Original Paper Received: June 1, 2007 Accepted: December 26, 2007 Published online: April 29, 2008
Dig Surg 2008;25:126–132 DOI: 10.1159/000128169
Cholangiocarcinoma Complicating Primary Sclerosing Cholangitis: A 24-Year Experience G. Morris-Stiff a C. Bhati a S. Olliff b S. Hübscher c B. Gunson a D. Mayer a D. Mirza a J. Buckels a S.R. Bramhall a Departments of a Hepatobiliary and Liver Transplant Surgery, b Radiology and c Histopathology, Queen Elizabeth Hospital, Birmingham, UK
Key Words Cholangiocarcinoma ⴢ Primary sclerosing cholangitis ⴢ Transplantation ⴢ Resection
Abstract Aim: To report the prevalence and outcome of cholangiocarcinoma arising in primary sclerosing cholangitis for a British tertiary referral centre. Methods: All patients diagnosed with primary sclerosing cholangitis and concurrent cholangiocarcinoma were identified from a prospectively maintained departmental database, and the mode of presentation, management and outcome were determined. Results: Of 370 patients with primary sclerosing cholangitis, 48 patients (13%) were diagnosed with a cholangiocarcinoma within a median time of 0.51 months (range: 0–73.12) from presentation to the unit. Mode of presentation included: inoperable tumours (n = 14); incidental findings in transplant hepatectomy specimens (n = 13); primary sclerosing cholangitis follow-up (n = 9); transplant work-up (n = 5); transplant waiting list (n = 5); suspected tumour confirmed at transplant (n = 1), and incidental finding at cholecystectomy (n = 1). The diagnosis was confirmed by: radiology-guided biopsy (n = 27); MRI (n = 3); CT (n = 2); laparoscopy or laparotomy (n = 2), and frozen section at transplant (n = 1). Management consisted of: transplantation (n = 14, including 1 abandoned); hepatic resection (n = 8), and palliation through stenting
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(n = 26). The overall median survival of the cohort was 4.9 months (range: 0.09–104.5). Median survival ranged from 2.6 months (range: 0.09–35.3) for palliation to 7.6 months (range: 0.6–99.6) for transplantation and 52.8 months (range: 3.7– 104.5) for resection. There was no difference in survival between the transplant and resection groups (p = 0.14). Conclusions: Cholangiocarcinoma is a common finding in primary sclerosing cholangitis and regular screening of this cohort of patients at referring centres is advocated to detect early tumours, as surgical treatment at an early stage offers significantly better outcomes for this cohort of patients. Copyright © 2008 S. Karger AG, Basel
Introduction
Primary sclerosing cholangitis represents a common indication for liver transplantation. In Europe, 1,731 patients had received grafts for primary sclerosing cholangitis by 2000 [1]. Patients with primary sclerosing cholangitis are at high risk of hepatobiliary malignancies, including hepatocellular carcinoma, pancreatic carcinoma and cholangiocarcinoma [2]. The risk for development of cholangiocarcinoma is in the order of 8–12% [3] and appears to be greatest within the first year of diagnosis (which probably represents a heightened awareness among clinicians investigating patients with primary G. Morris-Stiff 1 Golygfa’r Eglwys, Maesycoed Pontypridd CF37 1JL (UK) Tel. +44 1443 650 625, E-Mail
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sclerosing cholangitis) [2]. Burak et al. [4] identified cholangiocarcinoma in 7% of new primary sclerosing cholangitis cases over an 11.5 year period, giving an incidence of 0.6% per year and a relative risk of 1,560:1 compared with the general population. Cholangiocarcinoma usually presents with jaundice, pruritus, weight loss and abdominal pain, and thus symptoms are difficult to differentiate from those of primary sclerosing cholangitis. The diagnosis of cholangiocarcinoma is difficult as differentiation between benign and malignant strictures is not easy because the cholangiocarcinomas are often diffuse and not mass-forming types [3]. Ca19-9 has been advocated; however, it has a relatively low sensitivity and specificity when performed alone [5]. It has been that suggested that the combination of Ca19-9 with carcinoembryonic antigen is superior [6]. Another approach to the diagnosis of cholangiocarcinoma is cholangiography, using endoscopic retrograde cholangiopancratography (ERCP) [7–9], computed tomography (CT) cholangiography [8–10] or magnetic resonance cholangiopancreatography (MRCP) [9, 10]. Change in cholangiographic appearance, such as rapid and progressive stricture formation, should raise suspicion of cholangiocarcinoma. An ERCP has the advantage of allowing brush cytology [11], and the use of cytological techniques, such as digital image analysis and fluorescence in situ hybridisation, looking for aneuploidy increase the diagnostic yield of the procedure [3]. More recently, the role of endoscopic ultrasound [12] and positive emission tomography (PET) with 18-fluorodeoxyglucose [13] have shown some promise in the diagnosis of cholangiocarcinoma in the non-primary sclerosing cholangitis setting. The presence of lymphadenopathy on a CT scan is not a reliable indicator of malignancy as this is frequently observed in uncomplicated primary sclerosing cholangitis [14]. Until recently, therapeutic options for cholangiocarcinoma arising in primary sclerosing cholangitis have been limited. Resection is often not an option as many patients have advanced cirrhosis at presentation and are therefore poor candidates for extended resections. The Johns Hopkins experience of 25 patients with cholangiocarcinoma on a background of primary sclerosing cholangitis was that 16 were unresectable at presentation, 4 were candidates for liver transplantation and 5 were suitable for resection [15]. Of those resected, the 1- and 5-year survival rates were 56% and 28%, respectively. Results of orthotopic liver transplantation for cholangiocarcinoma in the setting of primary sclerosing cholangitis have been poor, with the 5-year survival following orthotopic liver transCholangiocarcinoma and Primary Sclerosing Cholangitis
plantation for known cholangiocarcinoma at 29%, rising to 55% if the cholangiocarcinoma was an incidental finding [16]. Furthermore, up to 75% of tumours recur after orthotopic liver transplantation [17]. As a result, cholangiocarcinoma is regarded as a contraindication for orthotopic liver transplantation within the British Society of Gastroenterology guidelines [18]. However, Sudan et al. [19] and Rea et al. [20] have recently published new data in favour of transplantation when cholangiocarcinomas are hilar in location, consisting of combined radiotherapy and chemotherapy. Rea et al. report 1- and 5-year survival rates of 92 and 82%, respectively [20]. The aim of this study is to review a 24-year experience with cholangiocarcinoma arising in primary sclerosing cholangitis at the Queen Elizabeth Hospital (QEH), Birmingham, including presentation, diagnosis, management and outcome.
Methods All patients referred with a diagnosis of primary sclerosing cholangitis or who had a diagnosis of primary sclerosing cholangitis established following referral to the liver unit at QEH were identified from the hepatology and liver transplant databases. This cohort was then analysed to determine all patients who had either a synchronous or metachronous cholangiocarcinoma diagnosed during the course of their follow-up. In addition, patients undergoing resection for cholangiocarcinoma were identified from the liver surgery database and their histology assessed for the presence of known or undiagnosed primary sclerosing cholangitis. For all patients identified, medical records were obtained and reviewed. Pathology, radiology and biochemistry results from the time of presentation at QEH to December 2004 were analysed. In all cases, the diagnosis of primary sclerosing cholangitis was determined using well established cholangiographic criteria [21] and histological confirmation was also obtained, again using established criteria for diagnosis [22]. The diagnosis of cholangiocarcinoma, when established preoperatively, was based on clinical and radiological suspicion and confirmed by histological assessment of biopsy specimens in all cases. The cholangiocarcinomas were all staged using cross-sectional imaging consisting of CT and/or MRI with MRCP. The screening strategies for cholangiocarcinoma were modified during the study. In cases of incidental cholangiocarcinoma, the diagnosis was based on the same histological features as the preoperatively diagnosed tumours, as all explanted livers were subject to full examination by a consultant histopathologist. Medical records and the computerised databases provided patient demographics and details regarding presentation and follow-up. Symptoms and signs reported by patients were noted; these included jaundice, pain, fatigue, pruritus, weight loss, and rigors. The presence and treatment of associated inflammatory bowel disease was documented. Intervals between presentation and diagnosis of cholangiocarcinoma were also recorded. Opera-
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Table 1. Demographic and presenting features of patients with
Results
cholangiocarcinoma Median age, years 50.1 Gender Male 36 Female 12 Mean interval from presentation to diagnosis, months 0.51 Jaundice 43 (90%) Pain 26 (54%) Fatigue 22 (46%) Pruritus 21 (44%) Weight loss 15 (31%) History of inflammatory bowel disease 41 (85%) 208 Mean bilirubin at diagnosis, mol/l Mean akaline phosphatase at diagnosis, U/l 1,312 Mean CA19-9 at diagnosis, U/ml 161
Table 2. Mode of presentation of cholangiocarcinoma
Incidental finding in OLTx hepatectomy specimen Whilst on waiting list for OLTx During OLTx work-up During follow-up of PSC Following cholecystectomy During OLTx (abandoned)
13 5 5 9 1 1
OLTx = Orthotopic liver transplantation.
Table 3. Methods utilised in establishing the diagnosis of cholangiocarcinoma
Incidental findings in hepatectomy specimens Frozen section during OLTx Laparoscopy Laparotomy MRI – 2 resection and 1 metastatic CT – resection Guided biopsies after suspicious radiology
13 1 1 1 3 2 27
OLTx = Orthotopic liver transplantation.
tive details, such as extent of resection and curative intent, were obtained from the medical records. Collected pathological data included the location and stage of the cholangiocarcinoma while biochemical data included collection of bilirubin, alkaline phosphatase and CA19-9 results. Statistical analysis was conducted using SPSS 15 (SPSS Inc, Chicago, Ill., USA). Survival was assessed though Kaplan-Meier analysis, and significance ascertained using the log rank test. In all cases, significance was taken at the 5% level.
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During the period 1981–2004, 370 patients with primary sclerosing cholangitis were managed at QEH, of which 207 underwent orthotopic liver transplantation. The cohort included 265 males and 105 females and the mean age was 49.2 years (range: 14.6–86.6). The median follow-up for the group was 4.89 years (range: 0–18.9). A cholangiocarcinoma was diagnosed in 48 patients (13%; 36 males and 12 females). The mean patient age at presentation of those with cholangiocarcinoma was 50.2 years (range: 28.9–67.9) and the median interval from initial presentation to diagnosis of cholangiocarcinoma was 0.51 months (range: 0–73.12). The frequency of symptoms reported in the cholangiocarcinoma group and the results of laboratory investigations undertaken are summarised in table 1. The majority of patients were jaundiced, and all jaundiced patients experienced deterioration in clinical and biochemical jaundice prior to the diagnosis of cholangiocarcinoma. The mean bilirubin at diagnosis of cholangiocarcinoma was 208 mol/l and was associated with a significantly deranged alkaline phosphatase, and a raised CA19-9 at 161 U/ml in 22 of the 48 patients in whom it was measured. The remaining non-specific symptoms were seen in up to half of all patients. Of patients with primary sclerosing cholangitis developing cholangiocarcinoma, 41 had a history of inflammatory bowel disease, of whom 24 had confirmed ulcerative colitis and 7 had Crohn’s disease. There was no significant difference between any of these factors and subsequent management of the patient. The mode of presentation is summarised in table 2. In 19 patients the diagnosis of cholangiocarcinoma was made following investigations performed after initial presentation to QEH, either in primary sclerosing cholangitis follow-up (n = 9), transplant work-up (n = 5) or during surveillance whilst on the transplant waiting list (n = 5). Cholangiocarcinoma was an incidental finding in the hepatectomy specimen in 13 of 207 (6%) patients undergoing liver transplantation, the diagnosis not having been suspected pre-operatively. This represents an unsuspected cholangiocarcinoma rate of 6%. In 1 case the cholangiocarcinoma was diagnosed in the cystic duct of a patient undergoing cholecystectomy and in the final case, a patient with a suspected but unconfirmed cholangiocarcinoma was found to have an advanced tumour at the time of transplantation and the procedure was abandoned.
Morris-Stiff /Bhati /Olliff /Hübscher / Gunson /Mayer /Mirza /Buckels /Bramhall
Cholangiocarcinoma and Primary Sclerosing Cholangitis
1.0
Resection (n = 8) Transplantation (n = 13) Palliation (n = 27)
0.8 Cumulative survival
The techniques used in establishing the diagnosis are summarised in table 3. The most common means of diagnosis was a targeted biopsy, which was used in 27 cases, following which was an incidental histological finding following orthotopic liver transplantation (n = 13). Imaging alone, without preoperative biopsy was preferred in patients deemed suitable for resection. The most common means of treatment was palliation through insertion of stents, placed either endoscopically or percutaneously. Fourteen patients were among a cohort of 207 undergoing transplantation for end-stage primary sclerosing cholangitis. The subsequently diagnosed cholangiocarcinomas were not suspected in 13 cases whilst in 1 case there was a suspicious area but biopsy had been negative for cholangiocarcinoma. During laparotomy at the time of potential transplantation, metastatic omental disease was identified that had not been appreciated on cross-sectional imaging. Eight patients underwent attempted resection of their cholangiocarcinomas, which were extrahepatic in 5 cases and intrahepatic in the remaining 3 patients. The intrahepatic tumours were resected by means of right hepatectomy (n = 2) and left hepatectomy (n = 1). Surgical procedures performed for extrahepatic cholangiocarcinomas included right trisectionectomy (n = 3) and right hepatectomy (n = 1). In all cases of extrahepatic cholangiocarcinoma the biliary tree was resected and reconstructed, and lymphadenectomy performed. In the patient with a cholangiocacrinoma diagnosed in the cystic duct at cholecystectomy, an extrahepatic bile duct resection and reconstruction was performed but not a hepatic resection. The median survival for the group as a whole was only 4.9 months (range: 0.09–104.5). Median survival ranged from 2.6 months (range: 0.09–35.3) for palliation through 7.6 months (range: 0.6–99.6) for orthotopic liver transplantation to 52.8 months (range: 3.7–104.5) for those undergoing resection (fig. 1). In the palliative group, 3 patients survived more than 1 year, dying on day 371, day 506 and day 1,075, respectively. The remaining 24 patients died within a year of diagnosis. The 5-year actuarial survival was 74% in the resection group, compared to 46% in the transplant group and 0% in the palliation group. There were statistically significant differences between the survival of resection (p ! 0.000) and transplant (p = 0.031) cohorts versus control, but no significant difference between the resection and transplant groups (p = 0.14). The 2 late deaths in the transplant group were not related to the recurrence of cholangiocarcinoma.
0.6
0.4
0.2
0 0
20 40 60 80 100 Time post cholangiocarcinoma diagnosis (months)
Months Resection Transplantation Palliation
0 8 13 27
20 7 6 1
40 6 6 0
60 6 6 0
80 5 6 0
120
100 5 6 0
Fig. 1. Kaplan-Meier survival plot for patients with cholangiocar-
cinoma undergoing palliative treatment, transplantation or resection.
In the transplant group, the recurrences occurred within the first year of transplantation, whereas in the resection group there was a slow and steady attrition due to recurrent disease throughout the study.
Discussion
In this large cohort of patients with primary sclerosing cholangitis, the prevalence of cholangiocarcinoma was 13%, which is identical to that report by Siqueira et al. [11] and comparable to that reported by Heimbach et al. in their review of the condition [3]. At 2.6:1, the male to female ratio was identical to that reported by Burak et al. [4]; however, our population was significantly older at the time of presentation with primary sclerosing cholangitis. The interval between initial presentation with primary sclerosing cholangitis and diagnosis of cholangiocarcinoma was short, which is in keeping with the previously documented observation that the majority of cases of cholangiocarcinoma arising in primary sclerosing cholangitis are diagnosed during the first year as a result of increased awareness of the problem among specialist units [2]. It is likely that the vast majority of these tuDig Surg 2008;25:126–132
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mours were present prior to referral but had not been appreciated, the diagnosis being made as a result of superior imaging available at specialist centres. The most common means of identifying the cholangiocarcinoma was radiological detection at the time of presentation with primary sclerosing cholangitis, thus confirming the importance of early evaluation of patients with liver dysfunction by a specialist multidisciplinary team. Radiology is of major significance and correct interpretation of the nature of malignant strictures in among the background of primary sclerosing cholangitis is key to early diagnosis. In a further 13 patients, the cholangiocarcinoma was an incidental finding in the explanted liver at the time of transplantation. This represents 6% of the 207 patients with primary sclerosing cholangitis undergoing orthotopic liver transplantation during the period covered by this study. This is in stark contrast to the experience of Burak et al. [4], where all cases were confirmed preoperatively and there were no incidental findings of cholangiocarcinoma. This probably reflects the more aggressive policy towards imaging adopted by units in the United States. For the majority of the study period, the investigation and follow-up policy at our institution was a baseline ultrasound scan followed by annual screening for all patients with primary sclerosing cholangitis. Further imaging was performed when suspicious lesions were identified or when a sudden deterioration in liver function occurred. With the increasing availability of MRI in referring units, and given the number of unsuspected lesions seen in the explanted specimens, it is likely that over time we will perform more cross-sectional imaging rather than USS. The tumour marker CA19-9 has also shown promise in identifying cholangiocarcinomas and is now incorporated into the screening schedule. The most common technique for establishing the diagnosis was targeted biopsy using either ultrasound or CT to localise the area of suspicion, this being performed in 27 of 48 (56%) cases. When potentially resectable mass lesions (n = 5) were identified on CT or MRI then a decision was made to proceed directly to surgery, in a further 2 cases an exploration was performed due to concerns regarding resectability. In a large cohort the diagnosis was made on evaluation of the explanted liver. Unfortunately, 54% of patients had unresectable tumours and were only candidates for palliation by means of intrabiliary stents. This is comparable to the experience at Johns Hopkins [15] where 16 of 25 (64%) tumours were not suitable for transplant or resection. Of 14 patients undergoing transplantation, the procedure was carried out successfully in 13 cases, the cholangiocarci130
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nomas being incidental histological findings, and 1 procedure was abandoned due to the presence of metastatic tumour. This patient had a suspicious lesion on preoperative imaging but a biopsy had failed to identify any malignant tissue. Eight patients underwent extended hepatic resection. Ahrendt et al. [15] performed 11 procedures for known cholangiocarcinomas, including 5 resections and 5 orthotopic liver transplantations, whereas Rea et al. [20] report that the Mayo clinic has adopted a more aggressive approach with liver transplantation and neoadjuvant chemoradiation and has the largest experience, with 26 resections and 38 orthotopic liver transplantations. Excellent results were reported by this aggressive approach, with 1- and 5-year survival at 92 and 82%, respectively [20]. However, it must be remembered that only 37.5% of patients in the Mayo series had primary sclerosing cholangitis, and not all of the patients in the transplant group had end-stage liver disease, so the cohort is not directly comparable with standard transplant series. Furthermore, only 8 patients had unequivocal preoperative histology and tumour was not identified in all of the explant specimens, it being assumed a completed response had occurred. Despite these concerns, if these data are replicated in other studies, it may become routine to consider transplantation for those patients with extrahepatic cholangiocarcinomas on a background of primary sclerosing cholangitis. The median survival for the group as a whole was only 6.3 months, ranging from 2.8 months for palliation through 7.6 months for orthotopic liver transplantation to 62.8 months for those undergoing resection. The survival of the palliated patients with cholangiocarcinoma in primary sclerosing cholangitis is inferior to that of a non-primary sclerosing cholangitis setting, where the median survival in large series is in the order of 6 months following drainage [23]. The results of orthotopic liver transplantation were disappointing since the tumours were incidental findings. In the context of incidental hepatocellular carcinomas, the survival is usually excellent, exceeding that of transplantation for known hepatocellular carcinoma [24]. In contrast, extended resection of cholangiocarcinomas provided good long-term results with a median survival of 62.8 months, including a 1-year survival of 67% and 5-year survival of 56%. This is better than the 20–40% reported by Hemibach et al. in their review [3]. In this historical series, only a minority of patients were candidates for resection; however, with more formalised screening using modern imaging a higher proportion of resectable cases may be identified at an earMorris-Stiff /Bhati /Olliff /Hübscher / Gunson /Mayer /Mirza /Buckels /Bramhall
lier stage, before they develop end-stage liver disease and become unsuitable for resection. Whilst there is good evidence that patients with primary sclerosing cholangitis should be screened for the development of cholangiocarcinoma, it must not be forgotten that there is still a risk for the development of a tumour in recurrent primary sclerosing cholangitis. This occurs in up to 20% of patients, based on cholangiographic and histological features [25]. Whilst it was not seen in this cohort there is a case reporting de novo cholangiocarcinoma in the setting of primary sclerosing cholangitis following orthotopic liver transplantation [26]. There is now increasing evidence for 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) in the diagnosis and staging of cholangiocarcinoma [27]. This functional imaging may also aid in the differentiation of benign and malignant strictures in patients with primary sclerosing cholangitis [28]. Prytz et al. [27], reporting on behalf of the Swedish Internal Medicine Liver Club, found FDG-PET to be superior to conventional imaging for both the detection and exclusion of cholangiocarcinoma in patients with primary sclerosisng cholangitis listed for hepatic transplantation. Our experience has lead us to develop a more aggressive approach to screening for cholangiocarcinoma, with baseline cross-sectional imaging of all patients referred to the unit with primary sclerosing cholangitis. This allows a precise anatomical localisation of strictures and provides a comparison for future studies. We have also
advocated early tertiary referral for patients with primary sclerosing cholangitis who are potential candidates for transplantation or resection so that these patients can enter a screening program, including 6-monthly ultrasound and CA19-9 estimations. A high degree of suspicion of the results of these tests allows further cross-sectional imaging. Lesions which are identified as suspected malignancy are brushed endoscopically, but if the cytology is negative and a mass lesion is present this is targeted by means of an image-guided biopsy. The role of FDG-PET in the differentiation between benign and malignant strictures is currently being evaluated.
Conclusions
During the past 30 years there have been numerous changes in the investigation and management of cholangiocarcinoma arising on the background of primary sclerosing cholangitis and so this study gives an overview of this evolutionary process rather than the current state. However, it is certain that cholangiocarcinoma is an important and not uncommon finding in primary sclerosing cholangitis and all patients with primary sclerosing cholangitis should be referred early to a regional liver unit where they should be regularly reviewed and screened for the development of a cholangiocarcinoma as early surgical treatment is the best means of increasing survival.
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