3. Introduction
• Cholangiocarcinoma has been used to refer to bile duct cancers
arising in the intra-hepatic, peri-hilar, or distal (extra-hepatic)
biliary tree, exclusive of gallbladder or ampulla of Vater
• Arise from the epithelial cells of the bile ducts
• Intra-hepatic type originate from either small intra-hepatic
ductules (peripheral cholangiocarcinomas) or large intra-
hepatic ducts proximal to the bifurcation of the right and left
hepatic ducts
4. Introduction
• Extra-hepatic bile ducts are divided into peri-hilar (including
the confluence itself) and distal segments with the transition at
the point where the common bile duct lies posterior to the
duodenum
• Tumors arising in the peri-hilar region classified according to
involvement of the hepatic ducts – Bismuth-Corlette
classification
• Tumors involving the proper hepatic duct bifurcation are
referred to as Klatskin tumors or hilar cholangiocarcinoma
Bismuth H et al. Ann Surg 1992; 215:31
6. Introduction
• Tumor distribution
– Peri-hilar tumors 50%
– Distal extra-hepatic tumors 40%
– Intra-hepatic tumors 10%
DeOliveira ML et al. Ann Surg 2007; 245:755
7. Epidemiology
• 3% of all GI malignany
• Prevalence in autopsy studies – 0.01%-0.46%
Vauthey JN et al. Semin Liver Dis 1994; 14:109.
• Incidence varies from 5% in Japan and 20% in Korea to 90%
Thailand
Primary liver cancer in Japan. Liver Cancer Study Group of Japan. Ann Surg 1990; 211: 277–87
Jung MY et al. J Pusan Med Assoc 1993; 29: 29–37
Parkin DM et al.Cancer Epidemiol Biomarkers Prev 1993; 2: 537–44.
• The high prevalence in Asian descent is attributable to
endemic chronic parasitic infestation
8. Epidemiology
• In the United States -1 to 2 cases per 100,000 population and
in Israel - 7.3 cases per 100,000 population
• Intra-hepatic variety has been rising over last two decades in
Europe, N. America, Asia, Japan, Australia
• Incidences of extra-hepatic variety are declining
internationally
Patel T. Hepatology 2001; 33:1353
Patel T.. BMC Cancer 2002; 2:10
Welzel TM et al. J Natl Cancer Inst 2006; 98:873
Jepsen P et al. J Natl Cancer Inst 2007; 99:895
• This increase may be attributable to new diagnostic methods
for obstructive jaundice and changes in ICD classification
Khan SA et al. J Hepatol 2012; 56:848.
Jarnagin WR. Semin Surg Oncol 2000; 19:156
9. Epidemiology
• Highest prevalence rate in males and females in their 60s and
70s
• The male-to-female ratio - 1:15 in <40 yrs of age
1:2.5 in 60s & 70s
11. Risk factors
• Primary sclerosing cholangitis (PSC)
– 30% cholangiocarcinoma diagnosed in PSC ± UC
– Develops at younger age (30-50yrs) in PSC
– Lifetime risk of cholangiocarcinoma in PSC – 10-15%
Burak K et al. Am J Gastroenterol 2004; 99:523
Claessen MM et al. J Hepatol 2009; 50:158
– Alcohol consumption to be a risk factor for development of
cholangiocarcinoma in PSC
Bergquist A et al. Hepatology 1998; 27:311
12. Risk factors
– Difficult to diagnose because of abnormal biliary tree. 1/3rd
cases are diagnosed within 2 yrs of initial diagnosis of PSC
– Screening strategies are used to diagnose disease at early &
treatable stages; Annual CA 19-9, USG, ERCP with brush
cytology in whom cellular atypia on initial ERCP
de Groen PC. Hepatology 2000; 31:247.
13. Risk factors
– Efficacy of tumor markers as screening tests for
cholangiocarcinoma in PSC – not established
• 3yr, prospective study
• 75 pts, PSC without clinical signs of
cholangiocarcinoma
• CEA, CA 19-9, CA 50, CA 242
Hultcrantz R etal. J Hepatol 1999; 30:669
– Study of 208 pts, using CA 19-9 level 129U/ml
• Sensitivity-78%
• specificity -98%
Levy C et al. Dig Dis Sci 2005; 50:1734
14. Risk factors
• Fibro-cystic liver disease
– Caroli’s syndrome, congenital hepatic fibrosis, choledochal
cysts – 15% risk of malignant change
– Related to biliary stasis, reflux of pancreatic juice or
deconjugation of carcinogens
– Average age at diagnosis – 34
– Incidence in pts with untreated cysts – 28%
Lipsett PA et al. Ann Surg 1994; 220:644
15. Risk factors
• Parasitic infection
– Liver flukes: Clonorchis and Opisthorchis
– Intra-hepatic cholangiocarcinoma
– Chronic inflammation in proximal biliary tree
– Thailand
• Cholelithiasis & hepatolithiasis
– Strong risk factor for gall bladder cancer
– Association with cholangiocarcinoma, less well established
– Strong association between hepatolithiasis and
cholangiocarcinoma
17. Risk factors
• Viral hepatitis
– HCV, HBV, cirrhosis – risk factors for intra-hepatic
cholangiocarcinoma
– Prospective study from Japan reported risk of
cholangiocarcinoma in cirrhosis related to HCV – 3.5% at
10 yrs.
Kobayashi M et al. Cancer 2000; 88:2471
– Data are less compelling for association between HBV and
cholangiocarcinoma
18. Molecular pathology
• Precursors to cholangiocarcinoma
– Biliary intra-epithelial neoplasia (BilN) – more common
– Intra-ductal papillary neoplasm (IPMN)
• Precursors harbor mutations in p53 & loss of SMAD4
• Molecular defects involves oncogenes & tumor suppresor
genes
– Oncogenes
• K-ras, c-erbB-2, BRAF, PIK3CA, CTNNB1, EGFR
– Tumor suppressor genes
• p53, SMAD4, CDKN2A
19. Molecular pathology
• Neoplastic transformation - association with a constitutive
production of IL-6, which has positive cytoplasmic immuno-
hisotchemical staining and over-expression of IL-6 messenger
RNA and protein in cholangiocarcinoma cells
Sugawara H et al. Histopathology 1998;33(2):145–53
• Cholangiocarcinoma growth facilitated by increased
angiogenesis mediated by over-expression of VEGF, COX-2,
and TGF-b1
Sirica AE et al. Hepatology 2005;41(1):5–15
20. Molecular pathology
• p16INK4a promoter point mutation – contribution in initiation
and progression of cholangiocarcinoma in PSC
Taniai M et al. Gastroenterology 2002; 123:1090
• Intra-hepatic cholangiocarcinoma and HCC shares common
carcinogenic steps
– Loss of heterozygosity of chromosome 4q and 6q
– Inactivation of tumor suppresor genes on chromosome 1p
Momoi H et al. Clin Cancer Res 2001; 7:2648
21. Pathology
• Adenocarcinoma - >90%
– Sclerosing
• Most common type
• Characteristic feature - desmoplastic reaction
• Extensive fibrosis – pre-operative diagnosis difficult
• Early invasion of bile duct wall – low resectibility and
cure rate
Nakeeb A et al. Ann Surg 1996; 224:463
22. Pathology
– Nodular
• Presented as constricting annular lesion of bile duct
• Highly invasive – most pts have advanced diseases at
time of diagnosis
• Very low resectibility and cure rate
– Papillary
• Rarest
• Usually present as bulky mass in CBD lumen causing
biliary obstruction in early period
• Highest resectibility and cure rates
Jarnagin WR et al. Ann Surg 2005; 241:703
23. Tumor Classification
• Based on the extent of ductal involvement by the tumor
• As per revised classification, the TNM classification for
intrahepatic, hilar, and distal cholangiocarcinomas were
separated and expanded
American Joint Committee on Cancer Staging Manual, 7th, Springer, New York 2010. p. 201
• These changes have improved the prognostic stratification of
TNM classification
Okabayashi T et al. Cancer 2001; 92:2374
24. Tumor Classification
TX Tumor can't be assessed
T0 No evidence of primary tumor
Tis Intra-ductal tumor
T1 Solitaty tumor, no vascular invasion
T2a Solitary tumor + vascular invasion
T2b Multiple tumors ± vascular invasion
T3 Perforation of visceral
peritoneum/involvement of local extra-
hepatic structure
T4 Periductal invasion
N1 Regional nodal metastasis
M1 Distant metastasis
Stage 0 Tis, N0, M0
Stage I T1, N0, M0
Stage II T2, N0, M0
Stage III T3, N0, M0
Stage IV A T4, N0, M0
Any T, N1, M0
Stage IV B Any T, Any N, M1
TNM stagging for Intra-
hepatic cholangiocarcinoma
25. Tumor Classification
T1 Confined to bile duct, extension up to
muscle layer or fibrous tissue
T2a Invasion to surrounding adipose tissue
T2b Invasion to adjacent hepatic parenchyma
T3 Invasion of unilateral branches of PV or HA
T4 Invasion of main PV or its b/l branches or
CHA or 2nd order biliary radicals b/l or u/l
biliary radicals with c/l PV or HA
N1 Metastasis to nodes along CBD, HA, PV
N2 Metastasis to nodes along periaortic,
pericaval, SMA, CA
M1 Distant metastasis
Stage 0 Tis, N0, M0
Stage I T1, N0, M0
Stage II T2a-b, N0, M0
Stage III A T3, N0, M0
Stage III B T1-3, N1, M0
Stage IV A T4, N0-1, M0
Stage IV B Any T, N2, M0
Any T, Any N, M1
TNM stagging for Peri-hilar
cholangiocarcinoma
26. Tumor Classification
T1 Histologicaly confined to bile duct
T2 Invasion beyond bile duct
T3 Invasion of gall bladder, pancreas,
duodenum, other adjacent organs without
involvement of celiac axis or SMA
T4 Involvement of celiac axis or SMA
N1 Regional nodal metastasis
M1 Distant metastasis Stage 0 Tis, N0, M0
Stage I A T1, N0, M0
Stage I B T2, N0, M0
Stage II A T3, N0, M0
Stage II B T1-3, N1, M0
Stage III T4, Any N, M0
Stage IV Any T, Any N, M1
TNM stagging for Distal
cholangiocarcinoma
27. Clinical Presentation
• Cholangiocarcinomas become symptomatic when the tumor
obstructs the biliary drainage system, causing painless
jaundice
• Common symptoms
– Pruritus – 66%
– Abdominal pain – 30-50%
– Weight loss – 30-50%
– Fever – up-to 20%
• Cholangitis is unusual
• Signs
– Jaundice – 90%
– Hepatomegaly - 25-40%
– Right upper quadrant mass – 10%
28. Diagnosis
• Laboratoty investigations
– T.bilirubin > 10mg%
– Elevated both toal and direct bilirubin
– 2- 10 fold increase ALP
– SGOT, SGPT – initially normal, elevated in chronic biliary
obstruction
29. Diagnosis
• Tumor markers
– Presence of certain tumor markers in serum or bile may
have diagnostic value
– Most of studies have been done toward identification of
cholangiocarcinoma in PSC.
30. Diagnosis
– CEA
• Neither sufficiently sensitive nor specific to diagnose
cholangiocarcinoma
• Elevated CEA – gastritis, PUD, diverticulitis, COPD, DM,
liver disease
• S. CEA >5.2ng/ml – sensitivity 68%, specificity 82%
– 333 pts with PSC
– 13% diagnosed with cholangiocarcinoma by histological
confirmation
Siqueira E et al. Gastrointest Endosc 2002; 56:40
• Biliary CEA elevated five-fold compared to those with
benign strictures
Nakeeb A et al. Am J Surg 1996; 171:147
31. Diagnosis
– CA 19-9
• Widely used for detecting cholangiocarcinoma,
particularly in PSC
• Elevated CA 19-9 – pancreatic exocrine and neuro-
endocrine tumors, biliary cancer, HCC, gasrtric cancer,
colo-rectal cancer, acute cholangitis, cirhhosis
• Some tumor produce low level or no CA 19-9
32. Diagnosis
• S. CEA 19-9 – 129U/ml – sensitivity- 79%, specificity-
99%, +ve predictive value- 57%
– 218 pts with PSC (14 pts with PSC +
cholangiocarcinoma)
Levy C et al. Dig Dis Sci 2005; 50:1734
• In study of 73 pts with PSC, 37% had CA 19-9
>129U/ml – not have cholangiocarcinoma / not detected
during 30 month follow-up.
Sinakos E et al. Clin Gastroenterol Hepatol 2011; 9:434
33. Diagnosis
• Optimal cutoff value (for malignancy) – influenced by
cholangitis, cholestasis
– Cutoff ≥37 U/ml
• Without cholangitis or cholestasis - sensitive
78%, specificity 83%
• presence of cholangitis or cholestasis -
specificity 42%
– Cutoff ≥300 U/ml
• presence of cholangitis or cholestasis -
sensitivity 40%, specificity 87%
Kim HJ et al. Am J Gastroenterol 1999; 94:1941
• In setting of acute cholangitis- re-evaluate S. CA 19-9
after recovery
34. Diagnosis
– CEA + CA 19-9
• Combined index = CA 19-9 + (CEA X 40)
– Correctly identified 10/15 pts with
cholangiocarcinoma (radiographically occult disease
in 6 pts)
Ramage JK et al. Gastroenterology 1995; 108:865
• In 333 pts with PSC, 45 had both tests
– Sensitivity -100%, specificity – 78% for CEA (>5.2
ng/ml) + CA 19-9 (>180 U/ml)
Siqueira E et al. Gastrointest Endosc 2002; 56:40
35. Diagnosis
– Biliary insulin like growth factor
• Pilot study
• Insulin like growth factor secreted by
cholangiocarcinoma cells
• Biliary levels highly accurate in differentiating
cholangiocarcinoma from pancreatic cancers.
Alvaro D et al. Ann Intern Med 2007; 147:451
36. Diagnosis
• Radiographic evaluation
– Most of jaundiced pt undergo initial USG abdomen to
confirm biliary ductal dilatation, localize site of obstruction
and exclude gallstones.
– Subsequent evaluation is different for hilar lesion compared
to distal lesion
• Hilar lesion – MRCP is imaging technique of choice
(intra-hepatic ductal dilatation, normal extra-hepatic
ducts)
37. Diagnosis
– USG
• In study of 429 pts with surgical obstructive jaundice
over 10 year – sensitivity-94%, specificity- 96%
Sharma MP et al. Trop Gastroenterol 1999; 20:167
• Intra-hepatic lesions - mass lesion, dilatation of intra-
hepatic ducts alone
• Peri-hilar and extra-hepatic lesions - intra-hepatic and
extra-hepatic ductal dilatation.
Saini. N Engl J Med 1997; 336:1889
• Obstructing lesion suggested by ductal dilatation
(>6mm) in absence of stones.
38. Diagnosis
• Klatskin tumors - segmental dilatation and non-union of
RHD and LHD
• Papillary tumor - polypoidal intra-luminal masses
• Nodular lesions – smooth masses with mural thickening
Bloom CM et al. Radiographics 1999; 19:1199
• Tumor with PSC or cirrhosis - bile ducts may not visibly
dilated
39. Diagnosis
• Advantage – evaluation of vascular involvement.
(compression, encasement, thrombosis)
• Detection of HV involvement – sensitivity 81%,
specificity- 97%, +ve predictive value- 87%
Hann LE et al. Radiology 1998; 206:651
• Detection of PV involvement – sensitivity- 93%,
specificity- 99%, +ve predictive value – 97%
Bach AM et al. Radiology 1996; 201:149
40. Diagnosis
– CT scan
• Widespread availability
• Useful for detection of intra-hepatic tumors, level of
biliary obstruction, liver atrophy
• Klatskin tumor – ductal dilataion in both lobes,
contracted gall bladder, non-union of RHD and LHD ±
thickened wall
41. Diagnosis
• CBD tumor – distended gall bladder, dilated inntra-
hepatic and extra-hepatic ducts
• PV branch invasion – biliary duct dilatation within
atrophied lobe with hypertrophic c/l lobe
• Tri-phasic CT
– Differentiate benign from malignant intra-hepatic
ductal strictures (particularly in PV phase)
Valls C et al. Abdom Imaging 2000; 25:490.
Choi SH et al. Radiology 2005; 236:178
42. Diagnosis
– Peripheral intra-hepatic tumors – hypodense lesion
with peripheral enhancement, biliary dilatation,
contrast enhancement on delayed images
– Small sized intra-hepatic cholangiocarcinoma –
enhancement in arterial phase and mimic HCC
– Peri-hilar tumors – limited sensitivity for extra-
regional nodal disease
• 55pts with peri-hilar cholangiocarcinoma
• Accuracy 83.6%
Lee HY et al. Radiology 2006; 239:113
43. Diagnosis
• Limitations
– Extent of intra-ductal tumor spread
– Resectibility (Periductal infiltritative tumor)
Feydy A et al. AJR Am J Roentgenol 1999; 172:73.
Tillich M et al. AJR Am J Roentgenol 1998; 171:651
• CT vs MRI
– 20 pts of intra-hepatic tumor
– Extent of tumor enhancement- 45% vs 55%
– Detection of bile ductal dilatation – 65% by either
method
– Relationship of tumor to vessel and surrounding
organ – more easily evaluated on CT
Zhang Y et al. J Comput Assist Tomogr 1999; 23:670
44. Diagnosis
– MRCP
• Non-invasive technique for evaluation of duct system
• Not require contrast material
• Cholangiocarcinoma –
– T1- image – Hypo-intense lesion
– T2- image – Hyper-intense lesion
– Central hypo-intensity (fibrosis)
Manfredi R et al. Semin Liver Dis 2004; 24:155
45. Diagnosis
• Peripheral tumors – pooling of contrast on delayed
images in dynamic study
• MRCP vs ERCP
– 40 pts with peri-hilar cholangiocarcinoma
– 100% accuracy rate for detection of biliary
obstruction in both techniques
– MRCP superior in defining anatomic extent of
tumor and cause of jaundice
Yeh TS et al. Am J Gastroenterol 2000; 95:432
46. Diagnosis
• MRCP + spiral CT replaced invasive cholangiography
in obstructive jaundice due to proximal lesion
Freeman ML et al. Rev Gastroenterol Disord 2003; 3:187
• Disadvantages:
– Understaging of disease in 20%
Zidi SH et al. Gut 2000; 46:103
– High level technical expertise
– Should be performed before biliary drainage since
evaluation is difficult if biliary tree is collapsed
47. Diagnosis
– Cholangiography
• ERCP or PTC
• Preoperative cholangiography (diagnostic or
therapeutic) in biliary obstruction
• MRCP + spiral CT replaced invasive cholangiography
in obstructive jaundice due to proximal lesion
• Still cholangiography is indicated in;
– Distal obstruction
– Pre-operative biliary drainage is needed
– Tissue diagnosis
Freeman ML et al. Rev Gastroenterol Disord 2003; 3:187
48. Diagnosis
• ERCP vs PTC
– ERCP preffered in PSC as stricturing of intra-
hepatic biliiary tree makes PTC difficult
– PTC preferred for imaging of proximal biliary
system if complete obstruction of distal biliary tree
• +ve cytology in bile sampling by ERCP or PTC – 30%
of tumors
Mansfield JC et al. Gut 1997; 40:671
49. Diagnosis
• Endoscopic brush cytology – sensitivity 35-70%
• Endoscopic cytology + biopsy – sensitivity 43-88%
Sugiyama M et al. Am J Gastroenterol 1996; 91:465
• Brush cytology + tumor marker – better diagnostic
accuracy.
– 333pts with PSC
– +ve brush cytology + CA 19-9 > 180 U/ml –
sensitivity – 88%, specificity- 97%
Siqueira E et al. Gastrointest Endosc 2002; 56:40
50. Diagnosis
– Endoscopic ultrasound
• Indications
– To visualize local extent of primary tumor and status
of regional nodes in distal bile duct lesion
– EUS-guided FNAB of tumors / enlarged nodes
• Advantage
– No contamination of biliary tree
• EUS + FNAB – greater sensitivity in distal tumors than
ERCP + brushing cytology.
Abu-Hamda EM, Baron TH. Semin Liver Dis 2004; 24:165
51. Diagnosis
• In proximal tumors its role is uncertain
Fritscher-Ravens A et al. Am J Gastroenterol 2004; 99:45
• EUS vs USG, CT & angiography
– 73 pts either cholangiocarcinoma (n=19) or
pancreatic cancer
– All underwent EUS, USG, CT scan and angiography
– Sensitivity Modality (For tumor)
96% EUS
86% CT scan
81% USG
59% Angiography
52. Diagnosis
– Sensitivity Modality (For PV invasion)
95% EUS
65% CT scan
55% USG
75% Angiography
Sugiyama M et al. Abdom Imaging 1997; 22:434
53. Diagnosis
– Intra-ductal USG
• Advantages
– Detection of early lesion
– Longitudinal tumor extent
– Better evaluation of proximal biliary system
– Tumor extension into adjacent organs & major
blood vessels, specificity- 100%
Tamada K et al. Endoscopy 1995; 27:573
• Disadvantages
– Distant tissue examination is difficult due to less
depth of penetration
– Can’t be used to perform FNAB
54. Diagnosis
– PET scan
• Visualization of cholangiocarcinoma is possible due to
high glucose uptake of bile duct epithelium
• Detect nodular tumor up-to 1cm
• Less helpful in infiltrating tumors
• Most important role in identifying occult metastasis
Kim YJ et al. Eur J Nucl Med Mol Imaging 2003; 30:1467
Anderson CD et al. J Gastrointest Surg 2004; 8:90
55. Diagnosis
• Possible role in screening PSC pts for
cholangiocarcinoma
Prytz H et al. Hepatology 2006; 44:15
• Possibility of acute cholangitis causing false +ve study
in PSC
56. Diagnosis
• Pre-operative tissue diagnosis
– Necessity depends upon clinical situation
– Important in following;
• Stricture of indeterminate origin (previous bile tract
surgery, bile duct stones, PSC)
• Prior to chemotherapy or radiation therapy
• Surgeon/pt reluctant to proceed with surgery without
tissue diagnosis
57. Treatment
• Pre-operative biliary drainage
– Cholestasis, liver dysfunction, biliary cirrhosis develop
rapidly with un-relieved obstruction.
– Liver dysfunction increases post-operative mortality and
morbidity
– S.Bili > 10 mg% - Pre-operative biliary drainage to bring
down to 2.5-3.0 mg%
Roger et al. Surg Clin N Am 2008; 1409-28
58. – Preoperative biliary drainage may not reduce the peri-
operative risk in pts undergoing Whipple’s procedure
– But for hilar cholangiocarcinoma, to undergo safe hepatic
resection, biliary drainage is mandatory
Nimura et al. HPB, 2008; 10: 130-133
– Endoscopically or percutaneously placed stent for
decompression in obstructive jaundice – controversial
Laurent A et al. HPB (Oxford) 2008; 10:126-128
59. – Meta-analysis of eleven studies;
• No difference in death rate or length of post-operative
stay
• Infectious complication rates is adversely affected
• In absence of evidence of clinical benefit, pre-operative
biliary decompression in hilar tumor + jaundice
shouldn’t be performed.
Liu F et al. Dig Dis Sci 2011; 56:663
60. – In study of impact of liver resection in jaundiced pts;
• 20 pts with obstructive jaundice
• Liver resection without pre-operative drainage
• Matched with 27 pts without jaundice undergoing liver
resection
• Mortality – 5% vs 0
• Post-operative liver failure- 5% vs 0
• Morbidity – 50% vs 15%
• Supports benefit for pre-operative biliary drainage
Cherqui D et al. Arch Surg 2000; 135:302
61. – Percutaneous vs endoscopic
• Retrospective series and 2 trials
• Pts with obstructive jaundice from proximal
cholangiocarcinoma or gall bladder tumor
• Early cholangitis low in percutaneous drainage
• Bile leak and bleeding – more
Piñol V et al. Radiology 2002; 225:27
Saluja SS et al. Clin Gastroenterol Hepatol 2008; 6:944
– Percutaneous drainage left to open drainage external to
body – inconvinient to pt
– So, in most institutes initial endoscopic attempt is preferred
62. • Pre-operative portal vein embolisation (PVE)
– Most patients with hilar cholangiocarcinoma(type II, III,
IV) require major hepatectomy
– Future liver remnant volume may not be adequate
– More likely to have post-operative liver failure
Abdalla et al. Surgery 2004; 135:404-10
– Pre-operative PVE is a valuable adjunct to major liver
resection
63. – PVE can initiate hypertrophy of the anticipated future liver
remnant to enable an extended resection in normal liver or
major resection in a well compensated cirrhotic patient.
– Thus it permits margin –ve resection in who otherwise
considered unresectable
– Aims to induce lobar hypertrophy in whom predicted post-
operative remnant liver volume of <25%
– Biliary decompression is mandatory to reduce the
complications, improve liver function and post-PVE
hypertrophy
64. – Benefits
• Post-resection morbidity is diminished, as evidenced by
minimal changes in liver function
• Subclinical disease or rapid progression may be
detected prior to definitive surgery, thus avoiding an
unnecessary operation
• Abdalla EK et al. Br J Surg 2001; 88:165
65. – Two techniques for PVE
• Trans-ileocolic portal embolization (TIPE)
– Performed via a mini-laparotomy and requires
general anesthesia
• Percutaneous trans-hepatic portal embolization (PTPE)
– More commonly used
– Can be performed with local anesthesia and sedation
66. – In a meta-analysis of data from 37 published series
• Total 1088 pts underwent PVE prior to liver resection
• 4 weeks after PVE, overall increase in liver volume of
between 10 %- 12%
• 85% pts underwent laparotomy for attempted major
hepatectomy
• Of who underwent laparotomy, resection was not
possible in 27 pts, because of advanced, unresectable
disease
• Following resection, 23 patients had transient liver
failure and 7 pts died of acute liver failure
Abulkhir A et al. Ann Surg 2008; 247:49
67. • Neo-adjuvant therapy
– The majority of pts are jaundiced and have a poor
functional status at presentation
– So neo-adjuvant therapy is not an option for
cholangiocarcinoma
– In a report of 45 pts undergoing concurrent chemo-
radiotherapy in resected extra-hepatic cholangiocarcinoma,
• Neo-adjuvant treatment – 12 pts
• complete pathologic response - 3 pts
68. • R0 resection – 11 pts.
• Neoadjuvant chemo-radiotherapy had longer 5-yr survival
(53% vs 23%)
• Rates of grade 2 to 3 surgical morbidity were no higher (16%
vs 33%) compared with those treated in the post-operative
setting
Nelson JW et al. Int J Radiat Oncol Biol Phys 2009; 73:148
– Although results are promising, pre-operative chemo-
radiotherapy can’t yet be considered a standard approach to
treatment
– Support the need for randomized trials testing this strategy
69. • Surgical treatment
– Resectability rates
• Distal 91%
• Intrahepatic 60%
• Perihilar 56%
Nakeeb A et al. Ann Surg 1996; 224:463
– Tumor-free margins
• In 20 - 40 % of proximal tumors
• In 50% of distal tumors
Burke EC et al. Ann Surg 1998; 228:385
– Resectability rates have increased over time, due to more
aggressive operative strategies and broadened criteria for
resectability
70. – Criteria for resectaibility
• Absence of retro-pancreatic and para-celiac nodal
metastases or distant liver metastases
• Absence of invasion of the portal vein or main hepatic
artery
• Absence of extra-hepatic adjacent organ invasion
• Absence of disseminated disease
Rajagopalan V et al. Oncology (Williston Park) 2004; 18:889
71. – Radiological criteria for unresectability of peri-hilar tumors
• B/L hepatic duct involvement up to secondary radicles
b/l
• Encasement or occlusion of the main PV proximal to its
bifurcation
• Atrophy of one liver lobe with encasement of the c/l PV
branch
• Atrophy of one liver lobe with c/l secondary biliary
radicle involvement
• Involvement of b/l hepatic arteries
Burke EC et al. Ann Surg 1998; 228:385
72. – True resectability is determined at surgery, particularly with
peri-hilar tumors
Su CH et al. Ann Surg 1996; 223:384
– Due to their location within the upper hepato-duodenal
ligament, these tumors extend into the liver and major
vascular structures.
– Pre-operative evaluation of resectability is often difficult.
– Surgical exploration is the appropriate for proximal bile
duct carcinomas whenever feasible.
73. – Prognostic factors
• Tumor location
• Stage of the primary tumor
• Extent of surgery
• Co-morbidities
Tsao JI et al. Ann Surg 2000; 232:166
• Histologic margin status
• Lymph node status
Rea DJ et al. Arch Surg 2004; 139:514
74. – Distal cholangiocarcinoma
• Treated with pancreatico-duodenectomy
• A pylorus-preserving operation is preferable and
feasible
• 5-yr survival rates - 23% - 50%
• 62% in pts undergone complete resection of a node-
negative tumor
Murakami Y et al. World J Surg 2007; 31:337
75. – Intra-hepatic cholangiocarcinoma
• To achieve –ve resection margins - hepatic resection
• The benefit of routine portal lymph node dissection
should be weighed against risks (CBD
devascularization)
• For a peripheral localized tumor, not to perform a
routine portal lymphadenectomy node dissection
76. • For centrally located tumors in which an extra-hepatic
bile duct resection is required, perform portal
lymphadenectomy at the same time
• 5-yr survival rates for patients who undergo complete
(R0) resection are 30% - 67%
DeOliveira ML et al. Ann Surg 2007; 245:755
77. – Peri-hilar cholangiocarcinoma
• Type I & II tumors - En bloc resection of extra-hepatic
bile ducts & gallbladder + 5-10 mm bile duct margins +
regional lymphadenectomy + Roux-en-Y hepatico-
jejunostomy
• Type III tumors - Above operations + hepatic lobectomy
Nagino M et al. Hepatogastroenterology 1998; 45:7
• Type II and III tumors often involve the ducts of the
caudate lobe, many surgeons recommend routine
caudate lobectomy
78. • Type III & IV tumors - Multiple hepatic segment
resection with PV resection (hilar en bloc resection)
achieve –ve margins
Neuhaus P et al. Ann Surg Oncol 2012; 19:1602
• 5-yr survival rates are 20% - 50%, with the best results
reported from Japan
Chamberlain RS et al. Ann Surg Oncol 2000; 7:55
• Margin-ve resections is >75% when partial hepatectomy
+ resection of the caudate lobe is added to the bile duct
resection
Rea DJ et al. Arch Surg 2004; 139:514
Nakeeb A et al. Surgery 2002; 132:555
80. • These improvements accompanied by higher mortality
rates (7-10% vs 2- 4%) in most series
Kosuge T et al. Ann Surg 1999; 230:663
Anderson CD, et al. Oncologist 2004; 9:43
• In series of 109 pts with proximal cholangiocarcinomas,
the 1-yr, 3-yr, 5-yr survival rates were 68%, 30% &
11%, respectively
• Addition of hepatic lobectomy didn’t alter the survival
rate. R0 resection was achieved only in 26%of patients
Lillemoe KD et al. J Hepatobiliary Pancreat Surg 2000; 7:115
81. • A report of 65 pts with peri-hilar cholangiocarcinoma,
suggests trans-mural extension to the gallbladder,
histologic type (papillary better than adenosquamous)
and gender (females better than males) significantly
affected survival
Kosuge T et al. Ann Surg 1999; 230:663
• Post-operative chemo-radiotherapy therapy contributed
to the improved outcomes in last decade
Nakeeb A et al. Surgery 2002; 132:555
82. • Another retrospective study of 49 pts with hilar tumors
suggests pre-operative s. albumin <3 g/dL and total
bilirubin >10 mg/dl has adverse prognostic impact.
Su CH et al. Ann Surg 1996; 223:384
83. • Adjuvant therapy
– Following surgical resection, the most common relapse
pattern is local, with subsequent bile duct obstruction, liver
failure, and recurrent sepsis
Jarnagin WR et al. Cancer 2003; 98:1689
– Radiation therapy (RT)
• Indications
– After incomplete resection
– Symptomatic, locally unresectable tumors
– Recurrence
• Usually with concurrent chemotherapy
84. • No randomized trial available for benefit in completely
resected disease
• Techniques
– EBRT
– Brachytherapy with iridium-192
– Stereotactic radiotherapy
– Chemo-radiotherapy
• Data suggest synergistic effect of chemotherapy and
radiation on cholangiocarcinoma cells, providing the
rationale for combined treatment
Pederson LC et al. Cancer Res 1997; 57:4325
85. • In series by Kim
– 84 patients with extra-hepatic bile duct cancer underwent
post-operative external beam RT + bolus 5-FU
– Surgical resection
• R0 - 47 pts,
• R1 - 25 pts
• R2 -12 pts
– 5-yr survival rates
• R0 – 36%
• R1 – 35%
• R2 – 0
– 50% of patients with node-negative disease were alive at
five years
Kim S et al. Int J Radiat Oncol Biol Phys 2002; 54:414
86. – Chemotherapy
• Initial recurrence involved a distant site in 41% of pts
with a hilar cholangiocarcinoma
Jarnagin WR et al. Cancer 2003; 98:1689
• No evidence suggest adjuvant chemotherapy alone
improves survival in patients with completely or
incompletely resected cholangiocarcinomas
• Multi-institutional randomised trial from Japan
– Comparison of post-operative chemotherapy with
surgery alone
– 508 pts with resected pancreatico-biliary malignancy
(cholangiocarcinoma, n=139)
87. – Overall survival – not significantly better
• Chemotherapy – 27%
• Surgery alone – 24%
– In R1 & R2 resection, 5-yr survival
• Chemotherapy – 8%
• Surgery alone – 16%
Takada T et al. Cancer 2002; 95:1685
88. • Liver transplantation
– Mayo Clinic reported a 5-yr survival rate of 82% in pts
with initially unresectable cholangiocarcinoma arising in
PSC who were treated with pre-operative chemo-
radiotherapy followed by exploratory laparotomy to
exclude metastatic disease before transplantation
Rea DJ et al. Ann Surg 2005; 242:451
– More recent report of the Mayo experience of all pts who
were enrolled into the protocol regardless of whether they
were transplanted or not revealed 1-, 3- and 5-yr survival
rates 82%, 63% & 55%, respectively.
Rosen CB et al. HPB (Oxford) 2008; 10:186
89. – Systematic review of published reports of OLT for
cholangiocarcinoma
• 1 -,3 - and 5-yr survival rates were 63%, 46% and 22%,
respectively. Median survival - 11.8 months
• Recurrence in 52% of pts. The mean follow-up was 53
months.
• Adjuvant and neo-adjuvant chemotherapy did not appear to
improve survival
• Better prognosis in negative lymph nodes and no residual
disease after surgery.
• There were insufficient data for conclusions regarding
patient, tumor, or transplant characteristics that were
associated with a favorable prognosis
90. – Because of highly selected nature of these patients, the
poor sensitivity of non-invasive staging for
cholangiocarcinoma and issues with donor allocation, OLT
cannot be considered a standard therapy for locally un-
resectable cholangiocarcinoma at present
Panjala C et al. Liver Transpl 2012; 18:594
91. • Palliation of jaundice
– Surgical biliary-enteric bypass or endoscopic/percutaneous
stenting
– Surgical bypass performed typically during unsuccessful
attempt at resection
– Stenting is preferred since it is associated with similar rates
of successful palliation and survival but less morbidity
compared to the surgical approach
Paik WH et al. Gastrointest Endosc 2009; 69:55
92. – In pts with obstructive jaundice from proximal
cholangiocarcinomas or gallbladder cancer successful
palliation of jaundice is more likely, and rates of early
cholangitis may be lower with percutaneous approach to
biliary drainage
Piñol V et al. Radiology 2002; 225:27
Saluja SS et al. Clin Gastroenterol Hepatol 2008; 6:944
Paik WH et al. Gastrointest Endosc 2009; 69:55
– Unilateral stent placement will be adequate because only 25
– 30% of the liver needs to be drained to relieve jaundice .
However, it may not relieve jaundice completely and may
increase the risk of cholangitis.
Dowsett JF et al. Gastroenterology 1989; 96:1180
93. • NCCN guidelines
– Guidelines for post-operative therapy in resectable
cholangiocarcinoma
• Extra-hepatic cholangiocarcinoma
– For resected, margin-negative, negative regional nodes -
Observation or Fluoropyrimidine-based chemo-
radiotherapy
– For positive regional lymph nodes, carcinoma in situ at
the margins, or positive margins with invasive disease -
Fluoropyrimidine-based chemo-radiotherapy should be
considered.
94. • Intra-hepatic cholangiocarcinoma
– For no residual local disease, no adjuvant therapy
recommendations
– For positive margins – Re-resection, ablation, or
Fluoropyrimidine or Gemcitabine-based chemo-
radiotherapy
95. – Guidelines for unresectable cholangiocarcinoma
• Extra-hepatic cholangiocarcinoma
– For locally advanced unresectable disease -
Fluoropyrimidine-based chemo-radiotherapy,
Fluoropyrimidine or Gemcitabine- basedchemotherapy,
or supportive care
– For resected, margin-positive disease -
Fluoropyrimidine-based chemo-radiotherapy followed by
additional Fluoropyrimidine-based or Gemcitabine-based
chemotherapy, or if the nodes are positive,
Fluoropyrimidine-based or Gemcitabine-based
chemotherapy alone.
96. • Intra-hepatic cholangiocarcinoma
– For locally advanced unresectable disease -
Fluoropyrimidine-based chemo-radiotherapy,
Fluoropyrimidine or Gemcitabine-based chemotherapy,
or supportive care.
– For positive margins (microscopic or macroscopic) – Re-
resection, ablation, or Fluoropyrimidine chemo-radiation
or chemotherapy with a Fluoropyrimidine-based regimen
or Gemcitabine