Update on Biliary Neoplasms

Arief Suriawinata, M.D.

Professor of Pathology and Laboratory Medicine

Geisel School of Medicine at Dartmouth

Department of Pathology and Laboratory Medicine

Dartmouth-Hitchcock Medical Center

Outline

• Update on epidemiology and clinical features

• Update on classification of biliary neoplasms

– Intrahepatic, perihilar and distal cholangiocarcinoma

– Cholangiolocarcinoma

– Intraductal papillary neoplasm of bile duct

– Intraductal tubulopapillary

• Update on pathogenesis, staging and treatment

– Histopathogenesis

– TNM

– Molecular pathogenesis and treatment

CholangiocarcinomaDefinition

Cholangiocarcinoma (CC) = adenocarcinoma arising from the

malignant transformation of bile duct epithelium anywhere along

the biliary tree from :

Small bile ducts and ductules

(intrahepatic CC)

Segmental to large bile ducts at hilum of

liver or outside of liver (extrahepatic CC)

Cholangioca in common bile ductBile duct & ductules

Cholangiocarcinoma

• Aggressive tumor

• “Silent” & advanced stage at presentation

• Anatomically difficult to access

• Highly desmoplastic & paucicellular

Epidemiology of CC

• 15-20% of primary liver malignancy in the U.S.

• Incidence rate*:

0.95 cases per 100,000 adults in U.S.0.2 cases per 100,000 adults in Australia96 cases per 100,000 men in Thailand*Incidence rate varies depending on local risk factors, genetics and classification

• U.S. SEER data – 3X increase of CC between 1975-99****Confirmed by data from Western Europe & Japan

• Inconsistent trends due to inconsistent classification

• Increase incidence of intrahepatic CC

Decrease incidence of carcinoma of unknown primary

Improvement on accuracy and availability of diagnostic tools

Cholangiocarcinoma

• Majority are de novo malignancy

• Definite risk factors– Primary sclerosing cholangitis

– Liver fluke infection (Opistorchis viverrini)

– Hepatolithiasis

– Biliary malformation (choledochal cysts, Caroli's diease)

– Thorotrast

• Probable risk factors– Liver fluke infection (Clonorchis sinensis)

– Hepatitis C

– Cirrhosis

– Toxins (dioxin, polyvinyl chloride)

– Biliary-enteric drainage procedures

Cholangiocarcinoma (CC)

Intrahepatic CC Extrahepatic CC

Peripheral CC = Peripheral ICC= Mass forming ICCSmall intrahepatic bile ducts, ductulesand canals of Hering

Perihilar CCSecond order bile duct

Hilar CC“Klatskin tumor”At or near junction of R and L hepatic ducts

Distal CCCommon bile duct

Classification of CholangiocarcinomaWHO vs UICC/AJCC

• Majority - no clear association with liver disease• Advanced liver disease/cirrhosis and chronic viral

hepatitis infection• Benign biliary lesions and malformations

• Primary sclerosing cholangilitis• Hepatolithiasis• Parasitic biliary infestation• Biliary malformations

Perihilar CCLobar extrahepaticbile duct

Intrahepatic CC (20%)Small intrahepatic bile ducts, ductules and canals of Hering, to second order bile ducts

Perihilar CC (50%)Second order bile ducts to cystic duct, incl. “Klatskintumor”

Distal CC (30%)Common bile duct

Blechaz, et al. Nat Rev Gastroenterol Hepatol. 2012

Classification of Cholangiocarcinoma

Extrahepatic CC

Classification of Intrahepatic Cholangiocarcinoma Based on Growth Pattern

Yamasaki S. Hepatobiliary Pancreat Surg. 2003

Mass forming type60%

Periductal infiltrating type20%

Mixed type20%

Blechaz, et al. Nat Rev Gastroenterol Hepatol. 2012

Histological Subtypes of Intrahepatic Cholangiocarcinoma

Large duct type

• Columnar cells with abundant mucin S100P+

• High CEA & CA19-9

• Perineural invasion, lymph node metastasis

• KRAS mutation

• Worse survival

Small duct type

• Cuboidal or low columnar cells with no or rare mucin

• N-cadherin +, NCAM +

• IDH 1&2 mutation, FGFR2 translocation

• Better survival

Hayashi, et al. Am J Surg Pathol 2016

ICC Small Duct Type

Hayashi, et al. Am J Surg Pathol 2016

Risk Factors of Intrahepatic CC

• Majority of patients had no associated liver

disease or cirrhosis – de novo

• Risk factors: primary sclerosing cholangitis,

inflammatory bowel diseases, nonspecific

cirrhosis, alcoholic liver disease, HCV infection

• Chronic hepatitis C virus is a risk factor for ICC

– HCV cirrhosis -> ~1000-fold increase of risk to develop HCC

Advanced chronic liver disease (including HBV) -> increase risk

Peripheral/Intrahepatic CC and Hepatitis C Infection

• Association between peripheral CC and HCV infection – 30-60%

• Gerber, et al (1997) – epithelial damage of small intrahepatic duct is a characteristic of HCV infection

• Torbenson, et al (2007) - 53% cases of bile duct dysplasia were in the setting of chronic HCV infection

• Other possibilities:

– infection of the ductular epithelium

– interface hepatitis – chronic inflammation of ductules and canals of Hering

HCV – interface hepatitis CK19 – bile ductules & canals of Hering

Intrahepatic CC and Hepatitis C Infection

Role of Hepatic Stem/Progenitor Cells

Recent studies have reported:

• HPC’s residing in canals of Hering can differentiate into

hepatocytes and cholangiocytes

• HPC’s are activated in most advanced chronic liver diseases

• Neural cell adhesion molecule (NCAM) is expressed in early

ductal development and disappears with maturation of bile

duct

– Ductular reaction often express NCAM

– Canals of Hering and ductular reaction are positive for c-kit (HPC

marker)

Canals of Hering and reactive bile ductules in advanced chronic liver disease are candidate for hepatic progenitor cells

Komuta M, et al: Hepatology 2008;47:1544-56

Cholangiolocellular carcinoma (CLC)

• Associated with HCC, cholangiocarcinoma or pure• “Mixed/combined HCC-CC, stem cell type”

Cholangiolocellular carcinoma (CLC)

CK7, CK19, N-CAM and p53 (+)

N-CAM p53

Cholangiolocellular Carcinoma vs. Mixed HCC-CC

• Mixed HCC-CCAs are heterogeneous– Classical & stem cell types

• Cholangiolocellular carcinoma is a distinct entity– Chromosomal instability, active TGF beta signaling

Moeni, et al. Journal of Hepatology 2017

Spectrum of Liver Tumors

HepatocyteStem cell

compartmentDuctule & small duct

Bile Duct

Other Etiology of Intrahepatic CC

• Malignant transformation of benign or

premalignant cholangiocellular lesions

– Biliary hamartoma/von Meyenburg complexes

– Bile duct adenoma

– Biliary adenofibroma

Perihilar Cholangiocarcinoma

• UICC/AJCC - Second order branch of bile ducts to cystic duct

– Includes “Klatskin tumor” (= hilar CC – WHO)

• Different biology and management

• Periductal-infiltrating form is the most common

– Perineural invasion and lymph node metastasis

• Painless jaundice and cholangitis, hypertrophy–atrophy complex

• Increased CA19-9, r/o IgG4 cholangiopathy

• Challenging tissue diagnosis

Intrahepatic CC • Small intrahepatic bile ducts,

ductules and canals of Hering• Mass forming

Perihilar CC • Large bile ducts• Associated with BilIN• Infiltrate along large bile ducts

Intrahepatic CC • Small intrahepatic bile ducts,

ductules and canals of Hering• Mass forming

Perihilar CC Large bile ducts• Associated with BilIN• Infiltrate along large bile ducts

Distal (Extrahepatic) Cholangiocarcinoma

• Tumor growing along the common bile duct between the cystic duct and the ampulla of Vater

– “cholangiocarcinoma” vs “bile duct carcinoma”

• Clinical presentation similar to perihilar CC

– Cholestasis, cholangitis

• Lymph node metastasis is less common than perihilar CC

Biliary Tract and Pancreas

• Close anatomical location and related embryology

– Ventral pancreas derives from biliary tract

• Share many features

– Peribiliary glands contains pancreatic acini and enzymes

– Similar lining epithelium

– Similar metaplastic changes (intestinal, gastric and oncocytic)

• Similar nonneoplastic and neoplastic diseases

Nakanuma Y, et al., 2013

Biliary Intraepithelial Neoplasia (BilIN)

• Analogous to other intraepithelial neoplasia– pancreas – PanIN, prostate – PIN

• Microscopic flat or low-papillary dysplastic epithelium, – Aka biliary dysplasia, atypical biliary epithelium, or carcinoma in situ

• Occurs more often in chronic biliary diseases - hepatolithiasis, choledochal cysts, and primary sclerosing cholangitis

• p21, p53, cyclin D1 and SMAD4 are involved in the carcinogenesis of BilIN, similar to PanIN

Biliary Intraepithelial Neoplasia (BilIN)

New two tier system Previous three tier system Dysplasia

BilIN low gradeBilIN-1 Mild

BilIN-2 Moderate dysplasia

BilIN high grade BilIN-3 Severe dysplasia = CIS

Benign BilIN

Invasive CaInvasive Ca

Intraductal Papillary Neoplasm of Bile Duct (IPNB)

• Analogous to IPMN of pancreas

• Dilated and cystic biliary system

• Multifocal papillary epithelial lesions

+/- mucin production

• Extrahepatic > intrahepatic bile duct

• May give rise to invasive carcinoma

(up to 74%)

• IPNB Type 1– Histologically similar to IPMN of the pancreas– Mucin production– Intrahepatic and hilar bile duct– Gastric > oncocytic>intestinal types– Less aggressive

• IPNB Type 2– Histologically different from IPMN of pancreas– Less mucin production– Extrahepatic bile duct– High grade, complex histological architecture with

irregular papillary branching or with foci of solid-tubular components

– More aggressive

Intraductal Tubulopapillary Neoplasm

• Analogous to ITPN of the pancreas

• Mass forming, exophytic, within biliary tree

• Intrahepatic (70%), perihilar (20%), extrahepatic (10%)

• Typical tubular pattern, solid, with abortive papillae & often necrosis

Katabi, et al. Am J Surg Pathol 2012 Schlitter, et al. Modern Pathology 2015

MUC1 +MUC2 –MUC6 +MUC5AC -

• Commonly associated with invasive tubular carcinoma (80%), but favorable prognosis

• Invasive carcinoma – small duct type > large duct type

• Mutations in KRAS, PIK3CA, and loss of SMAD4 are rare

• Overall combined survival rates showed favorable prognosis

Schlitter, et al. Modern Pathology 2015

Intraductal Tubulopapillary Neoplasm

Molecular Pathogenesis of Biliary Intraductal Lesions

Lining Epithelium

Peribiliary glands

Intraductal Papillary Neoplasm

KRAS, GNAS

Intraductal TubulopapillaryNeoplasm

PIK3CA, CDKN2A, p16

Invasive Carcinoma

KRAS-TP53Dependent

KRAS-TP53Independent

Biliary IntraepithelialNeoplasia

KRAS, p21, cyclin D1, SMAD4

Modified from Schlitter, et al. Modern Pathology 2015

2017 AJCC TNM Staging 8th EditionIntrahepatic Bile Ducts

T 2010 AJCC 7th Ed 2017 AJCC 8th Ed

T0 No evidence of primary tumor No evidence of primary tumor

Tis Carcinoma in situ (intraductal tumor) Carcinoma in situ (intraductal tumor)

T1 Solitary tumor without vascular invasion Solitary tumor without vascular invasion, ≤5cm or >5cm

T1a Solitary tumor ≤5cm without vascular invasion

Solitary tumor >5cm without vascular invasion

T2 Solitary tumor with intrahepatic vascular invasion or multiple tumors, with or without vascular invasion

T2a Solitary tumor with vascular invasion

T2b Multiple tumors, with or without vascularinvasion

T3 Tumor perforating visceral peritoneum Tumor perforating visceral peritoneum

T4 Tumor with periductal invasion Tumor involving localextrahepatic structures by direct invasion

2017 AJCC TNM Staging 8th EditionPerihilar Bile Ducts

T 2010 AJCC 7th Ed 2017 AJCC 8th Ed

T0 No evidence of primary tumor No evidence of primary tumor

Tis Carcinoma in situ Carcinoma in situ / high grade dysplasia

T1 Tumor confined to bile duct, with extension up to the muscle layer or fibrous tissue

Tumor confined to bile duct, with extension up to the muscle layer or fibrous tissue

T2a Tumor invades beyond the wall of bile duct to surrounding adipose tissue

Tumor invades beyond the wall of bile duct to surrounding adipose tissue

T2b Tumor invades adjacent hepatic parenchyma Tumor invades adjacent hepatic parenchyma

T3 Tumor invades unilateral branches of the portal vein or hepatic artery

Tumor invades unilateral branches of the portal vein or hepatic artery

T4 Tumor invades main portal vein or its branchesbilaterally; or the common hepatic artery; or the second-order biliary radicals bilaterally; or unilateral second order biliary radicals with contralateral portal vein or hepatic artery involvement

Tumor invades main portal vein or its branchesbilaterally; or the common hepatic artery; or unilateral second order biliary radicals with contralateral portal vein or hepatic artery involvement

2017 AJCC TNM Staging 8th EditionDistal Bile Ducts

T 2010 AJCC 7th Ed 2017 AJCC 8th Ed

T0 No evidence of primary tumor No evidence of primary tumor

Tis Carcinoma in situ Carcinoma in situ / high grade dysplasia

T1 Tumor confined to bile duct histologically Tumor invades the bile duct wall with a depth <5mm

T2 Tumor invades beyond the wall of bile duct Tumor invades the bile duct wall with a depth greater than 5-12mm

T3 Tumor invades the gallbladder, pancreas,duodenum or other adjacent organs without involvement of the celiac axis, or the superior mesenteric artery

Tumor invades the bile duct wall with a depth >12mm

T4 Tumor involves the celiac axis, or the superior mesenteric artery

Tumor involves the celiac axis, or the superior mesenteric artery, and/or common hepatic artery

Clinical Staging

• Tumor location

• Tumor growth pattern

• Size and number of intrahepatic masses

• Presence of vascular invasion

• Presence of cirrhosis

• Evaluation of biliary tree

• Metastasis

Clinical Staging

• Multiphasic contrast-enhanced CT

• MRI with MR cholangiopancreatography

• Cholangiography (PTC, ERCP, MRCP)

• PET/CT

HCC vs CCTumors > 2cm, vascular involvement

Evaluation of biliary treeBiliary brushing

Occult metastasis

Ancillary Diagnostic Tests• FISH polysomy on cytology brush specimen

– 1q21, 7p12, 8q24, and 9p21

– sensitivity 93%, specificity 100%

• Next generation sequencing

– KRAS, TP53, and CDKN2A

– sensitivity 85%

• miRNA on bile

– sensitivity 67%, specificity 96%

• Circulating tumor DNA (ctDNA)

– Differentially methylated regions on HOXA1, PRKCB, CYP26C1, and PTGDR

– sensitivity 83%, specificity 93%Barr Fritcher, et al. Gastroenterology 2015Dudley, et al. J Mol Diagn 2016Li, et al. Hepatology 2014Yang, et al. Gastroenterology 2017

Treatment for Intrahepatic CC

• Surgical resection remains the mainstay of potentially curative treatment

– Median disease free survival = 12-36mos

– Cirrhosis is an unfavorable independent factor

• Liver transplantation after neoadjuvant chemoradiationfor early stage peripheral CC

– 5 year survival for tumor <2cm = 65-73%

– 5 year survival for tumor >2cm or multiple = 45%

• Transarterial chemoembolization

• Radioembolization

• EB & IM radiotherapy

AdvancedUnresectable

Treatment for Perihilar CC

Rizvi, et al. Clinical Oncology 2018

Treatment of Distal CC

Rizvi, et al. Clinical Oncology 2018

Emerging Molecularly-directed Therapies

Rizvi, et al. Nature 2018