Update on Biliary Neoplasms - Pathology · PDF file Biliary Neoplasms Arief Suriawinata, M.D....

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Transcript of Update on Biliary Neoplasms - Pathology · PDF file Biliary Neoplasms Arief Suriawinata, M.D....

  • 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