cholangiocarcinoma
TRANSCRIPT
Cholangiocarcinoma
Presented by: Dr Happy Kagathara
4th August, 2012
Dept of GI surgery
Sir Ganga Ram Hospital
• Introduction• Epidemiology• Risk Factors• Molecular pathology• Pathology• Tumor Classification• Clinical presentation• Diagnosis• Treatment
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
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
Bismuth-Corlette classification
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
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
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 internationallyPatel 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
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
Risk factors
• Primary sclerosing cholangitis• Fibrocystic liver disease• Parasitic infection• Cholelithiasis and hepatolithiasis• Lynch syndrome & biliary papillomatosis• Viral Hepatitis• Toxins• Diabetes• Obesity• HIV
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
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.
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
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
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
Risk factors
• Toxic exposures– Thorotrast – strong association– Smoking, alcohol – doubtful role– Auto, rubber, wood finishing industry
• Lynch syndrome & biliary papillomatosis– Malignant transformation – 83%– Premalignant condition
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
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
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
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
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
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
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, 7 th, Springer, New York 2010. p. 201
• These changes have improved the prognostic stratification of TNM classification
Okabayashi T et al. Cancer 2001; 92:2374
Tumor ClassificationTX 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, M0Any T, N1, M0
Stage IV B Any T, Any N, M1
TNM stagging for Intra-hepatic cholangiocarcinoma
Tumor ClassificationT1 Confined to bile duct, extension up to
muscle layer or fibrous tissueT2a 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 orCHA 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, M0Any T, Any N, M1
TNM stagging for Peri-hilar cholangiocarcinoma
Tumor ClassificationT1 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
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%
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
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.
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
confirmationSiqueira 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
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
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
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
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
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
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)
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.
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
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
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
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
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
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 CTZhang Y et al. J Comput Assist Tomogr 1999; 23:670
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
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
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
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
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
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
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
Diagnosis
• In proximal tumors its role is uncertainFritscher-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
Diagnosis
– Sensitivity Modality (For PV invasion)
95% EUS
65% CT scan
55% USG
75% AngiographySugiyama M et al. Abdom Imaging 1997; 22:434
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
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 metastasisKim YJ et al. Eur J Nucl Med Mol Imaging 2003; 30:1467
Anderson CD et al. J Gastrointest Surg 2004; 8:90
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
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
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
– 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
– 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
– 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
– 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
• 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 failureAbdalla et al. Surgery 2004; 135:404-10
– Pre-operative PVE is a valuable adjunct to major liver resection
– 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
– 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
– 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
– 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
• 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
• 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
• 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
– 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 diseaseRajagopalan V et al. Oncology (Williston Park) 2004; 18:889
– 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
– 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.
– 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
– 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
– 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
• 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
– 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 lobectomyNagino 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
• 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
Outcome of surgical resection in hilar cholangiocarcinoma
• 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
• 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
• 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
• 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
• 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
• 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
– 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)
– 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
• 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
– 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
– 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
• 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
– 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
• 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.
• 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
– 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.
• 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