1. Primary Sclerosing Cholangitis and Cholangiocarcinoma A Multidisciplinary Approach
KV Narayanan Menon, MD, FRCP, FAASLD
Medical Director of Liver Transplantation
Digestive Disease Institute
Cleveland Clinic

2. Definition (PSC) Chronic cholestatic liver disease that
occurs more commonly in males,
characterized by diffuse inflammation
and fibrosis of both intra- and extra-
hepatic bile ducts, and may lead to
cirrhosis, portal hypertension, and liver
failure.

3. Diagnosis of PSC Cholestatic biochemical profile
Characteristic cholangiography (multifocal strictures with segmental dilatations)
Exclusion of secondary causes
Autoantibodies have no role in the diagnosis of PSC

4. Imaging - MRCP
MRCP : Sensitivity is around 80% and specificity is around 87%
Early changes may be missed on MRCP and ERCP may be necessary
A small group of paitents may not have extrahepatic disease (25%)
Very unusual to get only extrahepatic disease (<5%)

5. ERCP

6. MRCP

7. Liver Biopsy Not essential for the diagnosis of PSC
Classic periductal “onion peel” is seen infrequently in liver biopsy
Useful in
Determining stage of fibrosis
Presence of overlap such as autoimmune hepatitis

8. Natural history of PSC Mean OLT free survival ~10 years
Asymptomatic patients appear to have better survival compared to those with symptoms
Bambha et al. Gastroenterology 2003

9. Mayo Risk Score Provides useful prognostic information Age Bilirubin
AST
History of variceal bleeding
Estimated probablility of survival years 1-4

10. Complications of PSC Complications of cholestasis (bile stasis)
Specific complications of PSC
Complications of portal hypertension

11. Specific complications of PSC
Bacterial cholangitis
Bile duct strictures
Cholangioarcinoma
Hepatocellular carcinoma

12. Endoscopic therapy Most patients will develop dominant strictures
Stenosis with diameter <1.5mm in the CBD or <1mm in HD
Repeated endoscopic interventions are often needed
Antibiotic therapy mandatory
Stents tend to occlude earlier –exchange in 2 – 3 months
Balloon dilatation alone may be preferred
Brush cytology and biopsy before endoscopic therapy to exclude malignancy
Limitations
High grade stenosis >2cm above the bifurcation –consider percutaneous cholangiography

13. Liver transplantation
Only effective therapy
Excellent survival rates (>90% at 1 year)
However, PSC recurs in 15-20% of cases and recurrence may be often associated with loss of the graft
These patients also have a higher frequency of other post OLT complications including hepatic artery thrombosis (HAT)

14. Survival following liver OLT Menon et al AJT 2004
Etiology of liver disease†
PBC
PSC (0.5,2.9)
Alcohol (1.5,8.8)
Alpha-1-antitrypsin def (1.4,11.7)
Autoimmune hepatitis (0.9,8.3)
Malignancies (0.8,12.3)
Viral Hepatitis (1.1,6.1)
Other (1.6,9.4)
† Relative to a diagnosis of PBC

15. Cholangiocarcinoma Malignancy of the biliary epithelium
Proximal ducts: Cholangiocarcinoma – applied to intrahepatic and hilar tumors
Distal ducts: Extrahepatic bile duct cancer

16. Cholangiocarcinoma

17. Established Risk Factors
Parasitic infestations (O viverrini and C sinensis)
Bile duct cysts – Types I and IV have the higher incidences (Asians 18% risk of CC, US 6%)
PSC – life time risk is 6-36%, incidence 7%
Hepatolithiasis
Thorotrast

18. Clinical Features Obstructive jaundice Cholangitis
In patients with PSC
Worseing jaundice
Weight loss

19. Diagnosis
Biochemical
Radiological
Endoscopic
Pathological

20. Biochemical Diagnosis
> 100 may have predictive value
7% of the population are red blood cell Lewis phenotye negative and will have non-detectable CA 19-9
also elevated in
Cancers of the stomach, colon and pancreas
Bacterial cholangitis
Smoking
Gynecological malignancies

21. ERCP

22. Cholangioscopy

24. FISH for Cholangiocarcinoma Lazaridis et al
FISH for Cholangiocarcinoma Lazaridis et al. Hepatology 2005;128:
The red color probe indicates chromosome 3, the green color probe specifies chromosome 7, the gold color probe points to chromosome 9, and aqua identifies chromosome 17. Normal cholangiocytes (A) have 2 duplicates of each probe, as anticipated for normal diploid cells. Malignant
cholangiocytes (B) show gains of chromosomal probes, thus suggesting
polysomy.

25. Treatment Surgical Resection Liver Transplantation Palliative
Chemotherapy (Cisplatin and gemcitabine)
Biliary stenting
Photodynamic therapy

26. Exclusion Criteria for Surgical Resection of Hilar CCA
Extension into both sides of the liver
Unilobar disease with encasement of the contralateral portal vein or hepatic artery branch
Bilateral portal vein or hepatic artery branch encasement
Intrahepatic or distant metastases
Distant lymph node metastases
Significant comorbidities

27. Liver Transplantation
Original protocol was performed at Nebraska
Mayo Clinic has published a number of reports on transplantation
UNOS has recently awarded patients with cholangiocarcinoma exception MELD points if they are in an accepted protocol

28. Protocol External Beam Irradiation (4500 cGy, 150 cGy twice daily)
5 FU 225 mg/m2/day
Transcatheter Irradiation with Iridium
(2000 – 3000 cGy at 1 cm radius)
Exploratory Laparotomy
Oral capecitabine
(2000 mg/m2 per day in 2 divided doses, 2 out of every 3 weeks)
Liver Transplantation

29. Survival following OLT for CCA. Heimbach JK
Survival following OLT for CCA Heimbach JK. Transplantation 2006:82:1703-7

30. Comparision of resection and OLT. Rae DJ
Comparision of resection and OLT Rae DJ. Annals of Surgery 2005;242:
From 1993 to 2004
125 patients with cholangiocarcinoma
Transplant protocol : n=71
38 underwent OLT
Surgical resection: n=54
26 underwent resection
28 unresectable disease

31. Patient survival from operation

32. Patient survival after resection

33. Recurrence free survival

35. Accounts for 3% of biliary malignancies
Second most common primary hepatic malignancy (10-25% worldwide)
Higher incidence in men 1:

36. Incidence SE Asia 113 / 50 per 100,000 men and women Australia
United States
ICC : 0.58 per 100,000
ECC: 0.88 per 100,000
Differing exposure to risk factors are responsible
for the varying rates

37. Possible Risk Factors Inflammatory bowel disease
Choledocholithiasis and cholangitis
Chronic viral hepatitis and cirrhosis
Alcohol
Smoking
Obesity and diabetes

38. CA 19-9 in Cholangiocarcinoma Sinakos E
CA 19-9 in Cholangiocarcinoma Sinakos E. Clin Gastroenterol & Hepatol 2011;9:434-9

41. CA 19-9 concentration of 503 U/mL at initial diagnosis
sensitivity of 67%,
specificity of 74%,
PPV of 82%,
NPV of 57%
with an area under the curve (AUC) of 0.77

42. Radiologic Diagnosis Short dominant stricture on cholangiography
Polypoid masses
Rapid progression of stricturing
Hilar mass on imaging
PET scanning – may be more useful in nodular lesions and lymph node mets
EUS – hilar mass lesions / lymph nodes

43. Histological Diagnosis
Histopathology of tissue obtained by biopsy of tumors
Routine cytology of bile duct strictures
Advanced molecular techniques in cytology - FISH

44. Long term outcome of positive FISH in PSC
Long term outcome of positive FISH in PSC Lindor et al Hepatology 2010, 51:
Fig. 2. Kaplan-Meier curve comparing survival of FISH polysomy, trisomy 3/7/tetrasomy, and FISH-negative PSC patients.

46. Diagnosis
1. Biliary stricture with positive endoscopic biopsy or cytology, or
2. Dominant hilar stricture plus one or more of the following:
i) A hilar mass lesion,
ii) CA 19-9 >100 in the absence of cholangitis,
iii) Polysomy by FISH

47. Treatment Surgical Resection Five year survival rates of 22 to 44%
R0 resection
absence of lymph node metastases / vascular invasion

48. Inclusion Criteria
Lesion is located at the hilum with the stricture above the cystic duct
2. Patient must be suitable candidates for radiation therapy, chemotherapy and liver transplantation
3. No evidence of metastatic disease (intra-hepatic or extra-hepatic)

49. Inclusion Criteria (cont)
4. If a mass lesion is present, it should be less than or equal to approximately 3 cm in radial direction
5. The tumor is considered unresectable on the bass of technical considerations or underlying liver disease (eg., primary sclerosing cholangitis)
6. Negative regional lymph nodes on endoscopic ultrasound and fine needle aspiration

50. Exclusion criteria 1. Patients with prior abdominal radiation
2. Patients who have undergone a transperitoneal biopsy of the tumor or open exploration with violation of the tumor plane.
3. Diagnosis of a previous malignancy within the prior 5 years (excluding superficial skin and cervical cancers)

51. Exclusion criteria (cont)
4. Presence of intrahepatic metastases and / or extrahepatic disease.
5. Presence of lymph node metastases
6. Patients younger than 18 and older than 70 years of age

53. Comparision of resection and OLT. Rae DJ
Comparision of resection and OLT Rae DJ. Annals of Surgery 2005;242:

54. Patient survival from start of neo-adjuvant therapy

55. Survival after operation for patients without PSC

56. Resection vs OLT Hong JC. Arch Surg 2011;146:683-689
57 patients with cholangiocarcinoma
37 intrahepatic
20 hilar
OLT 38
RR 19
Adjuvant therapy in 35 patients

57. Multivariate Analysis of Predictors of Tumor Recurrence–Free Survival
Multivariate Analysis of Predictors of Tumor Recurrence–Free Survival Hong JC. Arch Surg 2011;146:
Variable HR P Value
Surgical therapy
RR (vs OLT)
Tumor location
Hilar (vs intrahepatic)
Tumor histology and extension
Perineural invasion
Multifocal
Tumor size
>3 (hilar) and > 5 cm (intrahepatic)

58. OLT offered better recurrence free survival than resection
Among the OLT group patients with neoadjuvant therapy did better

59. Liver Transplantation Outcomes