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Background: Currently, the potential benefits of additional resection after positive proximal intraoperative frozen sections (IFS) in perihilar cholangiocarcinoma (pCCA) on residual disease and oncological outcome remain uncertain. Therefore, the aim of this study is to investigate the number of R0 resections after additional resection of a positive proximal IFS and the influence of additional resections on overall survival (OS) in patients with pCCA., Materials and Methods: A retrospective, multicenter, matched case-control study was performed, including patients undergoing resection for pCCA between 2000 and 2019 at three tertiary centers. Primary outcome was the number of achieved 'additional' R0 resections. Secondary outcomes were OS, recurrence, severe morbidity and mortality., Results: Forty-four out of 328 patients undergoing resection for pCCA had a positive proximal IFS. An additional resection was performed in 35 out of 44 (79.5%) patients, which was negative in 24 (68.6%) patients. Nevertheless, seven out of these 24 patients were eventually classified as R1 resection due to other positive resection margins. Therefore, 17 (48.6%) patients could be classified as "true" R0 resection after additional resection. Ninety-day mortality after R1 resections was high (25%) and strongly influenced OS. After correction for 90-day mortality, median OS after negative additional resection was 33 months (95%CI:29.5-36.5) compared to 30 months (95%CI:24.4-35.6) after initial R1 (P = 0.875) and 46 months (95%CI:32.7-59.3) after initial R0 (P = 0.348)., Conclusion: There were only 17 patients (out of a total of 328 patients) that potentially benefitted from routine IFS. Additional resection for a positive IFS leading to R0 resection was not associated with improved long-term survival., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: The authors declare no conflicts of interest. There was no source of funding.

Background: Approximately 15% of patients undergoing resection for presumed perihilar cholangiocarcinoma (PHC) have benign disease at final pathological assessment. Molecular imaging targeting tumor-specific biomarkers could serve as a novel diagnostic tool to reduce these futile surgeries. Imaging agents have been developed, selectively binding integrin α ν β 6, a cell receptor upregulated in pancreatobiliary malignancies, for both (preoperative) PET and (intraoperative) fluorescent imaging. Here, expression of integrin α ν β 6 is evaluated in PHC, intrahepatic cholangiocarcinoma (ICC), hepatocellular carcinoma (HCC) and benign disease mimicking PHC using immunohistochemistry., Materials & Methods: Three tissue microarrays (TMA) including 103 PHC tumor cores and sixty tissue samples were selected from resection specimens of pathologically proven PHC (n = 20), ICC (n = 10), HCC (n = 10), metastatic PHC lymph nodes (n = 10) and benign disease (presumed PHC with benign disease at pathological assessment, n = 10). These samples were stained for integrin α ν β 6 and quantified using the H-score., Results: Immunohistochemical staining for integrin α ν β 6 showed membranous expression in all twenty PHC whole mount slides (100%) and 93 out of 103 (92%) PHC tumor cores. Mean H-score of PHC samples was 195 ± 71, compared to a mean H-score of 126 ± 57 in benign samples (p = 0.013). In both benign and PHC samples, inflammatory infiltrates and pre-existent peribiliary glands showed integrin α ν β 6 expression. The mean H-score across ten ICC was 33 ± 53, which was significantly lower compared to PHC (p < 0.001) but too weak to consistently discriminate ICC from HCC (H-score 0)(p = 0.062)., Conclusion: Integrin α ν β 6 is abundantly expressed in PHC and associated metastatic lymph nodes. Expression is significantly higher in PHC as compared to benign disease mimicking PHC, ICC and HCC, emphasizing its potential as a target for tumor-specific molecular imaging., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Portal vein embolization (PVE) is performed to reduce the risk of liver failure and subsequent mortality after major liver resection. Although a cut-off value of 2·7 per cent per min per m 2 has been used with hepatobiliary scintigraphy (HBS) for future remnant liver function (FRLF), patients with perihilar cholangiocarcinoma (PHC) potentially benefit from an additional cut-off of 8·5 per cent/min (not corrected for body surface area). Since January 2016 a more liberal approach to PVE has been adopted, including this additional cut-off for HBS of 8·5 per cent/min. The aim of this study was to assess the effect of this approach on liver failure and mortality., Methods: This was a single-centre retrospective study in which consecutive patients undergoing liver resection under suspicion of PHC in 2000-2015 were compared with patients treated in 2016-2019, after implementation of the more liberal approach. Primary outcomes were postoperative liver failure (International Study Group of Liver Surgery grade B/C) and 90-day mortality., Results: Some 191 patients with PHC underwent liver resection. PVE was performed in 6·4 per cent (9 of 141) of the patients treated in 2000-2015 and in 32 per cent (16 of 50) of those treated in 2016-2019. The 90-day mortality rate decreased from 16·3 per cent (23 of 141) to 2 per cent (1 of 50) (P = 0·009), together with a decrease in the rate of liver failure from 19·9 per cent (28 of 141) to 4 per cent (2 of 50) (P = 0·008). In 2016-2019, 24 patients had a FRLF greater than 8·5 per cent/min and no liver failure or death occurred, suggesting that 8·5 per cent/min is a reliable cut-off for patients with suspected PHC., Conclusion: The major decrease in liver failure and mortality rates in recent years and the simultaneous increased use of PVE suggests an important role for PVE in reducing adverse outcomes after surgery for PHC., (© 2020 The Authors. BJS Open published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Preoperative biliary drainage (PBD) is used routinely in the evaluation of patients with potentially resectable perihilar cholangiocarcinoma to relieve cholestasis and improve the liver's resilience to surgery. Little preclinical or translatational data are, however, currently available to guide the use of PBD in this patient group. The effect of PBD on hepatic gene expression profiles was therefore studied by microarray analysis. Drainage affects inflammatory and fibrotic gene signatures., (© 2018 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Aim: Perihilar cholangiocarcinoma (PHC) is a challenging disease and requires aggressive surgical treatment in order to achieve curation. The assessment and work-up of patients with presumed PHC is multidisciplinary, complex and requires extensive experience. The aim of this paper is to review current aspects of diagnosis, preoperative work-up and extended resection in patients with PHC from the perspective of our own institutional experience with this complex tumor., Methods: We provided a review of applied modalities in the diagnosis and work-up of PHC according to current literature. All patients with presumed PHC in our center between 2000 and 2016 were identified and described. The types of resection, surgical techniques and outcomes were analyzed., Results and Conclusion: Upcoming diagnostic modalities such as Spyglass and combinations of serum biomarkers and molecular markers have potential to decrease the rate of misdiagnosis of benign, inflammatory disease. Assessment of liver function with hepatobiliary scintigraphy provides better information on the future remnant liver (FRL) than volume alone. The selective use of staging laparoscopy is advisable to avoid futile laparotomies. In patients requiring extended resection, selective preoperative biliary drainage is mandatory in cholangitis and when FRL is small (< 50%). Preoperative portal vein embolization (PVE) is used when FRL volume is less than 40% and optionally includes the left portal vein branches to segment 4. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) as alternative to PVE is not recommended in PHC. N2 positive lymph nodes preclude long-term survival. The benefit of unconditional en bloc resection of the portal vein bifurcation is uncertain. Along these lines, an aggressive surgical approach encompassing extended liver resection including segment 1, regional lymphadenectomy and conditional portal venous resection translates into favorable long-term survival.

Background: Tumor location of extrahepatic cholangiocarcinoma (CCA) might influence survival after resection., Methods: A consecutive series of 175 patients who had undergone a potentially curative resection of extrahepatic CCA was analyzed. We calculated concordance indices of different constructed prognostic models for survival including TNM (tumour-node-metastasis) staging and developed a nomogram of the most sensitive model., Results: Overall cancer-specific survival rates were 83%, 58%, and 26% at 1, 2, and 5 years, respectively. Cancer-specific survival according to location was 42% for proximal, 23% for mid, and 19% for distal CCA after 5 years. Tumor location was not an independent significant predictor (P = 0.06). A prognostic model using all potential prognostic variables predicted survival better compared with TNM staging (concordance index 0.65 versus 0.63). A reduced model containing only lymph node status, microscopically residual tumor status, and tumor differentiation grade, also outperformed TNM staging (concordance index 0.66)., Conclusions: Tumor location of extrahepatic CCA does not independently predict cancer-specific survival after resection. We developed a nomogram, based on a prognostic model with lymph node status, microscopically residual tumor status of resection margins, and tumor differentiation grade, that predicted survival better than TNM staging.

Background: Effective diagnosis and treatment of patients with hilar cholangiocarcinoma (HCCA) is based on the synergy of endoscopists, interventional radiologists, radiotherapists and surgeons. This report summarizes the multidisciplinary experience in management of HCCA over a period of two decades at the Academic Medical Center in Amsterdam, with emphasis on surgical outcome., Methods: From 1988 until 2003, 117 consecutive patients underwent resection on the suspicion of HCCA. Preoperative work-up included staging laparoscopy, preoperative biliary drainage, assessment of volume/function of future remnant liver and radiation therapy to prevent seeding metastases. More aggressive surgical approach combining hilar resection with extended liver resection was applied as of 1998. Outcomes of resection including actuarial 5-year survival were assessed., Results: Eighteen patients (15.3%) appeared to have a benign lesion on microscopical examination of the specimen, leaving 99 patients with histologically proven HCCA. These 99 patients were analysed according to three 5-year time periods of resection, i.e. period 1 (1988-1993, n=45), 2 (1993-1998, n=25) and 3 (1998-2003, n=29). The rate of R0 resections increased and actuarial five-year survival significantly improved from 20±5% for the periods 1 and 2, to 33±9% in period 3 (p<0.05). Postoperative morbidity and mortality in the last period were 68% and 10%, respectively., Conclusion: Extended surgical resection resulted in increased rate of R0 resections and significantly improved survival. Candidates for resection should be considered by a specialized, multidisciplinary team., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Surgical treatment of hilar cholangiocarcinoma (Klatskin tumours) is difficult because of its central location in the liver hilum. Recent developments in surgical techniques have improved the outcome after resection., Aim: To describe the surgical approaches currently applied in our centre and the impact of these strategies on outcome and criteria for resection., Methods: From 1988 to 2003, 99 consecutive patients underwent resection for hilar cholangiocarcinoma. Patients were analysed for rate of R0 resections in relation with Bismuth classification. Morbidity, mortality and survival were assessed., Results: The rate of hilar resections in combination with (extended) liver resections for type III and IV tumours increased from 24% to 95% in the last 5 years of the study period. Eight patients (8%) had Bismuth type IV tumours. Four of these patients underwent palliative local excisions of the hepatic duct confluence whereas the other four patients underwent hilar resection in combination with partial liver resection, resulting in microscopically radical resections. There was no mortality in this group. Overall postoperative morbidity and mortality were 68% and 10%, respectively., Conclusions: An aggressive surgical approach consisting of hilar resections combined with partial liver resections including segments 1 and 4, resulted in a higher rate of R0 resections. Even Bismuth type IV tumours may be resectable depending on the biliary anatomy of the hepatic duct confluence.

Around 80% of the patients with hilar cholangiocarcinoma are candidates for palliative management due to extensive co-morbidity for major surgery, metastases or advanced loco-regional disease. The primary aim of treatment is to provide biliary drainage with long-term relief from pruritus, cholangitis, pain and jaundice. Endoscopically placed self-expanding metallic biliary stent has low procedure-related complications and is probably the modality of choice for patients with unresectable tumour on preoperative assessment. Percutaneous biliary drainage has comparable results and is an alternative when endoscopic expertise is not available or has failed or there are multiple isolated segments with cholangitis. Surgical cholangiojejunostomy provides lasting biliary drainage but has limitations of associated morbidity and mortality. In the absence of high-quality studies, comparing these modalities the choice of biliary drainage procedure should be guided by the available local expertise. Other modalities of treatment like radiotherapy, chemotherapy and photodynamic therapy currently remain investigational.

Objective: To find out how patients fared after palliative endoscopic biliary drainage for inoperable hilar cholangiocarcinoma., Design: Retrospective study., Setting: University hospital, the Netherlands., Subjects: Between 1992 and 1999, 41 patients who were referred for resection had tumours that were considered unresectable after additional investigations, including an exploratory laparotomy in 16 patients. In all patients, biliary drainage was established by endoscopic retrograde cholangiography (ERCP) and insertion of endoprostheses. Twelve patients also had percutaneous transhepatic biliary drainage (PTBD)., Results: The patients who did not have an exploratory laparotomy had fewer complications (1/25) than those who had explorations (4/16). All patients in both groups had one or more long-term complications during follow-up, of which cholangitis, jaundice, and abdominal pain were the most often recorded. In 32 patients, endoprostheses had to be replaced, a mean of 4 times. Median survival was 9 months, with no significant difference between the groups (8 and 11 months). Adjuvant radiotherapy had no influence on survival., Conclusion: The patients in this series had relatively long survival times, during which they had a substantial number of complications predominantly related to biliary drainage. Because biliary-enteric bypass operations result in effective relief of symptoms and excellent palliation, we suggest that when an exploration is done for patients with type III and IV tumours, a bypass should be made.

Background: The differentiation between benign and malignant strictures at the hepatic hilum is difficult. The aim of this study was to assess the clinical and radiographical features of hilar lesions in a series of patients resected for a presumed cholangiocarcinoma., Methods: Of 132 consecutive patients undergoing resection for a suspicious lesion at the hepatic hilum, 20 (15 per cent) had a histopathologically proven benign tumour, diagnosed as chronic fibrosing or erosive inflammation, sclerosing cholangitis, or a granular cell tumour. All medical files and radiological examinations of the patients were reassessed., Results: Clinical symptoms were considered suspicious in 16 of 19 patients. At ultrasonography only one of 16 patients had an unsuspicious examination. In 14 of 18 patients cholangiographic images were considered suspicious. Overall reassessment confirmed a suspicious lesion in all 20 patients., Conclusion: Because of the limitations of current diagnostic tools, a false-positive preoperative diagnosis of malignancy resulted in a 15 per cent resection rate of benign lesions in this series of suspicious hilar strictures.

Aims: Pre-operative endoscopic retrograde cholangiopancreatography (ERCP) with biliary drainage is associated with a greater risk of implantation metastases after resection of proximal bile duct tumours. In a previous study among patients who had undergone biliary drainage before resection, eight patients (20%) developed implantation metastases, within 1 year following resection. The aim of this analysis was to evaluate the results of pre-operative irradiation with regard to a possible reduction of implantation metastases., Methods: Twenty-one patients with proximal bile duct tumours who had undergone resection following pre-operative irradiation were retrospectively analysed. Pre-operative radiation therapy consisted of three fractions of 3.5 Gy external beam irradiation of the hilar area., Results: Pre-operative biliary drainage was performed in 19 patients (90%). All patients received pre-operative radiotherapy during which no complications were noted. None of the patients developed implantation metastases within a follow-up time of 2 to 79 months., Conclusion: The results of this study suggest that pre-operative radiotherapy in patients with a resectable proximal bile duct tumour who have undergone pre-operative drainage, decreases the risk of implantation metastases. To be certain about the role of pre-operative radiotherapy, a randomized study is required. Until then, we advocate standard low dose radiotherapy preceding resection in all patients with lesions suggestive of a proximal bile duct tumour who have undergone biliary drainage.

Background: Hilar resection, especially in combination with liver resection, results in substantial morbidity and mortality, which clearly influences the overall outcome. In the present study, patients who underwent resection of a proximal bile duct tumor were analyzed with the aim of identifying risk factors for morbidity and mortality., Methods: Between 1983 and 1998, 112 consecutive patients underwent a local resection, which in 32 patients was combined with a hemihepatectomy (11 extended resections). Eighty-four percent of the patients underwent preoperative (endoscopic) drainage. For evaluation of different treatment strategies during the study, the period was divided in three 5-year intervals., Results: Postoperative complications occurred in 65% of the patients. The overall hospital mortality was 15% for local resections and 25% for hemi-hepatectomies. There was a significantly lower morbidity and no mortality after hilar resection during the last 5 years. A higher Bismuth classification showed significant correlation with postoperative morbidity. Extended liver resections and vascular resections and a preoperative albumin level below 35 g/L were found to be significant predictors of increased mortality in univariate analysis., Conclusions: The overall morbidity and mortality rate in this series is higher than most recently published series. More (extended) liver resections resulted in an increased rate of microscopic tumor-free resections, at the cost of higher hospital morbidity and mortality. Improved preoperative work-ups will result in a selection of patients who might benefit from these extensive resections.

Background: Granular cell tumors are rare tumors most often located in the oral cavity, skin or subcutaneous tissue. The occurrence of this tumor in the biliary tree is extremely rare., Methods: Two patients are described presenting with biliary obstruction due to a tumor at the hepatic duct confluence. One patient is a 38-year-old white male with concomitant cutaneous granular cell tumors, and the other a 50-year-old white female., Results: Hilar excision was performed in both patients. Histopathology of the tumors revealed a proliferation of cells with granular cytoplasm, diagnosed as granular cell tumor., Conclusion: At preoperative examination, hilar granular cell tumors are difficult to differentiate from cholangiocarcinoma, sclerosing cholangitis or more common benign biliary tumors. Treatment consists of surgical excision after which prognosis is favorable., (Copyright 2000 S. Karger AG, Basel)

Objective: To evaluate discrepancies between flow cytometry (FCM) and image cytometry (ICM), ploidy incidence and relation between DNA ploidies and survival in distal bile duct carcinomas (DBDCs)., Study Design: Forty-four archival tumor samples from patients with DBDC who underwent subtotal pancreatoduodenectomy from 1985 to 1996 were examined for DNA ploidy using FCM and ICM., Results: Overall, 59% (26/44) of the tumors were aneuploid by at least one of the two techniques. We detected more cases of aneuploidy with ICM than FCM in formalin-fixed, paraffin-embedded DBDCs, 62% (21/34) versus 33% (13/40), respectively. When results could be compared, moderate strength of agreement (kappa = .45) was demonstrated. No correlation was found between DNA ploidy by FCM, ICM or combined FCM-ICM and survival time (P = .80, P = .35, and P = .54, respectively)., Conclusion: Approximately 59% of DNA histograms contained aneuploid cell populations. Although ICM, as compared to FCM, is more sensitive in assessing the ploidy status of DBDC, both methods were complementary. Most discrepancies between FCM and ICM were due to the dilution of aneuploid populations by non-neoplastic diploid cells. DNA ploidy assessment in DBDC did not offer the possibility of improving the ability to predict survival.

Aims: To determine the incidence and prognostic value of p53 immunopositivity in resectable distal bile duct carcinoma (DBDC)., Methods: Forty-seven paraffin-embedded archival tumour samples of patients with DBDC, who underwent subtotal pancreatoduodenectomy from 1985 to 1996, were immunohistochemically examined for p53 positivity, using the anti-p53 antibody D07., Results: Nineteen (40%) of the 47 tumours demonstrated positive (>30%) p53 protein immunostaining. Focally positive or negative staining was seen in the remaining 28 (60%) cases. Patients in this low p53 category survived significantly longer than those in the high p53 category, with median survival durations of 29 and 13 months respectively (P=0. 039). p53 positivity was independent of age, sex, tumour size, radicality of resection, histopathological grading, lymph-node status, perineural invasion and vasoinvasive growth., Conclusions: This study indicates that low (0-30%) p53 expression is a favourable prognostic factor in patients with resected DBDC., (Copyright 1999 W.B. Saunders Company Ltd.)

Background: We found a high proportion of patients with implantation metastases during follow-up after resection of a proximal cholangiocarcinoma. A remarkable fact was that all these patients had undergone preoperative endoscopic retrograde cholangiopancreatography (ERCP) with placement of a stent. ERCP is frequently used in the assessment of the proximal extension of Klatskin tumors and is usually followed by stent insertion for biliary drainage. The aim of this study was to analyze the possible risk factors leading to implantation metastases in this series of patients., Methods: Fifty-two patients who had undergone resection of a Klatskin tumor were divided into 2 groups, comparing patients who had had preoperative ERCP and stent placement (n = 41) and patients without preoperative drainage (n = 11)., Results: Eight patients developed implantation metastases within 1 year after resection, all of whom had undergone preoperative stent placement (8/41, 20%). None of the patients without preoperative stenting developed implantation metastases. In 22 patients bile samples were taken during operation. Sixteen (72.7%) patients had malignant cells and 4 (18.2%) patients atypical cells in the bile sample. There was no difference in cytology results between the 2 groups., Conclusion: This study suggests that preoperative ERCP with biliary drainage is associated with a higher frequency of implantation metastases after resection of Klatskin tumors. A properly planned prospective study, however, is needed to determine whether bile duct stenting in patients with resectable bile duct tumors is a true risk factor for the development of implantation metastases.

During the past decade the mortality after pancreaticoduodenectomy decreased to 0-4% in centers with experience. The morbidity however remains high although a decrease has also been demonstrated. Leakage of the pancreatic anastomosis is the most severe complication associated with a high mortality reported between 8-40%. Resection of the pancreatic remnant is the most radical treatment but unfortunately associated with insulin dependent diabetes. Subtotal resection of the pancreas tail seems an alternative. The incidence of postoperative bleeding is decreasing in particular bleeding from ulcers. Bleeding from a pseudoaneurysm (2%) is leading to a high mortality up to 50% and early aggressive intervention is mandatory. Delayed gastric emptying is reported between 20-30%, the pathophysiology is still unknown but postoperative intra-abdominal complications proved to be a risk factor. It is now evident that mortality is strongly related with hospital experience and regionalization reduced overall mortality. These findings are arguments to favour centralization of surgery for biliopancreatic cancer.

Purpose: To perform an analysis of the results obtained with radiotherapy in patients with either resectable or unresectable cholangiocarcinoma of the proximal bile ducts. Emphasis will be paid to analyse the role of radiotherapy, particularly brachytherapy., Patients and Methods: Between 1985 and 1997, 109 patients received radiotherapy. In 71 patients (group I) tumor resection was combined with postoperative irradiation in 52 patients and pre- plus post-operative irradiation in 19 patients. Among this group, 41 patients had a boost of 10 Gy to the biliodigestive anastomosis using intraluminal brachytherapy. Median total dose was between 50-55 Gy. The other 38 patients (group II) had an unresectable tumor at laparotomy (16 patients) or were considered primary unresectable because locoregional tumor extension (22 patients). Brachytherapy boost through a nasobiliary approach was given to 19 patients (22-25 Gy). The median total dose varied between 60 to 68 Gy. Mean follow-up was 25 +/- 23 months., Results: In group I, the survival rates at 1, 3, and 5 year were 84%, 37%, and 24%, respectively. Median survival was 24 months. Sixteen patients did live longer than 4 years. Analysis of prognostic factors among resected patients showed the tumor differentiation grade, microscopically involved margins other than the upper (hepatic) and lower (choledocus) resection parameters analysed, only the total dose had influence on margins, and elevated alkaline phosphatase as factors which significantly influence survival. From the different radiotherapy prognosis, patients receiving a total dose above 55 Gy had a shorter survival. It is important to note that patients receiving brachytherapy boost did not have a better survival than patients treated with external beam irradiation alone. Preoperative radiotherapy did not have impact on survival but recurrences in the surgical scars were not observed as compared to 15% recurrences if preoperative radiotherapy was not given. In group II the median survival was 10.4 months. Survival rates at 1 and 2 year were 43% and 10%, respectively. The only significant prognostic factor found was if unresectability was defined primarily or during laparotomy. As it was the case in group I, brachytherapy boost did not have influence on prognosis as compared to external beam irradiation alone. Observed late complications consisted of duodenal stenosis, upper digestive tract bleeding and cholangitis. Probably these complications were not only attributable to radiotherapy, as tumor relapse was also present in the majority of the cases., Conclusions: The role of radiotherapy either as adjuvant or as primary treatment remains to be demonstrated in prospective randomised studies. From our results, it seems that high radiation doses could be dangerous and could detriment prognosis. Brachytherapy boost was not superior to treatment with external beam irradiation alone.

This retrospective study in 79 surgically treated patients with a proximal bile duct carcinoma revealed 12 patients with a median age of 59.5 years (range 21-73 years) who survived more than 5 years. These 12 patients were analyzed to identify specific patient characteristics for long-term survival. Fifteen patients died from postoperative complications and were excluded from this survival analysis. In relation with preoperative Bismuth classification, there were 3 (20%) long-term survivors of 15 patients with type I tumors and 9 (35%) long-term survivors of 26 patients with type II tumors. In the group of type III and IV tumors, there were no long-term survivors. Concerning the type of resection, 9 of 51 (18%) patients had long-term survival after local resection and 3 of 13 (23%) patients after local resection combined with hemihepatectomy. Complete tumor-free surgical specimen margins were found in only 4 of 64 cases (6%), among which only one patient survived more than 5 years. Negative proximal bile duct margins, absence of multifocality, and diploid tumors showed a significant correlation with long-term survival. There was no significant correlation between long-term survival and postoperative radiotherapy. Of the 12 long-term survivors, 5 died after 5 years: 2 had developed metastases and 1 a local recurrence; the other 2 died of a metastasis of an ovarian adenocarcinoma and cachexia, respectively. The remaining seven patients were still alive at the completion of this study. The mean survival of the 64 patients analyzed in this study (in which hospital mortality was excluded) was 33.7 months, with a median survival of 18.8 months. In conclusion, the preoperative Bismuth classification of the tumor, absence of multifocality, diploid-type tumors, and negative proximal bile duct margins at histopathologic examination were the only significant prognostic factors for long-term survival.

Biliopancreatic tumors that are potentially amenable to local resection include proximal bile duct tumors (Klatskin tumors), mid-choledochal duct tumors and tumors arising from the papilla of Vater. This paper reviews our experience in the AMC, with local resection of these conditions. From 1983-1997, 112 patients underwent surgical resection of a carcinoma of the hepatic duct confluence (Klatskin tumor). Local resection was undertaken in 80 patients (52 patients with type I and II tumors, and 28 patients with type III tumors) whereas in 32 patients with type III tumors, hilar resection was performed with liver resection. Negative surgical margins were achieved in 10 patients after local resection of type I and II tumors (19.2%), in 1 patient after local resection of a type III tumor (3.6%), and in 5 patients after hilar resection and liver resection (15.6%). Middle-third carcinomas of the extra-hepatic biliary tract are less common than proximal or distal bile duct tumors. From 1993-1998, 12 patients underwent resection of a mid-choledochal duct carcinoma. In 8 patients, local resection was performed and in 4 patients, subtotal pancreatoduodenectomy (PPPD) because of the close relationship of the tumor and the pancreas. Four patients had negative surgical margins, 2 after local resection (25%) and 2 after PPPD (50%). Although accepted for villous adenomas located in the ampulla, local resection for ampullary carcinoma is controversial. Nine patients underwent local resection of a presumed adenoma that proved to be an ampullary carcinoma. In 4 patients with T1 tumors, resection of the carcinoma was locally complete (44%). Additional PPPD was performed in 6 patients, including the 4 patients with complete local resections, showing no residual tumor at the previous site of excision, but, lymphnode metastases in two resection specimens (both of patients with presumed T1 tumors). Hence, local resection of a T1 ampullary carcinoma might result in tumor free margins, but does not deal with (usually retropancreatic) lymphnode metastases. In conclusion, local resection is applicable to Klatskin type I and II tumors. Local resection may be considered in the proximally located, mid-choledochal duct carcinomas but, when located closer to the pancreas, PPPD is the preferred treatment. For ampullary adenomas, local resection is feasible unless frozen section examination raises suspicion on a malignancy. Local resection of even limited ampullary carcinomas is not advisable because of lymphatic dissemination of the tumor and consequently, inadequate clearance.

Background: The aim of this study was to investigate the prognostic value of cell proliferation (Ki-67 antigen) and DNA content in patients resected for distal bile duct carcinoma (DBDC)., Methods: Formalin-fixed tumor specimens of 35 patients with resected DBDC and a long-term clinical follow-up were analyzed. MIB-1 antibody was used for Ki-67 antigen detection to determine the proportion of proliferating cells. DNA content was measured using flow cytometry., Results: A significant correlation was found between a low MIB-1 index (<20%) and survival (P <.05). Of the 35 tumor specimens, 34 specimens were evaluable by flow cytometry: 22 carcinomas were diploid (65%), and 12 were aneuploid (35%). The median DNA index of aneuploid tumors was 1.36 (range, 1.09 to 1.76). No correlation of DNA-ploidy with survival time was found., Conclusion: In contrast to DNA-ploidy pattern, Ki-67 antigen expression showed prognostic significance in resectable DBDC. A Ki-67 positive ratio of > or =20% was associated with decreased survival time.

Background and Objectives: The K-ras gene is one of the most extensively investigated oncogenes in a wide variety of human tumors, but has rarely been studied in distal bile duct carcinoma (DBDC). We sought to investigate the diagnostic and prognostic value of K-ras codon 12 mutations in this type of tumor., Methods: Forty-seven patients who had undergone resection for DBDC were analyzed to reveal the incidence of K-ras codon 12 mutations, the locus most frequently involved. A rapid and simple two-step, semi-nested polymerase chain reaction (PCR) technique was used to detect mutations in paraffin-embedded tumor samples., Results: The PCR mismatch amplification technique demonstrated that 35 (75%) of the 47 tumors harbored a point mutation in codon 12 of the K-ras oncogene. Patients with mutated tumors had no statistically different survival time compared to those patients without a mutation in the tumor. In contrast, negative microscopic margins proved to be a significant prognosticator., Conclusions: K-ras codon 12 mutations are common in DBDC and may be useful in the diagnosis and early detection of these tumors. However, no prognostic value of these mutations could be identified in this analysis. The results of this study also suggest that negative surgical margins remain the mainstay of prognostication in resectable DBDC. However, due to the small number of patients included in this study, the results obtained should be interpreted with care.

Proximal bile duct carcinoma (Klatskin tumour) is infrequent and difficult to treat. In principle, surgery is indicated. The usefulness of irradiation after resection is controversial in the literature. This article describes the experiences gained in the Academic Medical Centre of Amsterdam with pre- and postoperative irradiation of resectable Klatskin tumours. Preoperative irradiation (10.5 Gy) is administered to devitalize detached tumour cells in the bile, to prevent implantation metastases after resection. Postoperative irradiation has been administered since 1986 according to protocol. An analysis of 71 patients, of whom 48 had been irradiated after resection while 23 had not, showed a statistically significant prolongation of survival in the group irradiated postoperatively. Radiotherapy was administered externally (55 Gy) or in combination with internal radiotherapy (45 Gy external, 10 Gy internal). For internal irradiation, the source of radiation (Iridium-192) was introduced along the bile duct anastomoses via the soma formed by the blind end of the Roux-Y jejunal loop used for bile duct reconstruction. Since internal irradiation in combination with external irradiation caused more complications, while there was no difference of survival from patients only irradiated externally, the complete postoperative irradiation is currently being given from the outside. Pre- and postoperative irradiation may contribute to the success of the treatment of the resectable Klatskin tumour.

Background: In an attempt to identify prognostic factors in carcinoma of the hepatic duct confluence, the value of tumor DNA content was studied in 58 patients with this type of malignancy., Methods: Of 58 patients (ages 26 to 74 years) surgically treated for carcinoma of the hepatic duct confluence, tumor DNA content was assessed in relationship to clinical-pathologic characteristics and patient survival. Thirty-three patients underwent additive radiotherapy. Nuclear DNA content was analyzed by flow cytometry., Results: Resection was radical in only three patients with negative surgical resection margins and dissection (cleavage) margins. Twenty-eight patients (48%) had diploid tumors, and 30 patients (52%) had aneuploid tumors. No significant correlation was found between tumor DNA ploidy, degree of tumor differentiation, lymph node status, and hepatic infiltration. Aneuploid tumors were significantly associated with neural invasion. The median overall survival was 18 months. The survival period of patients with diploid tumors was significantly (p < 0.0003) longer than the survival period of those with aneuploid tumors (median survival, 26 months and 11 months, respectively). Additive radiotherapy improved survival significantly only in patients with aneuploid tumors. When tested by univariate survival analysis, DNA ploidy, additive radiotherapy, and the state of the surgical resection margins were significant prognostic factors. With multivariate survival analysis, only DNA ploidy, age, hepatic infiltration, and lymph node status were significantly related to prognosis., Conclusions: This survival analysis shows that DNA ploidy is a powerful prognostic determinant of carcinoma of the hepatic duct confluence.

The morphologic changes of the extrahepatic biliary tract during obstruction and the effects of biliary decompression by means of an endoprosthesis on the bile duct wall were studied by light microscopy and scanning electron microscopy. Common hepatic duct biopsy specimens and bile cultures were obtained during surgery from 30 patients with a distal common bile duct obstruction caused by a tumor. Thirteen patients had obstructed bile ducts of 3 weeks' duration (group A). Seventeen patients had had jaundice for a period of 4 weeks and had subsequently undergone preoperative endoscopic biliary stenting for a period of 4 weeks (group B). Three autopsy specimens from patients without hepatobiliary disease served as controls. The results showed that the initial dilatation and thickening of the obstructed ducts in group A were associated with a mild inflammation, a moderate degree of fibrosis, and local epithelial disintegration. The presence of an endoprosthesis, however (group B), induced severe inflammatory changes with considerable fibrosis and ulcerative lesions, resulting in markedly thickened ducts with lumina approximating the diameter of the stent. Three of 13 (24%) bile cultures in group A were positive and 14 of 17 (82%) in group B were positive.

In the present study we discuss our early results and some technical aspects of a new surgical approach in dealing with high-lying malignant biliary obstruction. After transection of the common bile duct we proceed through a cephalad reflection of its proximal end in a meticulous dissection of the intrahepatic biliary tree. During dissection we follow the intrahepatic course of the right and left portal vein, which leads us to follow the respective course of the main right and left hepatic ducts and to reach the levels of their subsequent consecutive segmental bifurcations. By transecting at high levels, we excise completely or partially the tumor with the confluence of common hepatic duct. We reconstruct the biliary tree by multiple intrahepatic cholangiojejunostomies by use of a Roux-Y jejunal loop and a varied number of segmental hepatic ducts. Transanastomotic tubes were used only temporarily. Fifteen patients underwent operations by the described surgical approach without mortality. All were relieved of their jaundice completely and in all the tumor was either completely (5) or partially (10) removed. All patients had a good quality of postoperative life without being obliged to carry transanastomotic tubes and the complications and problems associated with them.