title: Immunohistochemical Markers Distinguishing Cholangiocellular Carcinoma (CCC) from Pancreatic Ductal Adenocarcinoma (PDAC) Discovered by Proteomic Analysis of Microdissected Cells.
abstract: Cholangiocellular carcinoma (CCC) and pancreatic ductal adenocarcinoma (PDAC) are two highly aggressive cancer types that arise from epithelial cells of the pancreatobiliary system. Owing to their histological and morphological similarity, differential diagnosis between CCC and metastasis of PDAC located in the liver frequently proves an unsolvable issue for pathologists. The detection of biomarkers with high specificity and sensitivity for the differentiation of these tumor types would therefore be a valuable tool. Here, we address this problem by comparing microdissected CCC and PDAC tumor cells from nine and eleven cancer patients, respectively, in a label-free proteomics approach. The novel biomarker candidates were subsequently verified by immunohistochemical staining of 73 CCC, 78 primary, and 18 metastatic PDAC tissue sections. In the proteome analysis, we found 180 proteins with a significantly differential expression between CCC and PDAC cells (p value < 0.05, absolute fold change > 2). Nine candidate proteins were chosen for an immunohistochemical verification out of which three showed very promising results. These were the annexins ANXA1, ANXA10, and ANXA13. For the correct classification of PDAC, ANXA1 showed a sensitivity of 84% and a specificity of 85% and ANXA10 a sensitivity of 90% at a specificity of 66%. ANXA13 was higher abundant in CCC. It presented a sensitivity of 84% at a specificity of 55%. In metastatic PDAC tissue ANXA1 and ANXA10 showed similar staining behavior as in the primary PDAC tumors (13/18 and 17/18 positive, respectively). ANXA13, however, presented positive staining in eight out of eighteen secondary PDAC tumors and was therefore not suitable for the differentiation of these from CCC. We conclude that ANXA1 and ANXA10 are promising biomarker candidates with high diagnostic values for the differential diagnosis of intrahepatic CCC and metastatic liver tumors deriving from PDAC.
authors.affiliation: From the ‡Medizinisches Proteom-Center, Ruhr-Universität Bochum, Germany; juliet.padden@rub.de.
authors.forename: Juliet
authors.initials: J
authors.lastname: Padden
authors.affiliation: From the ‡Medizinisches Proteom-Center, Ruhr-Universität Bochum, Germany;
authors.forename: Maike
authors.initials: M
authors.lastname: Ahrens
authors.affiliation: §Institut für Pathologie, Universitätsklinikum Essen, Universität-Duisburg-Essen, Germany;
authors.forename: Julia
authors.initials: J
authors.lastname: Kälsch
authors.affiliation: §Institut für Pathologie, Universitätsklinikum Essen, Universität-Duisburg-Essen, Germany;
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bertram
authors.affiliation: From the ‡Medizinisches Proteom-Center, Ruhr-Universität Bochum, Germany;
authors.forename: Dominik A
authors.initials: DA
authors.lastname: Megger
authors.affiliation: From the ‡Medizinisches Proteom-Center, Ruhr-Universität Bochum, Germany;
authors.forename: Thilo
authors.initials: T
authors.lastname: Bracht
authors.affiliation: From the ‡Medizinisches Proteom-Center, Ruhr-Universität Bochum, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Eisenacher
authors.affiliation: ¶Klinik für Allgemeinchirurgie, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Universität-Duisburg-Essen, Germany;
authors.forename: Peri
authors.initials: P
authors.lastname: Kocabayoglu
authors.affiliation: From the ‡Medizinisches Proteom-Center, Ruhr-Universität Bochum, Germany;
authors.forename: Helmut E
authors.initials: HE
authors.lastname: Meyer
authors.affiliation: ‖Institut für Pathologie und Neuropathologie, Abteilung Allgemeine Pathologie, Universitätsklinikum Tübingen, Germany.
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.affiliation: §Institut für Pathologie, Universitätsklinikum Essen, Universität-Duisburg-Essen, Germany;
authors.forename: Hideo A
authors.initials: HA
authors.lastname: Baba
authors.affiliation: From the ‡Medizinisches Proteom-Center, Ruhr-Universität Bochum, Germany;
authors.forename: Barbara
authors.initials: B
authors.lastname: Sitek
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017305:Annexin A1 / Q000378:metabolism*; D017302:Annexins / Q000378:metabolism*; D001650:Bile Duct Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000175:diagnosis* / Q000378:metabolism; D018281:Cholangiocarcinoma / Q000175:diagnosis* / Q000378:metabolism; D003937:Diagnosis, Differential; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood* / Q000378:metabolism / Q000556:secondary; D008297:Male; D042282:Microdissection; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D012680:Sensitivity and Specificity
chemical_list: C121387:ANXA10 protein, human; D017305:Annexin A1; D017302:Annexins; D014408:Biomarkers, Tumor