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From primary sclerosing
cholangitis to cholangiocarcinoma
L.KupcinskasKaunas university of medicine, Kaunas, Lithuania
5th EAGE Postgraduate school, Prague, May 8- 9th,
2009
The hallmarks of cancer
Mantovani A; Nature 2009; 457, 36-37
Cancer can be defined
by six hallmarks,
including uncontrollable
growth, immortality and
the ability to invade
other tissues
Increasing evidence
suggests that a seventh
feature should make this
list — inflammation.
Link between chronic gastrointestinal
inflammation and cancer
• H.pylori gastritis gastric cancer
• IBD colorectal cancer
• Gliutenic enteropathy lymphoma
• Chronic pancreatitis pancreatic cancer
• Chronic hepatitis B,C HCC
• PSC cholangiocarcinoma
Primary sclerosing cholangitis: definition
and course
Biliary obliteration
Biliary cirrhosis
Cirrhosis complications:
Variceal bleeding,
Ascitis
SPB
Liver failure,
HRS
Biliary inflammation
Cholangiocarcinoma
Death
8-14 %
PSC epidemiology:
• prevalence of 10/100,000 in Northern European
• annual incidence 1.01 per 100,000 in men, and 0.84 in women.
• inflammatory bowel disease (IBD), mostly ulcerative colitis (UC) was present in about 70 %.
• more prevalent in patients with pancolitis than in those with distal colitis (5.5% versus 0.5 %)
• in UC patients PSC presented in 7 % of cases
• patients with PSC have a five year survival of 88% and a median survival of 11.9 years from the time of diagnosis
Silveira MG, Lindor KD. Can J Gastroenterol. 2008; 22(8):689-98.
Etiology and pathogenesis: PSC as a
genetic disease
Pros:
• Increased prevalence of PSC among first-degree
relatives
• Association with certain MHC- and non-MHC-alleles
Cons:
• Association with HLA-haplotypes is only weak
• Studies on non-HLA polymorphisms are not reproducible or contradictory
Weismüller TJ, et al, J Hepatol. 2008; 48 Suppl 1:S38-57
Etiology and pathogenesis: PSC as an
autoimmune disease
Pros:
• Increased incidence of co-existing autoimmune diseases
• Presence of autoantibodies like pANCA
Cons:• No response on immunosuppressive treatment
• Male predominance
• Antibodies are not specific and do not correlate with clinical parameters
Etiology and pathogenesis: PSC as
inflammatory reaction on infectious agents
Pros:
• Co-expression of VAP-1 and MadCAM-1 in the gut and the liver of patients with PSC and IBD allows an enterohepatic lymphocyte circulation
• In a rat model small intestinal bacterial overgrowth lead to biliary strictures
• Helicobacter species can be found in 24–75% of PSC livers
Cons:
• In PSC without IBD enterohepatic lymphocyte circulation is not a conclusive concept
• No evidence of significant bacteraemia in UC
• No evidence of small intestinal bacterial overgrowth or disturbed intestinal permeability in PSC
• Helicobacter species are not found more often in livers of PSC patients than in non-cholestatic liver diseases
Weismüller TJ, et al, J Hepatol. 2008; 48 Suppl 1:S38-57
Etiology and pathogenesis: PSC as a
cholangiopathy
Pros:
• Knockout of the Mdr2 gene which encodes a canalicular
phospholipid transporter in mice, results in a sclerosing
cholangitis
• Biliary epithelial cells that are activated by serum autoantibodies produce cytokines and trigger inflammation
Cons:
• In human PSC patients a significant variation of the
corresponding MDR3-gene could not be found
PSC is a multifactorial disorder, developing in individuals with
a genetic predisposition when exposed to the appropriate
environmental (microflora?) stimulus
Ductal involvement at the time of
diagnosis PSC
• Intrahepatic & extrahepatic - 69%
• Intrahepatic 25%
• Extrahepatic 4%
Clinical variants of PCH
• “Classic” large-ducts – 90%
• “Small-ducts” –
normal cholangiogram – 5-15 %
• IgG4-related cholangitis:
associated with autoimmune pancreatitis,
more favorable prognosis
• Overlap with autoimmune hepatitis, especially in children (till 49%)
“Small-duct” PSH- a distinct clinical
entity?
• Typical cholestatic enzyme pattern
• Normal cholangiogram
• Do not progress to “large duct” PSH
• Do not progress to cholangiocarcinoma
Silveira MG et al, Can J Gastroenterol. 2008; 22(8):689-98.
Survival free of LT was significantly longer in patients
with small-duct in comparison to “classic” large-duct PSC
Bjornson E et al. Gastroenterology, 2008 Apr;134(4):975-80.
hazard ratio, 3.04; 95% CI: 1.82–5.06; P < 0.0001
Follow-up cholangiogram after 8 weeks of corticosteroid
therapy - complete resolution of strictures in
IgG4-related sclerosing colangitis
Small A et al. Nature Gastroenterol&Hepatol 2008; 5 (12), 707-12
Diagnostic algorithm for PSC
Jeans J et al Liver Transplantation, 2008; 14; 736-746
MR cholangiogram or ERCP?
• Because it is less invasive, MRCP is primarily used for diagnosing PSC
• ERCP is preferred if dilated bile ducts demonstrate a need for direct
intervention.
Primary sclerosing cholangitis. Liver biopsy
Portal tract with
moderately dense
inflammatory infiltrate
(mainly lymphocytes,
some eosinophils);
and concentric,
lamellated, periductal
(‘onion skin’) fibrosis
around the
interlobular bile duct
(center). (H&E)
Staging of histological findings in
PSC (Liudwig, 1981)
• Stage 1 - portal hepatitis, degeneration of
bile ducts with inflammatory cell infiltrate
• Stage 2 - extension of disease to periportal
area with prominent bile ductopenia
• Stage 3 - septal fibrosis and necrosis
• Stage 4 - frank cirrhosis
PSC: treatment
Ursodeoxycholic acid (UDCA):
• a choleretic effect,
• cytoprotective effect,
• immunomodulatory effect,
The traditional Chinese drug ‘Yutan’,
a powder preparation derived from
the dried bile of adult bears, has
been used in the treatment of
hepatobiliary disorders for 3000
years.
PSC: treatment
• Standard dose of UDCA (15 mg/kg/day) has shown some efficacy in
providing symptomatic relief, improving biochemical abnormalities,
and stabilizing hepatic inflammation, however, do not change
mortality and need for LT
• High dose UDCA (20-30 mg/kg/day) like immunosupresants,
antibiotics (metronidasole, vancomicine) and other agents should be
used only as part of a clinical trials
• Supplementation with calcium and fat soluble vitamins,
• Patients with a dominant stricture should undergo endoscopic therapy
(dilatation or stenting),
• biliary reconstructive procedures could be applied in selected patients
with predominantly extrahepatic damage,
• LT for end stage liver disease
Is high-dose ursodeoxycholic acid (17-23
mg/kg/d) effective for the treatment of patients
with primary sclerosing cholangitis?
Olsson R et al. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year
multicenter, randomized, controlled study. Gastroenterology (2005) 129: 1464–1472
Treatment with minocycline (100 mg twice daily, 1 year)
is related with significant improvement of AlkPhosph
and PSC Mayo risk score (a pilot study)
Variable Baseline Post-treatment P
Alkaline phosphatase, U/l (nr, 45–142)
330 (189–1040) 265 (108–737) 0.04
AST, U/l (nr, 8–48) 72 (32–202) 70 (24–174) 0.06
Total bilirubin, mg/dl (nr, 0.1–1.0) 0.9 (0.3–2.3) 0.6 (0.4–1.9) 0.11
Direct bilirubin, mg/dl (nr, 0.0–0.3) 0.3 (0.1–0.9) 0.2 (0.1–0.4) 0.11
Prothrombin time, s (nr, 8.3–10.8) 9.0 (8.4–10.6) 8.9 (8.0–10.4) 0.38
Albumin, g/dl (nr, 3.5–5.0) 4.0 (3.6–4.4) 4.0 (3.6–4.3) 0.73
Mayo risk score0.55 (-0.65–
0.91)0.02 (-0.89–
1.65) 0.05
Silveira MG et al.. Am. J. Gastroenterol. 2009, 104, 83–88
PSC: treatment
• Standard dose of UDCA (15 mg/kg/day) has shown some efficacy in
providing symptomatic relief, improving biochemical abnormalities,
and stabilizing hepatic inflammation, however, do not change mortality
and need for LT
• High dose UDCA (20-30 mg/kg/day) like immunosupresants, antibiotics
(metronidasole, vancomicine) and other agents should be used only
as part of a clinical trials
• Supplementation with calcium and fat soluble vitamins,
• Patients with a dominant stricture should undergo endoscopic therapy
(dilatation or stenting),
• biliary reconstructive procedures could be applied in selected patients
with predominantly extrahepatic damage,
• LT for end stage liver disease
Early liver transplantation in PSC
Pros:
Lee YM et al, Can J Gastroenterol. 2002 16(10):697-9.
• UDCA and other drugs have not been shown to affect the natural
history of the disease.
• Endoscopic dilation only relief symptoms and complications
related to dominant strictures,
• CC often not clinically apparent before surgery,
• There are no good serologic tests for early cancers,
• CC has such a dismal prognosis,
• Because it is the only procedure of proven benefit, patients with
PSC should be considered for liver transplantation early in the
course of the disease
Early liver transplantation for PSC
Cons:
Weismüller TJ, et al J.Hepatol. 2008;48 Suppl 1:S38-57.
(n=55)
(n=318)
(p < 0.01)
Primary sclerosing cholangitis: definition
and course
Biliary obliteration
Biliary cirrhosis
Cirrhosis complications:
Variceal bleeding,
Ascitis
SPB
Liver failure,
HRS
Biliary inflammation
Cholangiocarcinoma
Death
8-14 %
Cholangiocarcinoma epidemiology: rise in mortality
rates from intrahepatic CC across four continents
Khan SA et al, J Hepatol. 2002 Dec;37(6):806-13
Classification of cholangiocarcinoma
Classification of non-hilar cholangiocarcinoma
Classification of hilar cholangiocarcinoma
Cholangiocarcinoma: inflammation-
related risk factors
• PSC – 10 –15%,
• Liver flukes Opisthorchis viverrini(Thailand, Laos, Malaysia) or Clonorchis sinensis (Japan, Korea, Vietnam),
• Hepatitis B, C,
• Alcoholic liver disease
Burak K, et al Am J Gastroenterol (2004). 99 (3): 523–6.
Cholangiocarcinoma: non-
inflammatory risk factors
• Caroli disease - 7%
• Lynch II syndrome
• Biliary papillomatosis
• Hepatolithiasis, especially in Asia,
• Thorotrast (historical, baned 1950)
Taylor AC, et al. Eur J Gastroenterol Hepatol 1998. 10 (2): 105–8.
Lee S et al, Cancer 2004, 100 (4): 783–93.
Lee C, Wu C, Chen G J Gastroenterol Hepatol 2002, 17 (9): 1015–20.
Standard CC diagnostic tests:
• ERCP
• percutaneous transhepatic cholangiogram
• abdominal CT scan
• abdominal ultrasound
• MRI
• ultrasound or CT scan directed biopsy of the
biliary tract
• elevated tumor markers: CA 19-9 and
carcinoembryonic antigen (CEA)
In PSC patient with predominant stricture in biliary tree
CC should be suspected
• Brush cytology and/or endobiliary biopsy
If these are non-diagnostic,
• CA 19-9 and CEA in conjunction with
abdominal CT
• Fine needle aspiration under endoscopic
ultrasonographic or CT guidance
• Cholangioscopy
• Tumor suppressor genes (eg, p53,
SMAD4) and oncogenes (eg, K-ras, c-myc)
mutations
However, predominant biliary duct stenosis is present in 35% PSC patients
Charatcharoenwitthaya P, Enders FB, Halling KC, Lindor KD.Hepatology. 2008 Oct;48(4):1106-17.
Cholangioscopy
cholangiocalcinoma
Flexible cholangioscope (5 mm in diameter)
Rossi et al. BMC Medical Imaging 2004 4:3
Therapeutic algorithm in patients with primary
sclerosing cholangitis and cholangiocarcinoma
Jeans J et al Liver Transplantation, 2008; 14; 736-746
Should be screening of CC performed
in PSC patients?• There is no accepted screening program for CC in asymptomatic
patients with PSC,
• Curative options for confirmed CC in these patients are limited,
• Early CC are difficult to differentiate from benign strictures,
• Tumour markers are not sensitive enough to screen for early CC,
• Biliary dysplasia should be viewed as a pre-malignant condition, however, it detection is complicated,
• Standard investigations for CC with MRI/MRCP and ERCP with brush cytology still miss a significant proportion of CC,
• Dynamic FDG-PET, FISH, DIA and cholangioscopy, may be useful to in detecting early CC, however do not have enough sensitivity or specificity
Relative risk of first cancer after diagnosis of
primary sclerosing cholangitis (PSC)
Site of cancer RR (95% CI)
Hepatobiliary tract 106.9 (72.6 to 151.7)
Oesophagus cancer 0.0 (0 to 34.2)
Stomach 2.5 (0.1 to 14.1)
Small intestine 0.0 (0 to 56.8)
Colorectal 6.8 (2.7 to 14)
Pancreas 9.7 (2.0 to 28.4)
Bergquist et al. Postgrad Med J. 2007, 84(991):228-37.
Lifetime risk of cholangiocarcinoma and
colorectal cancer in PSC patients
• The risk of CC after 10 and 20 years was 9%
and 9%, respectively
• In patients with concomitant IBD the 10 and 20-
year risks for CRC were 14% and 31%,
• and significantly higher than for patients without
IBD (2% and 2%; P=0.008)
Claessen MM, Vleggaar FP, Tytgat KM, Siersema PD, van Buuren HR.J Hepatol. 2009 Jan;50(1):158-64.
Brume A et al. Clin oncol 2007 ;84:228-237
Absolute cumulative risk of colorectal neoplasia in patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC)
compared with those with UC alone
Summary of suggested screening and
surveillance tests for cancer in patients with
PSC
Cholangiocarcinoma All patients Annual MRI, CA19-9 with
ERCP in suspicious cases
Hepatocellular
carcinoma
Cirrhotic/severe fibrosis Ultrasound 6-monthly with
AFP test
Gallbladder All patients Annual ultrasound
Colonic carcinoma All patients
With UC and Crohn’s
colitis
Initial colonoscopy at
diagnosis of PSC
Annual colonoscopy
Pancreatic carcinoma All patients None suggested
Cancer Target group Method
Kitiyakara T, Postgrad Med J. 2008;84(991):228-37
Parli Ds, et al. Gastroenterology 2003;124:889-93
Chemoprevention in PSC patients: proportion of patients without dysplasia and CRC after
taking UDCA or placebo
p<0.01
Key points on chemoprevention
•UDCA appears to be chemoprotective against
colorectal neoplasia in patients with PSC
• There is some suggestions that UDCA may also be
chemoprotective for cholangiocarcinoma
• The role of 5-aminosalicylates in chemoprevention of
colorectal cancer in patients with PSC and ulcerative
colitis is still unclear
Kitiyakara T, Postgrad Med J. 2008;84(991):228-37.
Kaunas, Lithuania
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