update on cholangiocarcinoma - path · update on cholangiocarcinoma judy wyatt belfast, june 2017...
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Update on Cholangiocarcinoma
Judy WyattBelfast, June 2017
Update on Cholangiocarcinoma
• 1200 pa in England. • Around 20% operable, around 10% 5 yr survival
7%
20%
73%
Liver resections in Leeds, 12 years 2005-2017
cholangiocarcinoma
hepatocellular carcinoma
metastatic NOS
0
200
400
600
800
1000
1200
liver and upper GI cancers, Yorks and Humber 1990 - 2014
total hepatobiliary
pancreas
oesophagus
stomach
7%
20%
73%
Liver resections in Leeds, 12 years 2005-2017
cholangiocarcinoma
hepatocellularcarcinoma
metastatic NOS
Resections for primary upper GI cancer Leeds, 12 years 2005 - 2017
liver
stomach
oesophagus
pancreas 0
100
200
300
400
500
600
700
Pub med “Cholangiocarcinoma + pathology” 1979 - 2015
reviews publications
Summary – update on cholangiocarcinoma
• Illustrate handling and reporting resection specimens
• Staging, prognostic factors
• Distinguish intrahepatic from perihilar CC
• New insights – stroma, cell of origin,
molecular pathology
58F
• Presented with painless jaundice and weight loss.
• MRI and CT – tumour in left lobe, cholangiocarcinoma
• Stenting right duct – relieved jaundice but caused pancreatitis
• Staging laparoscopy
• Left hepatectomy May 2017.
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CT portal venous phase,
Left lobe atrophy
Mass obstructing the ducts and stricturing the left portal vein
Staging laparoscopy – occult peritoneal disease
For radiologically occult diseaseHES data 2010-2015
Resectable? - 116/431 (27%) patients – of which
Laparoscopy: 31/114 (27%) had unresectable disease – 15 peritoneal, 16 locally advanced or liver mets
Laparotomy: 16/85 (13%) another 16 unresectable – 6 with peritoneal, 10 locally advanced, mets
Sensitivity for peritoneal disease 71% (15/21)
69/116 (59%) had successful resection, 14% of all patients
Conclusion: staging laparoscopy was useful in determining radiologically occult disease
Role of staging laparoscopy in the stratification of patients with perihilar cholangiocarcinoma
Bird N et al Liverpool Br J Surg 2017;104(4)418-425
Left hepatectomy, segments 2,3,4. 344gattached duct 35mm, GB, nodes 25mm
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Outside growing inor
Inside growing out??
Intrahepatic growing edge is cellular
Dilated intrahepaticducts
Perineuralinfiltration
Most is desmoplastic
common hepatic duct
Right ductmargin
Cholangiocarcinoma, perihilar and extrahepatic ducts
Variable univariate Relative risk multivariateDifferentiation <0.0001 1.73 0.0002Lymphatic invasion <0.0001Venous invasion <0.0001 1.38 0.0098Perineural invasion <0.0001 1.71 0.0067pT stage <0.0001 1.45 0.0038Nodal metastasis <0.0001 1.61 0.0005Resection margins <0.0001 1.51 0.0034
Significant prognostic factors in 442 patients (75% perihilar), 1977-2005
Igami T et al. Nagoya. Ann Surg 2009;249;296-302
3cm
1cm
6x3cm = 18cm
Circ. = π x diameter= 3.14cm
10 slices = 31.4cm
Circumferential margin: transverse or longitudinal sections?
1cm
3cm
Serial transverse sections Give better sampling of circumferential margin
Longitudinal sections giveextent of tumour infiltrationalong duct wall*
* Sakamoto E et al. Ann Surg 1998;227;405-11
?
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0
20
40
60
80
100
0 2 4 6 8 10
Dis
ease
-spe
cific
sur
viva
l (%
)
Time after surgery (years)
Radical operation for hilar cholangiocarcinoma in comparable Eastern and Western centres: Outcome analysis and prognostic factors.
Hirosaki (N=80)
Leeds (N=103)
P=0.767
Kimura N et al, Surgery 2017 epub May 24
Multivariate: predictive factors of survival, n=183:LN p=0.002; Margin p=0.005; differentiation p=0.029; vascular invasion p=0.046
Disease specific survivalHirosaki v Leeds – Margins:
Radical surgery for perihilar cholangiocarcinomaImpact of resection margins.
0
50
100
0 10
Hirosaki: n=8019% R1 resection
Leeds: n=10354% R1 resection
Largestlymph node25mm long
3/5 nodes were +ve
TNM6 2002= extrahepatic ducts
TNM7 2010 TNM8 2018
pTis Carcinoma in situ Inc. BilIN3
pT1 Ductal wall Confined to wall
pT2 Beyond ductal wall pT2a into surrounding adipose tissue
pT2b into adjacent hepatic parenchyma
pT3 Liver, GB, pancreas or unilateral vessels
Unilateral branch of PV or HA
pT4 Other adjacent organs or main vessels
Main PV or bilateral branches, or common HA or second order biliary radicals with contralateral PV or HA
pN1 Regional nodes +ve Regional nodes +ve pN1 1-3 nodes +vepN2 >3 nodes +veSample 15 nodes
TNM staging for Perihilar Cholangiocarcinoma
TNM6 2002= hepatocellular carcinoma
TNM7 2010 TNM8 2018
pTis Carcinoma in situ Inc. BilIN3
pT1 Single, no vascular inv. pT1a single, <5cmpT1b single, >5cm
pT2 Single with vascular inv. Or multiple <5cm
pT2a single with vascular invasion pT2 vascular invasion
or multiplepT2b multiple +/- vasc. invasion
pT3 Multiple >5cm or involvesmajor branch of portal or hepatic vein
Perforates visceral peritoneum or invades local extra-hepatic structures
Perforates visceral peritoneum
pT4 Direct invasion of adjacent organs other than GB or perforates visceral peritoneum
Tumour with periductal growth pattern
Invades local extra-hepatic structures
pN1 Regional nodes +ve Sample 6 nodes
TNM staging for Intrahepatic Cholangiocarcinoma Liver Cancer Study Group of Japan (1997)WHO: intrahepatic cholangiocarcinoma (2000)
• Mass forming – peripheral, large, sclerotic centre, cellular expansile margin
• Periductal infiltrating – arising from large ducts near hilum.
• Intraductal papillary – rare, good prognosis
early
late
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A novel approach to biliary tract pathology based on similarities to pancreatic counterparts:
is the biliary tact an incomplete pancreas?
Nakanuma Y. Pathology International 2010;60;419-429
•
A novel approach to biliary tract pathology based on similarities to pancreatic counterparts:
is the biliary tact an incomplete pancreas?
Biliary tree pancreas
IgG4 related sclerosing cholangitis Lymphoplasmacytic sclerosing pancreatitis
Primary sclerosing cholangitis Idiopathic duct-centric chronic pancreatitisConventional cholangiocarcinoma Invasive duct carcinoma
Bil IN 1-3 Pan IN 1-3
Intraductal papillary neoplasm - IPNB IPMN-P
Biliary cystic tumour with bile duct communication (cystic IPN)
IPMN-P with cystic change
Mucinous cystic neoplasm Mucinous cystic neoplasm
Nakanuma Y. Pathology International 2010;60;419-429
Previously ‘cystadenoma’
AJCC Cancer staging manual 8th edition 2017:Intrahepatic bile ducts
• Anatomically, the intrahepatic bile ducts extend from the periphery of the liver to the second-order bile ducts.
• Therefore, it may be difficult to distinguish central intrahepatic from hilar cholangiocarcinoma, particularly in the presence of a periductalinfiltrating growth pattern.
Staging - perihilar v intrahepatic
Two different types of cholangiocarcinoma
Outside growing inor
Inside growing out??
Definition:Perihilar - main lobar (left, right) ducts distal to segmental ducts and proximal to cystic duct.
- needs to extend to 2nd order bile ducts
Dichotomy in intrahepatic cholangiocarcinomasbased on histological similarities to hilar cholangiocarcinoma.
47 cases of intrahepatic CC 21 perihilar type 26 peripheral type.
Perihilar type Peripheral type
Dichotomy in intrahepatic cholangiocarcinomas based on histological similarities to hilar cholangiocarcinoma.47 cases of intrahepatic CC – 21 perihilar type, 26 peripheral type.
Akita M, Fujikura K, Ajiki T et al …… Zen Y. Modern Pathology 2017 epub
Perihilar (n=21) Peripheral (n=26)
Chronic liver disease 15% 62%
Mass forming 29% 100%Perineural infiltration 91% 23%
BilIN 29% 0%
pT1, pT4 5%, 38% 19%, 0%
Differences in p53, MUC5ac, SMAD4, Bap1, IDH5 year survival 21% 63%
Perihilar – closely match ‘hilar’ CC in all of these
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More about stroma
• Cancer associated fibroblasts, signalling etc
CK19 SMA
Bile ducts and their stroma – non-neoplastic examples
Portal plate, extrahepatic biliary atresia
Ductal plate, biliary embryogenesis
PSC
Epithelial to mesenchymal transition and cancer invasiveness: what can we learn from cholangiocarcinoma?
Metastasisation requires 4 steps:• Reducing cell-cell contacts, rearrange cytoskeletal architecture
in favour of a motile phenotype
• Impair integrity of basement membrane and invade surrounding stroma – cross-talk with mesenchymal and inflammatory cells which in turn support their invasiveness
• Disseminate through vascular channels• Engraftment at distant sites
Brivio S et al. J Clinical Medicine 2015:4:2028-41
Epithelial-to-mesenchymal transition transcription factors in cancer-associated fibroblasts (CAF)
• EMT transcription factors (EMT-TF) Snail, Twist, ZEB –essential metastasis and chemoresistance-promoting molecules.
• Expressed in both cholangiocarcinoma and cancer associated fibroblasts
• TGFbeta and IL6 important in CC, induce Twist1, activates CAF.
• CAF expressing EMT-TFs promote expression of these factors in adjacent tumour cells. Stromal expansion precedes tumour expression.
• Microenvironment changes stimulate EMT-TF expression in tumour cells that sustains stemness, increases tumour cell motility and chemoresistance.
Baulida J Molecular Oncoloty 2017 in press
Expression pattern of cancer-associated fibroblasts and its clinical relevance in intrahepatic cholangiocarcinoma
Zhang XF et a. Human Pathology 2017;epub
‘Immature’ fibroblasts – plump, SMA+ve,Associated with LN mets, late stage,
Independent factor for poor survival
Cancer associated fibroblasts:
Alpha-smooth muscle actin-positive fibroblasts (CAF) promote biliary cell proliferation and
correlate with poor survival in cholangiocarcinoma (CC).
• high expression of alpha-SMA in cholangiocarcinoma (CC) fibroblasts had a statistically significant correlation with
larger tumour size (P=0.009) and shorter survival time (P=0.013).
• Biliary epithelial cells and CC cell lines -CC fibroblasts have proliferative effects which may directly effect tumour promotion and progression of biliary epithelial cells
Chuaysri C et al. From Liver fluke and CC research centre, Thailand Oncol Rep 2009;21;957-969
Fibroblasts from:Skin Liver
CC
Biliary epithelial cells
CC cell lines
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Periductal infiltrating:
peripheral mass forming
Origin of cholangiocarcinoma
• Perihilar – ducts with peribiliary glands– ? Originate from cells in peribiliary glands
• Peripheral – from small ducts/progenitor cells /canals of Hering
• Molecular for Intrahepatic CC
Sia D et al. Gastroenterology 2013;144;829-840
Intra-biliary hepatic metastasis of colorectal carcinoma mimicking primary cholangiocarcinoma
CK7- CK20+ CDX2+
Can also be papillary – do IHC
Dong et al. Case reports in Pathology 2016;
71M painless jaundice10 years after rectosigmoid cancer pT1N0Liver resection for metastasis 4 years ago
MRI: 1.4cm intraductal mass at hepatic hilum
Pathology – papillary tumour colonising ductAlso conventional CRC mets
CDX2 CK7
Mr DT, age 69Resection of CRC liver metastasis, Post chemotherapy
Two lesions complete regression
Two lesions Viable adenocarcinoma in duct
CK7
Treatment trialsAdjuvant capecitabine for biliary tract cancer:
The BILCAP randomized study.
Post-Surgery Capecitabine ‘Should Become Standard of Care’ in Biliary Tract Cancers J Clin Oncol 35, 2017 (suppl; abstr 4006) June 4, 2017
• 447 participants were randomized to Cape (n = 223) or Obs (n = 224) from 44 UK sites between 2006-2014.
– R1 38%, N1 54%.• Median survival 53 months v 36 months (p=0.028)
Others:• ACTICCA-1 – adjuvant gemcitabine and
cisplatin after resection
• ABC-06 – 5FU and oxaliplatin in advanced biliary tract cancers
Dataset for liver cancer resections – 2nd 2010
• New proformas for intrahepatic cholangiocarcinoma,– Mass forming, periductal infiltrating– Different histological patterns– New staging
(already 32 pages instead of 23)
Dataset for liver cancer resection specimens - 3rd ed 2017 – in progress……
Minor revision for change in TNM staging.
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Summary – update on cholangiocarcinoma
• Illustrate handling and reporting resection specimens
• Staging, prognostic factors
• Distinguish intrahepatic from perihilar CC
• New insights – stroma, cell of origin,
molecular pathology
Helicobacter associated with cholangiocarinoma – many countries, not just associated with liver flukes,
CC associated with CagA+ve toxigenic strains of H. pylori……………………………………………………Thailand – up to 100/100,000 incidence of CC
Opisthorchis – humans - fresh water snails - fresh water fish – humans
Juvenile flukes in raw fish excyst in duodenum, migrate into bile ducts, mature (1cm) and shed eggs. Cause inflammation ++
H pylori in gut of Opishorchis
The end.
Thanks to –• Colleagues in Leeds – Darren Treanor, Olorunda Rotimi• Hepatobiliary MDT team
UK Liver Pathology Group -• To promote excellence in liver histopathology services in the UK and
Ireland, across all levels of specialisation, through professional collaboration in education, quality assurance and research.
• http://www.virtualpathology.leeds.ac.uk/eqa/specialist/liver/