OBJECTIVETo investigate the aberrant methylation of fragile histidine triad (FHIT) gene and to explore possible relationship between the aberrant methylation of FHIT and clinicopathological features in hepatocellular carcinoma (HCC).

METHODSThe hypermethylation of FHIT was detected by the methylation specific PCR (MSP) method in 45 patients with HCC (tumoral and nontumoral tissue), 14 cases of normal livers and 4 HCC cell lines (SK-Hep-1, Hep-G2, Hep-3B and Huh7). The correlation of FHIT methylation and clinicopathological features was analyzed.

RESULTSThe frequencies of hypermethylation of FHIT in tumoral and nontumoral tissue, normal liver and cell lines were 71.1%, 64.4%, 14.3% and 75.0%, respectively. A significant relation between hypermethylation of FHIT and poor survival was present (P = 0.0430).

CONCLUSIONSHypermethylation of FHIT is a frequent and early event in HCC, it might relate to a poor prognosis for patients with HCC.

Acid Anhydride Hydrolases ; genetics ; Adult ; Carcinoma, Hepatocellular ; genetics ; pathology ; surgery ; DNA Methylation ; Female ; Humans ; Liver Neoplasms ; genetics ; pathology ; surgery ; Male ; Middle Aged ; Neoplasm Proteins ; genetics ; Prognosis

OBJECTIVEThe postoperative presence of alpha-fetoprotien (AFP) mRNA in the peripheral blood of patient with hepatic cellular carcinoma (HCC) may suggest that carcinomatous cells still exist in the peripheral blood which may someday develop into metastasis. Therefore, the expression of AFP mRNA in postoperative peripheral blood is detected and its correlation with recurrence of HCC is investingated.

METHODSAFP mRNA in peripheral blood of HCC patients and non-hepatic cellular carcinoma patients treated by partial hepatectomy on the first, 7th, 14th postoperative day was examined by means of RT-PCR/ Southern blot. All HCC patients were followed up for 36 months.

RESULTSOf the 29 HCC patients, 18 (62.1%) had recurrence, and 17 (58.6%) was found to have AFP mRNA expression in peripheral blood during postoperative period. Fourteen of these 17 patients (82.4%) with positive AFP mRNA expression developed recurrence, but only 4 patients (33.3%) with negative AFP mRNA expression had recurrence. The difference between two groups was statistically significant (P < 0.05).

CONCLUSIONOur preliminary results suggest that detection of AFP mRNA during postoperative period may be helpful in predicting recurrence for hepatic cellular carcinoma.

Carcinoma, Hepatocellular ; genetics ; pathology ; surgery ; Female ; Follow-Up Studies ; Hepatectomy ; Humans ; Liver Neoplasms ; genetics ; pathology ; surgery ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; Postoperative Period ; Prognosis ; RNA, Messenger ; blood ; genetics ; Reverse Transcriptase Polymerase Chain Reaction ; alpha-Fetoproteins ; genetics

Owing to the progress of imaging techniques, benign hepatocellular nodules are increasingly discovered in the clinical practice. This group of lesions mostly arises in the context of a putatively normal healthy liver and includes either pseudotumoral and tumoral nodules. Focal nodular hyperplasia and hepatocellular adenoma are prototypical examples of these two categories of nodules. In this review we aim to report the main pathological criteria of differential diagnosis between focal nodular hyperplasia and hepatocellular adenoma, which mainly rests upon morphological and phenotypical features. We also emphasize that for a correct diagnosis the clinical context such as sex, age, assumption of oral contraceptives, associated metabolic or vascular disturbances is of paramount importance. While focal nodular hyperplasia is a single entity epidemiologically more frequent than adenoma, the latter is representative of a more heterogeneous group which has been recently and extensively characterized from a clinical, morphological, phenotypical and molecular profile. The use of the liver biopsy in addition to imaging and the clinical context are important diagnostic tools of these lesions. In this review we will survey their systematic pathobiology and propose a diagnostic algorithm helpful to increase the diagnostic accuracy of not dedicated liver pathologists. The differential diagnosis between so-called typical and atypical adenoma and well differentiated hepatocellular carcinoma will also be discussed.
Adenoma/*diagnosis/surgery ; Carcinoma, Hepatocellular/diagnosis ; Diagnosis, Differential ; Focal Nodular Hyperplasia/*diagnosis/surgery ; Hepatocyte Nuclear Factor 1-alpha/metabolism ; Humans ; Liver/pathology ; Liver Neoplasms/*diagnosis/surgery ; beta Catenin/genetics/metabolism

Owing to the progress of imaging techniques, benign hepatocellular nodules are increasingly discovered in the clinical practice. This group of lesions mostly arises in the context of a putatively normal healthy liver and includes either pseudotumoral and tumoral nodules. Focal nodular hyperplasia and hepatocellular adenoma are prototypical examples of these two categories of nodules. In this review we aim to report the main pathological criteria of differential diagnosis between focal nodular hyperplasia and hepatocellular adenoma, which mainly rests upon morphological and phenotypical features. We also emphasize that for a correct diagnosis the clinical context such as sex, age, assumption of oral contraceptives, associated metabolic or vascular disturbances is of paramount importance. While focal nodular hyperplasia is a single entity epidemiologically more frequent than adenoma, the latter is representative of a more heterogeneous group which has been recently and extensively characterized from a clinical, morphological, phenotypical and molecular profile. The use of the liver biopsy in addition to imaging and the clinical context are important diagnostic tools of these lesions. In this review we will survey their systematic pathobiology and propose a diagnostic algorithm helpful to increase the diagnostic accuracy of not dedicated liver pathologists. The differential diagnosis between so-called typical and atypical adenoma and well differentiated hepatocellular carcinoma will also be discussed.
Adenoma/*diagnosis/surgery ; Carcinoma, Hepatocellular/diagnosis ; Diagnosis, Differential ; Focal Nodular Hyperplasia/*diagnosis/surgery ; Hepatocyte Nuclear Factor 1-alpha/metabolism ; Humans ; Liver/pathology ; Liver Neoplasms/*diagnosis/surgery ; beta Catenin/genetics/metabolism

Gene expression is suppressed by DNA methylation. The goal of this study was to identify genes whose CpG site methylation and mRNA expression are associated with recurrence after surgical resection for hepatocellular carcinoma (HCC). Sixty-two HCCs were examined by both whole genome DNA methylation and transcriptome analysis. The Cox model was used to select genes associated with recurrence. A validation was performed in an independent cohort of 66 HCC patients. Among fifty-nine common genes, increased CpG site methylation and decreased mRNA expression were associated with recurrence for 12 genes (Group A), whereas decreased CpG site methylation and increased mRNA expression were associated with recurrence for 25 genes (Group B). The remaining 22 genes were defined as Group C. Complement factor H (CFH) and myosin VIIA and Rab interacting protein (MYRIP) in Group A; proline/serine-rich coiled-coil 1 (PSRC1), meiotic recombination 11 homolog A (MRE11A), and myosin IE (MYO1E) in Group B; and autophagy-related protein LC3 A (MAP1LC3A), and NADH dehydrogenase 1 alpha subcomplex assembly factor 1 (NDUFAF1) in Group C were validated. In conclusion, potential tumor suppressor (CFH, MYRIP) and oncogenes (PSRC1, MRE11A, MYO1E) in HCC are reported. The regulation of individual genes by methylation in hepatocarcinogenesis needs to be validated.
Adult ; Aged ; Carcinoma, Hepatocellular/*genetics/pathology/surgery ; CpG Islands ; *DNA Methylation ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Liver/pathology ; Liver Neoplasms/*genetics/pathology/surgery ; Male ; Middle Aged ; Neoplasm Recurrence, Local/*genetics ; Oligonucleotide Array Sequence Analysis ; Proportional Hazards Models ; RNA, Messenger/biosynthesis ; Transcriptome/genetics

OBJECTIVETo investigate diagnostic values of the detection of TMPRSS2-ERG gene fusion in metastatic prostate cancer.

METHODSA total of 32 fine needle aspiration (FNA) specimens of metastatic prostate carcinomas were retrieved from the pathology files at MD Anderson Cancer Center. The metastatic sites included the pelvic and remote lymph nodes, liver, bone, and thyroid gland. Immunohistochemical staining for PSA, PAP, synaptophysin, chromogranin A was performed. TMPRSS2-ERG gene fusion was evaluated on sections of cell blocks by fluorescence in situ hybridization (FISH) using ERG gene break-apart probes.

RESULTSThe mean age of the patients was 67 years. Twenty-six patients had a previous history of prostatic adenocarcinoma, while 6 patients presented initially with metastasis. In 11 patients, the metastatic lesions showed characteristic features of small cell carcinoma (SCC) and were positive for synaptophysin (9/9), chromogranin A (7/8), but negative for prostatic specific antigen (7/7). FISH analysis demonstrated a rearrangement of ERG gene in 10 of 32 cases (31.3%), and the rearrangement was associated with deletion of the 5' ERG gene in 6 cases. In addition, the copy number of ERG rearrangement gene locus was increased in 8 cases. Among the 11 cases with SCC features, a rearrangement of ERG gene was present in 5 cases, of which a deletion of the 5' ERG gene and increased copy number were seen in 3 cases.

CONCLUSIONSTMPRSS2-ERG gene fusion can be evaluated in FNA specimens of metastatic prostate cancer. Metastatic prostate cancers have a high prevalence of TMPRSS2-ERG gene fusion along with a frequent copy number increase of ERG gene. TMPRSS2-ERG gene fusion persists in metastatic prostate cancers and even in those with poorly differentiated SCC features. Therefore, an identification of the TMPRSS2-ERG gene fusion may be used to establish the prostatic origin of metastasis.

Acid Phosphatase ; Adenocarcinoma ; genetics ; metabolism ; pathology ; secondary ; surgery ; Aged ; Aged, 80 and over ; Biopsy, Fine-Needle ; Carcinoma, Small Cell ; genetics ; metabolism ; pathology ; secondary ; surgery ; Chromogranin A ; metabolism ; Follow-Up Studies ; Gene Fusion ; Gene Rearrangement ; Humans ; In Situ Hybridization, Fluorescence ; Liver Neoplasms ; genetics ; metabolism ; pathology ; secondary ; surgery ; Lymphatic Metastasis ; Male ; Middle Aged ; Oncogene Proteins, Fusion ; genetics ; metabolism ; Prostate-Specific Antigen ; metabolism ; Prostatic Neoplasms ; genetics ; metabolism ; pathology ; surgery ; Protein Tyrosine Phosphatases ; metabolism ; Synaptophysin ; metabolism

BACKGROUND/AIMS: We aimed to determine the association between the co-expression patterns of Notch1, Snail, and p53 proteins (NSP) and the postoperative prognosis of hepatocellular carcinoma (HCC). METHODS: The immunoblot data for molecular expression (147 HCC/corresponding non-HCC tissues and 15 dysplastic nodules) and the sequencing data for p53 mutations (110 HCCs) were obtained from our previous study. Data analyses were restricted to cases with HCC differentiation grade III (n=47), due to its high p53 mutation rate. RESULTS: Nineteen of the 47 patients (40.4%) -comprising 12 in the liver and 7 in distant organs-had relapsed at 1-2 years after surgery. There was no relationship between p53 mutation and postoperative recurrence in the grade III HCCs. Seven (87.5%) of the eight relapsed cases with Notch1, Snail, and p53 (wild) co-expression experienced recurrence only within the liver, and all tumors were smaller than 5 cm in diameter. Extrahepatic relapse occurred mostly in HCC patients with tumors larger than 5 cm in diameter, without any deviation in the NSP pattern. CONCLUSIONS: The results of this preliminary study suggest that the co-expression of Notch1, Snail, and p53 (wild) is not inferior to the patterns with p53 mutation as an indicator of postoperative recurrence of grade III HCC.
Adult ; Aged ; Carcinoma, Hepatocellular/*metabolism/pathology/surgery ; Female ; Humans ; Liver Neoplasms/*metabolism/pathology/surgery ; Male ; Middle Aged ; Mutation ; Neoplasm Staging ; Postoperative Period ; Prognosis ; Receptor, Notch1/*metabolism ; Recurrence ; Transcription Factors/*metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism

OBJECTIVETo study the relationship between peripheral blood hepatocellular carcinoma cells-associated AFP mRNA and tumor relapse and metastasis.

METHODSTo detect several blood samples from the HCC patients by nested RT-PCR to find out AFP mRNA after 24 h, 72 h and one week and 4 weeks after surgery, and followed up the HCC patients for 1, 2, 3 years.

RESULTSThere were 7 patients occurred relapse or distant metastasis in 12 patients with AFP mRNA positive (7/12, 58.3%), there were 5 patients occurred relapse in 19 patients with AFP mRNA negative (5/19, 26.3%) within 1 year, there was 4 patients occurred relapse in second year (9/19, 47.3%); 5 patients occurred relapse in third year (10/19, 52.6%). Obvious connection between patients AFP mRNA positive and AFP mRNA negative was observed (P < 0.01).

CONCLUSIONSHCC with AFP mRNA positive has more change to be recurrent compared with HCC patients with AFP mRNA negative.

Adult ; Carcinoma, Hepatocellular ; blood ; pathology ; surgery ; Female ; Follow-Up Studies ; Humans ; Liver Neoplasms ; blood ; pathology ; surgery ; Male ; Middle Aged ; Neoplasm Metastasis ; Neoplasm Recurrence, Local ; Neoplastic Cells, Circulating ; Postoperative Period ; RNA, Messenger ; blood ; alpha-Fetoproteins ; genetics ; metabolism

OBJECTIVETo assess the level of alpha-fetoprotein (AFP) messenger RNA (mRNA) in peripheral blood of nude mice, and to study its relationship with tumor recurrence and metastasis after curative resection of hepatocellular carcinoma (HCC).

METHODSThe metastatic model of human HCC in nude mice LCI-D20 was used in this study. Curative resection was performed at 10th day after tumor implantation in 28 nude mice. Interferon alpha-1b (IFN alpha-1b) was administered subcutaneously from the next day after resection, at doses of 3 10(7)U/kg/d (8 nude mice), 1.5 10(7) U/kg/d (8 nude mice) respectively in the treatment groups, and normal saline alone in the controlled group (12 nude mice). Thirty-five days after treatment, one milliliter of peripheral blood was taken and AFP mRNA was quantitatively analyzed using TaqMan real-time quantitative RT-PCR. The mice were sacrificed. The size of recurrent tumor was measured and the presence of lung metastases was observed.

RESULTSThe liver recurrent rate, lung metastatic rate and positivity of AFP mRNA in the controlled group were all 100% (12/12), whereas it was 62.5% (5/8), 0% (0/8), 87.5% (7/8) respectively in the IFN alpha-1b 1.5 10(7)U/kg/d treated group. The recurrent tumor in liver of the IFN alpha-1b 1.5 10(7)U/kg/d treated group was much smaller than that of the controlled group (25 mm(3) 2 mm(3) vs 1143 mm(3) 3 mm(3), t =9.27, P<0.01), and the level of AFP mRNA was also lower than that of the controlled group [(85 6)copies/mug vs (955 2) copies/mug, t =4.33, P<0.01]. In the IFN alpha-1b 3 10(7)U/kg/d treated group, there was only one recurrent tumor (0.5 mm(3)), no lung metastasis, and the positivity of AFP mRNA was 0% (?(2)=11.67, P<0.01).

CONCLUSIONSThese results suggest that the level of AFP mRNA in peripheral blood may indicate recurrence and/or metastasis after curative resection of HCC. TaqMan real time quantitative RT-PCR is a very sensitive and convenient method for detecting circulating cancer cells.

Animals ; Biomarkers, Tumor ; analysis ; genetics ; Carcinoma, Hepatocellular ; secondary ; surgery ; Disease Models, Animal ; Liver Neoplasms ; pathology ; surgery ; Mice ; Mice, Nude ; Neoplasm Metastasis ; RNA, Messenger ; analysis ; Recurrence ; alpha-Fetoproteins ; analysis ; genetics

Aged ; CD5 Antigens ; metabolism ; Chromosomes, Human, Pair 11 ; Chromosomes, Human, Pair 14 ; Cyclin D1 ; metabolism ; Diagnosis, Differential ; Female ; Humans ; Liver Neoplasms ; genetics ; metabolism ; pathology ; surgery ; Lymphoma, B-Cell ; metabolism ; pathology ; Lymphoma, Follicular ; metabolism ; pathology ; Lymphoma, Mantle-Cell ; genetics ; metabolism ; pathology ; surgery ; Pseudolymphoma ; metabolism ; pathology ; Translocation, Genetic