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Although living-donor liver transplantation (LDLT) of right lobe graft is becoming a popular option for adult patients, management of venous outflow remains controversial. We report a successful extended-right lobe liver transplantation using a recipient's left portal vein as a graft from the middle hepatic vein. Preoperative three-dimensional computed tomography (3D-CT) of the donor revealed a small right hepatic vein (RHV) without inferior RHV and a large middle hepatic vein (MHV) draining segments 5 and 8. During the donor operation, right lobe graft was harvested with the MHV, preserving the drainage vein from segment 4. The donor recovered uneventfully except for mild transient hyperbilirubinemia. The recipient's condition rapidly improved, and was discharged from hospital 49 days postoperation. A 3D-CT after LDLT also clearly revealed successful vascular anastomosis. Preoperative and postoperative 3D-CT was useful for determination of the vascular anatomy and the decision about the line of transection in the donor hepatectomy, as well as for evaluation of the vascular anastomoses after transplantation.

Background. Preoperative percutaneous transhepatic portal vein embolization (PTPE) increases the safety of liver resection and improves the outcome after surgery for hepatocellular carcinoma. Scintigraphy with 99mTc-galactosyl human serum albumin (GSA) causes specific binding to viable hepatocytes and serves as an index of liver function. Materials and methods.99mTc-GSA scintigraphy was performed before and 2 weeks after PTPE of the right portal vein in 16 patients. The total receptor index, reflecting overall liver function, right receptor index (right lobe), and left receptor index (left lobe) were calculated. Results. After PTPE, the proportion of the volume of the nonembolized lobe (left lobe) increased (P = 0.0002). The total receptor index slightly decreased after PTPE (P = 0.090), the right receptor index decreased (P < 0.0001), and the left receptor index increased (P < 0.0001). The average increase rate in the left receptor index was 30% of the pre-PTPE value. In 2 patients with portal hypertension (≥30 cm H2O) after PTPE, the left receptor index did not change. In 4 patients whose left receptor index after PTPE (including the 2 patients with portal hypertension) was

Patients with hepatolithiasis are known to be complicated with bile stasis and bacterial infections in the stone-containing ducts. It has been suspected that a decrease in portal venous flow is important in the progression of hepatolithiasis. This study was done to find if the affected liver in hepatolithiasis is inflamed or has lowered local immunity by an examination of the distribution of secretory immunoglobulin A and proliferating cell nuclear antigen in the intrahepatic biliary tracts in operative specimens of 36 patients with hepatolithiasis. The number of biliary epithelia stained for the immunoglobulin was greater when the cholangitis was more severe up to a point; in advanced cholangitis, with severe parenchymal atrophy or proliferating epithelia, there were fewer cells stained for the immunoglobulin than in mild cholangitis. In hepatolithiasis, secretory immunoglobulin A decreases when inflammatory changes become severe and there is parenchymal atrophy caused by stenosis or obstruction of portal branch.

To identify clinicopathologic features of distant metastatic recurrence (DMR) after hepatic resection for hepatocellular carcinoma, we investigated 352 recurrent patients. Of them, 261 with only intrahepatic recurrence were compared with 91 with DMR. Between two groups, there was significantly difference with respect to preoperative liver function, positive tests for protein induced by vitamin K absence or antagonist-II (PIVKA-II), major resection, tumor-free interval, tumor diameter, extrahepatic progression of the tumor, single nodular configuration, and portal vein invasion. Survival rates at 1 and 5 years after intrahepatic recurrence were 73% and 17%, while these were 57% and 18% when recurrences were DMR (p = .0362). DMR was frequent when a resected tumor was large, extrahepatic, ill defined or multinodular or associated with portal vein invasion, good preoperative liver function, or PIVKA-II positivity. Such patients should receive particularly careful follow-up during the first 2 years after hepatic resection focusing on early detection of DMR.

Despite progress in therapeutic modalities for hepatocellular carcinoma, chemotherapy is the only remaining option for a considerable number of patients because of severe advanced disease and/or cirrhosis. Repeated hepatic arterial infusion chemotherapy with portal branch ligation and decollateralization using a silicone rubber sheet was performed for hepatocellular carcinoma. Tumor size and serum concentration of alpha-fetoprotein markedly decreased after hepatic arterial infusion chemotherapy. Although the patient had no recurrent tumor, he died of hepatorenal failure 7 years after treatment. Hepatic arterial infusion chemotherapy combined with portal branch occlusion and decollateralization is a new therapeutic method for unresectable hepatocellular carcinoma.

The mixed type of combined hepatocellular carcinoma and cholangiocarcinoma is particularly rare. Hepatic resection was performed for two patients with mixed hepatocellular carcinoma and cholangiocarcinoma. In case 1, a 55-year-old Japanese man was found to have a hepatic tumor on ultrasonography. Since ultrasonically-guided needle biopsy revealed that the tumor was poorly differentiated hepatocellular carcinoma, the patient underwent a limited hepatic resection. Histologic and immunohistochemical examination revealed that the tumor had elements of both hepatocellular carcinoma and cholangiocarcinoma. Six months after surgery, the patient died of systemic recurrences. In case 2, a 58-year-old man was found by ultrasonography to have a hepatic tumor occupying the entire right hepatic lobe. Computed tomography revealed that the tumor had a portal tumor thrombus. The diagnosis of hepatocellular carcinoma was made because of a markedly elevated serum alpha-fetoprotein concentration, and a right hepatic lobectomy was performed. Histologic and immunohistochemical examination confirmed that the lesion was mixed hepatocellular and cholangiocellular carcinoma. The patient died of multiple recurrent tumors in the remnant liver 3 months after surgery. Surgical control of mixed hepatocellular carcinoma and cholangiocarcinoma is difficult.

The prognosis after curative resection for patients with carcinoma of the papilla of Vater is relatively better than that for other peripancreatic cancer. However, prognostic factors after resection of the carcinoma have not been identified.From 1983 to 1999, 16 patients with carcinoma of the papilla of Vater underwent standard pancreatoduodenectomy and dissection of regional lymph nodes. We followed the patients for 63 days to 17 years (median, 27 months) and analyzed clinicopathologic variables in relation to prognosis.The survival rate at 5 years was 50.5%. The morphologic factors predicting poor outcome were macroscopic ulcer formation and microscopic pancreatic, venous, or perineural invasion. Tumors with ulcer formation tended to infiltrate into the duodenum and pancreas, but not into veins or the perineural space. Eight of 16 patients died due to recurrence of the cancer; liver metastasis (n = 6) or peritoneal dissemination (n = 2).Patients with carcinoma of the papilla of Vater demonstrating ulcer formation or invasion into the pancreas, vein, or perineural space may benefit from adjuvant therapy to reduce the risk of liver metastasis. Careful observation is essential for liver metastasis or peritoneal dissemination after surgery; especially in patients with ulcer formation or venous invasion.

A 65-year-old Japanese man with chronic hepatitis C was found to have a hepatic tumor by ultrasonography. Both dynamic computed tomography and hepatic angiography showed a hypervascular tumor with a central defect. Since a diagnosis of hepatocellular carcinoma was made, transcatheter arterial embolization was performed. However, the tumor metastasized to systemic lymph nodes and the patient died 3 months after treatment. An autopsy was performed. Histologic examination of the hepatic tumor revealed that the peripheral part was completely necrotic and the central area was composed of strands of pleomorphic cells with focal gland formation surrounded by fibrosis. No production of mucin or bile was evident. The microscopic findings of metastatic lymph nodes were similar to those of the central portion of the hepatic tumor. Immunohistochemical strains of the hepatic tumor and lymph node metastases showed diffuse positivity for cytokeratins 7 and 19, while hepatocyte paraffin 1 was focally reactive. These findings suggest that the hepatic tumor was a combined hepatocellular carcinoma and cholangiocarcinoma. Since the tumor expressed dual phenotypic markers of both hepatocytes and bile duct cells, the tumor might have an intermediate phenotype between hepatocytes and bile duct cells.

We examineded the clinical effects of serum hepatitis B e antigen (HBeAg) positivity on clinicopathologic findings and prognosis after liver resection for hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. A series of 56 patients who underwent curative resection were divided into two groups: 25 HBeAg-positive patients (group 1) and 31 HBeAg-negative patients (group 2). The mean age was significantly lower in group 1 than in group 2 (p = 0.0021), and the proportion of patients with symptoms was significantly higher in group 1 than in group 2 (p = 0.037). There were no significant differences in other clinical findings between the two groups, including laboratory test results, coexisting medical conditions, and operative methods. Although tumor size, degree of differentiation of the main tumor, and the prevalence of vascular invasion did not differ between the groups, the prevalence of intrahepatic metastasis and the proportion of patients with active hepatitis were significantly higher in group 1 than in group 2 (p = 0.009 and p = 0.043, respectively). Tumor-free and cumulative survival rates were significantly lower in group 1 than in group 2 (p = 0.022 and p = 0.0001, respectively). Multivariate analysis of various possible risk factors demonstrated serum HBeAg positivity to be an independent risk factor for recurrence [risk ratio (RR) 2.49; 95% confidence interval (CI) 1.12-5.49; p = 0.032] and an independent unfavorable factor for the survival time (RR 7.58; 95% CI 2.10-27.8; p = 0.0020). We concluded that the prognosis after liver resection for HCC is worse for HBeAg-positive patients than for HBeAg-negative patients.

The separate-lesion type of combined hepatocellular carcinoma and cholangiocarcinoma is particularly rare. We treated two such patients with hepatic resection after performing dynamic computed tomography. In case 1, a 64-year-old Japanese man with chronic hepatitis C underwent right hepatic lobectomy for two hepatic tumors; both tumors originally were thought to be hepatocellular carcinomas because both were hypervascular. However, histologic examination revealed that one tumor was hepatocellular carcinoma and another tumor was tubular adenocarcinoma. In case 2, a 73-year-old man, a second lesion was detected 8 months after transcatheter arterial embolization for hepatocellular carcinoma associated with chronic hepatitis C. The newer lesion in case 2 showed delayed enhancement by dynamic computed tomography. We diagnosed the lesion as cholangiocarcinoma and performed right hepatic lobectomy and dissection of lymph nodes in the hepatoduodenal ligament. Histologic examination confirmed that the new lesion was tubular adenocarcinoma. Case 1 and 2 respectively represent synchronous and metachronous occurrence of the separate-lesion variety of combined hepatic cancer.

Background. The clinicopathologic features of cystic neoplasms of the liver, such as cystadenoma and cystadenocarcinoma, are poorly defined because these lesions are extremely rare. Methods. Clinicopathologic findings in six patients who underwent surgery for a cystic hepatic neoplasm were reviewed retrospectively to determine the best surgical strategy to treat this condition. Results. Five patients had a multilocular cyst or elevated lesions detected on preoperative imaging studies. The remaining patient had elevated serum concentrations of carcinoembryonic antigen and carbohydrate antigen 19-9, even though preoperative imaging studies of the hepatic cystic lesion revealed no imaging features of cystadenocarcinoma. Cytology failed to detect malignant cells in the cyst contents of any patient. One patient underwent palliative resection because pleural dissemination was present, and five patients underwent curative resection. Three patients had cystadenoma diagnosed in the surgical specimen. One patient with cystadenocarcinoma has survived for more than 8 years after a curative resection that was limited to the cyst wall, and another patient died of recurrence 13 months after surgery. Conclusions. When a cystic neoplasm is suspected of being cystadenocarcinoma, hepatic resection should be considered, because reliable criteria for distinguishing cystadenoma from cystadenocarcinoma clinically do not exist.

The prognosis of patients with intrahepatic cholangiocarcinoma is different for the different macroscopic types of this tumor. This study correlated clinicopathologic features and outcome after surgery with macroscopic types of intrahepatic cholangiocarcinoma to determine prognostic predictors.Resected intrahepatic cholangiocarcinomas were classified into the following growth types: mass-forming (n = 10), periductal-infiltrating (n = 11), mass-forming plus periductal-infiltrating (n = 14), and intraductal (n = 2). Intraductal tumors were not considered further. The prognostic significance of clinicopathologic features was determined by univariate and multivariate analyses.Perineural invasion (P = 0.00051), lymphatic invasion (P = 0.0088), and positive resection margin (P = 0.028) were less frequent in patients with mass-forming tumors than with mass-forming plus periductal-infiltrating tumors. Patients with mass-forming plus periductal-infiltrating tumors had shorter survival than those with mass-forming tumors (P = 0.0072). By univariate analysis, an elevated serum carcinoembryonic antigen concentration, lymphatic invasion, lymph node metastasis, intrahepatic metastasis, and positive resection margin predicted shorter survival after surgery. An elevated serum carcinoembryonic antigen concentration, lymphatic invasion, and positive resection margin were independent prognostic factors on multivariate analysis. The macroscopic type did not correlate independently with prognosis.Extended hepatic resection should be performed in patients with intrahepatic cholangiocarcinoma to obtain a tumor-free margin of resection.

Treatment for dissemination of hepatocellular carcinoma to the peritoneum has not yet been established. A case of a 62-year-old man who underwent curative resection for hepatocellular carcinoma 1 month after ultrasonically guided needle biopsy is presented. At 23 months after surgery, computed tomography revealed a mass in the abdominal cavity. At laparotomy 3 months later, a peritoneal tumor deposit directly invading the colon was resected in continuity with a portion of large intestine. The tumor was confirmed histopathologically to represent dissemination of hepatocellular carcinoma. No other lesions were detected 20 months after the second operation. Surgical treatment can locally control peritoneally disseminated hepatocellular carcinoma provided that lesions have limited extent.

The clinicopathologic findings in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) positive for biliary markers, those related to the hepatic progenitor cells, were investigated. Cytokeratin (CK) 19 was reactive for HCCs only in patients with prior hepatitis B virus (HBV) infection. The proportions of patients with prior HBV infection and poorly differentiated HCC were significantly higher among those with CK 19-positive HCC than among those with CK 19-negative HCC. Some HCCs develop from the hepatic progenitor cells in patients with HCV infection and prior HBV infection, which may affect the clinicopathologic findings of HCV-related HCCs.

Long-term survival following hepatectomy for intrahepatic cholangiocarcinoma has been poor, and specific factors influencing survival are unclear. In a retrospective study we sought to determine prognostic factors related to survival in these patients. In 28 patients who underwent hepatic resection for intrahepatic cholangiocarcinoma, we investigated the relations of several histologic factors to patient survival by univariate and multivariate analyses. No deaths occurred during the first 30 days. Median and mean survival times following hepatectomy were 409 and 935 days, respectively. The respective survival rates at 1, 3, and 5 years were 57%, 27%, and 27%. Resection margin status, intrahepatic metastasis, lymph node involvement, and lymphatic invasion were significant predictors of outcome. In a multivariate analysis using the Cox proportional hazards model, only lymphatic invasion independently predicted survival. Curative resection with clear margins was found to prolong survival after surgery. Hepatectomy for intrahepatic cholangiocarcinoma without lymphatic invasion offers hope for long-term survival.

Interferon therapy decreases the incidence of hepatocellular carcinoma in patients with chronic hepatitis C.To evaluate effects of interferon-alpha on recurrence after resection of hepatitis C virus-related hepatocellular carcinoma.Randomized, controlled trial.University hospital, medical center, and affiliated hospital in Osaka, Japan.30 men were randomly allocated after resection to the interferon-alpha group (n = 15) or the control group (n = 15).Patients in the interferon-alpha group received interferon-alpha, 6 MIU intramuscularly daily for 2 weeks, then three times weekly for 14 weeks, and finally twice weekly for 88 weeks.Recurrence rates after resection.Recurrent tumors were detected in 5 patients in the interferon-alpha group and in 12 control patients. The recurrence rate was significantly lower in the interferon-alpha group than in the control group (P = 0.037).Postoperative interferon-alpha therapy appears to decrease recurrence after resection of hepatitis C virus-related hepatocellular carcinoma.

One potential risk of percutaneous transhepatic biliary drainage is tumor seeding along the catheter tract. A 57-year-old woman with obstructive jaundice due to hilar cholangiocarcinoma underwent an extended left hepatic lobectomy, a regional lymph node dissection, and a right hepaticojejunostomy 2 weeks after percutaneous transhepatic biliary drainage. Multiple right pleural masses were found on a chest radiogram 14 months after the operation. No recurrent lesions were detected in the abdominal cavity. A right panpleuropneumonectomy was performed; however, the patient died of respiratory failure due to tumor recurrence 9 months after the second operation. Preoperative percutaneous transhepatich biliary drainage was considered to have resulted in pleural implantation.

Interferon (IFN) therapy decreases the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV). One hundred and fifty-nine consecutive patients who underwent liver resection for HCV-related HCC were studied. In 17 (group 1) of the 159 patients, HCC was detected during or after IFN therapy. The incidences of recurrence after surgery in the group 1 patients and the other 142 patients (group 2) were compared. Eight patients had a complete response to IFN, 4 had a partial response, and 5 had no response. The proportion of patients without HCV viremia was significantly higher in the group 1 patients (P < 0.0001). The tumor-free survival rate was significantly higher in the group 1 patients (P = 0.0010). By multivariate analysis of various risk factors for recurrence, no previous IFN was a significant independent risk factor for recurrence (risk ratio = 6.336; 95%CI, 1.512 - 26.50). The patients with HCC who underwent IFN therapy previously are good candidates for liver resection because recurrence after the operation was rarely observed.

A 39-year-old woman with acute cholecystitis and gallstones underwent laparoscopic cholecystectomy. She suffered from recurrent episodes of cholangitis due to injury of the major bile ducts during laparoscopic cholecystectomy. Hepatobiliary scintigraphy with Tc-99m Sn-N-pyridoxyl-5-methyltryptophan was performed. Although normal bile excretion was found from the left hepatic duct to the percutaneous transhepatic biliary drainage (PTBD) tube, excretion from the right hepatic lobe was prolonged. Scintigraphy with Tc-99m diethylenetriaminepentaacetic acid-galactosyl human serum albumin demonstrated atrophy of the right hepatic lobe and enlargement of the left hepatic lobe. Cholangiography via the PTBD tube revealed complete obstruction of the left hepatico-jejunal anastomosis and could not enhance the right intrahepatic bile duct. A right hepatic lobectomy was performed because of the atrophy, glissonitis and the absence of an appropriate bile duct for reconstruction. Postoperatively she was active and exhibited no evidence of recurrent cholangitis.

A 56-yr-old man with complaint of abdominal pain and body weight loss was admitted to our hospital. Contrast-enhanced computed tomography on admission revealed a pancreatic tumor. Contrast-enhanced computed tomography 1 m.o. after admission revealed rapid growth of this tumor. We performed exploratory laparotomy with only a needle biopsy of the unresectable tumor because of extensive spread, including liver metastases. Further histological and immunohistochemical examination revealed that both the pancreatic tumor and the hepatic metastases featured malignant spindle-shaped cells. Despite radiotherapy, the patient died 40 d after laparotomy.

BACKGROUND Risk factors for recurrence after resection of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) require more precise definition. METHODS Forty patients who underwent liver resection for HBV-related HCC were studied. Their clinical findings, laboratory data (including viral status), pathologic findings, and operative methods were evaluated for recurrence risk in univariate and multivariate analyses. RESULTS The HB envelope (HBe) antigen, wild-type HBV, intrahepatic metastases, elevated serum activities of aspartate aminotransferase and alanine aminotransferase, and moderately or severely active hepatitis were more likely to be found in patients with a high viral load than in patients with a low viral load. Precore mutant-type HBV was more likely to be found in patients with a low viral load than in patients with a high viral load. The platelet count was significantly lower in the patients with a high viral load. A high viral load, the presence of wild-type HBV, the absence of anti-HBe, the absence of precore mutant-type HBV, Child score B, a low platelet count, and a positive surgical margin were risk factors for recurrence in univariate analysis. A nonanatomic resection tended to be a risk factor. A high viral load and positive surgical margin were independent risk factors for recurrence. CONCLUSIONS The measurement of viral load and detection of anti-HBe, wild-type HBV, and precore mutant-type HBV are useful for estimating a patient's prognosis after resection of HBV-related HCC. Cancer 2000;88:1016–24. © 2000 American Cancer Society.

A 65-year-old man with chronic hepatitis C showed a markedly elevated serum alpha-fetoprotein concentration. Computed tomography revealed a huge tumor occupying the entire right hepatic lobe. Three months later, the tumor regressed spontaneously from 12 cm to 7 cm in diameter without any medical treatment. A right hepatic lobectomy was performed 4 months after the initial diagnosis. The main tumor, located in the posterior inferior segment, was completely necrotic, and had a thick fibrous capsule. Many inflammatory cells had also infiltrated into the tumor. Only a small portion of a tumor thrombus in the portal vein and one of three intrahepatic metastases contained viable cancer cells. The tumor was found to be poorly differentiated hepatocellular carcinoma. Tumor regression may have been caused by a disturbance in hepatic circulation associated with the portal vein thrombus.

The relationship between multicentric occurrence of hepatocellular carcinoma (HCC) and the histology of noncancerous hepatic tissue was investigated in 252 patients infected with hepatitis C virus (HCV) and surgically treated for HCC. One type of multicentric HCC had at least one tumor consisting of well-differentiated HCC, together with moderately or poorly differentiated HCC located in a separate region. The other type had an area of well-differentiated component around HCC with less differentiation in all occurrences. Noncancerous hepatic tissues were assessed using a histologic activity index score. Serum alanine aminotransferase (ALT) activity, the concentration of type 4 collagen, the grading score (severity of active hepatitis), and the staging score (degree of fibrosis) were significantly higher in patients with multicentric HCCs than in those without them. Platelet count was significantly lower in patients with multicentric HCCs. The prevalence of multicentric HCCs increased as the grading score and staging score increased. On univariate analysis, a low platelet count and high grading and staging scores were risk factors for multicentric HCCs. A high ALT activity and a high concentration of type 4 collagen tended to be risk factors. On multivariate analysis, high grading score and high staging score were independent risk factors. These findings indicate that active hepatitis and extensive fibrosis are responsible for the development of multicentric HCCs. Measurement of platelet count, ALT activity, and the concentration of type 4 collagen, and histologic assessment of noncancerous hepatic tissue provide information useful for estimation of the potential for multicentric carcinogenesis.

Serological research suggests that hepatitis B virus (HBV) and hepatitis C virus (HCV) are associated with the development of hepatocellular carcinoma (HCC). It is unclear how genes of hepatitis viruses participate in hepatocarcinogenesis in patients infected with HCV. We investigated the expression of hepatitis virus-related RNAs in resected liver from 51 patients with HCV antibodies (Ab) and without hepatitis B surface antigen (HBsAg). mRNA transcripts of the genes HBx, HBc, HBs, nonstructural (NS) region 3 of HCV, the 5'-untranslated region (UTR) of HCV, and the 5'-UTR of hepatitis G virus (HGV) were amplified by reverse-transcription polymerase chain reaction (RT-PCR) with specific primers for each gene. The HBx transcript was detected in 19 (37%) tumors and in 8 (16%) specimens of noncancerous tissues (P =.014). The NS3 gene of HCV was detected in 35 (69%) tumors and 41 (80%) noncancerous tissues. HGV RNA was detected in 3 tumors (6%). Patients with HBx transcripts were younger than patients without HBx transcripts (P =.012). HBx transcripts were detected in 3 (33%) of 9 well-differentiated HCCs, in 8 (31%) of 26 moderately differentiated HCCs, and in 8 (50%) of 16 poorly differentiated HCCs. Codon 130 (AAG) and codon 131 (GTC) of HBx were changed to ATG and ATC, respectively, in all HCCs with HBx transcripts. In conclusion, we found that the HBx gene was expressed in many HCCs; the gene might promote hepatocarcinogenesis in patients with HCVAb and without HBsAg, but HGV is not closely related to hepatocarcinogenesis in such patients.

Percutaneous transhepatic portal vein embolization (PTPE) produces regenerative hypertrophy in the nonembolized part of the liver, but the regenerative capacity after PTPE in patients with chronic hepatitis is unknown. We studied 34 patients with hepatocellular carcinoma and chronic hepatitis who underwent PTPE at the right portal vein. Hepatic lobular volumes were calculated by computed tomography before and 2 weeks after PTPE. The increase in left lobular volume was analyzed using a stepwise multiple regression method incorporating 11 factors: age; portal venous pressure; proportional volume of the right lobe; indocyanine green retention test; platelet count; serum levels of aspartate transaminase, alanine transaminase, total bilirubin, and albumin; and histological inflammatory grade and stage of fibrosis, according to the criteria of the International Association for the Study of the Liver recommended at their 1994 meeting. The median volume of the left lobe had increased from 405 to 554 cm3 (P < 0.0001) by 2 weeks after PTPE. Inflammatory grade was the only independent factor predicting regenerative hypertrophy (regeneration ratio (%) = 80.3 − 20.1 × grade; standard correlation coefficient = −0.566; P = 0.0014). Histological inflammatory activity was the essential factor regulating liver regeneration after PTPE in patients with chronic hepatitis.

We investigated polyamine metabolism in hepatocellular carcinorma (HCC) with respect to tumor volume doubling time, degree of differentiation, and prevalence of portal invasion and intrahepatic metastasis. Ornithine decarhoxylase (ODC) activity and the spermidine/spermine ratio were correlated with tumor volume doubling time. ODC activity was higher in moderately and poorly differentiated HCC than in well-differentiated HCC. The prevalence of portal invasion and intrehapatic metastasis was higher in patients with high ODC activities. We conclude that polyamine metabolism in HCC estimates the degree of malignancy.

Hepatocellular carcinoma with chondrosarcomatous variation is very rare. We report a case with the results of pathology examination, and review the literature. The patient, a 72-year-old may had a very large tumor in the liver revealed during follow-up for diabetes mellitus. The liver mass, which was 14 cm in diameter, was diagnosed as hepatocellular carcinoma by abdominal ultrasonography. Anterior segmentectomy and partial liver resection were performed. Histopathology examination revealed that the tumor consisted of two different components: the major one was hepatocellular carcinoma (HCC), which occupied most of the tumor; and a sarcomatous component, which occupied a smaller area, and included spindle-shaped cells with chondroscarcomatous variation. Intrahepatic metastases and tumor thrombi of HCC were also found in portal and hepatic veins. Investigations of the immunohistochemical localization of keratin (KRT), vimentin (VMT), and S-100 protein (S 100) were performed by the avidin-biotin complex method. Some of the spindle cells were immunohistochemically positive for both KRT and VMT, and the chondrosarcomatous cells were positive for S 100. These results strongly suggested that the sarcomatous lesion resulted from a sarcomatous change of HCC.

Background: Although transcatheter arterial embolization is advocated as initial therapy for ruptured hepatocellular carcinoma (HCC), hepatic resection is necessary for cure. The effectiveness of delayed hepatic resection for ruptured HCC was determined. Methods: The records of 10 patients who underwent delayed hepatic resection for ruptured HCC were reviewed. Results: All patients were men, and the mean age was 63 years. For hemostasis, transcatheter arterial embolization was performed in three patients, whereas in the other patients bleeding stopped without special procedures. Mean interval from rupture to hepatic resection was 74 days. Liver function test results before hepatic resection were almost normal. Trisegmentectomy in one and bisegmentectomy in four patients were performed, whereas minor hepatic resection was performed for four extrahepatic HCCs. There were no operative or hospital deaths. Four patients had cirrhosis. The mean tumor diameter was 7.5 cm. Of seven patients with recurrence, two with dissemination had tumors that ruptured on the inferior aspect of the liver. The 1- and 3-year survival rates were 77% and 48%, respectively. Conclusions. Because delayed hepatic resection for ruptured HCC was safe and compared similarly with that for other patients who underwent resection for HCC, it should be used. However, when HCC ruptures in an inferior location, recurrence of tumor as dissemination is likely. (Surgery 1998;124:33-7.)

In the cirrhotic and precirrhotic liver, there may be small foci with increased cellularity and amphophilic cytoplasm. These are microscopic lesions that do not form macroscopically detectable nodules, which differ from the macroscopically apparent nodules of dysplastic nodules. In the present study, we assessed the proliferating activity of 12 hyperplastic foci in 11 patients with cirrhosis or chronic hepatitis, by staining for agyrophilic nucleolar organizing regions (AgNOR). The mean AgNOR count per nucleus in the hyperplastic foci ranged from 0.96 to 1.36 (mean, 1.13; SD 0.12), and from 0.81 to 1.06 (mean, 0.94; SD 0.08) in the controls. The AgNOR count in the hyperplastic foci was significantly higher than that in the controls (P < 0.01). Small hyperplastic foci show increased proliferative activity. Further study on these foci is required to clarify their relation to hepatocarcinogenesis.

Background: Alcohol abuse is a risk factor for hepatocellular carcinoma (HCC) and the recurrence of HCC after resection. We therefore investigated polyamine metabolism, which is important in cell proliferation, HCC tissue, and noncancerous hepatic tissue. Methods: In 30 patients who underwent liver resection for HCC, 13 patients had drunk 86 gm or more ethanol per day for at least 10 years (group 1), whereas the remaining 17 patients were nondrinkers or occasional drinkers (group 2). The control subjects were five patients who did not have liver disease or abuse alcohol. Tissue ornithine decarboxylase (ODC) activity and polyamine concentrations were measured. Results: ODC activity in the HCC tissue was significantly higher in group 1 than in group 2. ODC activity in noncancerous tissue was significantly higher in group 1 than in group 2 and the control group. The ratio of spermidine/spermine in the HCC tissue was significantly higher in group 1 than in group 2. The ratio in noncancerous tissue was significantly higher in groups 1 and 2 than in the control group. Conclusions: Alcohol abuse affects polyamine metabolism, which influences the grade of malignancy of HCC. Hepatic tissue has greater potential for carcinogenesis in patients with chronic liver disease and alcohol abuse than in patients without them. (Surgery 1998;123:205-11.)

The phase S ratio in cell cycles were analyzed in livers with hyperplastic foci (HPF) and in livers without HPF by nuclear DNA determinations using flow cytometry, and by staining with argyrophilic proteins of the nucleolar organizer region (AgNOR). Flow cytometric analysis was done on 50 fresh frozen specimens of livers resected from 50 patients with hepatocellular carcinoma (HCC). Paraffin sections from the same patients were analyzed using AgNOR staining. There were 25 cases each with and without HPF. We examined the stage of fibrosis and the grade of inflammatory activity according to the modified Scheuer and Desmet scale. The incidence of HCC recurrence among these patients was also studied. The average phase S ratio of the livers of the patients with HPF was 6.5 +/- 3.2%, and that of the livers of the patients without HPF was 4.0 +/- 2.5%. The ratio differed significantly between the two groups (P0.01). The average AgNOR score for HPF lesions of the HPF-positive cases was 1.60 +/- 0.34, that for non-HPF lesions in the HPF-positive cases was 1.29 +/- 0.12, and that for the HPF-negative cases was 1.19 +/- 0.14. Significant differences were found between the average AgNOR scores for HPF lesions of the HPF-positive cases and the non-HPF lesions of the HPF-positive cases (P0.01), as well as between the non-HPF lesions in the HPF-positive cases and the HPF-negative cases (P0.05). Severe fibrosis (stage 3) and cirrhosis (stage 4) were found in 76% of HPF-positive cases and 48% of HPF-negative cases. The livers of HPF-positive patients were significantly more cirrhotic than those of HPF-negative patients (P0.05). The association between HPF and the inflammatory grade was not significant (P0.05). The incidence of HCC recurrence among HPF-positive cases was significantly higher than that among the HPF-negative cases (P0.05). The average phase S ratio of the recurrent HPF-positive patients was 7.48 +/- 3.48%, significantly higher than that of HPF negative cases (5.57 +/- 3.06%, P0.05). Hyperplastic foci of the liver was shown to be a highly proliferative lesion. The proliferative activity of the non-HPF lesions in the HPF-positive patients was also higher than that of the HPF-negative patients. Hyperplastic foci tended to be present in cirrhotic livers, but it was not associated with the grade of inflammatory activity of the liver. Hyperplastic foci may represent an important predictor of recurrence after hepatic resection.

Hepatocellular carcinoma (HCC) is supplied only with arterial blood and has capillaries instead of sinusoids, unlike the normal hepatic tissue. In order to reveal the sequential changes of sinusoidal structure and blood supply during hepatocarcinogenesis, we examined hyperplastic nodules (HPN), atypical hyperplastic nodules (AHPN) and HCC in F344 rats fed with 2-acetylaminofluorene for 25-35 weeks. The extent of arterial blood supply and the degree of sinusoidal capillarization were assessed by the staining of hepatic nodules with arterially infused ink and by immunohistochemical and ultrastructural analyses of the sinusoids, respectively. The proportion of arterialized nodules was 47% in HPN, 57% in AHPN and 85% in HCC, which indicates that arterialization begins at the stage of HPN and a few HCC still receive portal venous blood. The proportion of Factor-VIII-related antigen (F-VIII)-positive nodules was 25% in HPN, 40% in AHPN and 100% in HCC. Non-arterialized nodules did not express F-VIII, while some F-VIII-negative nodules were already arterialized. Electron microscopically, non-arterialized HPN exhibited normal features of sinusoids, while arterialized HPN showed disappearance of Kupffer cells and partial defenestration of sinusoidal endothelial cells. In non-arterialized and arterialized AHPN, basement membrane became continuous and lipid droplet-containing stellate cells were no longer seen. In HCC, endothelial fenestrae were diminished and basement membrane became thick. The present study has demonstrated that sinusoids are altered in the following order as hepatocarcinogenesis advances from HPN to HCC ; onset of arterialization and decrease of endothelial fenestrae, expression of F-VIII by endothelial cells, disappearance of Kupffer cells, diminution of lipid droplets in stellate cells and thickening of basement membrane.

Hepatolithiasis is a risk factor for cholangiocarcinoma. It is difficult to make an accurate diagnosis before treatment. In a retrospective study, we identified characteristic clinical features of 103 patients with hepatolithiasis (group H) and 10 patients with hepatolithiasis associated with cholangiocarcinoma (group HC), and examined the methods for diagnosis and treatment. The main symptoms were abdominal pain, fever, and jaundice, although few patients in group HC had jaundice. The incidence of abnormal serum levels of carcinoembryonic antigen (CEA) in group HC was higher than in group H. The incidence of cholangiocarcinoma in cases in which most of the stones were present in the intrahepatic ducts of the left lobe (type I-L) was higher than the incidence in the other patients. Of the patients who underwent portography in group HC, portal veins in the portion of the liver containing the cholangiocarcinoma were not seen, and this region was atrophic in the operative specimens. The incidence of portal obstruction in portograms in group HC was higher than that in group H. The possibility of carcinoma should be kept in mind if there are high levels of CEA, if the location of the stones is classified as type I-L, or if portal veins cannot be seen on portograms. In such patients, liver resection should be considered because there may be undiagnosed cholangiocarcinoma.

We evaluated the usefulness of preoperative portal vein embolization (PVE) in rats for increasing the safety of liver resection. During PVE, portal vein branches that perfused the central and left lobes of the liver were embolized. Liver weight, the elimination of indocyanine green, and the number of Kupffer cells were examined 7 days after PVE and in intact rats. Then we examined rats that had undergone PVE (PVE group), rats in which the embolized part of the liver was resected 7 days after PVE (PVE-Hx group), rats without PVE in which the same lobes of the liver were resected (Hx group), and rats that had undergone a sham operation (sham-operation group) for liver weight, the mitotic index of the hepatocytes, serum alanine aminotransferase activity, total bilirubin, and antithrombin III activity. Some rats in the four groups received an intravenous injection of 0.5 or 2.5 mg/kg endotoxin 48 hr after the operation (the second operation, if done), and the 24-hr survival rate was calculated. Some rats given 0.5 mg/kg endotoxin were killed 6 hr after the injection, and the extent of liver injury was examined biochemically and histologically. Seven days after PVE, the nonembolized part of the liver was about twice the weight of the corresponding lobes in the intact rats, the density of Kupffer cells was doubled, and the hepatic function per unit weight was about the same as that in these controls. Hepatic dysfunction and the endotoxin-induced liver injury were significantly slighter in the PVE and PVE-Hx groups than in the Hx group. Preoperative PVE could make hepatectomy safer.

When hepatic stellate cells were stimulated by UTP, ATP, or ADP, cellular levels of inositol phosphates significantly increased (UTP > ATP > ADP > 5′-O-(3-thiotriphosphate). Thirty min after incubation with 100 μM of UTP, ATP, or ADP, levels of inositol monophosphate increased to 1318 ± 116, 616 ± 87 and 591 ± 234% of control levels, respectively, with concomitant increase in the production of inositol trisphosphate and bisphosphate. These nucleotides transiently increased the [Ca2+]i of fura-2-loaded stellate cells. Moreover, UTP, ATP, ADP and adenosine 5′-O-(3-thiotriphosphate) were able to induce contraction of stellate cells as detected using the silicone-rubber membrane method. These results suggested that hepatic stellate cells have nucleotide receptors which react predominantly with extracellular UTP and ATP and trigger the receptormediated contraction of the cells.

In the treatment of hepatolithiasis, liver resection helps to prevent recurrence and may reduce the incidence of infection by removal of the atrophic tissue. This study was conducted to determine if the affected liver tissue in hepatolithiasis is inflamed or has lowered local immunity by examining the distribution of secretory immunoglobulin A (sIgA) and proliferating cell nuclear antigen (PCNA) in the intrahepatic biliary tracts of 27 patients with hepatolithiasis. Operative specimens were sectioned and stained with avidinbiotin complex, and the labeling index for both sIgA and PCNA was calculated as a percentage of the biliary epithelial cells stained. Cells stained for sIgA increased to a certain point as the cholangitis became more severe; however, in advanced cholangitis, with severe parenchymal atrophy or actively proliferating biliary epithelium, there were fewer cells stained for sIgA than in mild cholangitis. In hepatolithiasis, the decreased local immunity related to sIgA accompanied severe chronic proliferative cholangitis and parenchymal atrophy.

Liver resection is the most effective therapy for hepatocellular carcinoma (HCC), but associated chronic liver diseases such as cirrhosis of the liver often limit its use. We started to use portal vein embolization (PVE) with an adhesive mixture of fibrin as an adjuvant therapy to improve the outcome of surgical treatment. We investigated the clinical course after PVE and operative specimens in which PVE had been done. PVE strengthened the anticancer effect of transcatheter arterial embolization (TAE). PVE causes regeneration of the nonembolized lobe and atrophy of the embolized lobe, which extends the surgical indications for patients with HCC and makes surgery safer if the patients have cirrhosis. Nonrecurrence survival rates in the patients in whom preoperative PVE had been done tended to be better than in the patients without this treatment. PVE seems to be useful as preparation for surgery and as one therapy for unresectable HCC, usually to be done together with other treatments.

We studied, clinically and experimentally, hypertrophy of the part of the liver not embolized after portal vein embolization (PVE). The subjects of the clinical study were 29 patients with hepatocellular carcinoma (HCC) who underwent embolization of the right first portal branch; 19 patients had cirrhosis, and 10 did not. The volume of the liver was calculated from computed tomograms obtained before PVE and 2 weeks after. In all patients, the volume of the nonembolized (left) lobe increased significantly. For the experimental study, we used male Wistar rats. Normal rats were untreated, and in the other rats cirrhosis was induced with carbon tetrachloride. The portal branch that supplies 70% of the total volume of the liver was embolized. The rats underwent one of four procedures: 70% PVE, 70% portal vein ligation, 70% hepatectomy, or laparotomy only. Rats wre killed at different times after surgery, and the livers were removed and weighed. The mitotic index and DNA synthesis were measured in the nonembolized lobe (PVE group), in the lobe not supplied by the ligated branch (ligation group), or in the remaining liver (hepatectomy group). The liver weight, mitotic index, and DNA synthesis were high in the PVE, ligation, and hepatectomy groups for both normal rats and rats with cirrhosis. PVE caused cell proliferation and hypertrophy in the nonembolized part of the liver in the normal rats and even in those with cirrhosis. We concluded that PVE can extend the surgical indications for patients with HCC and underlying cirrhosis.

We tried a combination of percutaneous transhepatic portal vein embolization (PVE) or portal vein ligation (PVL) and hepatic arterial infusion chemotherapy (HAI, with or without a reservoir) or transcatheter arterial embolization (TAE) for five patients with hepatocellular carcinoma (HCC) in whom the tumors were not resected. The patients were from 50 to 70 years old, and all had cirrhosis. The tumors were classified as being in stage III or IV by the UICC classification. Three of the five patients underwent PVE and the other patients underwent PVL. Adriamycin (ADR), epi-Adriamycin (epi-ADR), mitomycin C (MMC), or mitoxantrone (MIT), or some combination was used during HAI. These combinations of therapy was effective for hepatic tumors in all patients, as judged by decreases in tumor size and serum levels of α-fetoprotein (AFP) after treatment. The combination of HAI and portal occlusion may be effective for unresectable HCC.

Advances in diagnostic imaging and new surgical techniques have improved the outcome for many patients with hepatocellular carcinoma (HCC). However, in Japan, more than 70% of patients with HCC have cirrhosis of the liver [1], and resection of the liver of such patients is often limited by the cirrhosis. Therefore, nonsurgical treatments such as transcatheter arterial embolization (TAE) or percutaneous ethanol injection therapy have been developed and are used widely as adjuvant therapy. TAE was first used to treat HCC patients by Goldstein et al. [2], who reasoned that most of the blood flow to the tumor is supplied by the hepatic artery. However, according to a study by the Liver Cancer Study Group of Japan [3], TAE is effective against the main tumor, but not against small intrahepatic metastases or tumor thrombi; it is particularly ineffective against tumor thrombi.