BACKGROUND: Glutamine synthetase (GS) and arginase 1 (Arg1) are widely used pathological markers that discriminate hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma; however, their clinical significance in HCC remains unclear. METHODS: We retrospectively analyzed 431 HCC patients: 251 received hepatectomy alone, and the other 180 received sorafenib as adjuvant treatment after hepatectomy. Expression of GS and Arg1 in tumor specimens was evaluated using immunostaining. mRNA sequencing and immunostaining to detect progenitor markers (cytokeratin 19 [CK19] and epithelial cell adhesion molecule [EpCAM]) and mutant TP53 were also conducted. RESULTS: Up to 72.4% (312/431) of HCC tumors were GS positive (GS+). Of the patients receiving hepatectomy alone, GS negative (GS-) patients had significantly better overall survival (OS) and recurrence-free survival (RFS) than GS+ patients; negative expression of Arg1, which is exclusively expressed in GS- hepatocytes in the healthy liver, had a negative effect on prognosis. Of the patients with a high risk of recurrence who received additional sorafenib treatment, GS- patients tended to have better RFS than GS+ patients, regardless of the expression status of Arg1. GS+ HCC tumors exhibit many features of the established proliferation molecular stratification subtype, including poor differentiation, high alpha-fetoprotein levels, increased progenitor tumor cells, TP53 mutation, and upregulation of multiple tumor-related signaling pathways. CONCLUSIONS GS- HCC patients have a better prognosis and are more likely to benefit from sorafenib treatment after hepatectomy. Immunostaining of GS may provide a simple and applicable approach for HCC molecular stratification to predict prognosis and guide targeted therapy.
Humans ; Carcinoma, Hepatocellular/metabolism* ; Sorafenib/therapeutic use* ; Liver Neoplasms/metabolism* ; Glutamate-Ammonia Ligase/metabolism* ; Hepatectomy ; Retrospective Studies ; Prognosis ; Neoplasm Recurrence, Local/surgery*

No abstract available.
Adult ; Anterior Temporal Lobectomy ; Bile Duct Neoplasms/*diagnostic imaging/surgery ; *Bile Ducts, Intrahepatic/surgery ; Carcinoma, Hepatocellular/diagnostic imaging ; Cholangiocarcinoma/*diagnostic imaging/surgery ; Cholangiopancreatography, Magnetic Resonance ; Diagnosis, Differential ; Humans ; Liver/diagnostic imaging/metabolism ; Liver Neoplasms/diagnostic imaging ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Tomography, X-Ray Computed

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

Hepatocellular carcinoma (HCC) is the fifth most common cancer in Korea. Diverse paraneoplastic syndromes can occur in patients with HCC, but parathyroid hormone-related peptide (PTH-rP)-induced hypercalcemia is uncommon. Hypercalcemia due to PTH or particularly PTH-rP-secreting HCC is associated with poor outcomes. We report a 71-year-old man who presented with symptoms of vague abdominal discomfort, somnolence, lethargy, nausea, vomiting, and weight loss. Imaging studies revealed a large HCC without metastasis. The laboratory findings showed elevated serum calcium level, low intact parathyroid hormone (iPTH) level and elevated PTH-rP level. These results led to a diagnosis of a PTH-rP-secreting HCC and paraneoplastic hypercalcemia. After emergency management of the hypercalcemia, the patient underwent an extended right hemihepatectomy with cholecystectomy. One year after the surgery, he is alive with normal calcium, PTH-rP, and iPTH levels. This case demonstrates that the rare phenomenon of life-threatening hypercalcemia caused by HCC should not be overlooked. These symptoms offer a good opportunity to diagnose HCC early. Radical tumor resection makes it possible to cure patients with PTH-rP-secreting HCC.
Aged ; Carcinoma, Hepatocellular/metabolism/pathology/*surgery ; Humans ; Liver Neoplasms/metabolism/pathology/*surgery ; Magnetic Resonance Imaging ; Male ; Parathyroid Hormone-Related Protein/metabolism/secretion ; Positron-Emission Tomography ; Tomography, X-Ray Computed

BACKGROUND/AIMS: To investigate sequential changes in laboratory markers after radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) and the relationship of these changes to the severity of the underlying liver disease. METHODS: This retrospective analysis included 65 patients (44 males, 21 females) who underwent RFA of HCC. Hematologic and biochemical markers were assessed at the pre-RFA period and 1 day, 2-3 days, and 1-2 weeks after RFA. We classified the subjects into two groups: Child-Pugh A (n=41) and Child-Pugh B (n=24). The ablative margin volume (AMV) of each patient was measured. We analyzed the changes in laboratory profiles from the baseline, and investigated whether these laboratory changes were correlated with the AMV and the Child-Pugh classification. RESULTS: Most of the laboratory values peaked at 2-3 days after RFA. AMV was significantly correlated with changes in WBC count, hemoglobin level, and serum total bilirubin level (Pearson's correlation coefficient, 0.324-0.453; P<0.05). The alanine aminotransferase (ALT) level varied significantly over time (P=0.023). CONCLUSIONS: Most of the measured laboratory markers changed from baseline, peaking at 2-3 days. The ALT level was the only parameter for which there was a significant difference after RFA between Child-Pugh A and B patients: it increased significantly more in the Child-Pugh A patients.
Adult ; Aged ; Aged, 80 and over ; Alanine Transaminase/blood ; Bilirubin/blood ; Biomarkers/metabolism ; Carcinoma, Hepatocellular/pathology/*surgery/ultrasonography ; Catheter Ablation ; Female ; Follow-Up Studies ; Humans ; Liver Neoplasms/pathology/*surgery/ultrasonography ; Male ; Middle Aged ; Retrospective Studies ; Severity of Illness Index

BACKGROUNDThe management of Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) is controversial due to the early recurrence after curative hepatectomy, and many variables were related to the prognosis. The purpose of this study was to predict the tumor recurrence in early postoperative period of the patients with BCLC stage B HCC.

METHODSFrom January 2004 to January 2012, 104 patients with BCLC stage B HCC underwent hepatectomy. Clinicopathological factors and follow-up data were statistically analyzed to establish a predicting scoring system.

RESULTSThe overall survival rates for one, three, and five years were 69.2%, 52.7%, and 42.3%, and the disease-free survival rates for one, three, and five years were 52.9%, 47.3%, and 37.5%, respectively. The multiple factors analysis showed that the micro-vessel invasion, lymph nodes metastasis, multiple lesions, and the high expression of HMGB1 were independent factors (P < 0.05). A scoring system was established to predict the early recurrence within one year after the surgery for BCLC stage B HCC, according to the analysis results with a specificity of 85.1% and a sensitivity of 80.3%.

CONCLUSIONVariant clinicopathological factors were associated with early postoperative recurrence for BCLC stage B HCC and recurrence early after hepatectomy was more likely in patients with a higher score of the scoring system.

Carcinoma, Hepatocellular ; metabolism ; pathology ; surgery ; Disease-Free Survival ; Female ; HMGA1a Protein ; metabolism ; Hepatectomy ; Humans ; Liver Neoplasms ; metabolism ; pathology ; surgery ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; Treatment Outcome

OBJECTIVETo explore the clinicopathological features and prognostic factors of three rare and poor-prognostic pathological subtypes of primary liver carcinoma, and improve the clinical diagnosis and surgical treatment.

METHODSA retrospective analysis of clinicopathological data of 69 patients with rare pathological subtypes of primary liver carcinoma, diagnosed by postoperative pathology in our hospital from October 1998 to June 2013 was carried out. The data of 80 cases of common poorly differentiated hepatocellular carcinoma treated in the same period were collected as control group. Kaplan-Meier method was used to analyze the survival rate, and Cox proportional hazards model was used for prognostic analysis in the patients.

RESULTSThirty-four cases were combined hepatocellular carcinoma and cholangiocarcinoma (CCC, 28 males, 6 females), with a median age of 52 years (range, 33 to 73). Ninteen cases were giant cell carcinoma (GCC, 16 males and 3 females), with a median age of 59 years (range, 38 to 66). Sixteen cases were sarcomatoid carcinoma (SC, 14 males and 2 females), with a median age of 57 years (range, 46 to 70). The survival analysis revealed that median survival time and the 1-, 3-, 5-year survival rates for these 3 groups were 20 months, 61.8%, 29.4%, and 20.6% in the CCC patients, 13 months, 52.6%, 31.6%, and 0% in the GCC patients, and 8 months, 31.3%, 0%, 0% in the SC patients, respectively. The median survival time and survival rate of the SC group were significantly lower than those of the other three groups (P < 0.05). However, in the SC group, the incidences of hilar lymph nodes metastasis, vascular tumor emboli and invasion of adjacent organs were significantly higher than those in the other three groups (P < 0.05). There were no statistically significant differences among the other three groups (P > 0.05). The levels of carcino-embryonic antigen were higher in the three rare subtype groups than that of the control group. The incidences of multiple tumors of the three rare subtype groups were higher than that of the control group (P < 0.05). Positive surgical margin was an independent unfavorable prognostic factor.

CONCLUSIONSThe combined hepatocellular carcinoma and cholangiocarcinoma, giant cell carcinoma and sarcomatoid carcinoma have a poor prognosis. Among them sarcomatoid carcinoma is the most malignant and poor prognostic one. Radical resection is recommended.

Adult ; Aged ; Carcinoembryonic Antigen ; metabolism ; Carcinoma, Giant Cell ; metabolism ; pathology ; surgery ; Carcinoma, Hepatocellular ; metabolism ; pathology ; surgery ; Carcinosarcoma ; metabolism ; pathology ; surgery ; Cholangiocarcinoma ; metabolism ; pathology ; surgery ; Female ; Follow-Up Studies ; Hepatectomy ; methods ; Humans ; Liver Neoplasms ; metabolism ; pathology ; surgery ; Lymph Node Excision ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Invasiveness ; Neoplastic Cells, Circulating ; Proportional Hazards Models ; Retrospective Studies ; Risk Factors ; Survival Rate

OBJECTIVETo study the clinical features, pathologic findings and prognosis of patients with dysplastic nodules of liver (DN) and early hepatocellular carcinomas (eHCC).

METHODSOne hundred and forty-five archival cases previously diagnosed as DN or eHCC or well-differentiated HCC during the period from 2000 to 2009 were retrieved and reevaluated with the new diagnostic criteria by two experienced pathologists, according to International Consensus Group for Hepatocellular Neoplasia (ICGHN) 2008. Immunohistochemical study (EnVision method) for CD34, HSP70, glutamine synthetase, glypican 3 and Ki-67 was carried out. The original diagnosis and diagnosis after review were compared and correlated with the survival data of the patients, with statistical analysis.

RESULTSWith the new criteria, 16 cases were diagnosed as low-grade DN, 50 cases as high-grade DN, 72 cases as DN with microinvasion, 7 cases as advanced HCC. Slide review showed no diagnostic discrepancy in 112 cases (77.2%). Amongst the 33 (22.8%) underdiagnosed cases, there were 7 cases of advanced HCC initially diagnosed as DN or DN with microinvasion and 26 cases of eHCC initially diagnosed as high-grade DN. Kaplan-Meier analysis showed that the diagnosis of high-grade DN or early HCC carried no statistically significant difference in overall survival (P = 0.778, 0.677) or disease-free survival (P = 0.949, 0.700) in all patients and in patients with no history of HCC. The co-existence of advanced HCC in patients with DN or eHCC significantly correlated with overall survival (P = 0.004) but not with disease-free survival (P = 0.079).

CONCLUSIONSThe new diagnostic criteria by ICGHN 2008 are useful in delineating high-grade DN and eHCC. The overall survival and disease-free survival of patients with eHCC or high-grade DN undergoing hepatectomy show no statistically significant difference. Patients with DN or eHCC have better prognosis than patients with advanced HCC, though there is still a high risk of tumor recurrence.

Antigens, CD34 ; metabolism ; Carcinoma, Hepatocellular ; metabolism ; pathology ; surgery ; Cell Transformation, Neoplastic ; Disease-Free Survival ; Female ; Follow-Up Studies ; HSP70 Heat-Shock Proteins ; metabolism ; Hepatectomy ; Humans ; Kaplan-Meier Estimate ; Ki-67 Antigen ; metabolism ; Liver Cirrhosis ; metabolism ; pathology ; surgery ; Liver Neoplasms ; metabolism ; pathology ; surgery ; Male ; Middle Aged ; Survival Rate

BACKGROUND/AIMS: The current study examines the expression of molecular biomarkers in hepatocellular carcinoma (HCC) and whether these findings correlate with the clinicopathologic features of the disease and patient survival. METHODS: We analyzed the immunohistochemical expression of p53, mammalian target of rapamycin (mTOR), c-Met, and insulin-like growth factor 1 receptor (IGF-1R) heat shock protein 70 (HSP70) with the clinicopathologic features of 83 HCCs. RESULTS: p53 expression was higher in the male patients with undifferentiated histological tumor grades, cirrhosis, and portal vein invasion. High 48 c-Met expression correlated with cirrhosis, and high mTOR expression correlated with the tumor grade and cirrhosis. High IGF-1R expression correlated with the tumor grade and cirrhosis. A multivariate analysis identified a significant relationship between the high expression of p53, tumor grade, and portal vein invasion. In addition, a high expression of mTOR was related to tumor grade and cirrhosis, and a high expression of HSP70 was related to portal vein invasion in a multivariate analysis. The Kaplan-Meier survival curve for patients with high versus low Edmondson grades and p53 expression was statistically significant. CONCLUSIONS: p53, mTOR, and IGF-1R expression correlated with the Edmondson tumor grade in a univariate analysis, while p53 and mTOR correlated with the Edmondson tumor grade in a multivariate analysis. In addition, the tumor grade was found to predict survival. p53 was primarily related to the clinicopathologic features compared to other markers, and it is a poor prognostic factor of survival.
Adult ; Aged ; Carcinoma, Hepatocellular/*metabolism/surgery ; Disease-Free Survival ; Female ; HSP70 Heat-Shock Proteins/metabolism ; Humans ; Liver Neoplasms/*metabolism/surgery ; Male ; Middle Aged ; Prognosis ; Proto-Oncogene Proteins c-met/metabolism ; Receptor, IGF Type 1/metabolism ; Retrospective Studies ; Risk Factors ; TOR Serine-Threonine Kinases/metabolism ; Treatment Outcome ; Tumor Markers, Biological/*metabolism ; Tumor Suppressor Protein p53/metabolism