title: Immunohistochemical molecular analysis indicates hepatocellular carcinoma subgroups that reflect tumor aggressiveness.
abstract: Histopathologic parameters and molecular markers are widely accepted as useful predictors of tumor aggressiveness in hepatocellular carcinoma (HCC). However, few studies have analyzed immunohistochemical profiles comprehensively in one series, a fact that has resulted in fragmentation of information that could be applied in clinical practice. We conducted immunohistochemical expression analysis of biliary/stem cell markers (cytokeratin 19, sal-like protein 4, epithelial cell adhesion molecule, and CD133), Wnt/β-catenin signaling-related molecules (β-catenin and glutamine synthetase), p53, and cell proliferation markers (Ki-67 and mitosis) in 162 HCCs surgically resected from 142 patients and analyzed the results with respect to clinicopathological features. Immunohistochemical analysis broadly identified 3 groups: the biliary/stem cell marker-positive group, the Wnt/β-catenin signaling-related marker-positive group, and the biliary/stem cell marker-negative and Wnt/β-catenin signaling-related marker-negative group. p53 was frequently positive in the biliary/stem cell marker-positive group, but it was rarely positive in the Wnt/β-catenin signaling-related marker-positive group. The biliary/stem cell marker-positive group exhibited poor tumor differentiation, increased frequency of portal vein invasion and/or intrahepatic metastasis, and highly proliferative activity. In contrast, the biliary/stem cell marker-negative and Wnt/β-catenin signaling-related marker-negative group exhibited better tumor differentiation, a decreased frequency of portal vein invasion and/or intrahepatic metastasis, and less proliferative activity. The Wnt/β-catenin signaling-related marker-positive group showed neither tendency. The biliary/stem cell marker-positive group had the shortest time to recurrence among the 3 groups. Immunohistochemical profiling of HCC reflects tumor aggressiveness and suggests the potential efficacy of immunohistochemistry-based subclassification of HCC.
authors.affiliation: Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Hanako
authors.initials: H
authors.lastname: Tsujikawa
authors.affiliation: Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Masugi
authors.affiliation: Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Yamazaki
authors.affiliation: Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Itano
authors.affiliation: Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kitagawa
authors.affiliation: Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan. Electronic address: msakamot@z5.keio.jp.
authors.forename: Michiie
authors.initials: M
authors.lastname: Sakamoto
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D006528:Carcinoma, Hepatocellular / Q000737:chemistry* / Q000401:mortality / Q000556:secondary / Q000601:surgery; D002454:Cell Differentiation; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000032:analysis; D008113:Liver Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D011237:Predictive Value of Tests; D012307:Risk Factors; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D051153:Wnt Proteins / Q000032:analysis; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D019394:Ki-67 Antigen; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051153:Wnt Proteins; D051176:beta Catenin
keywords: Aggressiveness; Biliary/stem cell marker; Hepatocellular carcinoma; Immunohistochemistry; Wnt/β-catenin signaling