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

Cholangiocarcinoma Definition

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 Australia 96 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 ICC Small intrahepatic bile ducts, ductules and canals of Hering

Perihilar CC Second order bile duct

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

Distal CC Common bile duct

Classification of Cholangiocarcinoma WHO 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 CC Lobar extrahepatic bile 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. “Klatskin tumor”

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 type 60%

Periductal infiltrating type 20%

Mixed type 20%

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

Hepatocyte Stem cell

compartment Ductule & 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