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

Z mutant-associated alpha 1-antitrypsin deficiency in human beings leads to hepatitis and, in some cases, hepatocellular carcinoma. To begin to delineate the molecular basis for the development of hepatocellular carcinoma in alpha 1-antitrypsin deficiency, we previously developed transgenic mice using human alpha 1-antitrypsin M and Z genomic clones. High-copy Z lineage mice (12 gene copies/haploid mouse genome; "Z#2") had hepatocytes distended with human alpha 1-antitrypsin deficiency globules. Hepatitis was present, and the morphological changes mimicked those observed in human alpha 1-antitrypsin deficiency-related liver disease. The numbers of hepatocytes containing alpha 1-antitrypsin globules decreased with age, and alpha 1-antitrypsin-negative nodular aggregates of hepatocytes increased in number and size. Hepatocytic dysplasia occurred as early as 6 wk and was almost universally present at 1 yr. Nodules of dysplastic cells demonstrating aneuploidy were seen as early as 10 wks. These became persistent, proliferative lesions. Dysplasia and aneuploidy distinctly increased with time and advancing microscopic stage as lesions progressed to malignancy. Tumors were seen after 1 yr as adenomas, which are aneuploid and most likely well-differentiated hepatocellular carcinoma, and borderline malignant lesions; and, in 82% of Z#2 mice 16 to 20 mo old, as invasive hepatocellular carcinoma. These observations suggest but do not conclusively prove that hepatocellular carcinoma in alpha 1-antitrypsin deficiency and other hepatic disorders arises as a result of a common, endogenously stimulated pathway for hepatocellular carcinogenesis.
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PMID:Hepatocarcinogenesis is the sequel to hepatitis in Z#2 alpha 1-antitrypsin transgenic mice: histopathological and DNA ploidy studies. 829 11

The present study describes morphometric analysis of nodular changes examined by using fine-needle aspiration biopsy guided ultrasonographically. A group of 49 patients with suspected neoplastic changes of the liver was studied including 4 hepatocellular carcinomas, 21 neoplasms metastasizing to the liver, 23 non-neoplastic changes. The whole material was divided into three major groups: A with neoplastic cells, B with non-neoplastic cells and C with suspected cells. In each case 100 cells were measured, and in each cell the surface area, maximal diameter and coefficient of shape of the cytoplasm, nucleus and nucleolus were measured. It was found that neoplastic cells have larger nuclei and nucleoli; the ratio of nucleus to cytoplasm was shifted in favour of the nucleus. The largest nucleoli are typical for hepatocellular carcinoma. Most rounded are cells of adenocarcinomas metastasizing to the liver. Morphometric measurements automatically isolate large liver cell dysplasia. The present study provides morphometric parameters of the hepatocytes in the cytological material, which may be the basis for further studies.
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PMID:Cytomorphometry of fine-needle aspiration biopsy material from the liver tumours. 830 31

To study the relationship between nodular regenerative hyperplasia of the liver (NRH) and hepatocellular carcinoma (HCC), we surveyed NRH in 11 autopsied noncirrhotic or nonfibrotic livers with HCC. NRH was found in one case, and focal nodular hyperplasia of hepatocytes (focal NRH-like changes) was noted in another four cases. Of particular interest was that these nodular hyperplastic areas did not show hepatocellular atypia such as liver cell dysplasia, nuclear atypia, pseudoglandular formation, and the loss or reduction of reticulin fibers. The one case of NRH and four cases of focal NRH-like changes had histories of transcatheter arterial embolization therapy or hepatic arterial infusion chemotherapy in which antineoplastic agents were directly infused into the feeding arteries of HCC. This treatment may produce intrahepatic microvascular damage, now accepted to be a potential cause of NRH. The results of this study suggested that in Japan NRH is a relatively rare underlying condition leading to HCC, and that the NRH or focal NRH-like changes in our cases might have developed secondarily to therapy for HCC administered via the hepatic vasculature.
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PMID:Nodular regenerative hyperplasia of the liver in hepatocellular carcinoma. An autopsy study. 838 67

To test the hypothesis that increased proliferative capacity of cells in a liver remnant is a risk factor for tumor recurrence in patients who have undergone liver resection for hepatocellular carcinoma, DNA flow-cytometric measurement and cell-cycle analysis of the nontumor parts of resected hepatocellular carcinomas (tumor size < 5 cm) were performed. The disease-free survival rates 1, 2, 3 and 4 yr after surgery were 64%, 58%, 43%, and 36%, respectively. Proliferative capacity (fractions of synthetic, postsynthetic and mitotic phases) of the nontumor parts, irrespective of liver pathology, was higher than that of normal liver and statistically lower than that of tumor parts from resected hepatocellular carcinoma specimens. Livers with chronic active hepatitis (+) and with hepatocyte dysplasia (-) had significantly lower proliferative activity than did those with chronic active hepatitis (-) and with hepatocyte dysplasia (+), respectively [corrected]. We saw no significant difference in proliferative capacity between patients with and without cirrhosis. Disease-free-survival analysis showed that the presence of liver pathology (hepatitis B infection, cirrhosis, chronic active hepatitis and hepatocyte dysplasia) was not the factor linked to tumor recurrence in the liver remnant and that a marked increase in proliferative capacity (> or = 18%), regardless of liver pathology, was the risk factor linked to tumor recurrence after liver resection. We conclude that there is some degree of increased proliferative capacity in the nontumor parts of resected hepatocellular carcinomas and that a marked increase in the proliferative capacity (> or = 18%) of the nontumor part is a significant risk factor in predicting tumor recurrence in the liver remnant after liver resection.
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PMID:Can determination of the proliferative capacity of the nontumor portion predict the risk of tumor recurrence in the liver remnant after resection of human hepatocellular carcinoma? 839 30

Ten cirrhotic patients with ultrasonically discernible focal liver masses underwent fine cutting needle biopsy. Specimens were obtained from the focal lesions under ultrasound guidance and histologically diagnosed as regenerative nodules. An image analyzer was then used to determine the cytoplasmic area, nuclear area, and nuclear/cytoplasmic ratio for 100 randomly selected cells from each specimen. Data were then compared with data for specimens of normal liver tissue and data from patients with alcoholic or posthepatic cirrhosis or well-differentiated hepatocellular carcinoma (HCC). The morphometric parameters for the group of regenerative nodule specimens fell within an intermediate range between those for HCC and the nondysplastic samples, strongly suggesting a preneoplastic nature. Nine of the 10 regenerative lesions showed liver cell dysplasia, and 3 of these patients developed HCC during follow-up. Ultrasonically discernible focal masses in a cirrhotic liver should be considered preneoplastic, if not neoplastic lesions and treated aggressively to prevent their progression to outright malignancy.
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PMID:Focal ultrasound lesions in cirrhotic liver diagnosed as regenerative nodules by biopsy. A morphometric analysis. 840 2

The prognosis of patients with hepatocellular carcinoma is dismal. Long-term survival and cure of patients with hepatocellular carcinoma (HCC) can be expected only after resection or hepatectomy followed by transplantation. Thus, prognosis primarily depends on the possibility of resective surgery, which is determined predominantly by anatomic extent of disease. This survey deals with factors that become effective after resection or transplantation and that have prognostic significance in univariate or multivariate analyses. Several studies have shown that resection for cure (R classification) and anatomical extent of the tumors (TNM) were the most important prognostic factors. Prognostic factors other than TNM and R can be grouped into clinical findings and pathological features. As to clinical findings, performance status is an important prognostic factor in one multivariate analysis. The effects of other factors as age, sex, tumor site, and hepatomegaly on prognosis were discussed controversially. As might be expected, studies on pathological factors yielded different results. Histological grade had an influence in one study, but not in another. Histological type and coexisting cirrhosis were important in multivariate analysis only in resected patients. The majority of factors (capsule formation, dysplasia of adjacent liver tissue, mitotic activity, bile production) were only investigated in univariate analyses. There are only few studies evaluating the prognostic importance of molecular pathology factors. None of them has shown convincing evidence that these parameters may give information more important than TNM and R classification. The prognostic importance of TNM for patients not treated by resective surgery is emphasized in many studies. Ascites, toxic syndrome, and laboratory variables as bilirubin, blood urea nitrogen, and serum albumin were independent predictors of survival. The prognosis of patients with cholangiocarcinoma is even worse than that of HCC-patients and only 25% patients resected with stage-II-tumors can be expected to survive for five years.
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PMID:[Prognostic factors in liver tumors]. 860 Jun 73

On the basis of the successful establishment of an animal model in tree shrews experimentally infected with human hepatitis B virus (HBV), a study on the hepatocarcinogenic effects of HBV and/or aflatoxin B1 (AFB1) was conducted. The results showed that the incidence of hepatocellular carcinoma (HCC) was significantly higher in the animals both infected with HBV and exposed to AFB1 (52.94%) than in those solely infected with HBV (11.11%) or exposed to AFB1 (12.50%). No HCC of precancerous lesions were found in the controls that were neither HBV-infected nor AFB-1 exposed. Precancerous lesions, including liver cell dysplasia and enzyme-altered hyperplastic hepatocyte foci, were observed before the occurrence of HCC, and the frequency of their appearance correlated well with the incidence of HCC. HBV DNA and the protein it encodes were detected in the cancer cells and/or the surrounding hepatocytes. Integration of HBV DNA into the host liver genome was found during hepatocarcinogenesis among the animals infected by HBV. These results suggest that exposure to HBV and AFB1 may play a synergistic role in the development of HCC, and support the viewpoint of an aetiological relationship between HBV and HCC.
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PMID:Human hepatitis B virus and hepatocellular carcinoma. II. Experimental induction of hepatocellular carcinoma in tree shrews exposed to hepatitis B virus and aflatoxin B1. 860 52

The cooperation of the c-myc oncogene with the growth factor transforming growth factor (TGF)-alpha in development of liver tumors in transgenic mice has been demonstrated previously. In this study, we analyzed the ploidy and karyotype of c-myc, TGF-alpha, parental control, and the double transgenic c-myc/TGF-alpha hepatocytes at 3 weeks of age when the liver is histologically normal and at 10 weeks when the c-myc/TGF-alpha liver is dysplastic and contains basophilic foci. Eighty % of the 10-week hepatocytes were aneuploid, and 32% had chromosomal breakage. Statistically significant breakage was observed in six different chromosomes. Breakage at band A5 and at the border of bands C4/5 of chromosome 1 was observed. Fragile sets on chromosome 4 were most frequent in the middle of the chromosome at bands C2 and C6. Chromosome 6 was fragile at band F2. The region of chromosome 7 at bands B5 and D3 was frequently broken and involved in translocations. Chromosome 12 was broken at bands D1 and D3. The breakage sites on chromosomes 1, 4, 7, and 12 correspond to sites of tumor susceptibility genes in the mouse. Although there was no consistent change in copy number, recurrent translocations between chromosomes 1, 4, 7, 12 and 19 were also observed. These studies demonstrate that the development of dysplasia and basophilic foci in the liver is correlated with aneuploidy and chromosome breakage. The specific fragile sites indicate genetic regions that are altered during early stages of hepatocarcinogenesis. Due to the conservation of genetic linkage groups between mice and humans, the identification of genetic alterations in the mouse during hepatocarcinogenesis may provide critical information about tumor susceptibility genes that are important in the early development of human hepatocellular carcinoma.
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PMID:Ploidy and karyotypic alterations associated with early events in the development of hepatocarcinogenesis in transgenic mice harboring c-myc and transforming growth factor alpha transgenes. 861 62

The aim of this study was to identify high-risk patients for hepatocellular carcinoma (HCC). Among 151 patients with histologically proven cirrhosis hospitalized from 1987 to 1990 and prospectively followed-up until June 1994, 31 developed HCC. We assessed the predictive value of 22 variables recorded at enrollment for HCC occurrence by the log rank test and the Cox proportional hazards model. Six clinical and biological variables summarized predictive information of HCC: age > or = 50 years (P = .01), male (P = .01), large esophageal varices (EV) (P = .03), prothrombin activity < 70% (P = .04), serum alpha-fetoprotein (AFP) > or = 15 ng/L (P = .06), and anti-hepatitis C virus antibodies (P = .08). A clinicobiological predictive score identified two groups of patients at low (n = 67; 3-year cumulative incidence, 0%) and high risk for HCC (n = 84; 3-year cumulative incidence, 24%). The predictive value of this score was confirmed using an independent population of 49 patients with cirrhosis. Furthermore, liver large-cell dysplasia (LCD) had an additional predictive value in high-risk patients (P = 10(-4), which thus helped to define a subgroup at very high risk for HCC (n = 12; 3-year cumulative incidence, 72%). In Western patients with cirrhosis, a limited number of usual variables can identify a group of patients at high risk for HCC. Among these patients, liver biopsy allows for the determination a subgroup of patients at very high risk for HCC requiring intensive screening or preventive measures.
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PMID:Predictive score for the development of hepatocellular carcinoma and additional value of liver large cell dysplasia in Western patients with cirrhosis. 862 Nov 42

We have previously shown that co-expression of c-myc and transforming growth factor (TGF)-alpha as transgenes in mouse liver results in major enhancement of neoplastic development in this organ as compared with expression of either of these transgenes alone. In this report we describe in detail the progression from liver cell dysplasia to hepatocellular carcinomas (HCCs) occurring in the liver of c-myc/TGF-alpha and c-myc transgenic mice. Despite morphological similarities in the sequence of events between the two transgenic lines, the dramatic acceleration, extent, and severity of hepatic lesions in c-myc/TGF-alpha mice clearly demonstrated the synergistic effects of this transgenic combination. Although c-myc/TGF-alpha and c-myc females displayed longer latency and lower tumor incidence, the pathological changes were the same as those seen in the male mice, including the formation of HCCs, which are absent in TGF-alpha single-transgenic females. Tumors in single- and double-transgenic mice showed induction of the endogenous c-myc and TGF-alpha and, most frequently, unchanged or decreased epidermal growth factor receptor, further indicating the collaborative role of c-myc and TGF-alpha in providing a selective growth advantage to tumor cells independently of the epidermal growth factor receptor levels. To identify possible tumor precursors, we focused particularly on the dysplastic changes preceding and accompanying the appearance of preneoplastic and neoplastic lesions in the double-transgenic mice. Early on, these changes were characterized by the appearance of large dysplastic hepatocytes, mostly pericentrally, expressing high levels of TGF-alpha and uPA, as well as TGF-beta 1, particularly in apoptotic cells. After a short period of replication and expansion into the liver parenchyma, as well as penetration into the central veins, these cells underwent apoptotic cell death while preneoplastic and neoplastic lesions were forming. The peritumorous tissues also contained small dysplastic hepatocytes and oval-like cells, similar to those found in the tumors. Transplantation of the transgenic liver tissues harboring only dysplasia with or without vascular lesions onto nude mice was able to yield HCCs composed of small diploid cells, suggesting that initiated cells are generated during the early dysplastic phase and can progress to HCC. It is therefore likely that large dysplastic hepatocytes undergo apoptosis, which may be closely associated with the up-regulation of TGF-beta 1 and uPA, whereas other cells evolve into the precursor population for HCC. Due to the simultaneous presence of c-myc, TGF-alpha, and dysplasia in premalignant human liver diseases, our transgenic mouse system appears to be an appropriate model for studying human hepatocarcinogenesis.
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PMID:Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-alpha. 870 81


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