Clinicopathological characteristics of cholangiocarcinoma : comparison between cholangiolar differentiation and bile ductal differentiation

의과대학/석사Recently intrahepatic cholangiocarcinoma (ICC) has been subclassified into cholangiolar differentiation and bile ductal differentiation; however their clinicopathological and molecular characteristics have not been fully understood. We studied 142 human ICC cases of Severance hospital from 1997 to 2013, and there were 20 cases (14.1%) of ICC with cholangiolar differentiation, and 122 cases (85.9%) of ICC with bile ductal differentiation. The expression of c-reactive protein (CRP), claudin 18 (CLDN18), N-cadnerin, Neural cell adhesion molecule (NCAM), vimentin, and epithelial-mesenchymal transition (EMT)-related markers (ZEB1, ZEB2, TWIST, SNAIL and loss of E-cadherin) were evaluated by immunohistochemistry or real-time PCR. The expression levels of these markers and clinicopathological features were compared between two groups. ICC patients with cholangiolar differentiation revealed higher incidence of female and viral hepatitis, and less incidence of hepatolithiasis, ductal epithelial dysplasia compared to those with the ICC with bile ductal differentiation (P <0.05, for all). The mass-forming gross type was found in all of ICCs with cholangiolar differentiation in contrast that it was detected in 72 cases (59%) of ICCs with bile ductal differentiation (P = 0.005). The ICCs with cholangiolar differentiation showed less perineural invasion compared to ICCs with bile ductal differentiation (P = 0.013). The protein expression of CRP, N-cadherin and NCAM was more frequently found in ICCs with cholangiolar differentiation compared to those with bile ductal differentiation (P < 0.05, for all). The protein expression of CLDN18 and ZEB1 was more frequently detected in ICCs with bile ductal differentiation compared to those with cholangiolar differentiation (P < 0.05, for all). The protein expression of TWIST and E-cadherin loss showed no significant difference between two groups. The mRNA expression levels of SNAIL and ZEB1 were lower in ICCs with cholangiolar differentiation compared to ICCs with bile ductal differentiation (P <0.05, for both), whereas that of ZEB2 showed no significant difference between two groups. ICCs with cholangiolar differentiation showed better overall survival compared to ICCs with bile ductal differentiation (P = 0.021). ICCs with CRP expression or N-cadherin expression revealed better prognosis compared those without (P <0.05, for all). In conclusion, ICC with cholangiolar differentiation and ICC with bile ductal differentiation are suggested to be distinct based on clinicopathological characteristics. ICC with cholangiolar differentiation is considered to be less aggressive type of ICC with better prognosis compared to ICC with bile ductal differentiation. CRP and N-cadherin are suggested to be good markers for cholangiolar differentiation.ope

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.ope

Increased expression of stathmin and elongation factor 1α in precancerous nodules with telomere dysfunction in hepatitis B viral cirrhotic patients.

BACKGROUND: Telomere dysfunction is important in carcinogenesis, and recently, stathmin and elongation factor 1α (EF1α) were reported to be up-regulated in telomere dysfunctional mice. METHODS: In the present study, the expression levels of stathmin and EF1α in relation to telomere length, telomere dysfunction-induced foci (TIF), γ-H2AX, and p21WAF1/CIP1 expression were assessed in specimens of hepatitis B virus (HBV)-related multistep hepatocarcinogenesis, including 13 liver cirrhosis specimens, 14 low-grade dysplastic nodules (DN), 17 high-grade DNs, and 14 hepatocellular carcinomas (HCC). Five normal liver specimens were used as controls. TIF were analyzed by telomere fluorescent in situ hybridization (FISH) combined with immunostaining, while the protein expressions of stathmin, EF1α, γ-H2AX, and p21WAF1/CIP1 were detected by immunohistochemistry. RESULT: The expressions of stathmin and EF1α gradually increased as multistep hepatocarcinogenesis progressed, showing the highest levels in HCC. Stathmin mRNA levels were higher in high-grade DNs than normal liver and liver cirrhosis, whereas EF1α mRNA expression did not show such a difference. The protein expressions of stathmin and EF1α were found in DNs of precancerous lesions, whereas they were absent or present at very low levels in normal liver and liver cirrhosis. Stathmin histoscores were higher in high-grade DNs and low-grade DNs than in normal liver (all, P<0.05). EF1α histoscores were higher in high-grade DNs than in normal liver and liver cirrhosis (all, P<0.05). Stathmin mRNA levels and histoscores, as well as EF1α histoscores (but not mRNA levels), were positively correlated with telomere shortening and γ-H2AX labeling index (all, P<0.05). EF1α histoscores were also positively correlated with TIF (P<0.001). Significantly greater inactivation of p21WAF1/CIP1 was observed in low-grade DNs, high-grade DNs, and HCC, compared to liver cirrhosis (all, P<0.05). p21WAF1/CIP1 labeling index was inversely correlated with TIF, stathmin mRNA level, and EF1α histoscore (all, P<0.05). CONCLUSION: Stathmin and EF1α are suggested to be closely related to telomere dysfunction, DNA damage, and inactivation of p21WAF1/CIP1 in HBV-related multistep hepatocarcinogenesis. Accordingly, assessment of stathmin and EF1α levels as a reflection of telomere dysfunction may be helpful in evaluating the biological characteristics of precancerous hepatic nodules in hepatitis B viral cirrhotic patients.ope

성별과 경찰과 직무만족 : Work-family conflict 를 중심으로

학위논문(석사) --서울대학교 대학원 :행정학과(행정학전공),2008.Maste