Contrast-enhanced ultrasonograpic studies on pancreatic carcinoma with special reference to staining and muscular arterial vessels.

Comparative study of contrast-enhanced ultrasonography (CE-US) and histopathology of surgically resected specimens in 13 patients with pancreatic carcinoma. A time intensity curve was used to determine the percentage brightness increase in cancerous and normal regions and the patients were divided into two groups, hyperperfusion, with a percentage brightness increase over 80% (n=6) and hypoperfusion, with an increase of less than 80% (n=7) on CE-US. The hyperperfusion group included well-differentiated tubular adenocarcinoma, adenosquamous cell carcinoma and acinar cell carcinoma, while all 7 patients in the hypoperfusion group had moderately differentiated tubular adenocarcinoma. Immunological staining (α-SMA and anti-CD34) of the resected specimens showed significantly higher microartery count (MAC) in the hyperperfusion group (p<0.005) than in the hypoperfusion group or normal pancreas. In the normal pancreas, the mean vessel diameter was significantly higher (over 100 µm) than in the hyperperfusion group (30 µm; p<0.005). It was concluded that a muscular arterial vessel density of less than 30 µm is an important factor in determining staining degree and carcinoma progression by CE-US in pancreatic carcinoma.

Management of hepatocellular carcinoma in Japan: Consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death not only in Japan but also worldwide. Clinical practice guidelines for HCC were first published in 2001 by the European Society of Study of the Liver (EASL) followed by the American Association for the Study of Liver Disease (AASLD) published in 2005 and updated in 2010. However, these guidelines have proven to be somewhat unsuitable for Japanese patients. In 2005, supported by the Japanese Ministry of Health, Labour and Welfare, evidence-based clinical practice guidelines for HCC were compiled in Japan. In 2009, a revised version of evidence-based guidelines was published. Based on both 'evidence-based' guidelines and the consensus of an expert panel on HCC, the Japan Society of Hepatology (JSH) published the Consensus-Based Clinical Practice Manual in 2007 and updated in 2010. In this article, the 2010 updated version of this manual, especially issues on prevention, surveillance, pathology, diagnosis, staging, and treatment algorithm are summarized.

Focal nodular hyperplasia-like nodule with reduced expression of organic anion transporter 1B3 in alcoholic liver cirrhosis.

We report a patient with alcoholic liver cirrhosis who had a 15 mm focal nodular hyperplasia (FNH)-like nodule in the liver. This FNH-like nodule was diagnosed as hepatocellular carcinoma (HCC) mainly based on hypervascularity during the hepatic arterial phase, washout pattern during the equilibrium phase and low signal intensity during the hepatobiliary phase in gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI; it was surgically resected. Its histology exhibited hepatocyte hyperplasia, fibrous septa containing unpaired small arteries accompanied by reactive bile ductules, remarkable iron deposits and sinusoidal capillarization, and was compatible with the diagnosis of an FNH-like nodule. When we analyzed the images of the present nodule retrospectively, low signal intensity on in-phase and isosignal intensity on opposed-phase T1-weighted MRI may have reflected iron deposits in the FNH-like nodule. In addition, a low signal intensity on T2-weighted MRI and no detection in diffusion-weighted MRI may help in distinguishing FNH-like nodules from HCC, since these image findings are inconsistent with typical HCC. Immunohistochemical analysis revealed a markedly reduced expression of organic anion transporter (OATP) 1B3 in this nodule, which implied decreased Gd-EOB-DTPA uptake by hepatocytes and accounted for the low signal intensity during the hepatobiliary phase on Gd-EOB-DTPA-enhanced MRI. To the best of our knowledge this is the first report in which an FNH-like nodule was assessed for OATP1B3 expression.

Effect of vitamin K2 on the recurrence of hepatocellular carcinoma.

UNLABELLED: Hepatocellular carcinoma (HCC) is characterized by frequent recurrence, even after curative treatment. Vitamin K2, which has been reported to reduce HCC development, may be effective in preventing HCC recurrence. Patients who underwent curative ablation or resection of HCC were randomly assigned to receive placebo, 45 mg/day, or 90 mg/day vitamin K2 in double-blind fashion. HCC recurrence was surveyed every 12 weeks with dynamic computed tomography/magnetic resonance imaging, with HCC-specific tumor markers monitored every 4 weeks. The primary aim was to confirm the superiority of active drug to placebo concerning disease-free survival (DFS), and the secondary aim was to evaluate dose-response relationship. Disease occurrence and death from any cause were treated as events. Hazard ratios (HRs) for disease occurrence and death were calculated using a Cox proportional hazards model. Enrollment was commenced in March 2004. DFS was assessed in 548 patients, including 181 in the placebo group, 182 in the 45-mg/day group, and 185 in the 90-mg/day group. Disease occurrence or death was diagnosed in 58, 52, and 76 patients in the respective groups. The second interim analysis indicated that vitamin K2 did not prevent disease occurrence or death, with an HR of 1.150 (95% confidence interval: 0.843-1.570, one-sided; P=0.811) between the placebo and combined active-drug groups, and the study was discontinued in March 2007. CONCLUSION: Efficacy of vitamin K2 in suppressing HCC recurrence was not confirmed in this double-blind, randomized, placebo-controlled study.

Pathological diagnosis at early stage: reaching international consensus.

Distinguishing small well-differentiated hepatocellular carcinoma (HCC) from dysplastic nodules (DN) is frequently difficult, and the precise pathological diagnosis is a key issue in clinical management of the patients. However, the morphologic criteria for confident diagnosis of early HCC are still controversial. To improve the consistency of pathological diagnosis of early HCC, the International Consensus Group for Hepatocellular Neoplasia comprising 34 pathologists and 2 clinicians from 13 countries was convened in 2002, and the group met on several occasions until 2007. The members discussed the diagnosis of resected nodules <2 cm in diameter at the first meeting and additional sets of small nodules at the second meeting. The overwhelming diagnostic challenge was the differentiation of high-grade DN from well-differentiated small HCC (early HCC). It has been recognized that the presence or absence of 'invasion' is of key importance in deciding if a tumor is malignant or benign. In early HCC, varying degrees of tumor cell invasion (i.e. stromal invasion) into the portal tracts within the tumor is the most helpful morphologic clue to distinguish early HCC from high-grade DN. After the first meeting, the kappa value for HCC rose from 0.30 to 0.49. In addition, it has been well understood that most early HCCs are hypovascular lesions and unlikely classical HCC which is a hypervascular lesion.

Pathology of early hepatocellular carcinoma: conventional and molecular diagnosis.

Recently, an East-West consensus on the histopathologic criteria for the diagnosis of high-grade dysplastic nodules (HGDN) versus early hepatocellular carcinoma (HCC) was reached. Next to classical morphologic criteria such as nucleocytoplasmic ratio, thickness of cell plates, mitotic index, and architectural disturbance like acinar structures, one of the most relevant criteria to diagnose early HCC is stromal invasion. Because a structured basement membrane is lacking along the hepatocytes in the liver, invasion cannot be defined as tumor growth through the basement membrane as in other tissues. However, the number of portal tracts that are present in a nodule gradually decrease because the tumoral hepatocytes start to show a destructive invading growth pattern in the mesenchyma/stroma of these portal tracts. This feature of stromal invasion is however sometimes difficult to recognize in needle biopsies because included portal tracts can be absent. Therefore, other diagnostic criteria are necessary. Based on molecular profiling, several additional markers for early malignant HCC have been found recently. Glypican-3, heat shock protein 70, and glutamine synthetase have been already validated and can be used as a panel of stains to confirm the pathologist's histopathologic diagnosis and to solve difficult cases.

Overall survival after transarterial lipiodol infusion chemotherapy with or without embolization for unresectable hepatocellular carcinoma: propensity score analysis.

OBJECTIVE: Although iodized oil transarterial chemoembolization (TACE) has been found to have survival benefit in the care of patients with unresectable hepatocellular carcinoma, iodized oil infusion chemotherapy without embolization has not been clearly found inferior to or equal to TACE. The purpose of this study was to determine whether one of these therapies is superior to the other or the two are equal in survival benefit and whether embolization with gelatin sponge particles is indispensable to prolonging survival. SUBJECTS AND METHODS: A prospective nonrandomized observational cohort study was conducted over 8 years. Among 11,030 patients with unresectable hepatocellular carcinoma, 8,507 underwent TACE, and 2,523 underwent transarterial infusion therapy with an emulsion of iodized oil and an anticancer agent as initial treatment. Patients with extrahepatic metastasis or any previous treatment were excluded. The primary end point was all-cause mortality. To minimize selection bias, propensity score analysis was used to compare the two groups. RESULTS: During the follow-up period, 5,044 patients (46%) died. In the analysis of all patients, TACE was associated with a significantly higher survival rate than infusion therapy without embolization (hazard ratio, 0.60; 95% CI, 0.56-0.64; p = 0.0001). The propensity score analysis showed that the hazard ratio for death in the TACE group (n = 1,699 patients) compared with the group who underwent infusion therapy without embolization (n = 1,699) was 0.70 (95% CI, 0.63-0.76; p = 0.0001). The median survival time of the TACE group was 2.74 years, and the 1-, 3-, and 5-year survival rates were 81%, 46%, and 25%. The corresponding values for the group who underwent transarterial infusion therapy without embolization were 1.98 years and 71%, 33%, and 16%. CONCLUSION: Propensity score analysis showed that in the treatment of patients with unresectable hepatocellular carcinoma, TACE was associated with significantly better overall survival rates than was transarterial infusion therapy without embolization. TACE can be recommended as initial treatment of these patients.

Clinicopathological study of hepatocellular carcinoma with peliotic change.

Peliosis hepatis-like blood-filled cavities are frequently observed in the tumors of hepatocellular carcinoma (HCC). This finding is generally referred to as 'peliotic change' in HCC. However, the clinicopathological features of HCC with peliotic change (PHCC) are not fully understood. These issues are addressed in the present study. Among 294 consecutively surgically resected HCCs, the clinicopathological features of PHCC were compared with those of a common type of HCC (control). PHCC was observed in 116 (39.5%) of 294 HCCs. The mean tumor diameter of 3.4±0.9 cm of the PHCC group was significantly larger than that of the 2.5±0.9 cm of the control, and the incidence of PHCC was related to increased tumor diameter. In the 116 PHCCs, the tumors were completely or incompletely encapsulated. On ultrasonography, PHCCs showed hyperechoic and/or mosaic patterns. The mean diameter of 3.5±0.8 cm of PHCCs with a hyperechoic and/or mosaic pattern was significantly larger than that of 2.3±0.9 cm in the control. In conclusion, it is necessary for clinicians and pathologists to discern the characteristics of peliotic change as a morphological feature that modifies ultrasound findings.

Characteristic expression pattern of oxidative stress in livers with cryptogenic hepatocellular carcinoma.

The mechanism responsible for the development of hepatocellular carcinoma (HCC) in the setting of oxidative stress has yet to be clearly defined. We studied the role of oxidative stress in hepatocarcinogenesis in subjects without underlying chronic viral hepatitis. The subjects were 24 patients negative for serum hepatitis B surface antigen and hepatitis C antibody tests, who underwent hepatic resection for HCC (Group N). Subjects were excluded if diagnosed with liver disease predisposing to HCC. Immunohistochemical staining for oxidative stress-related markers was performed on non-cancerous liver regions. Resected liver tissues adjacent to HCC from 24 patients with chronic hepatitis B (Group B) and 21 patients with chronic hepatitis C (Group C) were also examined. The percentage of 8-hydroxydeoxyguanosine-positive hepatocytes in Group N was significantly lower than that in Group B and that in the combined population of Groups B and C. The percentage of the area positive for 4-hydroxynonenal in Group N was significantly higher than that in Groups B or C. Meanwhile, the percentage of the area positive for manganese superoxide dismutase in Group N was not different from that in Groups B and C. In conclusion, the mechanism of hepatocarcinogenesis through oxidative stress for patients without known liver disease predisposing to HCC may differ from that for patients with chronic viral hepatitis.

Analysis of subendothelial leukocyte infiltration in the trabecular veins of septic spleen.

The splenic white pulp (WP) consists of CD20-positive lymph follicles (LFs) and CD3-positive periarteriolar lymphoid sheaths. Atrophy of the WP associated with a prolonged period of sepsis is a well-known pathological finding at autopsy. On the other hand, dense subendothelial leukocyte infiltration in the trabecular veins is also commonly observed in autopsy specimens of septic spleen. However, the characteristics and significance of this finding have not yet been well studied. In this study, autopsy spleens obtained from 55 sepsis and 45 non-sepsis patients were compared to determine the clinicopathological characteristics of subendothelial leukocyte infiltration in the trabecular veins, and its pathological significance was discussed. Severe and mild subendothelial leukocyte infiltration in the trabecular veins was observed in 45.5% of sepsis patients, but was absent in non-sepsis patients. Several clinicopathological characteristics of subendothelial leukocyte infiltration were identified. Firstly, the majority of infiltrated cells were lymphocytes. Secondly, both incidence and degree of infiltration were decreased at the late phase of sepsis accompanied by atrophy of the WP. Thirdly, types and compositions of infiltrated leukocytes reflected the histological findings of the spleen. Thus, the percentage of CD20-positive cells in the infiltrating cells into the subendothelium was proportional to the relative size of the CD20-positive area in the specimen, and the percentage of MUM1-p-positive cells in the infiltrating cells was proportional to the frequency of appearance of MUM1-p-positive cells in the red pulp. The CD20-positive area approximated the relative size of the WP in the septic cases, while the frequency of appearance of MUM1-p-positive cells was indicative of the differentiation levels of LFs into plasma cells upon antigen stimulation. Lastly, the intense subendothelial infiltration of CD20-positive cells was specific for the early stage of sepsis, and the morphological characteristics of these CD20-positive cells suggested their association with the marginal zone. Based on these clinicopathological characteristics and the fact that leukocyte infiltration into the subendothelium of trabecular veins became undetectable as atrophy of the WP progressed, it was suggested that the infiltrating cells had migrated from the WP, and this cell infiltration is an early activated immunological reaction in the spleen. Furthermore, the presence of possible efflux or drainage routes in the subendothelial spaces of trabecular veins was suggested.

Report of the 18th follow-up survey of primary liver cancer in Japan.

In the 18th Nationwide Follow-Up Survey of Primary Liver Cancer in Japan, 20 753 people were newly registered as patients with primary liver cancer at 544 medical institutions over a period of 2 years (from 1 January 2004 to 31 December 2005). Of these patients, 94.0% had hepatocellular carcinoma (HCC) and 4.4% had intrahepatic cholangiocarcinoma (ICC). In addition, 30 677 follow-up patients were registered in the survey. Epidemiological and clinicopathological factors, diagnosis and treatment were investigated in the newly registered patients. Compared with the 17th follow-up survey, this follow-up survey in HCC indicated an increase in elder patients and women, a decrease in patients positive for hepatitis B surface antigen and hepatitis C virus antibody, and a decrease in tumor size at the clinical diagnosis. In the local ablation therapy, ratio of radio frequency ablation therapy was increasing. The cumulative survival rates of newly-registered patients between 1994 and 2005 were calculated for each histological type (HCC, ICC, and combined HCC and ICC) and stratified by background factors and treatment. The cumulative survival rates of newly-registered patients between 1978 and 2005 divided into three groups (1978-1985, 1986-1995 and 1996-2005) were also calculated. The data obtained in this follow-up survey should contribute to future research and medical practice for primary liver cancer.

Value of liver parenchymal phase contrast-enhanced sonography to diagnose premalignant and borderline lesions and overt hepatocellular carcinoma.

OBJECTIVE: The objective of our study was to investigate whether liver parenchymal phase contrast-enhanced sonography can provide additional information for assessing histologic grades of hepatocellular carcinoma (HCC). SUBJECTS AND METHODS: Contrast-enhanced sonography using Levovist of 50 hepatic nodules was performed. The vascular and liver parenchymal perfusion patterns were evaluated. The sensitivity, specificity, and accuracy of the histologic diagnosis of the tumors using vascular phase imaging only and systematically combined vascular phase imaging with liver parenchymal phase imaging were calculated. We also performed histologic examination and immunostaining for the detection of Kupffer cells and calculated the Kupffer cell count in the tumorous tissue relative to that in the nontumorous tissue (Kupffer cell ratio) and quantitatively evaluated the relationship between the Kupffer cell ratio and the perfusion patterns seen on liver parenchymal phase imaging. RESULTS: The specificity and accuracy of contrast-enhanced sonography in the diagnosis of dysplastic nodules and of moderately and poorly differentiated HCCs were improved by adding liver parenchymal phase imaging (dysplastic nodules, 74% and 78% vs 83% and 86%, respectively; moderately and poorly differentiated HCCs, 74% and 86% vs 85% and 92%). The diagnostic accuracy of contrast-enhanced sonography for dysplastic nodules showed a trend of improvement with the addition of liver parenchymal phase imaging (p = 0.07). Kupffer cell ratios for tumors that showed hypoperfusion during the liver parenchymal phase were significantly lower than those for tumors showing isoperfusion (p < 0.05). CONCLUSION: Adding liver parenchymal phase imaging to contrast-enhanced sonography protocols may yield additional information that can be used to assess histologic grades of tumor and that leads to an improvement in the differential diagnosis of nodular lesions associated with the cirrhotic liver. Further case studies are required in larger numbers of patients for a longer follow-up period.

Angiosarcoma of the breast with silicone granuloma: a case report.

Angiosarcoma of the breast is a rare non-epithelial tumor and that accounts for less than 0.1% of primary malignancies of the breast. The disease has a relatively higher occurrence among young people, and its prognosis (3-year-survival of only 38%) is extremely poor compared to breast cancer. Here we present a case of an 87-year-old woman who had undergone bilateral breast augmentation with silicone injections in her youth. Although she became aware of a tumor in her right breast, she waited 8 years before seeking treatment. She felt the tumor growing and experienced swelling and pain, but she ended up declining therapy at that time. Two years later she was brought to our hospital by ambulance for continuous bleeding from the same tumor of the breast, which by that time was over 11 cm in diameter. We performed emergency mastectomy. The histological diagnosis was angiosarcoma of the breast with silicone granuloma.

[Epithelioid hemangioendothelioma of the liver diagnosed by laparoscopy guided biopsy].

A 35-year-old woman was admitted to our hospital for right upper quadrant pain and multiple liver tumor were detected by diagnostic imaging. Tumors located near the surface of the liver which accompanied capsular retraction. Diagnostic laparoscopy showed multiple white tone tumors with retraction of the adjacent liver capsule. Tumor targeted biopsy was performed. The pathologic diagnosis of epithelioid hemangioendothelioma (EHE) was made by the positive staining of factor VIII-related antigen. EHE tend to locate in peripheral and extend to the liver capsule. Therefore, we face difficulties in getting biopsy sample safely. Here we report a useful case of laparoscopic examination and biopsy in the diagnosis of EHE.

[A case of hepatic eosinophilic granuloma, which needs distinction with metastatic liver cancer].

A 68-year-old man was referred to our hospital because of eosinophilia in peripheral blood and pancreatic tumor on abdominal US. He was accustomed to eating the raw flesh of wild boar and keeping wild boar, and under medical treatment for Diabetes. Pancreatic tumor was diagnosed to the pancreatic ductal cancer by the imaging examination and endoscopic transpapillary brushing cytology for pancreatic duct. The diagnosis of hepatic eosinophilic granuloma was done by aspiration biopsy for hepatic multiple small nodules. Because of the strong positive finding for nematose in the assay of multi dot-ELISA for parasite, hepatic eosinophilic granuloma caused by visceral larva migrans was accidentally complicated by pancreatic cancer, and operation for the pancreatic cancer was done. To bear this disease in mind and to research his life history, is important to diagnose hepatic multiple nodules with eosinophilia.

Growth inhibitory effects of pegylated IFN-alpha2b and 5-fluorouracil in combination on renal cell carcinoma cell lines in vitro and in vivo.

We investigated the effects of pegylated IFN-alpha2b (PEG-IFN-alpha2b) alone and PEG-IFN-alpha2b plus 5-fluorouracil (5-FU) in vitro on the proliferation of renal cell carcinoma (RCC) cell lines. After the transplantation of RCC cells into nude mice, we administered IFN (PEG-IFN-alpha2b or IFN-alpha2b) alone, 5-FU alone, or IFN (PEG-IFN-alpha2b or IFN-alpha2b) plus 5-FU; and investigated tumor volume, tumor weight, the numbers of apoptotic cells and artery-like blood vessels, relative mRNA expression levels of enzymes which relate to 5-FU metabolism, angiogenesis factor, and type I interferon receptor. RCC cells in vitro were generally and relatively resistant to the anti-proliferative effects of PEG-IFN-alpha2b, but the addition of 5-FU augmented IFN-induced anti-proliferative effects with the induction of apoptosis. PEG-IFN-alpha2b in vivo presented stronger anti-tumor effects than IFN-alpha2b, and its combination with 5-FU augmented the effects. The significant anti-tumor effect of the combination treatment was the increase in apoptotic cell number, but there were no significant differences in the suppression of angiogenesis, expression of IFN receptor, and the actions of metabolic enzymes of 5-FU. In conclusion, PEG-IFN-alpha2b presents stronger anti-tumor effects than non-pegylated IFN, and the effects are augmented in the combination with 5-FU. Our findings suggest the clinical usefulness of PEG-IFN-alpha2b in the treatment of RCC.

Hepatocellular carcinoma with a "nodule-in-nodule" appearance reflecting an unusual dilated pseudoglandular structure.

We present a case of hepatocellular carcinoma (HCC), showing an atypical "nodule-in-nodule" appearance on ultrasonogram (US). In general, a "nodule-in-nodule" appearance is found as a hyperechoic tumor containing a hypoechoic nodule. In the present case, however, there was a hyperechoic subnodule in the center of the tumor, which was surrounded by a hypoechoic tumor area. Histologically, the subnodule consisted of moderately differentiated HCC with a markedly dilated pseudoglandular structure, and the outer tumor consisted of well-differentiated HCC with a thin-trabecular pattern. It should be noted that there is a rare HCC with dilated pseudoglandular structure showing the inversed "nodule-in-nodule" appearance.

Surgical resection vs. percutaneous ablation for hepatocellular carcinoma: a preliminary report of the Japanese nationwide survey.

BACKGROUND/AIMS: The treatment of choice for HCC remains controversial. We evaluated the therapeutic impact of surgical resection, PEI, and RFA for HCC on outcomes. METHODS: A database derived from a Japanese nationwide survey of 17,149 patients with HCC treated by resection, PEI, or RFA between 2000 and 2003 was used to identify 7185 patients with no more than 3 tumors (< or = 3 cm) and a liver function of Child-Pugh class A or B. The patients classified into either a resection (n=2857), RFA (n=3022), or PEI group (n=1306) and their long-term outcomes were compared. RESULTS: The median follow-up period was 10.4 months. The 2-year time-to-recurrence rate was 35.5%, 55.4%, and 73.3% in the resection, RFA, and PEI groups, respectively, while the number of recurrences was 2410, 2368, and 862. Although the number of deaths was 55 (1.9%), 49 (1.6%), and 39 (3.0%), the overall survival rates were not different. In a multivariate analysis, surgical resection was a significant negative factor for recurrence as compared with RFA (relative risk, 0.62 [95% confidence interval, 0.54-0.71], P<0.0001) and PEI (0.45 [0.38-0.52], P<0.0001). CONCLUSIONS: This preliminary report suggested that surgical resection may provide less time-to-recurrence rate than either RFA or PEI in patients with HCC.