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.
Schmitz
Klaus Jürgen
KJ
Institute of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany. Klaus-juergen.schmitz@uk-essen.de
Lang
Hauke
H
Kaiser
Gernot
G
Wohlschlaeger
Jeremias
J
Sotiropoulos
Georgios Charalambos
GC
Baba
Hideo Andreas
HA
Jasani
Bharat
B
Schmid
Kurt Werner
KW
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
D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D008668:Metallothionein