The alphavbeta6 integrin is a highly specific immunohistochemical marker for cholangiocarcinoma.
OBJECTIVE
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are common primary hepatic malignancies. Their immunohistological differentiation using specific markers is pivotal for treatment and prognosis. We found alphavbeta6 integrin strongly upregulated in biliary fibrosis, but its expression in primary and secondary liver tumours is unknown. Here, we aimed to evaluate the diagnostic applicability of alphavbeta6 integrin in differentiating primary liver cancers.


METHODS
Expression of alphavbeta6 integrin was evaluated in liver tissues from patients with CC, HCC, fibrolamellar HCC, combined CC/HCC, hepatic metastases of colorectal and pancreatic carcinomas, primary sclerosing cholangitis (PSC), and in human primary and tumour-derived liver cell lines by immunohisto- and cytochemistry, and by TaqMan PCR. Diagnostic performance of the beta6 subunit was compared with CK7, CK20, and HepPar 1.


RESULTS
In CC cells beta6 mRNA levels were induced 125-fold compared to primary cholangiocytes, while it was completely absent in hepatoma cells. In human tissues, beta6 transcripts were more than 100-fold upregulated in CC compared to normal liver. By immunohistochemistry, 88% of CC, 50% of PSC, 13% of colorectal carcinoma metastases, and 80% of pancreatic carcinoma metastases presented alphavbeta6, whereas all HCC, combined CC/HCC and fibrolamellar HCC stained negative. Specificity of beta6 immunohistochemistry for CC (100%) surpassed all other tested markers and sensitivity was equal to CK7 (86% vs. 90%).


CONCLUSIONS
The alphavbeta6 integrin is strongly expressed in human CC but not in HCC and therefore can be considered as a specific immunohistochemical marker in the differential diagnosis of primary liver tumours.
Institute of Clinical Pharmacology and Visceral Research, University of Bern, Murtenstrasse 35, Bern, Switzerland.
E
E
Patsenker
L
L
Wilkens
V
V
Banz
C H
CH
Osterreicher
R
R
Weimann
S
S
Eisele
A
A
Keogh
D
D
Stroka
A
A
Zimmermann
F
F
Stickel
D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism*; D001650:Bile Duct Neoplasms / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D015209:Cholangitis, Sclerosing / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D053554:Keratin-20 / Q000378:metabolism; D053552:Keratin-7 / Q000378:metabolism; D008113:Liver Neoplasms / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012680:Sensitivity and Specificity
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D016023:Integrins; D053554:Keratin-20; D053552:Keratin-7; C073878:integrin alphavbeta6