Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tim-3 is a member of the TIM family of proteins (T-cell immunoglobulin mucin) involved in the regulation of CD4+ T-cells. Tim-3 is a T(H)1-specific type 1 membrane protein and regulates T(H)1 proliferation and the development of tolerance. Binding of galectin-9 to the extracellular domain of Tim-3 results in apoptosis of T(H)1 cells, but the intracellular pathways involved in the regulatory function of Tim-3 are unknown. Unlike Tim-1, which is expressed in renal epithelia and cancer, Tim-3 has not been described in cells other than neuronal or T-cells. Using RT-PCR we demonstrate that Tim-3 is expressed in malignant and non-malignant epithelial tissues. We have cloned Tim-3 from an immortalized liver cell carcinoma line and identified a highly conserved tyrosine in the intracellular tail of Tim-3 (Y265). We demonstrate that Y265 is specifically phosphorylated in vivo by the interleukin inducible T cell kinase (ITK), a kinase which is located in close proximity of the TIM genes on the allergy susceptibility locus 5q33.3. Stimulation of Tim-3 by its ligand galectin-9 results in increased phosphorylation of Y265, suggesting that this tyrosine residue plays an important role in downstream signalling events regulating T-cell fate. Given the role of TIM proteins in autoimmunity and cancer, the conserved SH2 binding domain surrounding Y265 could represent a possible target site for pharmacological intervention.
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PMID:A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by its ligand galectin-9. 1706 54

This study aimed to clarify the clinical significance of the expression of KL-6 mucin, a type of MUC1, in primary liver cancer. Tissue specimens were collected from 21 patients with cholangiocarcinoma (CC), 78 with hepatocellular carcinoma (HCC), and 12 with combined hepatocellular and cholangiocarcinoma (cHCC-CC). Immunohistochemical analysis was done using a monoclonal antibody for KL-6 mucin as well as antibodies for Hep1 or CK7. KL-6 staining was positive in all the CC tissues examined, while it was not positive in any of the HCC tissues. Similar selectivity of KL-6 staining was also observed in the cHCC-CC specimens, and the cholangiocellular tissue could be clearly delineated by KL-6 staining. In contrast, 79.5% of HCC specimens and 25.0% of cHCC-CC specimens were positive for Hep1 in the hepatocellular tissues, while none of the CC or cHCC-CC specimens were positive in the cholangiocellular tissues. Staining for CK7 was positive in 95.2% of CC and 35.9% of HCC specimens, while 58.3 and 25.0% of cHCC-CC specimens displayed positivity for CK7 in the cholangiocellular and hepatocellular tissues, respectively. These results suggest that KL-6 may be a useful tumor marker for distinguishing CC from HCC. In addition, the high selectivity of KL-6 for cholangiocallular tissue may help to provide information for deciding the clinical strategy in cHCC-CC patients.
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PMID:KL-6 mucin is a useful immunohistochemical marker for cholangiocarcinoma. 1734 8

Since its first description 50 years ago, fibrolamellar carcinomas (FLCs) have been recognized as a unique type of primary liver cancer. FLCs occur principally in children and young adults and are not associated with chronic liver disease. Their etiology is unknown. The tumor is made up of large polygonal cells containing abundant eosinophilic cytoplasm, large vesiculated nuclei, and large nucleoli, with tumor cells that are embedded in lamellar bands of fibrosis. Although rare, the most common variant of FLC shows areas of glandular type differentiation with mucin production. The uniqueness of FLC extends to their molecular findings, as they show no evidence for involvement by many of the major pathways and genes that are dysregulated in typical hepatocellular carcinoma, including alpha-fetoprotein, TP53 mutations, and beta catenin mutations. FLCs are not indolent tumors, but have an overall better prognosis than hepatocellular carcinomas of the usual sort because of the younger age at presentation and lack of cirrhosis. The most important prognostic feature is resectability. Although their morphologic appearance on routine stains is well defined, their etiology is still unknown and much of their molecular biology remains poorly described and awaits future investigation.
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PMID:Review of the clinicopathologic features of fibrolamellar carcinoma. 1745 18

The morphologic characteristics and biologic behavior of small liver cancers with hepatic and biliary differentiation, and their histogenesis, remain unclear. In this study, 35 cases of hepatocellular carcinoma (HCC) smaller than 3 cm in diameter with biliary differentiation were divided into 3 groups, group 1 [cytokeratin (CK) 19-negative/mucin-negative], group 2 (CK 19-positive/mucin-negative), and group 3 (CK 19-positive/mucin-positive). Sixty-one HCCs without biliary differentiation were used as controls. We compared the histologic features of these tumors and the postoperative outcomes. Three morphologic features of HCCs with biliary differentiation were respectively observed in 40% (14/35), 60% (21/35), and 42.9% (15/35) as follows: (1) cancer cells with intermediate morphology, (2) prominent inflammatory cell infiltrate, (3) desmoplastic stroma; neural cell adhesion molecule and c-kit expression were noted in 25.7%(9/35) and 8.6%(3/35), respectively. Extrahepatic tumor recurrence after surgery occurred in 0% (0/16) of group 1, 33.3% (3/9) of group 2, 40.0% (4/10) of group 3, and 8.2% (5/61) of the ordinary HCCs. The tumor-related survival of group 3 patients was worse than that of patients with ordinary HCCs, but there were no differences between the survival of group 1, or group 2 patients and those with ordinary HCCs. Our results suggest that the biliary differentiation does occur even in small HCC, and a mucin-producing cancer cells indicates aggressive tumor behavior. The combination of intermediate cancer cells, inflammatory cell infiltrate, and desmoplastic stroma is likely to be related to the biliary differentiation of HCC.
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PMID:Histologic characteristics and prognostic significance in small hepatocellular carcinoma with biliary differentiation: subdivision and comparison with ordinary hepatocellular carcinoma. 1746 Apr 64

Clear cell cholangiocarcinoma is a very unusual variant of peripheral bile duct carcinoma. We present 3 cases on which we performed a broad spectrum of immunohistochemical analysis. The tumors showed a glandular and trabecular growth pattern with abundant desmoplastic stroma and clear cell change of about 80% of the tumor cells. Positive expression of CK7 indicated a cholangiocellular origin. A primary hepatocellular carcinoma and metastatic clear cell tumors of the kidney, gastrointestinal tract, and the thyroid gland were excluded by absence of CK20, CD10, HepPar1, and TTF1. No mucin could be detected within the cytoplasm of the clear cells. Electronmicroscopy revealed only a few glycogen granula, but numerous cytoplasmic lipoid vacuoles as a possible explanation for the clear cell phenotype. All 3 tumors exhibited positive expression of CD56 (NCAM) in a significant amount of the clear cells. Beside the clear cell component, one tumor also showed an adenocarcinomalike and a well-differentiated tubular component. CD56 expression was detected in all 3 tumor areas. This report of 3 cases demonstrates that clear cell cholangiocarcinomas are not only of unusual histomorphology. They also show CD56 expression which is a very uncommon finding for intrahepatic cholangiocarcinomas. As CD56 expression is also found in reactive bile ducts and bile duct adenomas, one may speculate that these rare neoplasms may originate from reactive bile ducts or cholangiomatous lesions.
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PMID:Intrahepatic clear cell cholangiocarcinoma: immunohistochemical aspects in a very rare type of cholangiocarcinoma. 1752 78

The immunoexpression of CK19 recently has been identified as a marker of poor prognosis in pancreatic endocrine tumors and hepatocellular carcinoma. Conversely, the loss of expression of CD99 has been suggested to play a role in the tumorigenesis and dedifferentiation and is associated with poor outcome in some malignancies. The purpose of this study was to explore CK19 and CD99 immunostaining in mucin-producing neuroendocrine (goblet cell) and classical carcinoids of the appendix. Eighteen goblet cell carcinoids (GCCs) and 20 classic carcinoids were stained with CK19, CD99, and Ki-67, and these results were correlated with known pathological features of aggression: extent of invasion, mitoses, necrosis, and histological pattern. All 18 GCCs were CK19 strongly positive, whereas 16/20 classic carcinoids were also CK19 positive. Fourteen of 18 GCCs and 14/20 classic carcinoids were CD99 positive. CK19/CD99 immunoexpression did not correlate with extent of tumor invasion and mesoappendiceal extension, mitotic activity, Ki-67 labeling index, presence of extracellular mucinous pools dissecting muscle, and angiolymphatic and perineural/neural invasion. There is no difference in the immunostaining for CK19 and CD99 between GCCs and classic carcinoids, and both types of neuroendocrine tumor show the same extent of expression of both markers.
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PMID:CK19 and CD99 immunoexpression profile in goblet cell (mucin-producing neuroendocrine tumors) and classical carcinoids of the vermiform appendix. 1765 31

Liver cirrhosis is reportedly one of the conditions preceding peripheral-type intrahepatic cholangiocarcinoma but not hilar/perihilar cholangiocarcinoma. Herein, we report a case of perihilar cholangiocarcinoma arising in a hepatitis C virus-related cirrhotic liver. The patient was a 69-year-old man. He was diagnosed with hepatitis C virus-related chronic hepatitis at the age of 56 years, and 9 years later, multiple hepatocellular carcinomas were detected by imaging modalities. Despite treatments, including chemotherapy, he died of hepatic failure at the age of 69 years. At autopsy, in addition to multiple nodules of hepatocellular carcinoma, we found a white mucinous and fibrous tumor spreading from the hepatic hilum to the periphery along the left lateral segmental bile ducts in the advanced cirrhotic liver. This tumor was histologically a cholangiocarcinoma that involved mainly the peribiliary glands and showed variable cystic dilation, suggesting that it might have been derived from these peribiliary glands. Immunohistochemically, the cholangiocarcinoma cells were positive for cytokeratin 7 and mucin core protein 1, and negative for cytokeratin 20 and mucin core protein 2. Hilar/perihilar cholangiocarcinoma arising in hepatitis C virus-related liver cirrhosis has rarely been reported. This case warrants further studies to clarify the possible involvement of hepatitis C virus in tumorigenesis of hilar/perihilar cholangiocarcinoma.
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PMID:Perihilar cholangiocarcinoma arising in hepatitis C virus-related liver cirrhosis with hepatocellular carcinoma. 1770 Nov 35

We present a unique case of hepatocellular carcinoma with mucin-producing gland formation. A 53-year-old man with hepatitis B infection presented with weight loss for the past month. Computed tomography demonstrated a 10 x 9.8 cm mass in the right hepatic lobe accompanied by cirrhotic changes in the hepatic parenchyma. Right hepatectomy was performed, and the tumor cut surface showed a poorly-circumscribed, white to pink tumor with numerous nodules and extensive necrosis. Microscopically, the tumor was composed of thick trabeculae and large, irregularly-shaped islands, both of which were filled with pleomorphic eosinophilic hepatoid cells or gland-forming columnar cells with mucin production. Those cells were immunoreactive for cytokeratin 19 in both the trabeculae and the glands. In some tumor cells, limited immunoreactivity for cytokeratin 7, epithelial membrane antigen and carcinoembryonic antigen was noted. The cells forming thick trabeculae were focally positive for hepatocyte paraffin 1 and alpha-fetoprotein. We suggest that this tumor shows bidirectional differentiation into hepatocytes and cholangiocytes, supporting the concepts that human hepatocarcinogenesis can be based on transformation of progenitor cells which can imply divergent differentiation.
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PMID:Hepatocellular carcinoma with characteristic mucin production: a case report. 1991 44

MUC1, membrane-associated mucins, has various types based on different glycoforms in its extracellular domain and is widely expressed in gastrointestinal tissues. Many investigations have showed that aberrant expression of MUC1 in gastrointestinal cancer tissue has clinicopathological and biological importance in cancer disease. KL-6 mucin, one kind of MUC1, was also investigated and suggested to have a significant relationship with a worse tumor behavior especially cancer cell invasion and metastasis in various gastrointestinal cancers. On the other hand, clinicopathological availability of KL-6 mucin varied among each gastrointestinal cancer. In colorectal and gastric cancer, circumferential membrane and/or cytoplasmic localization of KL-6 mucin were frequently detected in the cancer tissue of patients with the presence of deeper invasion and lymph node metastasis of cancer cells. Therefore, the subcellular localization of KL-6 mucin in cancer tissues can be used for predicting a worse outcome for patients. In primary liver cancer, KL-6 mucin expression was detected in cholangiocarcinoma but not in hepatocellular carcinoma tissues. Therefore, it can be used as a good marker for discriminating cholangiocarcinoma from hepatocellular carcinoma. While various significant clinicopathological detections were clarified, the nature of KL-6 mucin is not yet clearly known. Alteration in expression or glycoform of KL-6 mucin is suggested to influence the invasive and adhesive ability of cancer cells. To clarify the characteristics and biological functions of KL-6 mucin in cancer disease, the clinical applications and study of this antigen is expected to be expanded.
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PMID:Clinicopathology of sialomucin: MUC1, particularly KL-6 mucin, in gastrointestinal, hepatic and pancreatic cancers. 2010 51

Intrahepatic clear cell cholangiocarcinoma is very rare - only 8 cases have been reported. A 56-year-old Japanese man with chronic hepatitis B infection was diagnosed with a 2.2 cm hepatocellular carcinoma on imaging, and hepatic segmentectomy was performed. Histopathologically, the tumor cells had copious clear cytoplasm and formed glandular structures or solid nests. These pathological findings suggested the tumor was a clear cell variant of intrahepatic cholangiocarcinoma. Particular stains and radiological images suggested that the cause of the clear cell change had been glycogen, not mucin nor lipid. On immunohistochemical staining, cytokeratin (CK) 7 and CK19 were positive, whereas CK20 was negative. Vimentin was detected on the cell membranes, and CD56 was focally positive. The patient was given adjuvant chemotherapy and is currently free from the tumor 7 mo postoperatively. Careful follow-up with adequate postoperative supplementary chemotherapy is necessary because the characteristics of this type of tumor are unknown.
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PMID:A case of intrahepatic clear cell cholangiocarcinoma. 2050 60


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