Clinicopathological significance of altered Notch signaling in extrahepatic cholangiocarcinoma and gallbladder carcinoma

AIM:To investigate the role and clinicopathological significance of aberrant expression of Notch receptors and Delta-like ligand-4 (DLL4) in extrahepatic cholangiocarcinoma and gallbladder carcinoma.METHODS:One hundred and ten patients had surgically resected extrahepatic cholangiocarcinoma (CC) and gallbladder carcinoma specimens examined by immunohistochemistry of available paraffin blocks.Immunohistochemistry was performed using anti-Notch receptors 1-4 and anti-DLL4 antibodies.We scored the immunopositivity of Notch receptors and DLL4 expression by percentage of positive tumor cells with cytoplasmic expression and intensity of immunostaining.Coexistent nuclear localization was evaluated.Clinicopatho-logical parameters and survival data were compared with the expression of Notch receptors 1-4 and DLL4.RESULTS:Notch receptor proteins showed in the cytoplasm with or without nuclear expression in cancer cells,as well as showing weak cytoplasmic expression in non-neoplastic cells.By semiquantitative evaluation,positive immunostaining of Notch receptor 1 was detected in 96 cases (87.3%),Notch receptor 2 in 97 (88.2%),Notch receptor 3 in 97 (88.2%),Notch receptor 4 in 103 (93.6),and DLL4 in 84 (76.4%).In addition,coex- istent nuclear localization was noted [Notch receptor 1;18 cases (18.8%),Notch receptor 2;40 (41.2%),Notch receptor 3;32 (33.0%),Notch receptor 4;99 (96.1%),DLL4;48 (57.1%)].Notch receptor 1 expression was correlated with advanced tumor,node,metastasis (TNM) stage (P=0.043),Notch receptor 3 with advanced T stage (P=0.017),tendency to express in cases with nodal metastasis (P=0.065) and advanced TNM stage (P=0.052).DLL4 expression tended to be related to less histological differentiation (P=0.095).Coexistent nuclear localization of Notch receptor 3 was related to no nodal metastasis (P=0.027) and Notch receptor 4 with less histological differentiation (P=0.036),while DLL4 tended to be related inversely with T stage (P=0.053).Coexistent nuclear localization of DLL4 was related to poor survival (P=0.002).CONCLUSION:Aberrant expression of Notch receptors 1 and 3 play a role during cancer progression,and cytoplasmic nuclear coexistence of DLL4 expression correlates with poor survival in extrahepatic CC and gallbladder carcinoma.

Analysis of intrahepatic sarcomatoid cholangiocarcinoma:Experience from 11 cases within 17 years

BACKGROUND Intrahepatic sarcomatoid chonalgiocarcinoma(s-CCC) is an extremely rare disease, accounting for less than 1% of hepatobiliary system malignancies, and its pathophysiology is not well known. On the hypothesis that its clinical, serologic,or radiologic diagnosis are not fully understood and its prognosis is poor, we investigated the distinguishing features of s-CCC compared with those of intrahepatic bile duct adenocarcinoma [cholangiocellular carcinoma(CCC)] in patients from a single center.AIM To analyze the clinical, serologic, imaging, and histopathologic characteristics of intrahepatic s-CCC patients diagnosed in a single center.METHODS The clinical, serologic, imaging, and histopathologic features of 227 patients diagnosed with intrahepatic cholangiocarcinoma(IHCC) in a single medical center during the last 17 years were analyzed. The characteristics of 11 patients with s-CCC were compared with those of 216 patients with CCC.RESULTS The number of patients with s-CCC who presented fever and abdominal pain and past history of chronic viral hepatitis or liver cirrhosis(LC) was higher than that of patients with CCC. In imaging studies, patients with s-CCC showed relatively aggressive features. However, no clear distinction was observed between s-CCC and CCC based on other clinical, serologic or radiologic examination results. An accurate diagnosis could be made only via a histopathologic examination through immunohistochemical staining. The clinical course of s-CCC was generally aggressive, and patients had a relatively poor prognosis.CONCLUSION In patients with s-CCC, early diagnosis through biopsy and aggressive treatment,including surgical resection, are important.

Efficacy of hepatic arterial infusion chemotherapy in advanced hepatocellular carcinoma

AIM:To investigate the efficacy of hepatic arterial infusion chemotherapy(HAIC) using floxuridine(FUDR) in patients with advanced hepatocellular carcinoma(HCC) confined to the liver.METHODS:Thirty-four patients who had advanced HCC with unresectability or unsuccessful previous therapy in the absence of extrahepatic metastasis were treated with intra-arterial FUDR chemotherapy at ourhospital between March 2005 and May 2008.Among the 34 patients,9 patients were classified as Child class C,and 18 patients had portal vein tumor thrombus(PVTT).One course of chemotherapy consisted of continuous infusion of FUDR(0.3 mg/kg during day 1-14) and dexamethasone(10 mg on day 1,4,7 and 11),and this treatment was repeated every 28 d.RESULTS:Two patients(5.9%) displayed a complete response,and 12 patients(35.3%) had a partial response.The tumor control rate was 61.8%.The median overall survival times were 15.3 mo,12.4 mo and 4.3 mo for the patients who were classified as Child class A,Child class B and Child class C,respectively(P = 0.0392).The progression-free survival was 12.9 mo,7.7 mo and 2.6 mo for the patients who were classified as Child class A,Child class B and Child class C,respectively(P = 0.0443).The cumulative survival differed significantly according to the Child-Pugh classification and the presence of PVTT.In addition to hepatic reserve capacity and PVTT,the extent of HCC was an independent factor in determining a poor prognosis.The most common adverse reactions to HAIC were mucositis,diarrhea and peptic ulcer disease,but most of these complications were improved by medical treatment and/or a delay of HAIC.CONCLUSION:The present study demonstrates that intra-arterial FUDR chemotherapy is a safe and effective treatment for advanced HCC that is recalcitrant to other therapeutic modalities,even in patients with advanced cirrhosis.