Cholangiocarcinoma in primary sclerosing cholangitis
Author: Bergquist, Annika
Date: 2001-10-26
Location: Föreläsningssalen M63, Medicingatan 3, plan 6, Huddinge Universitetssjukhus
Time: 9.00
Department: Institutionen för medicin, Huddinge Sjukhus / Department of Medicine at Huddinge University Hospital
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thesis.pdf (1.866Mb)
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown causes closely associated with ulcerative colitis. PSC is a progressive disease leading to liver failure and need for liver transplantation. Cholangiocarcinoma (CC) occurs in 10-20% of patients with PSC. The prognosis for CC is poor, even after liver transplantation. It is of great importance to identify PSC patients at risk for malignant development and transplant them at an early stage. Tools for early diagnosis of CC and possibilities to detect pre-malignancy are lacking. The general purpose of this thesis was therefore to identify early diagnostic markers and risk factors for malignancy in PSC.
The first study was a case-control study comparing 20 PSC patients with CC and 20 patients with end stage PSC without cancer, the aims were to assess and compare clinical features in these groups and identify risk factors for the development of cancer. No difference was found in clinical presentation, laboratory or radiological findings. The number of patients being either current or former smokers was significantly higher in the cancer group than among controls (p<0.0004). To analyse the concept of bile duct dysplasia and the possibility of agreement of this morphological feature and determine reproducibility of the diagnosis, livers from 26 PSC patients with and 60 without concomitant CC were studied. Criteria for bile duct dysplasia were defined with reasonable level of agreement among three hepatopathologists, the kappa level for dysplasia being 0.44. Comparison of the frequency of bile duct dysplasia in livers from patients with PSC with and without CC showed dysplasia in 19% (5/26) of the cancer patients and in 0% (0/60) of non-cancer patients (p<0.001).
In CCs and in nontumourous liver tissue from 16 PSC patients with and 16 patients without CC, bile duct cell proliferation, apoptosis and expression of p53 and bcl-2 proteins were studied. Histological stage, presence of bile duct dysplasia and immunohistochemical staining for Ki-67, nuclear DNA fragmentation, p53 and bcl-2 in non-tumorous liver tissue from PSC patients with and without CC did not differ significantly. Patients with bile duct dysplasia (n=9) had a significantly higher frequency of moderate/marked bile duct proliferation than those without bile duct dysplasia (p< 0.01). In addition, evaluation of the ploidy of DNA in CCs from patients with and without PSC was made. CCs from patients with PSC displayed DNA aneuploidy significantly more often (8/10) than CCs from patients without PSC (7/18) (p<0.05). 12% (2/17) of large bile ducts from PSC patients without CC displayed aneuploidy of DNA. In a large cohort of Swedish PSC patients (n=604), we assessed the risk of malignancies in PSC compared to the general Swedish population. The frequency of hepatobiliary malignancies was 13.3%. The standardized incidence rate for hepatobiliary carcinoma was 16 1, and 14 for pancreatic carcinoma.
In conclusion, it is difficult in clinical settings to distinguish PSC patients with end stage disease from those with liver malignancy. PSC patients being current or former smokers are at an increased risk of developing hepatobiliary carcinoma. Criteria for bile duct dysplasia can be agreed on and the entity recognised in liver biopsies. The strong association of biliary dysplasia with cholangiocarcinoma in PSC suggests that occurrence of dysplasia can be used as a marker for current or developing malignancy. Increased bile duct proliferation may be used as a surrogate marker for premalignancy in PSC. The majority of CCs in PSC display DNA- aneuploidy. PSC patients also run an increased risk of developing pancreatic carcinoma.
The first study was a case-control study comparing 20 PSC patients with CC and 20 patients with end stage PSC without cancer, the aims were to assess and compare clinical features in these groups and identify risk factors for the development of cancer. No difference was found in clinical presentation, laboratory or radiological findings. The number of patients being either current or former smokers was significantly higher in the cancer group than among controls (p<0.0004). To analyse the concept of bile duct dysplasia and the possibility of agreement of this morphological feature and determine reproducibility of the diagnosis, livers from 26 PSC patients with and 60 without concomitant CC were studied. Criteria for bile duct dysplasia were defined with reasonable level of agreement among three hepatopathologists, the kappa level for dysplasia being 0.44. Comparison of the frequency of bile duct dysplasia in livers from patients with PSC with and without CC showed dysplasia in 19% (5/26) of the cancer patients and in 0% (0/60) of non-cancer patients (p<0.001).
In CCs and in nontumourous liver tissue from 16 PSC patients with and 16 patients without CC, bile duct cell proliferation, apoptosis and expression of p53 and bcl-2 proteins were studied. Histological stage, presence of bile duct dysplasia and immunohistochemical staining for Ki-67, nuclear DNA fragmentation, p53 and bcl-2 in non-tumorous liver tissue from PSC patients with and without CC did not differ significantly. Patients with bile duct dysplasia (n=9) had a significantly higher frequency of moderate/marked bile duct proliferation than those without bile duct dysplasia (p< 0.01). In addition, evaluation of the ploidy of DNA in CCs from patients with and without PSC was made. CCs from patients with PSC displayed DNA aneuploidy significantly more often (8/10) than CCs from patients without PSC (7/18) (p<0.05). 12% (2/17) of large bile ducts from PSC patients without CC displayed aneuploidy of DNA. In a large cohort of Swedish PSC patients (n=604), we assessed the risk of malignancies in PSC compared to the general Swedish population. The frequency of hepatobiliary malignancies was 13.3%. The standardized incidence rate for hepatobiliary carcinoma was 16 1, and 14 for pancreatic carcinoma.
In conclusion, it is difficult in clinical settings to distinguish PSC patients with end stage disease from those with liver malignancy. PSC patients being current or former smokers are at an increased risk of developing hepatobiliary carcinoma. Criteria for bile duct dysplasia can be agreed on and the entity recognised in liver biopsies. The strong association of biliary dysplasia with cholangiocarcinoma in PSC suggests that occurrence of dysplasia can be used as a marker for current or developing malignancy. Increased bile duct proliferation may be used as a surrogate marker for premalignancy in PSC. The majority of CCs in PSC display DNA- aneuploidy. PSC patients also run an increased risk of developing pancreatic carcinoma.
List of papers:
I. Bergquist A, Glaumann H, Persson B, Broome U (1998). "Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case-control study. " Hepatology 27(2): 311-6
Pubmed
II. Fleming KA, Boberg KM, Glaumann H, Bergquist A, Smith D, Clausen OP (2001). "Biliary dysplasia as a marker of cholangiocarcinoma in primary sclerosing cholangitis. " J Hepatol 34(3): 360-5
Pubmed
III. Bergquist A, Glaumann H, Stal P, Wang GS, Broome U (2001). "Biliary dysplasia, cell proliferation and nuclear DNA-fragmentation in primary sclerosing cholangitis with and without cholangiocarcinoma" J Intern Med 249(1): 69-75
Pubmed
IV. Bergquist A, Tribukait B, Glaumann H, Broome U (2000). "Can DNA cytometry be used for evaluation of malignancy and premalignancy in bile duct strictures in primary sclerosing cholangitis? " J Hepatol 33(6): 873-7
Pubmed
V. Bergquist A, Ekbom A, Olsson R, Kornfelt D, Loof L, Danielsson A, Hultkrantz R, Lindgren S, Prytz H, Sandberg-Gertzen H, Almer S, Granath F, Broome U (2001). "Hepatic and extrahepatic malignancies in primary sclerosing cholangitis." Journal of Hepatology (Submitted)
I. Bergquist A, Glaumann H, Persson B, Broome U (1998). "Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case-control study. " Hepatology 27(2): 311-6
Pubmed
II. Fleming KA, Boberg KM, Glaumann H, Bergquist A, Smith D, Clausen OP (2001). "Biliary dysplasia as a marker of cholangiocarcinoma in primary sclerosing cholangitis. " J Hepatol 34(3): 360-5
Pubmed
III. Bergquist A, Glaumann H, Stal P, Wang GS, Broome U (2001). "Biliary dysplasia, cell proliferation and nuclear DNA-fragmentation in primary sclerosing cholangitis with and without cholangiocarcinoma" J Intern Med 249(1): 69-75
Pubmed
IV. Bergquist A, Tribukait B, Glaumann H, Broome U (2000). "Can DNA cytometry be used for evaluation of malignancy and premalignancy in bile duct strictures in primary sclerosing cholangitis? " J Hepatol 33(6): 873-7
Pubmed
V. Bergquist A, Ekbom A, Olsson R, Kornfelt D, Loof L, Danielsson A, Hultkrantz R, Lindgren S, Prytz H, Sandberg-Gertzen H, Almer S, Granath F, Broome U (2001). "Hepatic and extrahepatic malignancies in primary sclerosing cholangitis." Journal of Hepatology (Submitted)
Issue date: 2001-10-05
Rights:
Publication year: 2001
ISBN: 91-7349-037-7
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