title: Metallothionein overexpression and its prognostic relevance in intrahepatic cholangiocarcinoma and extrahepatic hilar cholangiocarcinoma (Klatskin tumors).
abstract: 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.
authors.affiliation: Institute of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany. Klaus-juergen.schmitz@uk-essen.de
authors.forename: Klaus Jürgen
authors.initials: KJ
authors.lastname: Schmitz
authors.forename: Hauke
authors.initials: H
authors.lastname: Lang
authors.forename: Gernot
authors.initials: G
authors.lastname: Kaiser
authors.forename: Jeremias
authors.initials: J
authors.lastname: Wohlschlaeger
authors.forename: Georgios Charalambos
authors.initials: GC
authors.lastname: Sotiropoulos
authors.forename: Hideo Andreas
authors.initials: HA
authors.lastname: Baba
authors.forename: Bharat
authors.initials: B
authors.lastname: Jasani
authors.forename: Kurt Werner
authors.initials: KW
authors.lastname: Schmid
mesh_terms: D017209:Apoptosis; D001650:Bile Duct Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D005260:Female; D006500:Hepatic Duct, Common / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000378:metabolism; D018285:Klatskin Tumor / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis*; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D008668:Metallothionein