Comparison of the sixth and the seventh editions of the UICC classification for intrahepatic cholangiocarcinoma.

BACKGROUND: The current seventh edition of the TNM classification for intrahepatic cholangiocarcinoma (ICC) includes tumor number, vascular invasion, lymph node involvement but no longer the tumor size as compared to the sixth edition. The impact of the seventh edition on stage-based prognostic prediction for patients with ICC was evaluated. METHODS: Between 03/2001 and 02/2013, 98 patients with the diagnosis of an ICC were surgically treated at our center. Median survival times were calculated for these patients after separate classification by both sixth and seventh editions. RESULTS: Median overall survival was increased in patients classified to the lower tumor stages I and II using the seventh as compared to the sixth edition: stage I (54.9 vs. 47.3 months), stage II (19.9 vs. 18.9 months), stage III (17.2 vs. 19.9 months), and stage IV (23.2 vs. 15.3 months), respectively. The seventh edition definition of the T category resulted in an increased median survival regarding the T1 (50.4 vs. 47.3 months) as well as the T2 category (19.9 vs. 15.6 months) and revealed a reduced median survival of patients within the T3 (21.6 vs. 24.8 months) as well as the T4 category (19.9 vs. 27.0 months). CONCLUSIONS: The UICC seventh edition TNM classification for ICC improves separation of patients with intermediate stage tumors as compared to the sixth edition. The prognostic value of the UICC staging system has been improved by the seventh edition. Trial registration The data for this study have been retrospectively registered and the study has been approved by the ethic committee of the medical faculty of the University Hospital of Essen, Germany (license number 15-6353-BO).

Comparison of the sixth and the seventh editions of the UICC classification for perihilar cholangiocarcinoma.

BACKGROUND: The seventh edition of the TNM classification separates extrahepatic bile duct tumors into perihilar and distal tumors and further changes the definition of the TNM classification. The impact of the seventh edition on stage-based prognostic prediction for patients with perihilar cholangiocarcinoma was evaluated. METHODS: Between January 1998 and March 2010, 223 consecutive patients with perihilar cholangiocarcinoma underwent surgery at the West German Cancer Center. Median survival times were calculated for the 195 evaluable patients (excluding those with in-hospital mortality) after separate classification by both sixth and seventh editions. RESULTS: Median overall survival was increased in patients classified using the seventh compared with the sixth edition (UICC I: 56.5 vs 23.75 months; II: 45.9 vs 31.6 months; III: 21.3 vs. 8.76 months; IV: 7.03 vs 5.93 months). The T category of the seventh edition did not alter median survival times of T1 (54.07 months) and T4 (7.83 months) cases, but median survival was prolonged for T2 patients (29.4 vs 31.6 months), and shortened for T3 patients (19.43 vs 11.8 months) staged using the seventh edition. According to Cox proportional hazards regression analysis, patient survival was better predicted by the seventh edition UICC stage and pT categories (p=0.0014 and p=0.0396, respectively), than the corresponding sixth edition categories (p=0.4376 and p=0.0926, respectively). CONCLUSIONS: The UICC seventh edition TNM classification for perihilar cholangiocarcinoma improves separation of patients with intermediate stage tumors compared with the sixth edition. The prognostic value of the UICC staging system has been strengthened by the introduction of the seventh edition.

Metallothionein overexpression and its prognostic relevance in intrahepatic cholangiocarcinoma and extrahepatic hilar cholangiocarcinoma (Klatskin tumors).

Metallothionein is a group of small molecular weight cysteine-rich proteins with a broad variety of functions. Metallothionein has been shown to regulate apoptosis and proliferation. Overexpression of metallothionein frequently occurs in human tumors and is related to prognosis as well as therapy response. However, metallothionein expression and its clinical relevance in cholangiocarcinoma have not been investigated. The present study aimed to analyze metallothionein over-expression and its possible prognostic impact in intrahepatic cholangiocarcinoma and hilar extrahepatic cholangiocarcinoma (Klatskin tumors). We investigated the relationship of immunohistochemically demonstrated metallothionein expression with various clinicopathological parameters in a series of 56 intrahepatic and 56 extrahepatic cholangiocarcinoma. In noncancerous bile duct epithelia metallothionein was only occasionally weakly expressed; strong metallothionein overexpression (>50% metallothionein -positive tumor cells) was noted in 7 (12.5%) of 56 intrahepatic cholangiocarcinoma and 14 (25%) of 56 Klatskin tumors, which was associated with poor clinical outcome in univariate Kaplan-Meier testing in both intrahepatic cholangiocarcinoma (P = .002) and Klatskin tumors (P = .034). Moreover, strong metallothionein expression was identified as an independent prognostic parameter in multivariate Cox regression analysis in both intrahepatic cholangiocarcinoma (P = .005) and Klatskin tumors (P = .035). In contrast, cholangiocarcinoma with a papillary phenotype (8/112; 7.1%) exhibited a significant lack of strong metallothionein expression in all 8 of 8 cases. Strong metallothionein expression is identified as an independent poor prognostic parameter, and determination of the metallothionein expression may serve as an additional tool for the therapeutic management of patients with cholangiocarcinoma. In comparison, lack of metallothionein expression seems to be associated with cholangiocarcinoma with a papillary phenotype, which is generally recognized to have a better prognosis.

Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection.

BACKGROUND/AIMS: The aim of the study was to determine the prognostic relevance of AKT and extracellular regulated kinases (ERK1/2), which are implied in the regulation of cell proliferation and apoptosis, in hepatocellular carcinoma (HCC). METHODS: This study comprised a series of 208 patients incorporating HCCs treated either by surgical resection (n = 109) or liver transplantation (n = 99). Immunohistochemically demonstrated phospho-ERK1/2 (pERK1/2) and phospho-AKT (pAKT) was correlated with a series of clinico-pathologically relevant parameters (EGFR, Cyclin-D1, HCV/HBV infection, liver cirrhosis, chronic alcohol abuse), proliferative activity, and apoptosis. RESULTS: Activation of ERK1/2 correlated statistically with the presence of HCV infection. pERK1/2 (P < 0.001) and pAKT (P = 0.052) expression showed a significant correlation with a decreased overall survival (OS). In multivariate Cox regression analysis pERK1/2 was identified as an independent prognostic parameter in HCC (P = 0.026). CONCLUSIONS: Activation of ERK1/2 in HCC cancer indicates aggressive tumour behaviour and constitutes an independent prognostic factor. Furthermore our data confirm that HCV infection activates the ERK pathway and thereby might contribute to HCC carcinogenesis. Immunohistochemical determination of pERK1/2 status can thus be proposed as a promising candidate for the identification of high risk patients who may benefit from new anticancer drugs targeting the ERK-pathway.

Elevated expression of cyclooxygenase-2 is a negative prognostic factor for overall survival in intrahepatic cholangiocarcinoma.

The production of prostaglandins is regulated by cyclooxygenases (COXs), which also have a role in tumour development and progression in various human malignancies, including cholangiocarcinoma. Limited information is available of the correlation of COX-2 protein expression and prognosis in intrahepatic cholangiocarcinoma (ICC). The aim of the present study was to determine the clinical significance of COX-2 expression in ICC. In addition the correlation of COX-2 expression and apoptosis/proliferation was analysed. COX-2 expression was determined immunohistochemically in 62 resected ICCs. Proliferation was assessed using Ki67-immunohistochemistry, and apoptosis was measured with the TdT-mediated dUTP nick-end-labelling technique. COX-2 was identified as an independent prognostic factor (P = 0.028) in resected ICC by survival analysis. High levels of COX-2 expression were found to be associated both with reduced apoptosis and increased proliferation of tumour cells. This study demonstrates the independent prognostic value of the COX-2 expression in resected ICC, thus, offering a potential additional adjuvant therapeutic approach with COX-2 inhibitors.