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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/