Primary carcinoma of the liver.A study of 100 cases among 48,900 necropsies

Edmondson, Hugh A.; Steiner, Paul E.

doi:10.1002/1097-0142(195405)7:3<462::aid-cncr2820070308>3.0.co;2-e

Cited by 2,599 publications

(1,298 citation statements)

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“…All the specimens were collected after liver resection or autopsy. Cancer grade was determined by histology according to Edmondson criteria (Edmondson and Steiner, 1954). We designated the Edmondson grade I-II as (Table 1).…”

Section: Tumor Specimensmentioning

confidence: 99%

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

et al. 2007

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Transforming growth factor-b (TGF-b) signaling members, TGF-b receptor type II (TBRII), Smad2, Smad4 and Smad adaptor, embryonic liver fodrin (ELF), are prominent tumor suppressors in gastrointestinal cancers. Here, we show that 40% of elf þ /À mice spontaneously develop hepatocellular cancer (HCC) with markedly increased cyclin D1, cyclin-dependent kinase 4 (Cdk4), c-Myc and MDM2 expression. Reduced ELF but not TBRII, or Smad4 was observed in 8 of 9 human HCCs (Po0.017). ELF and TBRII are also markedly decreased in human HCC cell lines SNU-398 and SNU-475. Restoration of ELF and TBRII in SNU-398 cells markedly decreases cyclin D1 as well as hyperphosphorylated-retinoblastoma (hyperphosphorylated-pRb). Thus, we show that TGF-b signaling and Smad adaptor ELF suppress human hepatocarcinogenesis, potentially through cyclin D1 deregulation. Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs.

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Section: Tumor Specimensmentioning

confidence: 99%

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

et al. 2007

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“…However, even for the experienced pathologist, in some cases, determining the correct diagnosis may be extremely difficult and uncertain, particularly if only small biopsies are available as the main source for histological examination. In particular, differentiation between well-differentiated hepatocellular carcinoma (HCC) and benign alterations may be impossible based on morphologic criteria alone (1).…”

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confidence: 99%

Detection of Chromosomal Aberrations in Well-Differentiated Hepatocellular Carcinoma by Bright-Field In Situ Hybridization

et al. 2002

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Differentiation between well-differentiated hepatocellular carcinoma (HCC) and nonmalignant lesions with increased cellular proliferation may be difficult in needle biopsies. Based on recurrent chromosome aberrations known for HCC, we developed a nonfluorescent in situ hybridization technique that allows combination with morphological analysis in bright-field microscopy. Fourteen biopsies of HCC and 31 samples of regenerative nodules (n ‫؍‬ 10), chronic hepatitis (n ‫؍‬ 10), fibrosis or cirrhosis of unknown origin (n ‫؍‬ 5), focal nodular hyperplasia (n ‫؍‬ 2), primary biliary cirrhosis (n ‫؍‬ 2), steatosis (n ‫؍‬ 1), and adenomatous hyperplasia (n ‫؍‬ 1) were analyzed with probes specific for the centromeric regions of chromosomes 1, 6, 7, and 8. After microwave pretreatment and in situ hybridization, signals were detected using a tyraminebased system and AEC as substrate. Evaluation of signals was done by conventional bright-field microscopy. Using this approach, aberrant counts were seen for at least one chromosome in 12/14 cases of HCC. In contrast, none of the nonmalignant lesions revealed aberrant counts for any of the chromosomes analyzed. In conclusion, this new combination of in situ hybridization and tyramine amplification allows fast and reliable evaluation of chromosome aberrations in a histomorphological context similar to paraffin immunohistochemistry. Registration of imbalances contributes to a reliable differentiation between malignant and nonmalignant lesions of the liver. The fast and reliable differentiation between malignant and nonmalignant tumorlike lesions of the liver is of the utmost importance for the further treatment and surgical procedure of the patients. However, even for the experienced pathologist, in some cases, determining the correct diagnosis may be extremely difficult and uncertain, particularly if only small biopsies are available as the main source for histological examination. In particular, differentiation between well-differentiated hepatocellular carcinoma (HCC) and benign alterations may be impossible based on morphologic criteria alone (1). Detection of chromosomal aberrations within questionable tumors could contribute toward solving this problem. Because of the time and effort required for conventional cytogenetics, this technique is usually not appropriate. The recently developed comparative genomic hybridization (CGH) has revealed promising results (2,4,11,13,14), but it is also of limited value because of the duration and amount of tissue required. By contrast, fluorescence in situ hybridization (FISH) yields results that are evaluable by simple counting of fluorescence signals in conventional biopsies (12). A major limitation of this approach is, however, that most pathologists are not familiar with the morphology of the tumor in histological sections counterstained with fluorescent dyes. Furthermore, many histomorphological details remain undetected in the dark field required for evaluation. In addition, epifluorescence microscopy is based on expensive technica...

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“…Tumors were classified into three grades: well-, moderately, or poorly differentiated according to the grading system of The Liver Cancer Study Group of Japan. 51 According to the criteria of Edmondson and Steiner, 52 Western blots of partially purified AX-I using a monoclonal antibody as the probe. Twenty micrograms of the partially purified AX-I fraction of tumorous (T) and nontumorous (N) regions of HCC tissues, chronic hepatitis liver, and NL was subjected to SDS-PAGE and analyzed as described in Materials and Methods.…”

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confidence: 99%

Enhanced Expression of the Protein Kinase Substrate Annexin I in Human Hepatocellular Carcinoma

et al. 1996

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and chromobindins. 15 AXs were first described as glucocortiAnnexin (AX) constitutes a new family of Ca 2/ -depencoid-inducible inhibitory proteins of phospholipase A 2 . 13,14 dent membrane-binding proteins; 13 of them have been These proteins possess four or eight conserved 70 amino acid described. Among these, annexin-I (AX-I) has displayed repeats, which comprise the core domain, where Ca 2/ -and many biological functions in vitro. Its actual role in vivo, phospholipid-binding functions are located. Annexins have however, remains unknown. We already reported that unique N-terminal tails that vary in length and sequence. 3,15 AX-I was expressed in proliferating (regenerating) hepaSubsequent studies have shown that AX-I (molecular weight, tocytes at both protein and messenger RNA (mRNA) lev-35 kd) is identical to the Ca 2/ -dependent phospholipid-and els. The role of AX-I in human hepatocellular carcinoma actin-binding protein. 2,16,17 In particular, AX-I is the major (HCC) remains obscure. In this study, the amounts of substrate for epidermal growth factor receptor (EGFR) ki-AX-I at protein and mRNA levels, as well as its localizanase, [17][18][19][20][21][22][23] and also for serine/threonine kinases such as protion, have been determined in the normal human liver, tein kinase C. 24 Various AXs have been implicated in cellular chronic hepatitis liver, and nontumorous and tumorous processes, including modulation of phospholipase A 2 activity portions of HCC. AX-I was rarely found in normal and and inflammation, 13,14,25 exocytosis, 26-28 differentiation, 29,30 chronic liver tissues, whereas it is overexpressed at both proliferation, 31-33 blood coagulation, 34 immune response, 35 the transcriptional and translational levels in tumorous membrane-cytoskeletal linkage, 36 and intracellular signal and nontumorous regions of HCC. In addition, more AXtransduction. 37,38 Although the conservation of AXs during I was expressed in the tumorous portion than the nontuevolution argues strongly for their important physiological morous portion of HCC. AX-I was present in the hepatoroles, this notion remains confusing and controversial. cytes and HCC cells, localized mainly in the cytoplasm.The in vivo phosphorylation of AX-I is induced by stimula-AX-I was overexpressed in poorly differentiated cancer tion with EGFR, and it profoundly affects its Ca 2/ requirecells. Furthermore, AX-I was tyrosine-phosphorylated in ment for phospholipid binding. [18][19][20][21]23 Although these results HCC. We also found that some of the AX-I-positive hepaare consistent with the roles of AX-I in cell transformation tocytes in the nontumorous tissues were derived from a and stimulation of cell growth, 32 such roles have yet to be particular subset of parenchymal cells (stem or oval delineated. We earlier showed that AX-I levels increase in cells). These results indicate that AX-I plays an improliferative (or regenerative) hepatocytes, suggesting that portant role in the malignant transformation process it plays a specific role in this event....

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Primary carcinoma of the liver.A study of 100 cases among 48,900 necropsies

Cited by 2,599 publications

References 58 publications

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

Detection of Chromosomal Aberrations in Well-Differentiated Hepatocellular Carcinoma by Bright-Field In Situ Hybridization

Enhanced Expression of the Protein Kinase Substrate Annexin I in Human Hepatocellular Carcinoma

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