003). Multivariate analyses revealed that high MTDH expression (p=0.014), higher Barcelona-Clinic Liver Cancer (BCLC) stage (p<0.001), and Edmondson grade III (p=0.042) were independent predictors of shorter disease-free survival (DFS). Higher BCLC stage (p<0.001) and Edmondson grade III (p=0.047) were also independent predictors of shorter disease-specific survival.
Conclusions
High MTDH expression may be a prognostic predictor of shorter DFS in HCC patients after curative hepatectomy.
doi:10.5009/gnl.2013.7.2.206
PMCID: PMC3607775  PMID: 23560157
Metadherin; Hepatocellular carcinoma; Survival
15.  CHD1L Is a Marker for Poor Prognosis of Hepatocellular Carcinoma after Surgical Resection 
Korean Journal of Pathology  2013;47(1):9-15.
Background
The gene for chromodomain helicase/ATPase DNA binding protein 1-like (CHD1L) was recently identified as a target oncogene within the 1q21 amplicon, which occurs in 46% to 86% of primary hepatocellular carcinoma (HCC) cases. However, the prognostic significance of CHD1L in HCC remains uncertain. In this study, we investigated the roles of CHD1L in the prognosis of HCC.
Methods
We investigated the expressions of CHD1L in tumor tissue microarrays of 281 primary HCC patients who underwent surgical resection using immunohistochemistry. Prognostic factors of HCC were examined by univariate and multivariate analyses. The median follow-up period was 75.6 months.
Results
CHD1L expression was observed in 48 of the 281 HCCs (17.1%). CHD1L expression was associated with a younger age (p=0.033), higher Edmondson grade (p=0.019), microvascular invasion (p<0.001), major portal vein invasion (p=0.037), higher American Joint Committee on Cancer T stage (p=0.001), lower albumin level (p=0.047), and higher α-fetoprotein level (p=0.002). Multivariate analyses revealed that CHD1L expression (p=0.027), Edmondson grade III (p=0.034), and higher Barcelona Clinic Liver Cancer stage (p<0.001) were independent predictors of shorter disease-free survival.
Conclusions
CHD1L expression might be a prognostic marker of shorter disease-free survival in HCC patients after surgical resection.
doi:10.4132/KoreanJPathol.2013.47.1.9
PMCID: PMC3589617  PMID: 23482400
CHD1L; Carcinoma, hepatocellular; Survival
16.  Diagnosis of gastric epithelial neoplasia: Dilemma for Korean pathologists 
The histopathological diagnosis of gastric mucosal biopsy and endoscopic mucosal resection/endoscopic submucosal dissection specimens is important, but the diagnostic criteria, terminology, and grading system are not the same in the East and West. A structurally invasive focus is necessary to diagnose carcinoma for most Western pathologists, but Japanese pathologists make a diagnosis of cancer based on severe dysplastic cytologic atypia irrespective of the presence of invasion. Although the Vienna classification was introduced to reduce diagnostic discrepancies, it has been difficult to adopt due to different concepts for gastric epithelial neoplastic lesions. Korean pathologists experience much difficulty making a diagnosis because we are influenced by Japanese pathologists as well as Western medicine. Japan is geographically close to Korea, and academic exchanges are active. Additionally, Korean doctors are familiar with Western style medical terminology. As a result, the terminology, definitions, and diagnostic criteria for gastric intraepithelial neoplasia are very heterogeneous in Korea. To solve this problem, the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists has made an effort and has suggested guidelines for differential diagnosis: (1) a diagnosis of carcinoma is based on invasion; (2) the most important characteristic of low grade dysplasia is the architectural pattern such as regular distribution of crypts without severe branching, budding, or marked glandular crowding; (3) if nuclear pseudostratification occupies more than the basal half of the cryptal cells in three or more adjacent crypts, the lesion is considered high grade dysplasia; (4) if severe cytologic atypia is present, careful inspection for invasive foci is necessary, because the risk for invasion is very high; and (5) other structural or nuclear atypia should be evaluated to make a final decision such as cribriform pattern, papillae, ridges, vesicular nuclei, high nuclear/cytoplasmic ratio, loss of nuclear polarity, thick and irregular nuclear membrane, and nucleoli.
doi:10.3748/wjg.v17.i21.2602
PMCID: PMC3110921  PMID: 21677827
Intraepithelial neoplasia; Stomach; Dysplasia; Adenoma; Carcinoma; Japanese; Western; Consensus; Vienna
17.  Promoter Methylation of E-cadherin in Hepatocellular Carcinomas and Dysplastic Nodules 
Journal of Korean Medical Science  2005;20(2):242-247.
In order to clarify the significance of E-cadherin methylation in multistep hepatocarcinogenesis, we examined the methylation status of the E-cadherin promoter region, using methylation-specific polymerase chain reaction in 64 hepatocellular carcinomas (HCCs) and 13 dysplastic nodules (DNs), and correlated these results with E-cadherin protein expression and clinicopathologic factors of HCCs. Promoter methylation was detected in 1 of 13 (7.7%) DNs, in 5 of 13 (38.5%) Edmondson and Steiner grade I HCCs, and in 27 of 51 (52.9%) grade II or III HCCs, and a significant correlation was observed between the methylation status and the stepwise progression of hepatocarcinogenesis (p=0.004). Reduced E-cadherin immunoreactivity was found in 18 of 64 (28%) HCCs, but in none of DNs. E-cadherin methylation status in HCCs was significantly correlated with microvascular invasion (p=0.02) and tumor recurrence (p=0.04), but not with reduced E-cadherin immunoreactivity. The Kaplan-Meier method showed that methylation status did not have a significant influence on the recurrence-free survival of HCC patients (p=0.15). Our results indicate that methylation of the E-cadherin promoter region is a frequent event in HCC, which may play an important role in the stepwise progression of hepatocarcinogenesis. And the promoter methylation of E-cadherin in HCC was found to be significantly correlated with microvascular invasion and recurrence.
doi:10.3346/jkms.2005.20.2.242
PMCID: PMC2808600  PMID: 15831995
Carcinoma, Hepatocellular; Dysplastic Nodule; Cadherins; DNA Methylation
18.  IgG4-Related Sclerosing Mesenteritis 
doi:10.4132/jptm.2015.12.03
PMCID: PMC4963968  PMID: 26755359
19.  Clinicopathological and immunohistochemical characterization of papillary proliferation of the endometrium: A single institutional experience 
Oncotarget  2016;7(26):39197-39206.
Papillary proliferation of the endometrium is an unusual lesion that is composed of papillae with fibrovascular stromal cores covered with benign-appearing glandular epithelium. We studied the clinicopathological and immunohistochemical features of four cases of endometrial papillary proliferations. All patients were postmenopausal. Two lesions were incidental findings in hysterectomy specimens, and two lesions were detected in endometrial curettage specimens. Based on the degree of architectural complexity and extent of proliferation, we classified papillary proliferations histopathologically into “simple” or “complex” growth patterns. Three cases were classified as simple papillary proliferation, and one case was classified as complex papillary proliferation. Simple papillary proliferations were characterized by slender papillae with delicate stromal cores. In contrast, complex papillary proliferations had intracystic papillary projections and cellular clusters with frequent branching and occasional cytological atypia. All cases showed coexistent metaplastic epithelial changes, including mucinous metaplasia, eosinophilic cell change, and ciliated cell metaplasia. One patient with simple papillary proliferations had coexistent well-differentiated endometrioid carcinoma. One patient had subsequent hyperplasia without atypia, and another patient had subsequent atypical hyperplasia/endometrioid intraepithelial neoplasia; both patients underwent total hysterectomy within four months. Our observations are consistent with previous data demonstrating that endometrial papillary proliferations coexist with or develop into atypical hyperplasia/endometrioid intraepithelial neoplasia or endometrioid carcinoma. It is very important for pathologists to discriminate papillary proliferations from neoplastic lesions (including atypical hyperplasia/endometrioid intraepithelial neoplasia and well-differentiated endometrioid carcinoma) and benign mimickers (including papillary syncytial metaplasia).
doi:10.18632/oncotarget.10049
PMCID: PMC5129925  PMID: 27322430
papillary proliferation; endometrium; atypical hyperplasia/endometrioid intraepithelial neoplasia; endometrioid carcinoma; immunohistochemistry; Pathology Section
21.  Pathologic Evaluation of Breast Cancer after Neoadjuvant Therapy 
Breast cancer, one of the most common cancers in women, has various treatment modalities. Neoadjuvant therapy (NAT) has been used in many clinical trials because it is easy to evaluate the treatment response to therapeutic agents in a short time period; consequently, NAT is currently a standard treatment modality for large-sized and locally advanced breast cancers, and its use in early-stage breast cancer is becoming more common. Thus, chances to encounter breast tissue from patients treated with NAT is increasing. However, systems for handling and evaluating such specimens have not been established. Several evaluation systems emphasize a multidisciplinary approach to increase the accuracy of breast cancer assessment. Thus, detailed and systematic evaluation of clinical, radiologic, and pathologic findings is important. In this review, we compare the major problems of each evaluation system and discuss important points for handling and evaluating NAT-treated breast specimens.
doi:10.4132/jptm.2016.02.02
PMCID: PMC4876080  PMID: 27068026
Breast neoplasms; Neoadjuvant therapy; Pathologic response evaluation
22.  Interobserver Agreement on Pathologic Features of Liver Biopsy Tissue in Patients with Nonalcoholic Fatty Liver Disease 
Background:
The histomorphologic criteria for the pathological features of liver tissue from patients with non-alcoholic fatty liver disease (NAFLD) remain subjective, causing confusion among pathologists and clinicians. In this report, we studied interobserver agreement of NAFLD pathologic features and analyzed causes of disagreement.
Methods:
Thirty-one cases of clinicopathologically diagnosed NAFLD from 10 hospitals were selected. One hematoxylin and eosin and one Masson’s trichrome-stained virtual slide from each case were blindly reviewed with regard to 12 histological parameters by 13 pathologists in a gastrointestinal study group of the Korean Society of Pathologists. After the first review, we analyzed the causes of disagreement and defined detailed morphological criteria. The glass slides from each case were reviewed a second time after a consensus meeting. The degree of interobserver agreement was determined by multi-rater kappa statistics.
Results:
Kappa values of the first review ranged from 0.0091–0.7618. Acidophilic bodies (k = 0.7618) and portal inflammation (k = 0.5914) showed high levels of agreement, whereas microgranuloma (k = 0.0984) and microvesicular fatty change (k = 0.0091) showed low levels of agreement. After the second review, the kappa values of the four major pathological features increased from 0.3830 to 0.5638 for steatosis grade, from 0.1398 to 0.2815 for lobular inflammation, from 0.1923 to 0.3362 for ballooning degeneration, and from 0.3303 to 0.4664 for fibrosis.
Conclusions:
More detailed histomorphological criteria must be defined for correct diagnosis and high interobserver agreement of NAFLD.
doi:10.4132/jptm.2016.03.01
PMCID: PMC4876083  PMID: 27086596
Non-alcoholic fatty liver disease; Pathologic features; Interobserver agreement
23.  Hyalinizing trabecular tumor of the thyroid: diagnosis of a rare tumor using ultrasonography, cytology, and intraoperative frozen sections 
Ultrasonography  2015;35(2):131-139.
Purpose:
The goal of this study was to evaluate the clinicopathological and imaging features of thyroid nodules surgically diagnosed as hyaline trabecular tumor (HTT), and to assess the role of cytology and frozen sections (FS) in the diagnosis of HTT.
Methods:
This study included 21 thyroid nodules in 21 patients treated from August 2005 to March 2015 (mean age, 53.3 years) who were either diagnosed as HTT or had HTT suggested as a possible diagnosis based on cytology, FS, or the final pathology report. Patients’ medical records were retrospectively reviewed for cytopathologic results and outcomes during the course of follow-up. Sonograms were reviewed and categorized.
Results:
Twelve nodules from 12 patients were surgically confirmed as HTT. Ultrasonography (US)-guided fine needle aspiration (FNA) was performed on 11 nodules, of which six (54.5%) were papillary thyroid carcinoma (PTC) or suspicious for PTC and three (27.3%) were HTT or suspicious for HTT. Intraoperative FS suggested the possibility of HTT in seven nodules, of which four (57.1%) were confirmed as HTT. US-FNA suggested the diagnosis of HTT in 10 nodules, of which three (30.0%) were confirmed as HTT. Common US features of the 12 pathologically confirmed cases of HTT were hypoechogenicity or marked hypoechogenicity (83.4%), absence of calcifications (91.7%), parallel shape (100.0%), presence of vascularity (75.0%), and probable benignity (58.3%).
Conclusion:
HTT should be included in the differential diagnosis of solid tumors with hypoechogenicity or marked hypoechogenicity and otherwise benign US features that have been diagnosed as PTC through cytology.
doi:10.14366/usg.15054
PMCID: PMC4825213  PMID: 26639939
Thyroid gland; Thyroid nodule; Ultrasonography; Biopsy, fine-needle; Frozen sections
24.  Predicting Hepatic Steatosis in Living Liver Donors via Noninvasive Methods 
Medicine  2016;95(7):e2718.
Abstract
Hepatic steatosis assessment is of paramount importance for living liver donor selection because significant hepatic steatosis can affect the postoperative outcome of recipients and the safety of the donor. The validity of various noninvasive imaging methods to assess hepatic steatosis remains controversial. The purpose of our study is to investigate the association between noninvasive imaging methods and pathology to detect steatosis in living liver donors and to propose a prediction model for hepatic steatosis.
Liver stiffness measurements (LSMs) and controlled attenuation parameter values in vibration controlled transient elastography, ultrasonography, computed tomography (CT), and magnetic resonance imaging were used as pretransplant screening methods to evaluate living liver donors between 2012 and 2014. Only 1 pathologist assessed tissue sample for hepatic steatosis.
The median age of the 79 living donors (53 men and 26 women) was 32 years (16–68 years). The CT liver–spleen attenuation (L–S) difference and the controlled attenuation parameter values were well correlated with the level of hepatic steatosis on liver pathology. Multivariate analysis showed that liver stiffness measurement (LSM) (β = 0.903; 95% CI, 0.105–1.702; P = 0.027) and the CT L to S attenuation difference (β = −3.322; 95% CI, −0.502 to −0.142; P = 0.001) were closely associated with hepatic steatosis. We generated the following equation to predict total hepatic steatosis: Hepatic steatosis = 0.903 × LSM – 0.322 × CT L to S attenuation difference (AUC = 86.6% and P = 0.001). The values predicted by the equation correlated well with the presence of hepatic steatosis (r = 0.509 and P < 0.001).
The combination of nonenhanced CT L to S attenuation difference and transient elastography using vibration controlled transient elastography provides sufficient information to predict hepatic steatosis in living liver donor candidates.
doi:10.1097/MD.0000000000002718
PMCID: PMC4998612  PMID: 26886612
25.  Clinicopathologic Features and Molecular Characteristics of Glucose Metabolism Contributing to ¹⁸F-fluorodeoxyglucose Uptake in Gastrointestinal Stromal Tumors 
PLoS ONE  2015;10(10):e0141413.
Fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography–computed tomography (PET/CT) is useful in the preoperative diagnosis of gastrointestinal stromal tumors (GISTs); however, the molecular characteristics of glucose metabolism of GIST are unknown. We evaluated 18F-FDG uptake on preoperative PET/CT of 40 patients and analyzed the expression of glycolytic enzymes in resected GIST tissues by qRT-PCR, western blotting, and immunohistochemistry. Results of receiver operating characteristic curve analysis showed that the maximum standardized uptake value (SUVmax) cut-off value of 4.99 had a sensitivity of 89.5%, specificity was 76.2%, and accuracy of 82.5% for identifying tumors with a high risk of malignancy. We found that 18F-FDG uptake correlated positively with tumor size, risk grade, and expression levels of glucose transporter 1 (GLUT1), hexokinase 1 (HK1), and lactate dehydrogenase A (LDHA). Elevated HK and LDH activity was found in high-risk tumors. Among the isoforms of GLUT and HK, GLUT1 and HK1 expression increased with higher tumor risk grade. In addition, overexpression of glycolytic enzymes M2 isoform of pyruvate kinase (PKM2) and LDHA was observed in GISTs, especially in high-risk tumors. These results suggest that upregulation of GLUT1, HK1, PKM2, and LDHA may play an important role in GIST tumorigenesis and may be useful in the preoperative prediction of malignant potential.
doi:10.1371/journal.pone.0141413
PMCID: PMC4625049  PMID: 26509967

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