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Bannasch P, Ribback S, Su Q, Mayer D. Clear cell hepatocellular carcinoma: origin, metabolic traits and fate of glycogenotic clear and ground glass cells. Hepatobiliary Pancreat Dis Int 2017; 16:570-594. [PMID: 29291777 DOI: 10.1016/s1499-3872(17)60071-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 08/14/2017] [Indexed: 02/05/2023]
Abstract
Clear cell hepatocellular carcinoma (CCHCC) has hitherto been considered an uncommon, highly differentiated variant of hepatocellular carcinoma (HCC) with a relatively favorable prognosis. CCHCC is composed of mixtures of clear and/or acidophilic ground glass hepatocytes with excessive glycogen and/or fat and shares histology, clinical features and etiology with common HCCs. Studies in animal models of chemical, hormonal and viral hepatocarcinogenesis and observations in patients with chronic liver diseases prone to develop HCC have shown that the majority of HCCs are preceded by, or associated with, focal or diffuse excessive storage of glycogen (glycogenosis) which later may be replaced by fat (lipidosis/steatosis). In ground glass cells, the glycogenosis is accompanied by proliferation of the smooth endoplasmic reticulum, which is closely related to glycogen particles and frequently harbors the hepatitis B surface antigen (HBsAg). From the findings in animal models a sequence of changes has been established, commencing with preneoplastic glycogenotic liver lesions, often containing ground glass cells, and progressing to glycogen-poor neoplasms via various intermediate stages, including glycogenotic/lipidotic clear cell foci, clear cell hepatocellular adenomas (CCHCA) rich in glycogen and/or fat, and CCHCC. A similar process seems to take place in humans, with clear cells frequently persisting in CCHCC and steatohepatitic HCC, which presumably represent intermediate stages in the development rather than particular variants of HCC. During the progression of the preneoplastic lesions, the clear and ground glass cells transform into cells characteristic of common HCC. The sequential cellular changes are associated with metabolic aberrations, which start with an activation of the insulin signaling cascade resulting in pre-neoplastic hepatic glycogenosis. The molecular and metabolic changes underlying the glycogenosis/lipidosis are apparently responsible for the dramatic metabolic shift from gluconeogenesis to the pentose phosphate pathway and Warburg-type glycolysis, which provide precursors and energy for an ever increasing cell proliferation during progression.
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Affiliation(s)
| | - Silvia Ribback
- Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Qin Su
- Cell Marque, Millipore-Sigma Rocklin, USA
| | - Doris Mayer
- German Cancer Research Center, Heidelberg, Germany
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Casella ML, Parody JP, Ceballos MP, Quiroga AD, Ronco MT, Francés DE, Monti JA, Pisani GB, Carnovale CE, Carrillo MC, de Luján Alvarez M. Quercetin prevents liver carcinogenesis by inducing cell cycle arrest, decreasing cell proliferation and enhancing apoptosis. Mol Nutr Food Res 2013; 58:289-300. [PMID: 24124108 DOI: 10.1002/mnfr.201300362] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Revised: 07/04/2013] [Accepted: 07/09/2013] [Indexed: 12/12/2022]
Abstract
SCOPE Quercetin is the most abundant flavonoid in human diet. It has special interest as it holds anticancerous properties. This study aims to clarify the mechanisms involved in quercetin effects during the occurrence of preneoplastic lesions in rat liver. METHODS AND RESULTS Adult male Wistar rats were subjected to a two-phase model of hepatocarcinogenesis (initiated-promoted group). Initiated-promoted animals also received quercetin 10 and 20 mg/kg body weight (IPQ10 and IPQ20 groups, respectively). Antioxidant defenses were modified by quercetin administration at both doses. However, only IPQ20 group showed a reduction in number and volume of preneoplastic lesions. This group showed increased apoptosis and a reduction in the proliferative index. In addition, IPQ20 group displayed a reduction of cell percentages in G₁ and S phases, accumulation in G₂, and decrease in M phase, with reduced expression of cyclin D1, cyclin A, cyclin B, and cyclin-dependent kinase 1. Interestingly, peroxisome proliferator activated receptor-α levels were reduced in IPQ20 group. CONCLUSION The outcomes of this study represent a significant contribution to the current understanding on the preventive mechanisms of quercetin during the early stages of liver cancer development, demonstrating that in addition to its known proapoptotic characteristics, the flavonoid modulates the expression of critical cell cycle regulators and peroxisome proliferator activated receptor-α activity.
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Affiliation(s)
- María Laura Casella
- Instituto de Fisiología Experimental (IFISE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Rosario, Argentina
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BANNASCH P. Comparative Aspects of Rat and Human Hepatocellular Preneoplasia and Neoplasia. J Toxicol Pathol 2013. [DOI: 10.1293/tox..] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Peter BANNASCH
- German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg Germany
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BANNASCH P. Comparative Aspects of Rat and Human Hepatocellular Preneoplasia and Neoplasia. J Toxicol Pathol 2013. [DOI: 10.1293/tox] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Peter BANNASCH
- German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg Germany
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Bannasch P. Glycogenotic hepatocellular carcinoma with glycogen-ground-glass hepatocytes: A heuristically highly relevant phenotype. World J Gastroenterol 2012; 18:6701-6708. [PMID: 23239906 PMCID: PMC3520157 DOI: 10.3748/wjg.v18.i46.6701] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Revised: 09/21/2012] [Accepted: 11/15/2012] [Indexed: 02/06/2023] Open
Abstract
Glycogenotic hepatocellular carcinoma (HCC) with glycogen-ground-glass hepatocytes has recently been described as an allegedly “novel variant” of HCC, but neither the historical background nor the heuristic relevance of this observation were put in perspective. In the present contribution, the most important findings in animal models and human beings related to the emergence and further evolution of excessively glycogen storing (glycogenotic) hepatocytes with and without ground glass features during neoplastic development have been summarized. Glycogenotic HCCs with glycogen-ground-glass hepatocytes represent highly differentiated neoplasms which contain subpopulations of cells phenotypically resembling those of certain types of preneoplastic hepatic foci and benign hepatocellular neoplasms. It is questionable whether the occurrence of glycogen-ground-glass hepatocytes in a glycogenotic HCC justifies its classification as a specific entity. The typical appearance of ground-glass hepatocytes is due to a hypertrophy of the smooth endoplasmic reticulum, which is usually associated with an excessive storage of glycogen and frequently also with an expression of the hepatitis B surface antigen. Sequential studies in animal models and observations in humans indicate that glycogen-ground-glass hepatocytes are a facultative, integral part of a characteristic cellular sequence commencing with focal hepatic glycogenosis potentially progressing to benign and malignant neoplasms. During this process highly differentiated glycogenotic cells including ground-glass hepatocytes are gradually transformed via various intermediate stages into poorly differentiated glycogen-poor, basophilic (ribosome-rich) cancer cells. Histochemical, microbiochemical, and molecular biochemical studies on focal hepatic glycogenosis and advanced preneoplastic and neoplastic lesions in tissue sections and laser-dissected specimens in rat and mouse models have provided compelling evidence for an early insulinomimetic effect of oncogenic agents, which is followed by a fundamental metabolic switch from gluconeogenesis towards the pentose-phosphate pathway and the Warburg type of glycolysis during progression from preneoplastic hepatic glycogenosis to the highly proliferative malignant phenotype.
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Gong L, Li YH, Su Q, Chu X, Zhang W. Clonality of nodular lesions in liver cirrhosis and chromosomal abnormalities in monoclonal nodules of altered hepatocytes. Histopathology 2010; 56:589-99. [PMID: 20459569 DOI: 10.1111/j.1365-2559.2010.03523.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
AIMS To investigate the clonality and chromosome abnormalities of nodules of altered hepatocytes (NAH) in liver cirrhosis and determine whether there is a genetic link between monoclonal NAH and hepatocellular carcinoma (HCC). METHODS AND RESULTS First, 93 nodules from nine hepatitis B virus (HBV)-related liver cirrhosis patients were dissected by laser microdissection. Next, genomic DNA was extracted, pretreated with Hpa II or Hha I, and amplified via nested polymerase chain reaction for the phosphoglycerate kinase and androgen receptor genes. Finally, the chromosomal aberrations of 12 monoclonal NAH were studied using array-based comparative genomic hybridization (array-CGH). Loss of X chromosomal inactivation mosaicism was demonstrated in three large regenerative nodules and 12 NAH with small cell change (SCC), indicating their neoplastic nature. Among the 60 NAH without SCC, 29 (48.33%) were shown to be monoclonal, whereas four glycogen-storing foci and 14 regenerative nodules were found to be polyclonal. Array-CGH analysis revealed chromosomal abnormalities in one NAH with SCC. Moreover, a part of chromosomal abnormalities in the NAH with SCC coincided with those in HCC. CONCLUSIONS Some (48.33%) NAH in HBV-associated cirrhosis, particularly all those with SCC, are already neoplastic lesions. Occurrence of SCC is a late event during NAH progression, suggesting a premalignant phenotype.
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Affiliation(s)
- Li Gong
- Department of Pathology, The Fourth Military Medical University, Xi'an, Shaanxi Provice, China
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Gong L, Li YH, Su Q, Li G, Zhang WD, Zhang W. Use of X-chromosome inactivation pattern and laser microdissection to determine the clonal origin of focal nodular hyperplasia of the liver. Pathology 2009; 41:348-55. [PMID: 19404847 DOI: 10.1080/00313020902885029] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
AIM To determine the clonal origin of the whole lesion and each nodule of focal nodular hyperplasia (FNH) and elucidate its nature, simultaneously comparing the clonal composition with hepatocellular adenoma (HA). METHODS Nine FNHs from eight women, two HAs and four hepatocellular carcinomas (HCCs) were examined by clonality assays based on X-chromosomal inactivation mosaicism in females and laser microdissection. Genomic DNA was isolated from each nodule, the whole lesion and surrounding liver parenchyma, pretreated with Hpa II or Hha I, and amplified via nested PCR for phosphoglycerate kinase (PGK) and androgen receptor (AR) genes. The single nucleotide polymorphism at the PGK locus was identified by incubation with Bst XI and agarose gel electrophoresis, and the CAG repeat length polymorphism at AR locus was revealed on denaturing polyacrylamide gels and visualised by silver staining. RESULTS Monoclonality was confirmed in both of the two HAs and all of the four HCCs examined, while polyclonality was shown in all nine FNHs as determined by the whole lesions, demonstrating their distinction from neoplastic lesions. A total of 108 nodules, including 96 nodules of altered hepatocytes (NAH) and 12 ordinary regenerative nodules (ORN), were microdissected from eight of the nine FNH lesions. Loss of X-chromosomal inactivation mosaicism was demonstrated in 39 (40.6%) of 96 NAHs, indicating the monoclonal, neoplastic nature. In contrast, polyclonality was demonstrated in all of the 12 ORNs and the surrounding liver parenchyma. CONCLUSIONS FNH is composed of numerous NAHs and ORNs. The whole lesion shows a polyclonal cell composition, but neoplastic transformation has occurred in some of the nodules. Clonal assay is useful for its distinction from HA, and sampling the whole or larger part of the lesion is necessary.
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Affiliation(s)
- Li Gong
- Department of Pathology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi Province, China
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Borbath I, Leclercq IA, Abarca-Quinones J, Desaeger C, Lebrun V, Moulin P, Sempoux C, Horsmans Y. Inhibition of early preneoplastic events in the rat liver by the somatostatin analog lanreotide. Cancer Sci 2007; 98:1831-9. [PMID: 17900309 PMCID: PMC11158449 DOI: 10.1111/j.1349-7006.2007.00626.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2007] [Revised: 08/16/2007] [Accepted: 08/21/2007] [Indexed: 12/21/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death, and its incidence is increasing worldwide. Due to the known risk factors (mainly hepatitis B and C viruses), we believe there is a rationale for a chemopreventive approach to treat HCC. Here, based on described in vitro data, we evaluated the preventive effects of lanreotide, a somatostatin analog, on the induction of early carcinogenic events. We monitored preneoplastic foci induced by a two-stage initiation/promotion model of hepatocarcinogenesis in male Wistar rats, using diethylnitrosamine and 2-acetylaminofluorene. Lanreotide was given starting the day after the first diethylnitrosamine injection. By quantitative morphometry, we showed that lanreotide significantly decreases the size of induced preneoplastic foci. Analysis of proliferation and apoptosis assessed by immunohistochemistry, showed decreased proliferation and increased cell death in rats treated with lanreotide. As these events were associated with a significant decreased expression of the cell cycle regulator cyclin D1 and an increased expression of the cyclin-dependent kinase inhibitor p27(kip1) compared to the non-treated group, it is tempting to speculate that these factors are involved in the favorable effect of lanreotide. In conclusion, lanreotide significantly decreases early carcinogenic transformation in a two-step rat model. As lanreotide has a low toxicity profile, we believe it would be interesting to evaluate its effect in chemoprevention of HCC.
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Affiliation(s)
- Ivan Borbath
- Gastroenterology Laboratory, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Avenue Hippocrate, 10, Brussels 1200, Belgium.
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Borbath I, Leclercq I, Moulin P, Sempoux C, Horsmans Y. The PPARgamma agonist pioglitazone inhibits early neoplastic occurrence in the rat liver. Eur J Cancer 2007; 43:1755-63. [PMID: 17582756 DOI: 10.1016/j.ejca.2007.05.005] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2007] [Revised: 04/25/2007] [Accepted: 05/04/2007] [Indexed: 01/04/2023]
Abstract
Hepatocellular carcinoma (HCC) is increasing worldwide and is the fifth main cause of cancer-related death. HCC develops on a preneoplastic organ, the cirrhotic liver. Therefore, chemoprevention could play a role in the therapy of HCC. We evaluated the preventive effects of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on the induction of early carcinogenic events. We monitored pre-neoplastic foci induced by a two-stage initiation/promotion model of hepatocarcinogenesis in rats, using diethylnitrosamine and acetylaminofluorene. Pioglitazone treatment was initiated the day after the first diethylnitrosamine injection. By quantitative morphometry and Western blot, we showed that pioglitazone significantly decreases the size of pre-neoplastic foci. Analysis of proliferation and apoptosis, assessed by immunohistochemistry, demonstrated decreased proliferation but no effect on cell death in rats treated with pioglitazone. These events were associated with an increased expression of the cyclin-dependent kinase inhibitor p27(kip1), compared to the non treated group. In conclusion, pioglitazone inhibits early carcinogenic transformation in a two-step rat model. As pioglitazone has a low toxicity profile, we believe it would be interesting to evaluate its effect in chemoprevention of HCC in humans in a clinical setting.
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Affiliation(s)
- I Borbath
- Gastroenterology Laboratory, Cliniques Universitaires St-Luc, Université catholique de Louvain, 10, avenue Hippocrate, 1200 Brussels, Belgium.
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Parody JP, Alvarez MDL, Quiroga A, Ronco MT, Francés D, Carnovale C, Carrillo MC. Hepatocytes isolated from preneoplastic rat livers are resistant to ethacrynic acid cytotoxicity. Arch Toxicol 2007; 81:565-73. [PMID: 17340122 DOI: 10.1007/s00204-007-0183-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2006] [Accepted: 01/15/2007] [Indexed: 12/22/2022]
Abstract
Glutathione S-transferases (GSTs) are involved in the detoxification of xenobiotics, such as several cytostatic drugs, through conjugation with glutathione (GSH). Pi class GST (GST P) liver expression is associated with preneoplastic and neoplastic development and contributes with the drug-resistance phenotype. Ethacrynic acid (EA) is an inhibitor of rat and human GSTs. In addition, causes lipid peroxidation in isolated rat hepatocytes. Therefore, we decided to evaluate the role of the GST/GSH system in isolated hepatocytes from preneoplastic rat livers (IP) in the presence of EA and determine the cytotoxicity of the drug. Our results showed a resistance to the toxic effects of EA since viability and cellular integrity values were significantly higher than control. Initial levels of thiobarbituric acid reactive substances (TBARS) in IP hepatocytes were significantly higher than control and the presence of EA did not change TBARS levels. A diminution in intracellular total GSH was observed by treating with EA isolated hepatocytes from both groups. However, the initial total GSH levels were higher in IP hepatocytes than in control. Immunoblotting analysis showed the presence of GST P in IP animals only. Although alpha and mu class isoenzymes levels were decreased in IP hepatocytes, total GST activity was 1.5-fold higher than in control. In addition, multidrug-resistance protein 2 (Mrp2) showed fivefold decreased levels in IP hepatocytes. In conclusion, increased total GSH, decreased Mrp2 levels and the presence of GST P could be critical factors involved in the resistance of IP hepatocytes to the toxicity of EA.
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Affiliation(s)
- Juan Pablo Parody
- Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Instituto de Fisiología Experimental (IFISE-CONICET), Suipacha 570, 2000 Rosario, Santa Fe, Argentina
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Coleman WB. Mechanisms of Human Hepatocarcinogenesis: An Overview. HANDBOOK OF IMMUNOHISTOCHEMISTRY AND IN SITU HYBRIDIZATION OF HUMAN CARCINOMAS 2005:153-170. [DOI: 10.1016/s1874-5784(05)80019-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Terracciano LM, Tornillo L, Avoledo P, Von Schweinitz D, Kühne T, Bruder E. Fibrolamellar hepatocellular carcinoma occurring 5 years after hepatocellular adenoma in a 14-year-old girl: a case report with comparative genomic hybridization analysis. Arch Pathol Lab Med 2004; 128:222-6. [PMID: 14736278 DOI: 10.5858/2004-128-222-fhcoya] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
An unusual case of fibrolamellar carcinoma of the liver developed 5 years after removal of a hepatocellular adenoma in a 14-year-old girl belonging to a family with Carney syndrome. Both tumors were studied by light and electron microscopy, flow cytometry, and comparative genomic hybridization. The first tumor, removed at the age of 9, was a bulky well-circumscribed liver mass composed of large eosinophilic cells with a focal pseudoglandular pattern but without cytologic atypia or sclerosis. A diagnosis of hepatocellular adenoma was rendered. Five years later, another hepatic tumor was removed from the right lobe. Microscopic examination revealed polygonal cells, each with a large amount of eosinophilic cytoplasm and a round nucleus with a conspicuous nucleolus. These cells were arranged in nests and strands and separated by bands of dense fibrous tissue, leading to a diagnosis of fibrolamellar carcinoma. Comparative genomic hybridization analysis revealed no genetic alteration in the adenoma; however, several chromosomal aberrations (loss of chromosome regions 1p and 4p and gains of chromosome regions 6q, 13q, and Xq) were detected in the fibrolamellar carcinoma. To our knowledge, this is the first report of an association between hepatocellular adenoma and fibrolamellar carcinoma.
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Bannasch P, Haertel T, Su Q. Significance of hepatic preneoplasia in risk identification and early detection of neoplasia. Toxicol Pathol 2003; 31:134-9. [PMID: 12597458 DOI: 10.1080/01926230390173923] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Among the different types of liver tumor, hepatocellular neoplasms predominate by far in both animals and man. Consequently, preneoplastic foci of altered hepatocytes (FAH), preceding both hepatocellular adenomas and carcinomas, represent the most prevalent form of hepatic preneoplasia observed in animals for a long time, and identified in human chronic liver diseases associated with, or predisposing to, hepatocellular carcinomas more recently. Morphological, microbiochemical, and molecular biological approaches in situ revealed striking similarities in specific changes of the cellular phenotype of preneoplastic FAH developing in experimental and human hepatocarcinogenesis, irrespective of whether this was elicited by chemicals, hormones, viruses or radiation. The advantage of using FAH for risk identification (aiming at primary cancer prevention) in long-term and medium-term carcinogenesis bioassays has been well documented, but quantitative morphometric approaches appear to be indispensable for an appropriate evaluation of both bioassays. The detection of phenotypically similar FAH in various animal models and in humans prone to develop or bearing hepatocellular carcinomas favors the extrapolation from data obtained in animals to humans. Moreover, the recently reported frequent finding of FAH in fine-needle biopsies of patients suffering from chronic liver diseases opens new perspectives for secondary prevention of human hepatocellular carcinoma.
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Affiliation(s)
- Peter Bannasch
- Department of Cellular and Molecular Pathology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
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Agaimy A, Kaiser A, Wuensch PH. Severe Cytological Atypia (Large Cell Change) in Focal Nodular Hyperplasia with Numerous Mallory Bodies. A Benign (Adaptive) Change? Pathol Res Pract 2003; 199:509-11. [PMID: 14521270 DOI: 10.1078/0344-0338-00455] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Focal nodular hyperplasia (FNH) is a benign hepatocellular lesion composed of hyperplastic appearing hepatocytes arranged in nodules separated by fibrous septa that usually form a central stellate scar. Rare lesions that show unusual cytological or architectural features were reported as variants of focal nodular hyperplasia. We present the morphological features of a case of FNH with severe cytological atypia (so-called large cell change) in a 73-year-old man. In addition to diffuse cytological atypia, Mallory hyaline bodies were found in almost all lesional cells. This rare variant of FNH should be differentiated from other neoplastic lesions, in particular from the fibrolamellar variant of hepatocellular carcinoma.
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Affiliation(s)
- Abbas Agaimy
- Institute of Pathology, Clinical Center of Nuremberg, Germany
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Ittrich C, Deml E, Oesterle D, Küttler K, Mellert W, Brendler-Schwaab S, Enzmann H, Schladt L, Bannasch P, Haertel T, Mönnikes O, Schwarz M, Kopp-Schneider A. Prevalidation of a rat liver foci bioassay (RLFB) based on results from 1600 rats: a study report. Toxicol Pathol 2003; 31:60-79. [PMID: 12597450 DOI: 10.1080/01926230390173888] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
A rat liver foci bioassay (RLFB) based on an initiation-promotion protocol employing preneoplastic foci of altered hepatocytes (FAH) as an endpoint, was prevalidated in 5 different laboratories. FAH were identified by immunohistochemical demonstration of glutathione-S-transferase (placental form, GSTP) and by staining with hematoxilin/eosin (H&E), and their area fraction was quantified morphometrically. The four model hepatocarcinogens N-nitrosomorpholine, 2-acetylaminofluoren, phenobarbital, and clofibrate were selected according to characteristic differences in their presumed mode of action, and tested in a total of 1,600 male and female rats at 2 different dose levels. The chemicals were found to differ characteristically in their potency and dose-response relationship to induce FAH when given alone or when administered following initiation with diethylnitrosamine. The interlaboratory variation was small for results obtained with the GSTP-stain and somewhat larger with respect to H&E. The assessment of the carcinogenic potential of the four chemicals by the different laboratories was in the same range and the nature of their dose-response relationships did not differ essentially between laboratories. Our results suggest that this RLFB is a sensitive bioassay, providing potentially valuable information for risk assessment including the classification of carcinogenic chemicals according to their mode of action.
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Affiliation(s)
- Carina Ittrich
- Central Unit Biostatistics, German Cancer Research Center (DKFZ), P.O. Box 101949, D-69009 Heidelberg, Germany
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Abstract
Different lesions have been suggested to represent preneoplastic conditions in human liver. They include liver cell dysplasia, separated in large-cell change (LCC) and small-cell change (SCC), adenomatoid hyperplasia, and the more recently identified foci of altered hepatocytes (FAH) and nodules of altered hepatocytes (NAH). FAH have been demonstrated to represent preneoplastic lesions in various animal models of hepatocarcinogenesis. To demonstrate prevalence and significance of FAH in the human liver, the cellular composition, size distribution, and proliferation kinetics of these lesions were studied in 163 explanted and resected human livers with or without hepatocellular carcinoma (HCC). FAH including glycogen-storing foci (GSF), mixed cell foci (MCF), and basophilic cell foci were found in 84 of 111 cirrhotic livers, demonstrating higher incidences in cases with than without HCC. MCF, predominant in cirrhotic livers of the high-risk group, were more proliferative, larger and more often involved in formation of NAH than GSF. The results suggest that the FAH are preneoplastic lesions, MCF being more advanced than GSP. We also investigated the relationship of FAH to liver cell dysplasia. Occurrence of SCC, rather than that of LCC, confers FAH an increased proliferation activity and higher risk to nodular transformation, and, hence, should be considered a precancerous condition. Histological detection of FAH and SCC through needle-aspiration liver biopsy can be used for monitoring HCC development in high-risk populations, such as HBV carriers with chronic hepatitis and/or cirrhosis.
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Affiliation(s)
- Qin Su
- Department of Pathology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
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de Luján Alvarez M, Cerliani JP, Monti J, Carnovale C, Ronco MT, Pisani G, Lugano MC, Carrillo MC. The in vivo apoptotic effect of interferon alfa-2b on rat preneoplastic liver involves Bax protein. Hepatology 2002; 35:824-33. [PMID: 11915028 DOI: 10.1053/jhep.2002.32099] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
To determine whether interferon alfa (IFN-alpha) prevents in vivo oncogenesis in very-early-stage cancer cells, we evaluated the action of IFN-alpha2b over preneoplastic foci in rats. Animals were divided into 6 groups: subjected to a 2-phase model (diethylnitrosamine [DEN] plus 2-acetylaminofluorene [2-AAF]) of preneoplasia development (group 1), treated with IFN-alpha2b during the 2 phases (group 2), only during initiation with DEN (group 3), only during administration of 2-AAF (group 4), subjected only to an initiation stage (group 5), and treated with IFN-alpha2b during this period (group 6). The numbers of placental form of rat glutathione S-transferase (rGST-P)-positive foci per liver and the foci as percentage of liver were significantly reduced in groups 2, 3, and 6 but not in group 4. Rats treated with IFN-alpha2b showed a higher apoptotic index (AI) in altered hepatic foci (AHF). Levels of p53 and Bax protein in liver lysates were significantly increased in those animals. Similarly, levels of antiapoptotic proteins Bcl-2 and Bcl-x(L) in mitochondrial fraction were decreased. Finally, increased levels of Bax protein were localized in the mitochondria of rats that received IFN-alpha2b, at least during the DEN phase (groups 2, 3, and 6), whereas mitochondrial Bax expression was not increased in group 4. In conclusion, the preneoplastic hepatocytes in rats that received IFN-alpha2b during the initiation stage undergo programmed cell death as a primary result of a significant increase in the amount and translocation to the mitochondria of Bax protein.
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Affiliation(s)
- María de Luján Alvarez
- Instituto de Fisiología Experimental (IFISE-CONICET) and Area de Morfología, Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Rosario, Argentina
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Marchio A, Terris B, Meddeb M, Pineau P, Duverger A, Tiollais P, Bernheim A, Dejean A. Chromosomal abnormalities in liver cell dysplasia detected by comparative genomic hybridisation. Mol Pathol 2001; 54:270-4. [PMID: 11477144 PMCID: PMC1187080 DOI: 10.1136/mp.54.4.270] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/27/2001] [Indexed: 11/04/2022]
Abstract
BACKGROUND/AIM The pathogenetic relation between liver cell dysplasia and hepatocellular carcinoma (HCC) is poorly understood. The aim of this study was to determine whether there is a genetic link between liver cell dysplasia and HCC that could support the role of dysplasia as a tumour precursor lesion. METHODS Microdissection from paraffin wax embedded sections and degenerate oligonucleotide primed polymerase chain reaction (DOP-PCR) were combined to analyse chromosomal imbalances by comparative genomic hybridisation (CGH) in nine HCCs and nodules containing liver cell dysplasia and cirrhosis adjacent to the tumours. Seven cases of large cell changes (LCC) and three cases of small cell changes (SCC) were analysed. The genetic abnormalities detected in liver cell dysplasia were then compared with those present in the corresponding HCC. RESULTS No abnormalities were detected in LCC and cirrhotic nodules, arguing against the preneoplasic nature of these cell foci. In contrast, a subset of chromosomal alterations present in HCCs was found in the adjacent SCC. CONCLUSIONS These findings support the preneoplastic status of SCC in human hepatocarcinogenesis.
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Affiliation(s)
- A Marchio
- Unité de Recombinaison et Expression Génétique, INSERM U163, Institut Pasteur, 75724 Paris, France.
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Libbrecht L, Craninx M, Nevens F, Desmet V, Roskams T. Predictive value of liver cell dysplasia for development of hepatocellular carcinoma in patients with non-cirrhotic and cirrhotic chronic viral hepatitis. Histopathology 2001; 39:66-73. [PMID: 11454046 DOI: 10.1046/j.1365-2559.2001.01172.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
AIMS Hepatocellular carcinoma (HCC) frequently develops in patients with chronic viral hepatitis, especially in the cirrhotic stage. We retrospectively studied whether the presence of the putative preneoplastic lesions large liver cell dysplasia (LLCD) and/or small liver cell dysplasia (SLCD) in a needle liver biopsy of these patients are a risk factor for the development of HCC. METHODS AND RESULTS The presence of LLCD and SLCD in the needle liver biopsy taken at the initial work-up of 115 patients with chronic hepatitis B or C was assessed retrospectively. LLCD and SLCD were present in the initial biopsy of, respectively, 35 (30%) and 25 patients (22%). During a mean follow-up of 107 months, 16 patients (14%) developed HCC and this occurred significantly more frequently in patients with cirrhosis, age > or = 55 years, LLCD or SLCD. Cirrhosis and LLCD were independent risk factors for HCC development. CONCLUSIONS Our findings indicate that the presence of LLCD in a needle liver biopsy of patients with viral-induced chronic liver disease is an independent risk factor for the development of HCC. If these results are confirmed, the presence of LLCD can be used to identify a subgroup of patients at high risk for HCC requiring more intensive screening.
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Affiliation(s)
- L Libbrecht
- Department of Pathology, University Hospitals, University of Leuven, Leuven, Belgium.
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Radaeva S, Li Y, Hacker HJ, Burger V, Kopp-Schneider A, Bannasch P. Hepadnaviral hepatocarcinogenesis: in situ visualization of viral antigens, cytoplasmic compartmentation, enzymic patterns, and cellular proliferation in preneoplastic hepatocellular lineages in woodchucks. J Hepatol 2000. [PMID: 11059863 DOI: 10.1016/s0168-8278(00)80010-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIMS Hepadnaviral hepatocarcinogenesis induced in woodchucks with and without dietary aflatoxin B1 has been established as an appropriate animal model for studying the pathogenesis of human hepatocellular carcinoma in high-risk areas. Our aim in this study was the elucidation of phenotypic cellular changes in early stages of this process. METHODS Woodchucks were inoculated as newborns with woodchuck hepatitis virus (WHV), and partly also exposed to aflatoxin B1. Sequential hepatocellular changes in the expression of viral antigens, ultrastructural organization, cellular proliferation and apoptosis were studied in situ by electron microscopy, enzyme and immunohistochemistry. RESULTS A characteristic finding in WHV-infected animals (with and without aflatoxin B1) was proliferative areas of minimal structural deviation, which predominated periportally, comprised glycogen-rich, amphophilic, and ground-glass hepatocytes, and expressed the woodchuck hepatitis core and surface antigens. Two main types of proliferative foci emerged from minimal deviation areas, glycogenotic clear cell foci and amphophilic cell foci (being poor in glycogen but rich in mitochondria), giving rise to the glycogenotic-basophilic and the amphophilic preneoplastic hepatocellular lineages. A gradual loss in the expression of viral antigens appeared in both lineages, particularly early in the glycogenotic-basophilic cell lineage. Whereas glycogenosis was associated with an enzymic pattern suggesting an early activation of the insulin-signaling pathway, amphophilic cells showed changes in enzyme activities mimicking a response of the hepatocytes to thyroid hormone, which may also result from early changes in signal transduction. CONCLUSION Preneoplastic hepatocellular lineages in hepadnaviral and chemical hepatocarcinognesis show striking phenotypic similarities, indicating concordant and possibly synergistic early changes in signaling.
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Affiliation(s)
- S Radaeva
- Division of Cell Pathology, Deutsches Krebsforschungszentrum, Heidelberg, Germany
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Libbrecht L, Desmet V, Van Damme B, Roskams T. The immunohistochemical phenotype of dysplastic foci in human liver: correlation with putative progenitor cells. J Hepatol 2000; 33:76-84. [PMID: 10905589 DOI: 10.1016/s0168-8278(00)80162-2] [Citation(s) in RCA: 113] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIMS In previous studies we found strong evidence for the existence and activation in human liver of putative progenitor cells resembling oval cells in rat liver. In view of the known role of rat oval cells in regeneration and hepatocarcinogenesis, we investigated a possible correlation between human putative progenitor cells and different types of dysplastic foci. METHODS We determined the immunohistochemical phenotype of dysplastic foci found in 20 cirrhotic liver explants of various etiology, using specific antibodies against hepatocyte-type cytokeratin (CK) 8 and CK18, bile duct-type CK7 and CK19, chromogranin-A (chrom-A) and rat oval cell marker OV-6. RESULTS All 12 foci of large cell dysplasia had a phenotype similar to that of surrounding parenchyma. Oncocytic foci showed a strong cytoplasmic staining for CK7. Three out of six of these foci contained "progenitor cells", which are small cells immunoreactive for CK18, CK7, CK19, OV-6, chrom-A and stained more intensely for CK8 than surrounding hepatocytes. Four out of eight glycogen-storing foci contained CK7-positive intermediate hepatocyte-like cells and "progenitor cells". Sixteen out of 29 small cell dysplastic foci consisted of "progenitor cells" and intermediate hepatocyte-like cells which were immunoreactive for CK7, CK18, OV-6, chrom-A and showed a stronger cytoplasmic positivity for CK8 than surrounding hepatocytes. CONCLUSIONS Foci of large cell dysplasia show no correlation with putative progenitor cells. Half of the oncocytic and glycogen-storing foci contain "progenitor cells", while more than half of the foci of small cell dysplasia consist of small cells with the same immunohistochemical phenotype as putative progenitor cells and intermediate hepatocyte-like cells, suggesting that differentiating putative progenitor cells can give rise to foci of small cell dysplasia.
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Affiliation(s)
- L Libbrecht
- Laboratory for Histo- and Cytochemistry, University of Leuven, Belgium.
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Bannasch P, Klimek F, Mayer D. Early bioenergetic changes in hepatocarcinogenesis: preneoplastic phenotypes mimic responses to insulin and thyroid hormone. J Bioenerg Biomembr 1997; 29:303-13. [PMID: 9387091 DOI: 10.1023/a:1022438528634] [Citation(s) in RCA: 48] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Biochemical and molecular biological approaches in situ have provided compelling evidence for early bioenergetic changes in hepatocarcinogenesis. Hepatocellular neoplasms regularly develop from preneoplastic foci of altered hepatocytes, irrespective of whether they are caused by chemicals, radiation, viruses, or transgenic oncogenes. Two striking early metabolic aberrations were discovered: (1) a focal excessive storage of glycogen (glycogenosis) leading via various intermediate stages to neoplasms, the malignant phenotype of which is poor in glycogen but rich in ribosomes (basophilic), and (2) an accumulation of mitochondria in so-called oncocytes and amphophilic cells, giving rise to well-differentiated neoplasms. The metabolic pattern of human and experimentally induced focal hepatic glycogenosis mimics the phenotype of hepatocytes exposed to insulin. The conversion of the highly differentiated glycogenotic hepatocytes to the poorly differentiated cancer cells is usually associated with a reduction in gluconeogenesis, an activation of the pentose phosphate pathway and glycolysis, and an ever increasing cell proliferation. The metabolic pattern of preneoplastic amphophilic cell populations has only been studied to a limited extent. The few available data suggest that thyromimetic effects of peroxisomal proliferators and hepadnaviral infection may be responsible for the emergence of the amphophilic cell lineage of hepatocarcinogenesis. The actions of both insulin and thyroid hormone are mediated by intracellular signal transduction. It is, thus, conceivable that the early changes in energy metabolism during hepatocarcinogenesis are the consequence of alterations in the complex network of signal transduction pathways, which may be caused by genetic as well as epigenetic primary lesions, and elicit adaptive metabolic changes eventually resulting in the malignant neoplastic phenotype.
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Affiliation(s)
- P Bannasch
- Abteilung für Cytopathologie, Deutsches Krebsforschungszentrum, Heidelberg, Germany
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Fritz P, Behrle E, Zanger UM, Mürdter T, Schwarzmann P, Kroemer HK. Immunohistochemical assessment of human microsomal epoxide hydrolase in primary and secondary liver neoplasm: a quantitative approach. Xenobiotica 1996; 26:107-16. [PMID: 8851825 DOI: 10.3109/00498259609046692] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
1. Epoxide hydrolases form an enzyme family involved in the metabolism of a variety of xenobiotics including cytostatic drugs and carcinogens. Whether human microsomal epoxide hydrolase--one of the main members of the epoxide hydrolase family--is expressed in neoplasia of the liver has been the subject of a controversial discussion. 2. We therefore developed a quantitative immunohistochemical assay and monitored epoxide hydrolase expression in hepatocellular carcinomas (HCC, n = 20), cholangio-cellular carcinomas (CCC, n = 2) and liver metastases (n = 57) of tumours of various origins, and compared the expression intensities and patterns to normal liver tissue. 3. In normal liver tissue microsomal epoxide hydrolase displays expression of the constitutive type with non-zonal staining of all hepatocytes. 4. When using a quantitative immunohistochemical approach statistically significant differences in microsomal epoxide hydrolase expression were observed between normal tissue, hepatocellular carcinoma and liver metastases (mean optical density 2.35, 1.63 and 0.21 respectively, p = 2.9, 6.3 and 18.9). These data indicate differential expression in different types of liver neoplasm. 5. As microsomal epoxide hydrolase is involved in metabolism of different xenobiotics our findings may have implications for tumour progression.
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Affiliation(s)
- P Fritz
- Zentrum für Klinische Pathologie, Robert Bosch Krankenhaus, Stuttgart, Germany
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Affiliation(s)
- K Aterman
- Department of Biology, University of New Brunswick, Fredericton, Canada
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