External validation of ADNEX MR SCORING system: a single-centre retrospective study.

AIM: To evaluate the accuracy of the ADNEX MR SCORING system for characterising adnexal masses. MATERIALS AND METHODS: An institutional review board approved this retrospective study. The study population comprised 663 women who underwent magnetic resonance imaging (MRI) from January 2007 to December 2014 to characterise 778 adnexal masses that were indeterminate under ultrasonography (590 benign and 188 malignant). Two radiologists independently reviewed the MRI images. The masses were scored from 1 to 5 according to the ADNEX MR SCORING system. The diagnostic performance of the system was evaluated by receiver operating characteristic (ROC) analysis. Masses scored 4 or greater were considered malignant (including tumours of borderline malignancy or low malignant potential). RESULTS: The malignancy rates of masses with scores of 2, 3, 4 and 5 were 1.9% (8/419), 12.8% (19/149), 62.6% (57/91) and 87.4% (104/119) for reader 1 and 2.1% (9/424), 13.6% (20/147), 67.6% (71/105) and 86.3% (88/102) for reader 2, respectively. The areas under the ROC curves for the differentiation of benign and malignant masses were 0.929 and 0.923, respectively; the sensitivity, specificity and accuracy of diagnosis were 85.6% (161/188), 91.7% (541/590), and 90.2% (702/778) for reader 1 and 84.6% (159/188), 91.9% (542/590), and 90.1% (701/778) for reader 2, respectively. Tumours of borderline malignancy or low malignant potential had a higher rate of misclassification (46.1%) than other malignant tumours (6-7.4%). CONCLUSION: The ADNEX MR SCORING system was highly accurate in differentiating benign and malignant adnexal masses, although it may be less accurate for tumours of borderline malignancy or low malignant potential.

Fatty change in moderately and poorly differentiated hepatocellular carcinoma on MRI: a possible mechanism related to decreased arterial flow.

AIM: To clarify the frequency of fatty change in moderately and poorly differentiated hepatocellular carcinomas (mHCCs and pHCCs) and its relationship to arterial blood flow. MATERIALS AND METHODS: One hundred and thirty-six surgically resected HCC lesions were studied. All patients had undergone dynamic magnetic resonance imaging (MRI) with chemical-shift-encoded water-fat imaging (CSI). The presence of fat was identified by a signal drop-off on CSI and confirmed at pathology. Lesions were classified into four groups in the arterial phase; G1, hypointense; G2, isointense; G3, slightly and heterogeneously hyperintense; G4, markedly and homogeneously hyperintense. The number of cumulative arteries (CAs) in the tumours in the pathology examination were counted. RESULTS: A fat component was observed significantly more frequently in the pHCCs (13/21; 61.9%) compared to the mHCCs (32/101; 31.7%; p=0.013). The numbers of lesions in each group were as follows: (G1, G2, G3, G4) = (18, 9, 23, 4) in the HCCs with fat; (1, 6, 24, 51) in the HCCs without fat (p<0.001); (5, 5, 18, 4) in the mHCCs with fat; (0, 3, 19, 47) in the mHCCs without fat (p<0.001); (11, 0, 2, 0) in the pHCCs with fat; (0, 2, 3, 3) in the pHCCs without fat (p=0.001). The number of CAs in the fat-containing HCCs (5.5±2.9) was significantly lower than that in the HCCs without fat (10.8±5.3; p<0.001). CONCLUSION: A fat component was more commonly observed in the pHCCs than in the mHCCs. The present results showed a possible mechanism of fatty change in mHCCs and pHCCs in relation to decreased arterial blood supply.

Chronic immune-mediated reaction syndrome as the cause of late graft mortality in living-donor liver transplantation for primary biliary cirrhosis.

INTRODUCTION: Few studies to date have investigated the causes of late graft mortality after living-donor liver transplantation (LDLT) for primary biliary cirrhosis (PBC). PATIENTS AND METHODS: Fifty-five LDLTs for PBC were retrospectively reviewed. Factors prognostic of graft survival after LDLT were investigated, and histologic findings in patients with late graft loss were assessed. RESULTS: The 1-, 5-, and 10-year cumulative graft survival rates were 85.1%, 82.5%, and 66.9%, respectively. Multivariate Cox regression analysis found that male donor and ≥ 4 HLA mismatches were independently associated with poor graft survival. Among the 13 grafts lost, 5 were lost >1 year after LDLT, including 1 each due to chronic rejection, veno-occlusive disease, and obliterative portal venopathy, and 2 to other causes. Pathologic reviews of the serial biopsy specimens and explanted grafts from these 5 patients, with graft rejections from "chronic immune-mediated reaction syndrome," showed reciprocal changes over time. No patient died of recurrent PBC. CONCLUSIONS: Male donor and ≥ 4 HLA mismatches were independent factors associated with poor graft survival. Late graft mortality after LDLT for PBC in some patients was due to chronic immune-mediated reaction syndrome, including chronic rejection, veno-occlusive disease, and obliterative portal venopathy, but not to recurrent PBC.

Primary graft dysfunction after living donor liver transplantation is characterized by delayed functional hyperbilirubinemia.

The purpose of this study is to propose a new concept of primary graft dysfunction (PGD) after living donor liver transplantation (LDLT), characterized by delayed functional hyperbilirubinemia (DFH) and a high early graft mortality rate. A total of 210 adult-to-adult LDLT grafts without anatomical, immunological or hepatitis-related issues were included. All of the grafts with early mortality (n = 13) caused by PGD in LDLT had maximum total bilirubin levels >20 mg/dL after postoperative day 7 (p < 0.001). No other factors, including prothrombin time, ammonia level or ascites output after surgery were associated with early mortality. Thus, DFH of >20 mg/dL for >seven consecutive days occurring after postoperative day 7 (DFH-20) was used to characterize PGD. DFH-20 showed high sensitivity (100%) and specificity (95.4%) for PGD with early mortality. Among the grafts with DFH-20 (n = 22), those with early mortality (n = 13) showed coagulopathy (PT-INR > 2), compared with those without mortality (p = 0.002). Pathological findings in the grafts with DFH-20 included hepatocyte ballooning and cholestasis, which were particularly prominent in the centrilobular zone. PGD after LDLT is associated with DFH-20 caused by graft, recipient and surgical factors, and increases the risk of early graft mortality.

Prognostic importance of the gross classification of hepatocellular carcinoma in living donor-related liver transplantation.

BACKGROUND: The gross classification of hepatocellular carcinoma (HCC) has been reported to be a significant prognostic factor for patients with HCC undergoing partial hepatectomy. The present study investigated whether the gross classification of HCC is also a prognostic factor in living donor-related liver transplantation (LDLT). METHODS: Some 119 patients undergoing LDLT for HCC were identified retrospectively from a prospective institutional database containing information on all LDLTs carried out between 1996 and 2009. Patients were divided into three groups according to the gross classification of the largest tumour in the explanted liver: type 1 HCC, single nodular type (81 patients); type 2, single nodular type with extranodular growth (21); and type 3, contiguous multinodular type (17). Clinicopathological factors and recurrence-free survival rates were compared. RESULTS: Recurrence-free survival rates for the whole group were 87·7 per cent at 1 year, 83·5 per cent at 3 years and 81·0 per cent at 5 years after LDLT. Type 3 HCC was associated with large tumour size, poor histological grade, a high incidence of microvascular invasion and multiple tumours. Independent predictors of poor recurrence-free survival were preoperative serum level of des-γ-carboxy prothrombin exceeding 300 mAU/ml, microvascular invasion and type 3 HCC. CONCLUSION: The gross classification of HCC was an independent predictor for recurrence of HCC in patients undergoing LDLT.

Adenomatoid tumour of the liver.

An unusual primary adenomatoid tumour arising in the normal liver is described. Hepatectomy was performed, and the patient is alive and free of disease 1 year postsurgery. Grossly, the tumour showed a haemorrhagic cut surface with numerous microcystic structures. Histological examination revealed cystic or angiomatoid spaces of various sizes lined by cuboidal, low-columnar, or flattened epithelioid cells with vacuolated cytoplasm and round to oval nuclei. The epithelioid cells were entirely supported by proliferated capillaries and arteries together with collagenous stroma. Immunohistochemical studies showed that the epithelioid cells were strongly positive for a broad spectrum of cytokeratins (AE1/AE3, CAM5.2, epithelial membrane antigen and cytokeratin 7) and mesothelial markers (calretinin, Wilms' tumour 1 and D2-40). These cells were negative for Hep par-1, carcinoembryonic antigen, neural cell adhesion molecule, CD34, CD31 and HMB45. Atypically, abundant capillaries were observed; however, the cystic proliferation of epithelioid cells with vacuoles and immunohistochemical profile of the epithelioid element were consistent with hepatic adenomatoid tumour.

Proposal of a new staging and grading system of the liver for primary biliary cirrhosis.

AIMS: To define a new histological staging and grading system for primary biliary cirrhosis (PBC), to provide more information reflecting clinical laboratory data and the prognosis to hepatologists. METHODS AND RESULTS: First, 17 histological lesions of PBC were scored in 188 needle liver biopsy specimens. Factor analysis yielded three independent groups of factors: factor 1 (fibrosis, fibrous piecemeal necrosis, orcein-positive granules, bile plugs, Mallory bodies, feathery degeneration, bile duct loss and atypical ductular proliferation); factor 2 (portal inflammation, eosinophilic infiltration, lymphoid follicles, epithelioid granulomas, interface hepatitis and chronic cholangitis); and factor 3 (interface hepatitis, lobular hepatitis, acidophilic bodies and pigmented macrophages). The eight findings of factor 1, but not factors 2 and 3, were significantly correlated with clinical laboratory data and scores in the Mayo Clinic's prognostic model. Factor 1 lesions may reflect histological progression (staging), while factor 2 and 3 lesions may relate to necroinflammatory activity (grading). Then, we devised a staging and grading system using three lesions (bile duct loss, fibrosis and orcein-positive granules) from factor 1 and three from factors 2 and 3 (chronic cholangitis, interface hepatitis and lobular hepatitis). CONCLUSION: This new system might provide more pathological information on PBC patients for hepatologists.

Gastric mucin phenotype defines tumour progression and prognosis of intrahepatic cholangiocarcinoma: gastric foveolar type is associated with aggressive tumour behaviour.

AIMS: To identify the role of mucus core protein (MUC) in intrahepatic cholangiocarcinoma (ICC). METHODS AND RESULTS: We examined the expression profile of MUC2, MUC5AC and MUC6 by immunohistochemical staining in 100 ICCs and compared the clinicopathological factors and the immunohistochemical results. The expression frequency was: MUC2, 9%; MUC5AC, 40%; and MUC6, 21%. According to the gastric mucin expression profile, ICCs were classified into the following groups: null type (n = 43), gastric foveolar type (n = 36), pyloric gland type (n = 11) and gastric combined type (n = 10). Half of the gastric foveolar type and the gastric combined type were located in the hilar region, but the other types were predominant at the periphery (P = 0.0004). Well-differentiated components were more often detected in the gastric combined type and the pyloric gland type (P = 0.0281). The gastric foveolar type was associated with a higher incidence of lymph node metastasis (P < 0.0001). The pyloric gland type was associated with better survival and the gastric foveolar type was associated with worse survival. The gastric mucin phenotype was an independent prognostic factor by multivariate survival analysis. CONCLUSION: The gastric foveolar type of ICC was more often associated with aggressive tumour development, whereas the pyloric gland type exhibited less aggressive behaviour.

'Scirrhous' type hepatocellular carcinomas: a special reference to expression of cytokeratin 7 and hepatocyte paraffin 1.

AIMS: 'Scirrhous' hepatocellular carcinoma (scirrhous HCC) is extremely rare and its characteristics remain unclear. We investigated the clinicopathological and immunohistochemical features of scirrhous HCC, compared with those of ordinary hepatocellular carcinoma (ordinary HCC). METHODS AND RESULTS: We compared the clinicopathological and immunohistochemical features of 20 resected cases of scirrhous HCC with those of 69 resected cases of ordinary HCC. Scirrhous HCC was characterized by its gross and histological findings, such as a higher proportion of contiguous multinodular type tumours, the absence of a complete fibrous capsule around the tumour, the absence of tumour necrosis and highly preserved portal tracts in the tumour. The immunohistochemical results revealed a significantly higher expression of cytokeratin 7 and a significantly lower expression of hepatocyte paraffin 1 in scirrhous HCC than in ordinary HCC (P<0.0001, respectively). There were no significant differences in proliferative activity and survival curves between the patients with scirrhous HCC and those with ordinary HCC. CONCLUSION: Scirrhous HCC has several particular gross, histological and immunohistochemical features. In particular, we would like to emphasize the greater immunohistochemical expression of cytokeratin 7 and lower expression of hepatocyte paraffin 1 in scirrhous HCC than in ordinary HCC.

Angiopoietin switching regulates angiogenesis and progression of human hepatocellular carcinoma.

AIM: Angiopoietin 1 (Ang-1) and its antagonist, angiopoietin 2 (Ang-2), are novel ligands that regulate the Tie2 receptor. The Ang-2 gene is upregulated in the hypervascular type of human hepatocellular carcinoma (HCC). To gain a better understanding of the role of the Ang-Tie2 system in HCC the expression of these genes was investigated in a series of human HCCs. METHODS: The expression of the angiopoietin and Tie2 proteins was investigated in nine normal liver tissues and 52 surgically resected HCCs. In addition, the effects of hypoxic stimuli on Ang-1, Ang-2, vascular endothelial growth factor (VEGF), and erythropoietin (EPO) expression was investigated in Hep3B cells. RESULTS: Ang-1, rather than Ang-2, was more frequently expressed in the normal liver. Ang-1 was expressed in 68% of HCCs, whereas Ang-2 was expressed in 81%, and was significantly higher in poorly differentiated HCCs characterised by high vascularity (p = 0.02), and in tumours with a peliotic change (p = 0.02). Strong expression of Tie2 was seen in tumour vessels in accordance with Ang-2 expression. In Hep3B cells, hypoxic stimuli upregulated VEGF and EPO, but not Ang-1 or Ang-2. CONCLUSIONS: These data support the evidence that the reversal of Ang-1 and Ang-2 expression plays an important role in the angiogenic and dedifferentiation processes in HCC. The hypoxic stimuli were not responsible for Ang-2 upregulation, unlike that of VEGF, in human HCC cells.

c-erbB-2 and c-Met expression relates to cholangiocarcinogenesis and progression of intrahepatic cholangiocarcinoma.

AIMS: The c-erbB-2 and c-Met proto-oncogenes are important for tumour invasiveness and metastasis in many types of malignant tumours. Previous studies have indicated that these proteins are associated with carcinogenesis in intrahepatic cholangiocarcinoma. In this study, we examined c-erbB-2 and c-Met expression by immunohistochemistry in hepatolithiasis, intrahepatic cholangiocarcinoma and metastatic lymph node, in order to clarify whether these proteins play a role in carcinogenesis and tumour metastasis in intrahepatic cholangiocarcinoma. METHODS AND RESULTS: In hepatolithiasis, the staining for c-erbB-2 was positive in 14 of the 23 (61%) cases, while staining for c-Met was positive in eight of the 23 (35%) cases. In intrahepatic cholangiocarcinoma, staining for c-erbB-2 was positive in 45 of the 81 (55%) cases, while staining for c-Met was positive in 28 (35%) cases. The positivity of c-Met staining in intrahepatic cholangiocarcinoma was significantly higher in the differentiated type of cholangiocarcinoma than in the undifferentiated type. In addition, c-Met-positive staining had an inverted correlation with tumour size, the presence of perineural invasion and the presence of lymph node metastasis. c-Met staining had a significantly higher positivity in cases at an early stage of intrahepatic cholangiocarcinoma. In contrast, the positivity of c-erbB-2 staining in intrahepatic cholangiocarcinoma was significantly higher in cases with lymph node metastasis than in cases without. In metastatic lymph nodes, the staining for c-erbB-2 was positive in 20 of the 25 (80%) cases, while staining for c-Met was positive in six of the 25 (24%) cases. There was no difference in survival between c-erbB-2-positive and negative patients. However, the patients with c-Met-positive tumours had a significantly longer survival than those with c-Met-negative tumours in the medium survival term. The multivariate analysis showed the presence of lymph node metastasis, lymphatic permeation and histological differentiation to be independent prognostic factors. CONCLUSION: These results indicate that increased c-Met expression participates in cholangiocarcinogenesis and in the early developmental stages of intrahepatic cholangiocarcinoma, while increased c-erbB-2 expression contributes to the development of cholangiocarcinogenesis into an advanced stage associated with tumour metastasis.

Value of lymph node dissection during resection of intrahepatic cholangiocarcinoma.

BACKGROUND: Hepatectomy with extensive lymph node dissection is the standard operation for intrahepatic cholangiocarcinoma (IHCC). However, lymph node dissection may not always be effective at reducing tumour recurrence. METHODS: Forty-nine patients with IHCC who underwent hepatectomy were investigated to determine patterns of tumour recurrence and to estimate the value of lymph node dissection during resection. RESULTS: At hepatectomy most metastatic lymph nodes were identified at least to the level of group 2 lymph nodes. Among 23 patients who developed recurrence, 17 had liver metastases and the other six had recurrence at other sites, mainly in the peritoneum. Poorly differentiated histology was related to the development of liver metastases. No patient with the intraductal growth type of IHCC had tumour recurrence. Lymph node dissection did not appear to improve patient survival. Histological findings of lymph node metastases and intrahepatic metastases were independent indicators of poor prognosis. CONCLUSION: Lymph node metastases were seldom limited to the regional lymph nodes; most tumour recurrence occurred in the liver. Lymph node dissection did not appear to improve patient survival. Lymph node dissection alone is not likely to improve the prognosis without further control of liver metastases.

Altered expression of beta-catenin without genetic mutation in intrahepatic cholangiocarcinoma.

beta-catenin which has a role in E-cadherin mediated cell-to-cell adhesion, and is also involved in Wnt signaling pathways as a downstream signaling molecule accumulating in the cytoplasm and nucleus constitutively activates Tcf/LEF-associated transcription of oncogenic genes. We examined the expression pattern and the genetic alteration of beta-catenin to determine the role of beta-catenin in cancer formation and/or progression in intrahepatic cholangiocarcinoma (ICC). beta-catenin expression was immunohistochemically examined in 71 surgically resected ICC samples, and correlation between the expression pattern and clinicopathologic factors was investigated. Mutation analysis of beta-catenin exon 3, which included the responsible element for Wnt signaling was done in 55 samples, using PCR-SSCP and direct sequence methods. Immunohistochemical analysis revealed the reduced membranous expression of beta-catenin in 58 (82%) ICCs and aberrant nuclear expression in 11 (15%) ICCs. The membranous expression was preserved in 62% of the papillary adenocarcinomas, and was frequently reduced in tumors with a poorer histological differentiation (84%), with a significant difference (P =.01). Genetic analysis showed that none of the 55 ICCs examined carried mutations in beta-catenin exon 3. The present study indicates that reduced membranous expression of beta-catenin is associated with non-papillary ICCs which have a more malignant behavior, and that nuclear translocation of beta-catenin results in oncogenic events. Mutations in beta-catenin exon 3 do not appear to be responsible for nuclear translocation of beta-catenin in ICCs.

The role of overexpression and gene amplification of cyclin D1 in intrahepatic cholangiocarcinoma.

BACKGROUND/AIMS: Intrahepatic cholangiocarcinoma (ICC) is a primary liver malignant tumor with an extremely poor prognosis, but less attention has been directed to factors related to molecular carcinogenesis, including cell cycle proteins. We examined the expression and gene amplification of cyclin D1, the cell cycle regulating protein. Our objective was to evaluate correlations with clinicopathological factors in ICC. METHODS: Cyclin D1 overexpression and cellular proliferative activity (Ki-67 labeling index) were investigated immunohistochemically, and 20 cases were further investigated for cyclin D1 gene amplification, using differential PCR. We examined the correlation between the expression and gene amplification of cyclin D1 and clinicopathological factors, including overall survival in patients with ICC. RESULTS: Immunohistochemical analysis revealed an overexpression of cyclin D1 protein in 28 of 66 subjects with ICCs (42%). The cyclin D1 overexpression was associated with poor histological differentiation (P = 0.04), high cellular proliferative activity (P < 0.01), and a poor prognosis (P = 0.02) by univariate analysis, although it is not an independent prognostic factor by multivariate analysis. Cyclin D1 gene amplification was confirmed in five of the 20 patients. Of those five cases of ICC, all had poor histological differentiation, and four of the five ICCs (80%) showed evidence of cyclin D1 immunoreactivity. CONCLUSIONS: Overexpression and gene amplification of cyclin D1 are frequent and contribute to dedifferentiation and cellular proliferative activity of ICCs, and overexpression also indicates a poor prognosis for patients with ICC.

The role of p27kip1 protein expression on the biological behavior of intrahepatic cholangiocarcinoma.

Recent studies have reported that a decreased p27kip1 protein (p27) expression is associated with aggressive tumor behavior in several human malignancies. In this study, we examined the role of p27 expression in intrahepatic cholangiocarcinoma (ICC) and the noncancerous intrahepatic bile duct epithelium and assessed its association with clinicopathologic features, especially the influence of decreased p27 expression by the tumor on its prognosis as determined by immunohistochemistry. Almost all noncancerous bile duct epithelia show positive nuclear staining and reveal a faintly positive reaction in the cytoplasm. In 62 surgically resected ICCs, a variable degree of positive p27 nuclear staining is recognized. A subset (13 of 62 cases; 21.0%) of the carcinomas displayed cytoplasmic staining. We classified 62 cases into 2 groups, a low expression group (< 50% of p27 nuclear positive cells) and a high expression group (> or = 50% of p27 nuclear positive cells), and tested for the association between positive expression and clinicopathologic features. We found that a low expression of nuclear p27 was correlated with positive vascular invasion (P < .05). The survival curve of the group with low p27 nuclear expression was significantly lower than that of the group with high p27 nuclear expression (P < .005). According to the multivariate analyses, low p27 expression can be considered an independent prognostic factor whose occurrence indicates a worse prognosis. We conclude that a decreased p27 expression adds an independent parameter that can be used when determining the prognosis of patients with ICC.

The importance of hepatic resection for hepatocellular carcinoma originating from nonfibrotic liver.

BACKGROUND: Our study aimed to clarify the characteristics of hepatocellular carcinoma (HCC) in patients with a nonfibrotic liver and the role of surgical resection for HCC in nonfibrotic liver compared with patients with HCC in fibrotic or cirrhotic livers. STUDY DESIGN: A total of 516 patients who underwent hepatectomy between April 1985 and June 1999 were classified into two groups: a nonfibrotic liver group (n=65) and a fibrotic liver group (n=451), which included fibrotic or cirrhotic livers. Clinicopathologic variables were then compared between the groups, including disease-free survival rate and patient survival rate. RESULTS: Only 8 of 65 patients (12.3%) with a nonfibrotic liver showed a histologically completely normal liver. The numbers of men and patients with alcohol abuse in the nonfibrotic liver group were higher than in the fibrotic liver group. The numbers of patients with positive hepatitis B antigen and positive hepatitis C antibody in the nonfibrotic liver group were lower than in the fibrotic liver group. Results of liver function tests in the nonfibrotic liver group were better than those in the fibrotic liver group. The rates of both portal vein and hepatic vein invasion of cancer cells in the nonfibrotic liver group were higher than in the fibrotic liver group. The tumor size in the nonfibrotic liver group was larger than in the fibrotic liver group. The patient survival and disease-free survival rates in the nonfibrotic liver group were better than in the fibrotic liver group. CONCLUSIONS: Hepatic resection can be beneficial for patients with HCC originating from a nonfibrotic liver when compared with fibrotic or cirrhotic patients with HCC.