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