Diagnosis and Management of Cholangiocarcinoma: A Multidisciplinary Approach

Description

This book provides a comprehensive, state-of-the-art overview of cholangiocarcinoma (CCA). The text is structured to effectively present a broad yet concise overview of bile duct cancer, its relevant definitions, classification schemata, clinical management tenets, translational (including molecular and cellular) facets, and future directions. The book features numerous high-yield illustrations and is authored by an eclectic range of renowned experts in various areas of CCA, reflecting the multidisciplinary nature of the field. Filling a critical gap in the field, Diagnosis and Management of Cholangiocarcinoma: A Multidisciplinary Approach is a valuable resource for clinicians and practitioners who treat patients with bile duct cancer. Preface Acknowledgment Contents Contributors Part I: Anatomy and Histology of the Biliary Tree and Cholangiocarcinoma Chapter 1: Anatomy of the Biliary Tree: Normal, Anomalous, and Relationship to Cholangiocarcinoma Overview Anatomy of the Left Biliary System Anatomy of the Right Bile Ducts and the Biliary Confluence The Caudate Ducts The Gallbladder and Extrahepatic Bile Ducts Arterial Supply of the Biliary Tree and Its Implications for Resectability of Cholangiocarcinoma and Bilioenteric Reconstruction Conclusion References Chapter 2: Anatomic and Morphologic Classifications of Cholangiocarcinoma Introduction Intrahepatic Cholangiocarcinoma Morphology Mass Forming Periductal Infiltrating Intraductal Growing Staging Perihilar Cholangiocarcinoma Staging Systems Bismuth-Corlette MSKCC Classification AJCC TNM Distal Cholangiocarcinoma Staging Conclusion References Chapter 3: Intraductal Tumors of the Biliary Tract: Precursor Lesions and Variants Introduction Intraductal Papillary Neoplasms of the Bile Duct (IPNBs) Epidemiology and Risks Epidemiology Risk Factors Pathology Gross Features Location Along the Biliary Tree Main Tumors and the Surrounding Bile Duct Mucosa Histological Features Main Tumors Degree of Atypia of Intraepithelial Neoplasia (Dysplasia) Four Subtypes of IPNBs The Surrounding Mucosa Stromal Invasion Genetic and Molecular Alterations Noninvasive and Invasive IPNBs Subtyping and Type 1 and Type 2 Subclassifications New Subclassification of IPNBs Comparison of IPNB and Pancreatic IPMN Type 1 and 2 Subclassifications Diagnosis Main Clinical Features and Laboratory Data Imaging Findings Ultrasonography (US) Cross-Sectional Imaging Cholangiography Intraductal Ultrasonography (IDUS) Cholangioscopy Pathological Diagnosis Tissue and Cytology Sampling Findings in Tiny Tissue Specimens Cytological Findings Preoperative Assessment, Treatment, and Prognosis Preoperative Assessment Treatment Survival and Prognostic Factors Biliary Intraepithelial Neoplasms (BilINs) Clinical Features Risk Factors or Background Lesions Pathogenesis Other Intraductal Tumors of Biliary Tract Primary Intraductal Neoplasm of the Bile Duct Related Neoplasms Mimickers Conclusions References Chapter 4: Pathologic Basis and Classification of Biliary Epithelial Neoplasms Introduction Overview Biliary Intraepithelial Neoplasia (BilIN) Epidemiology and Clinical Presentation of BilIN Macroscopy and Microscopy of BilIN Pathogenesis and Molecular Pathology of BilIN Intraductal Papillary Neoplasm of the Bile Duct (IPNB) Epidemiology and Clinical Presentation of IPNB Macroscopy and Microscopy of IPNB Pathogenesis and Molecular Pathology of IPNB Intracholecystic Papillary Neoplasm (ICPN) Epidemiology and Clinical Features of ICPN Macroscopy and Microscopy of ICPN Pyloric Gland Adenoma of the Gallbladder (PGA-GB) Epidemiology and Clinical Presentation of PGA-GB Macroscopy and Histology of PGA-GB Molecular Pathology of PGA-GB Gallbladder Carcinoma (GB-CA) GB-AC: Biliary Type GB-AC: Papillary and Micropapillary Types GB-AC: Intestinal Type Mucinous Adenocarcinoma of the Gallbladder Signet-Ring Cell (Poorly Cohesive) Carcinoma of the Gallbladder Clear Cell Adenocarcinoma of the Gallbladder Squamous and Adenosquamous Carcinoma of the Gallbladder Hepatoid Adenocarcinoma of the Gallbladder Sarcomatoid Carcinoma of the Gallbladder Undifferentiated Carcinoma of the Gallbladder Pathogenesis and Molecular Pathology of GB-CA Extrahepatic Bile Duct Carcinoma (EHBD-CA) Epidemiology and Clinical Presentation of the EHBD-CA Macroscopy and Histology of the EHBD-CA Pathogenesis and Molecular Pathology of the EHBD-CA Mucinous Cystic Neoplasm (MCN) of the Liver and Biliary System Epidemiology and Clinical Presentation of MCN Macroscopy and Histology of MCN Pathogenesis and Molecular Pathology of MCN Intrahepatic Cholangiocarcinoma (iCCA) Epidemiology and Clinical Presentation of iCCA Macroscopy and Histology of iCCA Pathogenesis and Molecular Pathology of iCCA Combined Hepatocellular-Cholangiocarcinoma (c-HCC-CCA) Epidemiology and Clinical Presentation of cHCC-CCA Macroscopy and Histology of cHCC-CCA Pathogenesis and Molecular Pathology of cHCC-CCA Von Meyenburg Complex (VMC) Pathogenesis and Molecular Pathology of VMC Biliary Adenofibroma Pathogenesis of BAF Bile Duct Adenoma (BDA) Pathogenesis Neuroendocrine Neoplasms of the Gallbladder and Bile Ducts Epidemiology and Clinical Presentation of NENs Macroscopy and Histology of NENs Pathogenesis and Molecular Pathology of the GB and EHBD NENs Summary References Part II: Diagnosis and Management of Cholangiocarcinoma Chapter 5: Clinical Epidemiology of Cholangiocarcinoma Introduction Epidemiology Incidence of CCA Mortality Rate Risk Factors for CCA Host Factors Age and Sex Bile Duct Conditions Choledochal Cysts and Caroli’s Disease Hepatolithiasis, Cholelithiasis, and Choledocholithiasis Primary Sclerosing Cholangitis Liver Fluke Infection Chronic Liver Diseases Cirrhosis Viral Hepatitis B and C Infections Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH) Metabolic Conditions Diabetes Obesity Metabolic Syndrome Toxin and Environmental Exposure Alcohol Tobacco Thorotrast Asbestos Organic Solvents in Printing Industrial Work Genetic Polymorphisms Surveillance and Prevention Surveillance for CCA CCA Prevention Summary References Chapter 6: Biochemical Indicators of Cholangiocarcinoma Introduction Classification of CCA Classical Serum Markers Earlier Analyses of Gene Mutation and Amplification in CCA Challenges of Highly Specific Biomarkers Recent Classification of CCAs with Large-Scale Analysis of Multi-omics Future Perspective Combination of Standard Cancer Biomarker Plus CCA-Selective Biomarkers Cancer Therapy with an Infusion of Tumor Suppressor Genes and shRNA Vectors Conclusion References Chapter 7: Imaging of Cholangiocarcinoma Introduction Imaging Modalities Role of Non-invasive Imaging Approach to Imaging Transabdominal Ultrasound (US) (Figs. 7.1, 7.2, and 7.3) Introduction Technique Imaging Additional Considerations Computed Tomography (CT) (Fig. 7.1) Introduction Technique Imaging Additional Considerations MRI/MRCP (Figs. 7.1, 7.2, 7.3, 7.4, and 7.5) Introduction Technique Imaging Additional Considerations Hybrid/Molecular (PET/CT, PET/MR, New Molecular Agents) (Figs. 7.5 and 7.6) Introduction Technique Imaging Additional Considerations Conclusion References Chapter 8: Pathological Diagnosis of Cholangiocarcinoma Cholangiocarcinoma Diagnosis Tissue Acquisition Techniques Precursor Neoplastic Lesions Biliary Intraepithelial Neoplasia Intraductal Papillary Neoplasm of the Bile Ducts Mucinous Cystic Neoplasm of the Liver and Biliary System Peri-hilar and Distal Extrahepatic Bile Duct Adenocarcinomas Gross Evaluation Histology Differential Diagnosis of Extrahepatic Cholangiocarcinoma and Distal Bile Duct Carcinoma Intrahepatic Cholangiocarcinoma Gross Evaluation Histology Intrahepatic Cholangiocarcinoma: Small Duct Subtype Intrahepatic Cholangiocarcinoma: Large Duct Subtype Differential Diagnosis of Intrahepatic Cholangiocarcinoma Combined Hepatocellular-Cholangiocarcinoma Immunohistochemistry of Cholangiocarcinoma Albumin In Situ Hybridization Cytology Ancillary Techniques for Enhancing Biopsy Diagnosis Pathologic Grading and Staging Conclusion References Chapter 9: Challenges in Diagnosing Cholangiocarcinoma: Pulling Together Biochemical, Radiological, and Cytopathological Data Introduction Standard Diagnostic Work-Up iCCA pCCA dCCA Case Presentations Case 1: IgG4-Related Sclerosing Cholangitis Case 2: IgG4-Related Sclerosing Cholangitis II Case 3: Stone Disease Case 4: Infectious Disease Case 5: Infectious Disease II Case 6: Adenocarcinoma of Unknown Primary Case 7: Cirrhotic Liver Case 8: Primary Sclerosing Cholangitis Conclusion References Chapter 10: PSC-Associated Cholangiocarcinoma: Diagnostic and Therapeutic Considerations Primary Sclerosing Cholangitis: Background and Risk of Malignancies Pathogenesis of PSC-Associated CCA: The Archetype of a Premalignant Condition Sustained by Fibroinflammatory Lesions Clinical Presentation of PSC-Associated CCA: The Confounding Presence of Dominant Strictures Diagnosis of PSC-Associated CCA: Critical Issues and Multimodal Approach Laboratory Tests and Serum Biomarkers Novel Tumoral Biomarkers Surveillance Programs: Still Searching for the Way to Go Treatment: LT Is Often the Most Convenient Approach for PSC-Associated CCA Summary and Future Directions References Chapter 11: Fluke-Associated Cholangiocarcinoma: A Regional Epidemic Introduction The Parasites and Their Associated Illnesses Fascioliasis Opisthorchiasis Geographical Distribution and Mode of Transmission Diagnosis and Treatment Pathology of Opisthorchiasis and Cholangiocarcinogenesis Pathology of Opisthorchiasis Liver Fluke-related Cholangiocarcinogenesis Cholangiocarcinoma in Thailand Spectrum of Cholangiocarcinoma Risk Factors and CCA Subtypes Survival Studies of CCA in the Endemic Area of Liver Fluke A 3-Month Prospective Study A Retrospective Study of Resectable, Mass-Forming iCCA A Twofold Improved Survival in a Subset of Curative Resection for pCCA Long-Term Follow-Up Intraductal Papillary Neoplasm of the Bile Duct (IPNB) Adjuvant Chemotherapy Improves Survival Time in Resectable Patients Cancer Control for Cholangiocarcinoma in Thailand Primary Prevention: Liver Fluke Control Secondary Prevention: Ultrasonography Screening for Early CCA Conclusion References Chapter 12: Endoscopic Management of Cholangiocarcinoma Background Classification and Staging pCCA CCA in General Endoscopic Management Endoscopic Retrograde Cholangiopancreatography Endoscopy-Guided Therapy Cholangioscopy (SpyGlass) Endosonography Photodynamic Therapy Radiofrequency Ablation Endoscopic Palliation Endoscopic Stenting Technique Conclusion References Chapter 13: The Role of Endoscopic Ultrasound in Cholangiocarcinoma Introducstion Diagnosis and Staging Endosonographic Detection of Tumors and Strictures Sampling of Strictures via Fine Needle Aspiration Staging and Evaluating Resectability Assessment of Intrahepatic Cholangiocarcinoma Tumor Seeding Hindrances of EUS Adverse Events Associated with Hepatic FNA/B Conclusion References Chapter 14: Surgical Approach to the Treatment of Cholangiocarcinoma Introduction Anatomic Distribution Preoperative Evaluation of Cholangiocarcinoma Anatomic Classification and Initial Staging Future Liver Remnant and Portal Vein Embolization Periampullary Tumors: Distal Cholangiocarcinoma or Pancreatic Ductal Adenocarcinoma? Resection for Cholangiocarcinoma Defining Resectability Diagnostic Laparoscopy in CCA Resection of iCCA Resection of pCCA Resection for dCCA Transplantation for CCA Postoperative Morbidity and Mortality Adjuvant Therapy and Outcomes Following Surgery Postoperative Surveillance Future Directions in Surgery for Cholangiocarcinoma Conclusion References Chapter 15: Liver Transplantation for Cholangiocarcinoma Introduction Hilar Cholangiocarcinoma (hCCA) Neoadjuvant Therapy Patient Selection Comparing Transplantation with Resection Intrahepatic Cholangiocarcinoma (iCCA) Perioperative and Technical Considerations Preoperative Preparation Operative Considerations Conclusion References Chapter 16: Neoadjuvant and Adjuvant Therapy for Cholangiocarcinoma Introduction Prognostic Tools and Factors Adjuvant Chemotherapy Trials Completed Adjuvant Therapy Trials SWOG 0809 BCAT PRODIGE 12-ACCORD 18 BILCAP Ongoing Adjuvant Therapy Trials Adjuvant Therapy Trials: Conclusion Neoadjuvant Therapy Additional Therapies Radiotherapy for Cholangiocarcinoma Liver Transplantation for Cholangiocarcinoma Hepatic Arterial Infusion Pump Therapy Targeted Therapy Conclusions References Chapter 17: Palliative Chemotherapy and Radiotherapy for Cholangiocarcinoma Introduction Palliative Chemotherapy for Advanced BTCs First-Line Systemic Chemotherapy Tolerability Specific Considerations Alternative Gemcitabine-Based Regimens Adding Targeted Therapies to Chemotherapy First-Line Triplet Chemotherapy Second-Line Systemic Chemotherapy Summary Palliative Radiotherapy for Cholangiocarcinoma Management External Beam Radiotherapy: The Rationale Brachytherapy Chemoradiotherapy Stereotactic Body Radiotherapy Proton Beam Therapy The ABC-07 Trial Summary References Chapter 18: Interventional Radiology Therapies for Intrahepatic Cholangiocarcinoma Introduction Thermal Ablation Overview Efficacy and Safety Data Chemoembolization Overview Efficacy and Safety Data Radioembolization Overview Efficacy and Safety Data Conclusion References Chapter 19: Established and Emerging Biomarkers for Prediction, Early Detection, and Prognostication of Cholangiocarcinoma Introduction Established Serum Biomarkers CA19-9 CEA CA-125 Emerging Biomarkers Blood Biomarkers Extracellular Vesicles Nucleic Acid Biomarkers Proteins and Peptides Serum Metabolites Circulating Tumour Cells Bile Biomarkers Bile Metabolites Proteins and Peptides Extracellular Vesicles Genetic Biomarkers Serotonin Urine Biomarkers Volatile Organic Compounds Proteomic Profile Extracellular Vesicles Histological Markers Genomic Markers Transcriptomic Markers Immunohistochemical Markers micro-RNA Conclusion and Future Perspectives References Chapter 20: Cholangiocarcinoma Surveillance in Primary Sclerosing Cholangitis and IgG4-Related Sclerosing Cholangitis Introduction Primary Sclerosing Cholangitis Background Risk of Malignancy in Primary Sclerosing Cholangitis Diagnosis of Cholangiocarcinoma in Primary Sclerosing Cholangitis Therapies for Primary Sclerosing Cholangitis and Associated Cholangiocarcinoma Cancer Surveillance in Primary Sclerosing Cholangitis Overview Regarding Surveillance Evidence Supporting the Implementation of CCA Surveillance in PSC Take-Home Points Regarding CCA Surveillance in PSC Immunoglobulin G4-Related Sclerosing Cholangitis Background Therapies for Immunoglobulin G4-Related Sclerosing Cholangitis Risk of Malignancy in Immunoglobulin G4-Related Sclerosing Cholangitis Surveillance for Cholangiocarcinoma in Immunoglobulin G4-Related Sclerosing Cholangitis Future Directions Conclusions References Chapter 21: Novel Targeted Therapies in Clinical Use and on the Horizon for Cholangiocarcinoma Introduction Early Progress in Systemic Therapies Importance of Molecular Profiling Next-Generation Sequencing in Cholangiocarcinoma Isocitrate Dehydrogenase (IDH1/IDH2) Mutations Fibroblast Growth Factor Receptor 2 (FGFR2) Fusions Mechanisms of Resistance Smaller Targets in Cholangiocarcinoma KRAS B-raf BRCA1 and BRCA2: PPAR Inhibition Her2/neu Role of Immunotherapy in Cholangiocarcinoma Conclusion: Future Directions of Targeted Therapy References Part III: Experimental and Translational Facets of Cholangiocarcinoma Chapter 22: In Vitro and In Vivo Model Systems of Cholangiocarcinoma Introduction CCA In Vitro Culture Systems Two-Dimensional (2D) Cell Cultures Three-Dimensional (3D) Cell Cultures CCA in Vivo Models Carcinogen-Based Murine Models Genetically Engineered Mouse Models Transposon-Based Models Alternatives to HTVI for Targeted Gene Delivery Xenograft Models Syngeneic Models Conclusions References Chapter 23: Organoid Models of Cholangiocarcinoma The Case for Organoids Development of Organoid Models in CCA Establishment of CCA Organoids in Long-Term In Vitro Culture CCA Organoids Maintain the Histopathological Features of the Source Tumour CCA Organoids Maintain Histology and Metastatic Potential in Vivo CCA Organoids Retain Genetic Alterations Present in the Original Tumour Applications of Organoids in CCA Research A Biobank for CCA Research A Model to Understand CCA Carcinogenesis A Model of Intra-Tumoural Heterogeneity A Platform for the Identification of Novel Therapeutics in CCA Personalised Medicine and ‘Live’ Drug Screening in CCA Limitations of Organoid Models Summary References Chapter 24: The Tumor Environment: Cholangiocarcinoma-Associated Fibroblasts and Beyond Introduction to the Tumor Microenvironment in Cholangiocarcinoma Cancer-Associated Fibroblasts Origin and Heterogeneity Activation Pro- and Anti-tumorigenic Functions of CAF CAF and PDGF Signaling CAF and CXCL Signaling CAF and EGF Signaling CAF and Pro-angiogenic Signaling Druggable Targets in CAFs Extracellular Matrix Immune Cells Components of the Innate Immune Response Components of the Adaptive Immune Response Exosomes: Biological Role and Clinical Implications Conclusions References Chapter 25: Glycosylation in Cholangiocarcinoma Development and Metastasis: Diagnostic and Therapeutic Considerations Introduction Glycans and Glycosylation in Biology Biochemistry of Glycans Glycosylation Process The Significance of Glycans and Glycosylation in Medicine Clinical Relevance of Aberrant Glycosylation and Glycans in Cholangiocarcinoma N-Glycans O-Glycans O-GlcNAcylation Fucosylation Blood Group Antigens Terminal α1, 2-Fucose Glycans Carbohydrate Antigen-S27 Carbohydrate Antigen-S121 sLea or CA19–9 Fucosylated Fetuin-A and Kininogen Alpha-L-Fucosidase Sialylation Glycosphingolipids Conclusions and Perspectives References Chapter 26: The Investigative Therapeutic Pipeline for Cholangiocarcinoma: Insights from Model Systems Introduction Angiogenesis and Lymphangiogenesis Angiogenesis in CCA Lymphangiogenesis in CCA Angiogenesis Inhibition in Preclinical and Clinical Trials Epigenetic Modifications DNA Methylation Histone Modifications Noncoding RNAs Alterations in the Wnt/β-catenin Signaling Pathway Conclusions References Index