p53 protein expression and prognosis in gallbladder carcinoma and premalignant lesions.

BACKGROUND/AIMS: p53 protein expression in gallbladder carcinoma has recently been detected by immunohistochemical techniques, but the relationship between p53 expression and prognosis or clinico-pathological factors is still obscure. MATERIALS AND METHODS: We investigated 48 gallbladder carcinoma, 7 adenoma and 11 dysplasia cases for p53 expression by immunohistochemical techniques. RESULTS: p53 expression was positive in 39.6% of gallbladder cancer cases, but in no adenoma or dysplasia cases. No significant correlation was found between p53 overexpression and prognosis or recurrence in 20 patients with carcinoma involvement up to the subserosal layer. p53 overexpression was correlated with DNA aneuploidy pattern and the absence of stones, but was not correlated with clinical staging or lymph node metastasis. CONCLUSION: These results suggest that p53 gene mutation is related to the transition from premalignancy to malignancy in gallbladder carcinogenesis, as well as DNA ploidy alterations and carcinogenesis unassociated with gallstones, but has no bearing on the prognosis.

Changing trends in the management of extrahepatic cholangiocarcinoma.

A series of 107 patients with cholangiocarcinoma diagnosed between January 1980 and December 1991 is reported. Changing patterns of investigation and treatment in the periods 1980-1985 and 1986-1991 are analysed. There was a decrease in the use of percutaneous transhepatic cholangiography in the second period (86 versus 51 per cent of patients) but increased use of endoscopic retrograde cholangiography (19 versus 71 per cent) and computed tomography (8 versus 59 per cent). The overall resectability rate (17 per cent) was similar to those of other reported series but greater in the second period (8 versus 21 per cent). Palliation by endoscopic and percutaneous stenting was associated with a high incidence of recurrent cholangitis (55 per cent) and jaundice (35 per cent). During the second 6-year period, more effective palliation was achieved by segment III cholangiojejunostomy with a lower incidence of recurrent cholangitis (19 per cent) and jaundice (19 per cent). Overall prognosis for patients with this condition is grim and efforts must usually be aimed at providing the most appropriate palliation.

Tumor de Klatskin: tratamiento quirúrgico / Klatskin tumor: surgical treatment

Desde 1985 a junio de 1991, 13 de 15 pacientes (87//) con colangiocarcinoma hiliar fueron resecados. La resección completa se logró en 9, (69//) de las resecciones y al 60// de los pacientes remitidos. Se efectuaron 3 resecciones locales amplias y 6 que además necesitaron de resecciones hepáticas mayores. En 4 casos se incluyó la resección del lóbulo caudado y en 2 fueron necesarias resecciones parciales de la vena porta remanente. En las resecciones completas (9) la morbilidad fue del 55,5// y la mortalidad del 22,2//. Los completamente resecados sobrevivieron entre 13 y 50 meses. Los otros entre 3 y 13 meses. Un paciente con una forma papilar temprana lleva 30 meses libres de síntomas. Todos los fallecidos tuvieron recidiva local y 3 metástasis a distancia. La resección completa del tumor brinda la mayor supervivencia y de mejor calidad

Tumor de Klatskin: tratamiento quirúrgico / Klatskin tumor: surgical treatment

Desde 1985 a junio de 1991, 13 de 15 pacientes (87//) con colangiocarcinoma hiliar fueron resecados. La resección completa se logró en 9, (69//) de las resecciones y al 60// de los pacientes remitidos. Se efectuaron 3 resecciones locales amplias y 6 que además necesitaron de resecciones hepáticas mayores. En 4 casos se incluyó la resección del lóbulo caudado y en 2 fueron necesarias resecciones parciales de la vena porta remanente. En las resecciones completas (9) la morbilidad fue del 55,5// y la mortalidad del 22,2//. Los completamente resecados sobrevivieron entre 13 y 50 meses. Los otros entre 3 y 13 meses. Un paciente con una forma papilar temprana lleva 30 meses libres de síntomas. Todos los fallecidos tuvieron recidiva local y 3 metástasis a distancia. La resección completa del tumor brinda la mayor supervivencia y de mejor calidad

Outcomes after curative resections of cholangiocarcinoma.

OBJECTIVES: To elucidate the clinical and pathologic features of extrahepatic cholangiocarcinomas and to identify prognostic variables in patients treated surgically. DESIGN: Retrospective review of clinical records of patients undergoing surgical exploration for cholangiocarcinoma, with univariate and multivariate analyses of the clinical and pathologic factors that influenced patient survival. SETTING: Mayo Clinic, Rochester, Minn. STUDY PARTICIPANTS: One hundred seventy-one patients undergoing operative intervention for diagnostic, palliative, or curative reasons between 1976 and 1985. Follow-up was complete until death or for a minimum of 5 years for surviving patients. INTERVENTION: A curative surgical resection was performed in 29% of patients, while the remainder underwent tumor biopsy or a palliative procedure. MAIN OUTCOME MEASURE: Patient survival following operative treatment. RESULTS: The operative mortality in this patient cohort was 5% and median survival was 13 months. Overall 5-year survival was 16%, with 44% of patients having a curative resection still alive at 5 years. Using univariate analysis, curative resection, tumor stage, Eastern Cooperative Oncology Group performance status, total bilirubin concentration, lymph node status, liver invasion, tumor morphology, tumor grade, and site of tumor origin were significant determinants of prognosis. Using the Cox proportional hazards model for multivariate analysis, curative resection, Eastern Cooperative Oncology Group performance status, total bilirubin concentration, and tumor grade were the only variables predictive of patient outcome. A curative resection of a proximal cholangiocarcinoma had a similar chance of providing long-term survival as a curative distal ductal resection. CONCLUSIONS: Although the tumor extent and the patient's overall health will affect outcome, curative resection for cholangiocarcinoma at all sites should be undertaken since this treatment offers the best chance for long-term survival.

Possibility of hepatic resection in patients on maintenance hemodialysis.

A review of seven hepatic resections in six patients undergoing maintenance hemodialysis is presented. These cases consisted of hepatocellular carcinoma in four, and cholangiocellular carcinoma, myelolipoma and focal nodular hyperplasia in one each. The last preoperative hemodialysis was undertaken within 24 h prior to the operation with heparin. Intraoperatively, infused solutions containing no potassium, along with strict attention to preventing overhydration, allowed us to manage the patients without hemodialysis on the day of the operation. No specific intra-operative complications related to hemodialysis were noted. Postoperative hemodialysis was performed on the first or second day after operation, using nafamstat mesilate, a synthetic protease-inhibiting agent. The morbidity rate in the hemodialyzed patients was 85.7% (6/7), which was significantly higher than that in the non-hemodialyzed patients who underwent hepatic resections in our hospital. Fluid collection in the pleural and/or peritoneal cavities was frequent and difficult to control, but transient. Our experience suggests that hepatic resection is an acceptable procedure for hemodialyzed patients, when used in conjunction with careful perioperative management.

Increased arterial ketone body ratio as a prerequisite for recovery after hepatectomy.

It is reported that a prompt increase in the arterial ketone body ratio (acetoacetate/beta-hydroxybutyrate), which reflects the mitochondrial redox state of the liver graft, is a decisive prerequisite for graft survival in clinical liver transplantation. To contrast the rôle of hepatic mitochondrial redox state in partial hepatectomy with that in hepatic replacement, the changes in the ketone body ratio were investigated in 107 cases of hepatectomy. The ketone body ratio in uneventful cases (n = 70) in the first three days after hepatectomy was significantly higher than that in eventful cases. In the uneventful cases, the ketone body ratios were all increased to above 1.0 within two days after hepatectomy, except in diabetics, whose preoperative values did not reach 1.0 under oral glucose load. However, 20 (22.7%) out of 88 cases whose ketone body ratios promptly increased after hepatectomy had mild to moderate complications thereafter. It is suggested that the recovery of hepatic mitochondrial redox state is also a prerequisite in partial hepatectomy, where a reduced and often damaged liver confronts systemic metabolic load.

Aggressive surgical therapy for Klatskin tumors.

Thirty-one patients underwent limited hepatic resection with Roux-en-Y biliary-enteric anastomosis and placement of biliary stents for cholangiocarcinoma of the hepatic duct bifurcation (Klatskin tumor). Resection included wide tumor excision and bile duct resection at the liver hilum without major hepatic resection and was undertaken in all patients unless precluded by intraoperative evidence of vascular invasion. All patients were operated on by a single surgeon during the 10 years between 1981 and 1991. Similar procedures were performed for both curative (n = 17) and palliative (n = 14) treatment of this disease entity. In this series, the overall mean postoperative survival of these patients was 17 months. The mean postoperative survival of patients undergoing surgery with curative intent was 21 months in contrast to 12 months for those undergoing planned palliation. One patient in this series has been alive for more than 6 years with no evidence of disease. Five patients experienced major postoperative complications (16%), and there were two perioperative deaths (6%). This retrospective review supports an aggressive surgical approach in patients with Klatskin tumor.

[Long-term results of chemoembolization of primary liver cancer with epirubicin-lipiodol]. / Langzeitergebnisse nach Chemoembolisation primärer Leberkarzinome mit Epirubicin-Lipiodol.

This pilot study deals with the long-term results from lipiodol-epirubicin chemo-embolisation in 25 patients with hepatocellular or cholangiocellular carcinomas. In a three-and-a-half year follow-up period 16 of these 25 patients died, maximum survival time being 28.4 months. Survival varied from 9.2 to 28.4 months compared with a survival time of 2-8 months in untreated patients. In this case hypervascular tumours have a better prognosis than the rarer hypovascular tumours due to the improved deposition and activity of the chemotherapeutic agent inside the tumour itself.

Optimal timing for stent replacement in malignant biliary tract obstruction.

Endoscopic stent placement has become accepted palliative therapy for malignant biliary tract obstruction. Because stent occlusion remains a significant late complication, prophylactic replacement has been suggested, although the appropriate time interval remains unclear. Patients with malignant biliary strictures who received 10F or 11.5F stents were analyzed with respect to clinical response, occlusion rates at 3 and 6 months, and survival rates. Seventy stents were placed in 50 patients. Pancreatic carcinoma was the most common underlying malignancy. Overall, obstructive symptoms resolved in 94% of cases. Occlusion rates at 3 months (4.2%) and 6 months (10.8%) were not significantly different. Median overall survival averaged 22 weeks. Results were also stratified by underlying diagnosis, with the worst clinical response and survival being seen in the group of patients with metastatic cancer. Findings suggest that the time interval for stent replacement can be extended safely from 3 to 6 months, resulting in decreased patient discomfort and cost and obviating any replacement in that significant percentage of patients who expire before 6 months.

[Palliative therapy of primary liver tumors]. / Palliative Therapie primärer Lebertumoren.

In Europe and North America, primary liver tumors are rare. Resection is the only means of cure, but is possible in only 20-30% of the patients affected, so that in all other patients, i.e. the vast majority, only palliative treatment is possible. In a retrospective analysis we investigated the 68 patients we had treated for hepatocellular or cholangiocellular carcinoma of the liver. In 14 patients resection was possible, while 28 patients were treated by chemoembolization and 26 by intraarterial regional chemotherapy to the liver. There was no difference in tumor stage between the two groups receiving different palliative treatments. The patients in whom resection was performed, in contrast, mostly had less advanced tumors. For chemoembolization we used a mixture of Ethibloc, mitomycin, Adriamycin and cisplatin. Up to 1986, the intraarterial chemotherapy was performed with mitomycin and 5-FU. Since 1986 we have used Adriamycin and cisplatin. The overall median survival time was 8 months: after resection 17 months, after chemoembolization 6.5 months, and after intraarterial chemotherapy 6.5 months. There was a significant difference in survival between patients with tumor stage II and those with tumor stages III and IV. On comparing the survival time achieved with our treatments and that ensuing in the natural course of patients with liver tumor we found no improvement.

[Indications for liver transplantation in neoplasms of the liver]. / Indikation zur Lebertransplantation bei Malignomen der Leber.

Orthotopic liver transplantation for hepatic neoplasms is controversial. In the past, liver transplantation was utilized to treat various advanced hepatic neoplasms such as hepatocellular carcinoma including the fibrolamellar variant, cholangiocellular carcinoma, epithelioid hemangio-endothelioma, and liver metastases. In many cases, total hepatectomy with orthotopic liver replacement is the only treatment option with intent to cure because of reduced liver function in cirrhotic patients limiting resectability. On the other hand, results of transplantation are poor; for hepatocellular carcinoma, the 5-year-survival probability averages only 20%. Thus, hepatic neoplasms have to compete with benign liver diseases for a limited supply of donor organs. However, success rates of liver transplantation were higher for fibrolamellar carcinoma and for epithelioid hemangioendothelioma. New treatment strategies for hepatocellular carcinoma including neoadjuvant chemotherapy and chemoembolization are currently being investigated. Results of liver transplantation for cholangiocellular carcinoma or hepatic metastases have been disappointing. Single cases have been successfully treated with the "cluster operation" designed by Starzl in 1988.

Improvements in survival by aggressive resections of hilar cholangiocarcinoma.

The operative management of hilar cholangiocarcinoma has evolved because of advances in diagnostic imaging that have permitted improved patient selection, and refinements in operative techniques that have lowered operative mortality rates. Over a 4-year period, 48 patients with hilar cholangiocarcinoma were managed. Twenty-seven patients were treated by palliative measures. Preoperative investigation identified 29 patients who were judged fit for operation without proven irresectability by radiologic studies, and 21 of the 29 patients had tumor removal (72%). Twenty-three operative procedures were performed: local excision (n = 12) (two had subsequent hepatic resection), and hepatic resection primarily (n = 9). Eight patients had complications (35%), and one patient died (4.3%). The mean actuarial survival after local excision in 36 months, and after hepatic resection, 32 months. Palliation as assessed by personal interview was excellent for more than 75% of the months of survival. A combination of careful patient selection and complete radiologic assessment will allow an increased proportion of patients to be resected by complex operative procedures with low mortality rate, acceptable morbidity rate, and an increase in survival with an improved quality of life.

Cholangiocarcinoma: ultrasound features and correlation of tumor position with survival.

Cholangiography is the definitive imaging modality for assessing cholangiocarcinoma. This study was designed to evaluate the ultrasound (US) features of cholangiocarcinomas and assess the accuracy of US in mapping tumor site when compared to cholangiography. Findings were correlated with patient survival. Thirty-one patients with an US diagnosis of cholangiocarcinoma underwent cholangiography. The US diagnosis was correct in 29 of 31 cases. Complete agreement with cholangiography occurred in 23 (78%) cases. In six patients, there was discrepancy over the precise tumor location. US diagnosis of cholangiocarcinoma had a high predictive value (0.94) and proved an accurate method of mapping tumor site. Lesions arising in the hilar region carried a worse prognosis (50% were dead within 80 days).

Survival after hepatic resection for malignant tumours.

A retrospective analysis of 194 patients who underwent hepatic resection for primary or metastatic malignant disease from January 1962 to December 1988 was undertaken to determine variables that might aid the selection of patients for hepatic resection. Hepatic metastases were the indication for resection in 126 patients. The 5-year survival rate was 17 per cent. For patients with resected metastases from colorectal cancer (n = 104), the survival rate at 5 years was 18 per cent. The 5-year survival rate was 27 per cent when the resection margin was > 5 mm compared with 9 per cent when the margin was < or = 5 mm (P < 0.01). No patient with extrahepatic invasion, lymphatic spread, involvement of the resection margin or gross residual disease survived to 5 years, compared with a 23 per cent 5-year survival rate for patients undergoing curative resection (P < 0.02). The survival rate of patients with poorly differentiated primary tumours was nil at 3 years compared with a 20 per cent 5-year survival rate for patients with well or moderately differentiated tumours (P not significant). The site and Dukes' classification of the primary tumour, the sex and preoperative carcinoembryonic antigen level of the patient, and the number and size of hepatic metastases did not affect the prognosis. The 5-year survival rate for patients with hepatocellular carcinoma (n = 42) was 25 per cent. An improved survival rate was found for patients whose alpha-fetoprotein level was normal (37 per cent at 5 years) compared with those having a raised level (nil at 3 years) (P < 0.01). Involvement of the resection margin, extrahepatic spread and spread to regional lymph nodes were associated with an 8 per cent 5-year survival rate versus 44 per cent for curative resection (P < 0.005). The presence of cirrhosis, the presence of symptoms, and the multiplicity and size of the tumour did not affect the prognosis. The 5-year survival rate of 11 patients with hepatic sarcoma was 25 per cent. No patient with peripheral cholangiocarcinoma survived to 1 year in contrast to patients with hilar cholangiocarcinoma, all four of whom survived for more than 14 months.

Surgical treatment of intrahepatic cholangiocarcinoma: four patients surviving more than five years.

BACKGROUND: To find the rational surgical strategy for the treatment of intrahepatic cholangiocarcinoma (ICC), clinical features of ICC were studied in 20 patients who underwent hepatic resection in the National Cancer Center Hospital from 1980 to 1990. METHODS: According to the morphologic pattern, we classified the ICCs into two subcategories, mass-forming and infiltrating, which correlated with their biologic behavior. RESULTS: Of 10 patients who underwent hepatectomy for mass-forming ICC, three survived more than 5 years without recurrence. The 1-, 3-, and 5-year survival rates were 59.3%, 44.4%, and 44.4%, respectively. Of 10 patients who underwent hepatectomy for infiltrating ICC, one survived more than 5 years without recurrence. The 1-, 3-, and 5-year survival rates were 72.0%, 27.0%, and 27.0%, respectively. The pathologic findings and recurrences indicated that the salient feature of the mass-forming type was its tendency for intrahepatic metastasis especially near a main lesion, and of the infiltrating type was the infiltrative spread via Glisson's capsule and hilar lymph nodal metastasis. CONCLUSIONS: An anatomic and extensive liver resection should be performed for mass-forming ICC, whereas a hepatectomy with excision of the extrahepatic bile duct and hilar lymph nodal dissection is recommended for infiltrating ICC.

Four year experience with cholangiocarcinoma: a survey of patients, clinical presentation, management and prognosis in two hospitals.

Seventeen patients with cholangiocarcinoma diagnosed in Toa Payoh and Tan Tock Seng Hospitals from 1986-90 were studied retrospectively. There was a male preponderance (male:female = 12:5) with a mean age of 58 years (range 28-82 years). All presented with obstructive jaundice. Three had cholangitis. Biliary stones were associated in 3 (18%). Two patients (12%) had choledochal cysts. The level of obstruction was identified at the hilum in 12 (70.5%), lower third in 4 (23.5%) and at a choledochojejunostomy anastomosis in 1 (6%). Ultrasound and percutaneous cholangiography (PTC) were the commonest investigations used. Endoscopic retrograde cholangio-pancreatography (ERCP) was performed in 7 (41%) and computer tomography (CT) of abdomen in 6 (35%). Biochemically, a raised alkaline phosphatase (1.5-9 x normal) was typical. Biliary bypass surgery was performed in 7 (41%); Whipple's procedure in 2 (12%) and drainage only in 6 (35%). Nine operated upon survived an average of 6 months (range 2-11 months) and six by drainage survived an average of 62 days (range 13-155 days). Three (of which two declined treatment) were lost to follow up. Cholangiocarcinoma is an uncommon cancer occurring in the older age group. In younger patients, choledochal cyst seems to be an association. Survival is dismal with palliative treatment.

[The surgical treatment of malignant liver tumors]. / Khirurgicheskoe lechenie zlokachestvennykh opukholei pecheni.

From study of the data concerning 133 patients who underwent operation for tumor of the liver the authors found that 43 (32.2%) patients were treated by a radical operation and 34 (25.5%) were subjected to palliative interventions. Among the radical interventions hemihepatectomy was performed on 21 (48.8%) patients. The total number of complications after radical operations was 46.3%, the mortality rate 11.6%. The authors discuss problems of the prevention of some complications, intraoperative hemorrhages in the first place. Different variants of bile diversion accounted for most of the palliative interventions. Survival in radical operations was 38.56 months, in palliative operations 8.34 months, and in exploratory operations 5.9 months.