ABSTRACT
BACKGROUND AND OBJECTIVES: Although cholangiolocellular carcinoma is considered a combined hepatocellular and cholangiocarcinoma, we feel that this classification is not appropriate. Therefore, we compared the diagnostic imaging findings, surgical prognosis, and pathological features of cholangiolocellular carcinoma with those of other combined hepatocellular and cholangiocarcinoma subtypes, hepatocellular carcinoma, and cholangiocarcinoma. METHODS: The study patients included 7 with classical type combined hepatocellular and cholangiocarcinoma; 8 with stem cell feature, intermediate type combined hepatocellular and cholangiocarcinoma; 13 with cholangiolocellular carcinoma; 58 with cholangiocarcinoma; and 359 with hepatocellular carcinoma. All patients underwent hepatectomy or living-related donor liver transplantation from 2001 to 2014. RESULTS: cholangiolocellular carcinoma could be distinguished from hepatocellular carcinom, other combined hepatocellular and cholangiocarcinoma subtypes, and cholangiocarcinoma by the presence of intratumoral Glisson's pedicle, hepatic vein penetration, and tumor-staining pattern on angiography-assisted CT. Cholangiolocellular carcinoma was associated with a significantly lower SUV-max than that of cholangiocarcinoma on FDG-PET. Hepatocellular carcinoma, classical type, and cholangiolocellular carcinoma had significantly better prognoses than stem cell feature, intermediate type and cholangiocarcinoma. A cholangiocarcinoma component was detected in cholangiolocellular carcinoma that progressed to the hepatic hilum, and the cholangiocarcinoma component was found in perineural invasion and lymph node metastases. CONCLUSIONS: From the viewpoint of surgeon, cholangiolocellular carcinoma should be classified as a good-prognosis subtype of biliary tract carcinoma because of its tendency to differentiate into cholangiocarcinoma during its progression, and its distinctive imaging and few recurrence rates different from other combined hepatocellular and cholangiocarcinoma subtypes.
Subject(s)
Cholangiocarcinoma/diagnostic imaging , Cholangiocarcinoma/pathology , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/pathology , Aged , Biomarkers, Tumor , Biopsy , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/surgery , Cholangiocarcinoma/etiology , Cholangiocarcinoma/surgery , Clinical Decision-Making , Diagnosis, Differential , Diagnostic Imaging/methods , Disease Management , Female , Hepatectomy , Humans , Immunohistochemistry , Liver Neoplasms/etiology , Liver Neoplasms/surgery , Male , Middle Aged , Multivariate Analysis , Neoplasm Metastasis , Neoplasm Staging , Perioperative Period , Prognosis , Treatment OutcomeABSTRACT
Tumor-initiating cells (TICs) play a central role in tumor development, metastasis, and recurrence. In the present study, we investigated the effect of disulfiram (DSF), an inhibitor of aldehyde dehydrogenase, toward tumor-initiating hepatocellular carcinoma (HCC) cells. DSF treatment suppressed the anchorage-independent sphere formation of both HCC cells. Flow cytometric analyses showed that DSF but not 5-fluorouracil (5-FU) drastically reduces the number of tumor-initiating HCC cells. The sphere formation assays of epithelial cell adhesion molecule (EpCAM)(+) HCC cells co-treated with p38-specific inhibitor revealed that DSF suppresses self-renewal capability mainly through the activation of reactive oxygen species (ROS)-p38 MAPK pathway. Microarray experiments also revealed the enrichment of the gene set involved in p38 MAPK signaling in EpCAM(+) cells treated with DSF but not 5-FU. In addition, DSF appeared to downregulate Glypican 3 (GPC3) in a manner independent of ROS-p38 MAPK pathway. GPC3 was co-expressed with EpCAM in HCC cell lines and primary HCC cells and GPC3-knockdown reduced the number of EpCAM(+) cells by compromising their self-renewal capability and inducing the apoptosis. These results indicate that DSF impaired the tumorigenicity of tumor-initiating HCC cells through activation of ROS-p38 pathway and in part through the downregulation of GPC3. DSF might be a promising therapeutic agent for the eradication of tumor-initiating HCC cells.
Subject(s)
Carcinoma, Hepatocellular/enzymology , Disulfiram/pharmacology , Liver Neoplasms/enzymology , MAP Kinase Signaling System/drug effects , Neoplastic Stem Cells/pathology , Reactive Oxygen Species/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Aldehyde Dehydrogenase/metabolism , Animals , Antigens, Neoplasm/metabolism , Carcinogenesis/drug effects , Carcinogenesis/pathology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cell Adhesion Molecules/metabolism , Cell Count , Cell Line, Tumor , Cell Proliferation/drug effects , Disulfiram/therapeutic use , Enzyme Activation/drug effects , Epithelial Cell Adhesion Molecule , Flow Cytometry , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Glypicans/genetics , Glypicans/metabolism , Intracellular Space/drug effects , Intracellular Space/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Mice , Mice, SCID , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/enzymology , Spheroids, Cellular/drug effects , Spheroids, Cellular/pathology , Xenograft Model Antitumor AssaysSubject(s)
Bile Duct Neoplasms/diagnosis , Bile Duct Neoplasms/pathology , Bile Ducts/pathology , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/pathology , Endoscopy, Digestive System/methods , Liver Neoplasms/diagnosis , Liver Neoplasms/pathology , Aged , Diagnostic Imaging , Humans , Male , Neoplasm InvasivenessABSTRACT
A 50-year-old man was admitted because of increasing massive ascites. While lymphoma cells (diffuse large B-cell lymphoma: DLBCL) were detected in the ascites, pleural effusion, cerebrospinal fluid and bone marrow, no tumor masses other than a submucosal lymphoma lesion in the stomach only 1 cm in diameter were identified. The patient was treated with chemotherapy including rituximab (R-CHOP-ESHAP) and injection of methotrexate and dexamethasone into the medullary cavity as well as radiation to the whole brain, and achieved complete remission 4 months later. The present case suggests that DLBCL can initially manifest as a form of effusion lymphoma with minimum solid tumor component. The distinctive clinical features of Japanese patients with primary effusion lymphoma are also reviewed.