Hepato-Pancreato-Biliary Malignancies: Diagnosis and Treatment in the 21st Century 3030416828, 9783030416829

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Cataldo Doria Jason N. Rogart Editors

HepatoPancreatoBiliary Malignancies

Diagnosis and Treatment in the 21st Century

Hepato-Pancreato-Biliary Malignancies

Cataldo Doria • Jason N. Rogart Editors

Hepato-PancreatoBiliary Malignancies Diagnosis and Treatment in the 21st Century

With 227 Figures and 83 Tables

Editors Cataldo Doria, MD, PhD, MBA, FACS Medical Director, Capital Health Cancer Center Director, CH Pancreas Center of Excellence Director, CH Liver Center of Excellence Pennington, NJ, USA

Jason N. Rogart Director of Interventional Gastroenterology Capital Health Medical Center Pennington, NJ, USA

ISBN 978-3-030-41682-9 ISBN 978-3-030-41683-6 (eBook) https://doi.org/10.1007/978-3-030-41683-6 © Springer Nature Switzerland AG 2022, corrected publication 2022 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To my patients and their families who, every day, fearlessly walk through one of their darkest times in their lives. Cataldo Doria To my phenomenal colleagues and friends at home and all across the country who continue to inspire me; to all the nurses, techs, and staff who make my job an absolute joy even when things seem grim; and, especially to my family, who make it all worth it. Jason N. Rogart

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Preface

We are witnessing a rise in the incidence of cancers of the liver, pancreas, and biliary tract, with pancreatic cancer now accounting for the third most cancer deaths in the United States. These are devastating diseases with high mortality and morbidity. Because they continue to pose enormous challenges to all those involved in their diagnoses and treatment, they are typically managed by the same key providers comprising a multidisciplinary team. With this in mind, we recognized that there are few comprehensive resources available to healthcare providers who take care of these patients day in and day out, and hence our vision for developing Hepato-PancreatoBiliary Malignancies: Diagnosis and Treatment in the 21st Century. While we realize that more and more resources have moved to an electronic platform (including this one), we also understand that many of us still derive a profound satisfaction in holding a physical book, opening the cover, flipping the pages, and reading the ink. Perhaps it is this tactile sensation that helps ground us and reminds us of the journey, as healthcare providers, that we embarked upon so many years ago when committing a lifetime to help patients suffering from these terrible cancers. We, therefore, decided that it was important to publish a print version of Hepato-Pancreato-Biliary Malignancies: Diagnosis and Treatment in the 21st Century, which is what you are now holding in your hands. This book is intended to provide a comprehensive review of the current knowledge in the field of liver, pancreas, and bile duct cancers. We have approached the book’s content and organization by combining the collective expertise of an interventional gastroenterologist and a hepatobiliary-pancreatic surgeon to provide the readers with accurate, succinct, and pragmatic information needed to formulate the most appropriate clinical treatment plan, with the aim of the best possible outcomes for patients. Each section of this textbook is written by experts in their respective fields, from all across the world, summarizing the most state-of-the-art, contemporary diagnostic and therapeutic tools currently available. We are extremely fortunate to have assembled so many high caliber clinicians and authors into one book and recognize that their contributions have been extraordinary, particularly as many of these chapters were written during the height of the COVID19 global pandemic, perhaps the most challenging and unique time for healthcare providers during our lifetime. We believe the result of these herculean efforts is a book that will prove to be an invaluable clinical resource for all vii

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Preface

members of the multidisciplinary team caring for patients with hepatopancreato-biliary malignancies. We thank all the authors, editorial assistants, and everyone else involved in crafting this book, and hope that you, the reader, enjoy it, whether it becomes part of your daily routine or a reference to which you turn to from time to time. Pennington, NJ, USA September 2022

Cataldo Doria Jason N. Rogart

Contents

Part I

Hepatic Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1

1

Approach to the Patient with a Solid Liver Mass . . . . . . . . . Eyob Feyssa and Santiago J. Munoz

3

2

Diagnosis and Evaluation of Hepatocellular Carcinoma Naemat Sandhu and Simona Rossi

...

27

3

Hepatocellular Carcinoma Pathology . . . . . . . . . . . . . . . . . . Ronald Miick, Corrado Minimo, and Alessandro Bombonati

49

4

Metabolic Syndrome and Liver Cancer . . . . . . . . . . . . . . . . . Ariel Jaffe and Mario Strazzabosco

87

5

Reducing the Risk of and Screening for Liver Cancer . . . . . 105 Simranjit Bedi, Ashley Davis, and Victor Navarro

6

Medical Management of Hepatocellular Carcinoma . . . . . . . 125 Ahmad Safra

7

Surgical Management of Hepatocellular Carcinoma . . . . . . 131 Duilio Pagano, Giuseppe Mamone, Sergio Calamia, and Salvatore Gruttadauria

8

IR Liver-Directed Therapies for HCC . . . . . . . . . . . . . . . . . . 147 Ajay Choudhri

9

Clinical Presentation, Diagnosis, and Management of Uncommon Liver Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 Elizabeth Richardson, Scott Fink, and Jessica Fried

10

Epidemiology, Pathogenesis, and Prognosis of Uncommon Liver Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 Elizabeth Richardson and Scott Fink

11

Treatment of Liver Metastases from Colorectal Cancer . . . . 197 Richard S. Hoehn, Samer T. Tohme, and David A. Geller

12

Treatment of Isolated Liver Metastasis from Non-colorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 John B. Martinie, Benjamin M. Motz, and Jordan N. Robinson ix

x

Contents

Part II

Bile Duct Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235

13

Diagnosis and Evaluation of Cholangiocarcinoma . . . . . . . . 237 Tina Boortalary and David Loren

14

Cholangiocarcinoma: Epidemiology, Pathogenesis, and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 Yunseok Namn and Juan Carlos Bucobo

15

The Pathophysiology and Pathology of Intrahepatic and Extrahepatic Cholangiocarcinomas . . . . . . . . . . . . . . . . . . . . 295 Cindy Wang and Namrata Setia

16

Nonsurgical Management of Cholangiocarcinoma . . . . . . . . 307 Michael J. Breen, Osman S. Ahmed, Joshua Owen, and Chih-Yi Liao

17

Surgical Treatment of Intrahepatic Cholangiocarcinoma . . . 325 Ki-Hun Kim and Jeong-Ik Park

18

Endoscopic Palliative Management of Cholangiocarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333 Sanmeet Singh, Ajaypal Singh, and Uzma D. Siddiqui

19

Rare Tumors of the Bile Ducts . . . . . . . . . . . . . . . . . . . . . . . . 347 Earl V. Campbell III and Priya Jamidar

Part III Gallbladder Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363 20

Diagnosis and Evaluation of Gallbladder Cancer . . . . . . . . . 365 Unal Aydin

21

Pathogenesis, Epidemiology, and Prognosis of Gallbladder Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373 Lauren Margetich

22

Pathology of Gallbladder Carcinoma . . . . . . . . . . . . . . . . . . . 379 Namrata Setia and Katherine E. Boylan

23

Nonsurgical Management of Gallbladder Cancer . . . . . . . . . 387 Neel Gandhi and Timothy Chen

Part IV

Pancreatic Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395

24

Approach to the Patient with a Pancreatic Mass . . . . . . . . . . 397 Daniel Lew, Shreyas Srinivas, and Karl Kwok

25

Evaluation and Management of the Patient with a Pancreatic Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415 Suut Göktürk, Thiruvengadam Muniraj, and Harry R. Aslanian

Contents

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26

Diagnosis and Evaluation of Pancreatic and Periampullary Adenocarcinoma . . . . . . . . . . . . . . . . . . . . . . . 431 Daniel Lew and Karl Kwok

27

Pathogenesis, Epidemiology, and Prognosis of Pancreatic Adenocarcinomas . . . . . . . . . . . . . . . . . . . . . . . . . 461 Katherine Kim, Srinivas Gaddam, and Quin Liu

28

Pathology of Pancreatic Ductal Adenocarcinoma . . . . . . . . . 483 Xuebin Yang, Krister Jones, and Guoli Chen

29

Reducing the Risk of and Screening for Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519 Shivangi Kothari, Vivek Kaul, and Truptesh H. Kothari

30

Nonsurgical Management of Pancreatic Adenocarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535 H. Liang and S. Williamson

31

Surgical Management of Pancreatic Adenocarcinoma . . . . . 557 Antonio Di Carlo, Meredith Gunder, and Cataldo Doria

32

Intraoperative Radiation Treatment . . . . . . . . . . . . . . . . . . . 569 Yurie Sekigami, Theodoros Michelakos, and Cristina Ferrone

33

Palliative Endoscopic Therapy of Pancreatic Duct Adenocarcinoma (PDAC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579 Nicholas G. Brown and Amrita Sethi

34

Diagnosis and Management of Pancreatic Neuroendocrine Tumors and Other Rare Pancreatic Neoplasms . . . . . . . . . . 597 Andrew Foong and James Buxbaum

35

Epidemiology, Pathogenesis, and Prognosis of Pancreatic Neuroendocrine Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623 Tara Keihanian and Mohamed Othman

36

Pathology of Pancreatic Neuroendocrine Tumors . . . . . . . . . 639 Filippo Borri, Rita Bonfiglio, and Martina Mandarano

37

Non-surgical Management of Pancreatic Neuroendocrine Tumors (PNETs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683 Abhishek Chouthai, Michael Makar, and Avik Sarkar

38

Surgical Management of Pancreatic Neuroendocrine Tumors (PNET) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711 Candace Gonzalez, Anthony DeSantis, Meagan Read, and Andreas Karachristos

39

Emerging Endoscopic Therapies for Pancreatic Neuroendocrine Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735 Thomas E. Kowalski and Brianna J. Shinn

xii

Contents

Part V Emerging And Future Trends In Managing Hepatobiliary And Pancreatic Malignancies . . . . . . . . . . . . . . . . . . . 745 40

Molecular and Genetic Profiling for the Diagnosis and Therapy of Hepatobiliary and Pancreatic Malignancies . . . . 747 H. Liang, R. Remstein, and D. Lewis

41

Personalized Medicine for Patients with Liver, Biliary Tract, and Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . . 761 Monica Valente, Alessia Covre, Anna Maria Di Giacomo, and Michele Maio

42

The Role of Robotic Surgery in Treating Hepatobiliary and Pancreatic Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . 777 Anusak Yiengpruksawan

43

The Multidisciplinary Approach to Managing Hepatobiliary and Pancreatic Malignancies and Its Importance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787 V. Kostaras and S. Lakkasani

44

The Role of the Palliative Care Team in the Management of Hepatobiliary and Pancreatic Malignancies . . . . . . . . . . . 813 Carolyn Gaukler

45

Spiritual Thinking and Surgery . . . . . . . . . . . . . . . . . . . . . . . 827 Ignazio R. Marino

46

Integrative Medicine and Hepatobiliary and Pancreatic Cancer: What to Expect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835 Chloe Hriso, Anthony Bazzan, Daniel Monti, and Andrew Newberg

Correction to: Surgical Management of Pancreatic Adenocarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antonio Di Carlo, Meredith Gunder, and Cataldo Doria

C1

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847

About the Editors

Cataldo Doria, MD, PhD, MBA, FACS Medical Director, Capital Health Cancer Center Director, CH Pancreas Center of Excellence Director, CH Liver Center of Excellence Pennington, NJ, USA Dr. Cataldo Doria is an internationally renowned surgeon who specializes in surgical treatments of the liver, pancreas, and bile duct. Dr. Doria spent a quarter of a century in academic medicine, at the University of Pittsburg Medical Center in Pittsburgh first, and at Thomas Jefferson University Hospital in Philadelphia later. Dr. Doria was a major contributor to the startup of the European Medical Division of the University of Pittsburgh Medical Center, which resulted in a cultural and scientific cooperative agreement between the University of Pittsburgh and the University of Palermo – Italy. This partnership led to the development of the Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IsMeTT), a health-care delivery system that serves the entire Mediterranean Basin and specializes in solid organ transplantation and cancer care. From 1999 to 2003, Dr. Doria, played a major role in developing and leading the clinical enterprise of IsMeTT. At Thomas Jefferson University Hospital in Philadelphia, PA, he served as the surgical director of the Sidney Kimmel Cancer Center – Jefferson Liver Tumor Center at Jefferson Medical College, and director of the Jefferson Transplant Institute. During his 15 years’ tenure at Jefferson, Dr. Doria resurrected, first hand, a program in agony and made it one of the best in the country xiii

xiv

About the Editors

for volume, outcome, patient satisfaction, and innovative research. Dr. Doria received his medical degree at the University of Perugia School of Medicine in Italy, where he also completed his internship and residency. He completed a research fellowship and a clinical fellowship in multi-organ transplant surgery at the Pittsburgh Transplantation Institute, part of the University of Pittsburgh School of Medicine in Pittsburgh, PA. Dr. Doria is a PhD in biotechnology and transplant immunology; he is, also, one of the few doctors worldwide that successfully completed a clinical fellowship in living donor liver transplantation at the Organ Transplantation Center, part of Asan Medical Center in Seoul, South Korea. Dr. Doria is a 2016 Temple Fox School of Business graduate. Dr. Doria is currently the Medical Director of the Cancer Center at Capital Health in Hopewell, NJ. During the first 4 years of his tenure at Capital Health, under Dr. Doria’s leadership, the net revenue of the cancer center increased in excess of 25% every year. Dr. Doria re-branded and repositioned the Cancer Center at Capital Health. Dr. Doria has pioneered new surgical techniques, including bloodless liver surgery, ex vivo liver resection with liver auto-transplantation, and robotic-assisted hepato-pancreato-biliary surgery. He completed the first robotic-assisted Whipple procedure in the State of New Jersey.

Jason N. Rogart Director of Interventional Gastroenterology Capital Health Medical Center Pennington, NJ, USA As an interventional gastroenterologist and therapeutic endoscopist, Dr. Rogart performs the latest and most advanced procedures for the testing and

About the Editors

xv

non-surgical treatment of pancreato-biliary disorders and malignancies. He is nationally recognized as an expert in the fields of endoscopic ultrasound (EUS), endoscopic retrograde cholangiopancreatography (ERCP), pseudocyst drainage, enteral stent placement, advanced endoscopic imaging, and numerous other procedures which help in the care of patients with gastrointestinal malignancies. Dr. Rogart received his medical degree from Brown Medical School and completed his internship and residency at Yale University in the Department of Internal Medicine at Yale-New Haven Hospital, where he was also Chief Resident. He completed his fellowship training in digestive diseases at Yale University/Yale-New Haven Hospital and subsequently was an Advanced Endoscopy Fellow in the Division of Gastroenterology and Hepatology at Thomas Jefferson University Hospital in Philadelphia, PA. He holds an academic appointment at Rutgers – Robert Wood Johnson Medical School. He has published numerous original research articles and chapters in various national and international journals and resource textbooks. He has also been an invited speaker and faculty member at numerous locoregional and national conferences, including Digestive Diseases Week, the American Society for Gastrointestinal Endoscopy, the American College of Gastroenterology, and the Society of Gastrointestinal Nurses and Associates. He is a reviewer for several national and international clinical publications. Dr. Rogart has been awarded the honorable distinction of “Fellow” in both the American Society of Gastrointestinal Endoscopy (FASGE) and the American College of Gastroenterology (FACG) for his life-long contributions to the field of GI endoscopy and his dedication to patient care, research, teaching, and service.

Contributors

Osman S. Ahmed Section of Vascular and Interventional Radiology, Department of Radiology, University of Chicago Medical Center, Chicago, IL, USA Harry R. Aslanian Section of Digestive Diseases, Yale University, New Haven, CT, USA Unal Aydin Professor of Surgery; Private Clinician, Hepatopancreatobiliary Surgery, Izmir, Turkey Anthony Bazzan Department of Integrative Medicine and Nutritional Sciences, Thomas Jefferson University, Philadelphia, PA, USA Simranjit Bedi Einstein Medical Center of Philadelphia, Philadelphia, PA, USA Alessandro Bombonati Department of Pathology and Laboratory Medicine, Einstein Medical Center – Philadelphia, Philadelphia, PA, USA Rita Bonfiglio Department of Experimental Medicine and Surgery, University of Rome “Tor Vergata”, Rome, Italy Tina Boortalary Thomas Jefferson University, Philadelphia, PA, USA Filippo Borri UOC Anatomic Pathology, Oncology Department, A.Osp. San Donato, Azienda USL Toscana Sud Est, Arezzo, Italy Katherine E. Boylan University of Utah, Salt Lake City, UT, USA Michael J. Breen Section of Hematology/Oncology, Department of Medicine, University of Chicago Medical Center, Chicago, IL, USA Nicholas G. Brown Gastroenterology, NewYork-Presbyterian/Columbia University Medical Center, New York, NY, USA Juan Carlos Bucobo Stony Brook Medicine, New York, NY, USA James Buxbaum University of Southern California, Los Angeles, CA, USA Sergio Calamia Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS ISMETT (Istituto di Ricovero e Cura a Carattere Scientifico – Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), UPMC (University of Pittsburgh Medical Center) Italy, Palermo, Italy xvii

xviii

Earl V. Campbell III Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA Antonio Di Carlo Lewis Katz School of Medicine at Temple University Chief, Abdominal Organ Transplantation Temple University Hospital Chief, Transplantation St. Christopher’s Hospital for Children, Philadelphia, PA, USA Guoli Chen Geisinger Medical Laboratories, Geisinger Medical Center, Danville, PA, USA Timothy Chen Capital Health Cancer Center, Pennington, NJ, USA Ajay Choudhri Interventional Radiology, Capital Health, Pennington, NJ, USA Abhishek Chouthai Rutgers, Robert Wood Johnson Medical School, New Brunswick, NJ, USA Alessia Covre Center for Immuno-Oncology, Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Siena, Italy Ashley Davis Einstein Medical Center of Philadelphia, Philadelphia, PA, USA Anthony DeSantis Department of Surgery, University of South Florida Morsani College of Medicine, Tampa General Hospital, Tampa, FL, USA Cataldo Doria Medical Director, Capital Health Cancer Center, Director, CH Pancreas Center of Excellence, Director, CH Liver Center of Excellence, Pennington, NJ, USA Cristina Ferrone Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Eyob Feyssa Drexel University College of Medicine, Philadelphia, PA, USA Scott Fink Main Line Gastroenterology Associates, Collegeville, PA, USA Andrew Foong University of Southern California, Los Angeles, CA, USA Jessica Fried University of Michigan, Ann Arbor, MI, USA Srinivas Gaddam Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA Neel Gandhi Capital Health Cancer Center, Pennington, NJ, USA Carolyn Gaukler Palliative and Supportive Care, Capital Health, Pennington, NJ, USA David A. Geller Department of Surgery, Liver Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Anna Maria Di Giacomo Center for Immuno-Oncology, Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Siena, Italy

Contributors

Contributors

xix

Suut Göktürk Brooklyn Hospital Center, Brooklyn, NY, USA Candace Gonzalez Department of Surgery, University of South Florida Morsani College of Medicine, Tampa General Hospital, Tampa, FL, USA Salvatore Gruttadauria Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS ISMETT (Istituto di Ricovero e Cura a Carattere Scientifico – Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), UPMC (University of Pittsburgh Medical Center) Italy, Palermo, Italy Department of Surgery and Surgical and Medical Specialties, University of Catania, Catania, Italy Meredith Gunder General Surgery, Temple University Hospital, Philadelphia, PA, USA Richard S. Hoehn Department of Surgery, Liver Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Chloe Hriso Department of Integrative Medicine and Nutritional Sciences, Thomas Jefferson University, Philadelphia, PA, USA Ariel Jaffe Liver Center & Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA Priya Jamidar Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA Krister Jones Department of Pathology, Capital Health System, Pennington, NJ, USA Andreas Karachristos Department of Surgery, University of South Florida Morsani College of Medicine, Tampa General Hospital, Tampa, FL, USA Vivek Kaul Division of Gastroenterology & Hepatology, University of Rochester Medical Center, Rochester, NY, USA Tara Keihanian Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX, USA Katherine Kim Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA Ki-Hun Kim Division of Hepatobiliary surgery and Liver transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea V. Kostaras Saint Michael’s Medical Center in affiliation with New York Medical College, Newark, NJ, USA Shivangi Kothari Division of Gastroenterology & Hepatology, University of Rochester Medical Center, Rochester, NY, USA Truptesh H. Kothari Division of Gastroenterology & Hepatology, University of Rochester Medical Center, Rochester, NY, USA

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Thomas E. Kowalski Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA, USA Karl Kwok Division of Gastroenterology, Kaiser Permanente, Los Angeles Medical Center, Los Angeles, CA, USA S. Lakkasani Saint Michael’s Medical Center in affiliation with New York Medical College, Newark, NJ, USA Daniel Lew Kaiser Permanente, Baldwin Park Medical Center, Baldwin Park, CA, USA D. Lewis Capital Health Cancer Center, Pennington, NJ, USA H. Liang Capital Health Hematology Oncology Specialists, Capital Health Cancer Center, Pennington, NJ, USA Chih-Yi Liao Section of Hematology/Oncology, Department of Medicine, University of Chicago Medical Center, Chicago, IL, USA Quin Liu Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA David Loren Thomas Jefferson University, Philadelphia, PA, USA Michele Maio Center for Immuno-Oncology, Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Siena, Italy Michael Makar Rutgers, Robert Wood Johnson Medical School, Department of Internal Medicine, New Brunswick, NJ, USA Giuseppe Mamone Department of Diagnostic and Therapeutic Services, IRCCS ISMETT (Istituto di Ricovero e Cura a Carattere Scientifico – Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), UPMC (University of Pittsburgh Medical Center) Italy, Palermo, Italy Martina Mandarano Department of Medicine and Surgery, Section of Anatomic Pathology and Histology, Medical School, University of Perugia, Perugia, Italy Lauren Margetich Mount Sinai, NY, USA Ignazio R. Marino Thomas Jefferson University, Philadelphia, PA, USA John B. Martinie Atrium Health, Charlotte, NC, USA Theodoros Michelakos Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Ronald Miick Department of Pathology and Laboratory Medicine, Einstein Medical Center – Philadelphia, Philadelphia, PA, USA Corrado Minimo Department of Pathology and Laboratory Medicine, Einstein Medical Center – Philadelphia, Philadelphia, PA, USA Daniel Monti Department of Integrative Medicine and Nutritional Sciences, Thomas Jefferson University, Philadelphia, PA, USA

Contributors

Contributors

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Benjamin M. Motz Atrium Health, Charlotte, NC, USA Thiruvengadam Muniraj Section of Digestive Diseases, Yale University, New Haven, CT, USA Santiago J. Munoz Drexel University College of Medicine, Philadelphia, PA, USA Virtua Center for Liver Disease, Cherry Hill, NJ, USA Yunseok Namn Stony Brook Medicine, New York, NY, USA Victor Navarro Einstein Medical Center of Philadelphia, Philadelphia, PA, USA Andrew Newberg Department of Integrative Medicine and Nutritional Sciences, Thomas Jefferson University, Philadelphia, PA, USA Mohamed Othman Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX, USA Joshua Owen Department of Medicine, University of Minnesota, Minneapolis, MN, USA Duilio Pagano Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS ISMETT (Istituto di Ricovero e Cura a Carattere Scientifico – Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), UPMC (University of Pittsburgh Medical Center) Italy, Palermo, Italy Jeong-Ik Park Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea Meagan Read Department of Surgery, University of South Florida Morsani College of Medicine, Tampa General Hospital, Tampa, FL, USA R. Remstein Capital Health Cancer Center, Pennington, NJ, USA Elizabeth Richardson CT Gastroenterology Associates, Hartford, CT, USA Connecticut GI, Hartford, CT, USA Jordan N. Robinson Atrium Health, Charlotte, NC, USA Simona Rossi Division of Digestive Disease and Transplantation, Einstein Medical Center, Philadelphia, PA, USA Ahmad Safra Transplant and Hepato-Pancreato-Biliary surgery, Inova Fairfax Hospital, Falls Church, VA, USA Naemat Sandhu University Hospitals, Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA Avik Sarkar Rutgers State University, New Brunswick, NJ, USA Yurie Sekigami Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

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Amrita Sethi Gastroenterology, NewYork-Presbyterian/Columbia University Medical Center, New York, NY, USA Namrata Setia University of Chicago, Chicago, IL, USA Brianna J. Shinn Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA, USA Uzma D. Siddiqui Center for Endoscopic Research and Therapeutics (CERT), University of Chicago Medicine, Chicago, IL, USA Ajaypal Singh Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, USA Sanmeet Singh Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, USA Shreyas Srinivas Department of Internal Medicine, Kaiser Permanente, Fontana Medical Center, Fontana, CA, USA Mario Strazzabosco Liver Center & Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA Samer T. Tohme Department of Surgery, Liver Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Monica Valente Center for Immuno-Oncology, Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Siena, Italy Cindy Wang University of Chicago, Chicago, IL, USA S. Williamson Radiation Oncology, Capital Health Medical Center, Pennington, NJ, USA Xuebin Yang Department of Pathology, Capital Health System, Pennington, NJ, USA Anusak Yiengpruksawan Minimally Invasive Surgery Unit, Department of Surgery, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

Contributors

Part I Hepatic Malignancies

1

Approach to the Patient with a Solid Liver Mass Eyob Feyssa and Santiago J. Munoz

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5

2

Hepatic Hemangioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6

3

Pathogenesis and Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7

4

Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7

5

Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8

6

Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Hepatocellular Adenoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

8

Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

9

Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

10

Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

11 11.1

Imaging Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Ultrasonography and Contrast-Enhanced Ultrasonography . . . . . . . . . . . . . . . . . . . . . . 14

12

Computed Tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

13

Magnetic Resonance Imaging (MRI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

14

Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

15 15.1

Focal Nodular Hyperplasia (FNH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

E. Feyssa Drexel University College of Medicine, Philadelphia, PA, USA e-mail: [email protected] S. J. Munoz (*) Drexel University College of Medicine, Philadelphia, PA, USA Virtua Center for Liver Disease, Cherry Hill, NJ, USA e-mail: [email protected] © Springer Nature Switzerland AG 2022 C. Doria, J. N. Rogart (eds.), Hepato-Pancreato-Biliary Malignancies, https://doi.org/10.1007/978-3-030-41683-6_1

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E. Feyssa and S. J. Munoz 16

Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

17

Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

18

Clinical Presentation and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

19

Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

20

Nodular Regenerative Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

21

Pathophysiology and Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

22

Clinical Presentation and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Abstract

A solid liver mass could be benign or malignant. In most cases, a mass is identified incidentally in asymptomatic patient or on imaging study done for unrelated symptoms. When symptomatic, pain or discomfort is the usual presenting symptom for a subcapsular located liver mass and could also be due to local mass effect of large or growing lesion. The commonly encountered benign solid hepatic lesion includes hepatic hemangioma, hepatocellular adenoma, focal nodular hyperplasia, and nodular regenerative nodules. To narrow the differential diagnosis and choose the appropriate diagnostic test, a thorough and detailed history, physical examination, and review of available laboratory and imaging data is critical. In most cases, a specific dynamic cross-sectional imaging of the liver will suffice to establish diagnosis, and biopsy is rarely needed. Conservative management approach is suggested for most asymptomatic patients with small-size solitary liver mass. The risk of symptoms and/or bleeding of a benign hypervascular liver lesion correlates with the size, number, and location of the lesion(s). These factors must be considered to recommend specific treatment (surgical, embolization, or ablation). Recent advances in molecular analysis studies and immunohistochemical staining led to improved understanding of markers that signal the risk of malignant transformation in some of these benign solid liver lesions (e.g., hepatocellular adenoma). Specific therapy

should also be considered for lesions with characteristics of oncogenic potential. Hence, appropriate referral of cases to experienced centers and engaging multidisciplinary team (MDT) early for diagnosis and treatment recommendations is important to improve patient outcome. Keywords

Liver mass · Diagnosis · Hepatic Hemangioma · Hepatocellular Adenoma · Focal Nodular Hyperplasia Abbreviations

AFP CEA CEUS CRP CT FNH GdBOPTA GGT GS HCA HCC HNF1α IHC IL-6 LFABP MRI NRH OCs PET

α-fetoprotein carcinoembryonic antigen contrast-enhanced ultrasound C-reactive protein computed tomography focal nodular hyperplasia gadobenate dimeglumine γ-glutamyl transpeptidase glutamine synthase hepatocellular adenoma hepatocellular carcinoma hepatocyte nuclear factor 1α immunohistochemistry interleukin 6 liver fatty acid binding protein magnetic resonance imaging nodular regenerative hyperplasia oral contraceptives positron emission tomography

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Approach to the Patient with a Solid Liver Mass

RES RFA SAA SPECT TAE US VEGF

1

reticuloendothelial system radio frequency ablation serum amyloid A single-photon emission CT transcatheter arterial embolization ultrasound vascular endothelial growth factor

Introduction

Due to the widespread use of various diagnostic imaging modalities, there have been a dramatically increased incidental identification of focal liver lesions on scanning performed for other conditions and in asymptomatic cases. Generally, the differential diagnosis of solid liver mass is broad, and liver lesions are either solid or cystic and could be benign or malignant (Table 1). Similarly, diagnostic approach and management recommendations are varied by characterization of the lesion and specific diagnosis. A thorough and detailed history, physical examination, and review of available laboratory and imaging data is important to narrow the differential diagnosis and proceed with a more specific diagnosis testing. In most cases, specific diagnosis will be established using a specific dynamic cross-sectional imaging of the liver. The need for biopsy in the evaluation of liver lesions is reserved for atypical cases and in the event if the diagnosis cannot be made radiologically. If biopsy is needed, core biopsy is preferred over fine-needle aspiration for adequate tissue sampling and increased diagnostic accuracy. The critical initial component of diagnostic workup for a solid liver mass is gathering a detail medical history. At presentation, most patients are asymptomatic or present with vague symptoms or symptoms unrelated to liver mass. If present, liver mass-related symptoms include pain and discomfort due to the mass effect of a large lesion or the subcapsular location of the solid liver mass. Abdominal pain or discomfort could also be due to intratumoral complication, particularly internal bleeding or interval growth. Symptoms related to

5 Table 1 Classification of lesions of the liver Benign lesions Focal nodular hyperplasia, hepatocellular adenoma, nodular regenerative hyperplasia, regenerative nodule, dysplastic nodule Biliary Bile duct adenoma, biliary cystoadenoma, biliary hamartoma, biliary papillomatosis Mesenchymal Lipoma, leiomyoma, myeloid lymphoma, angiomyolipoma, fibrous mesothelioma, hamartoma, teratoma Vascular Hemangioma, infantile hemangioendothelioma, hereditary hemorrhage telangiectasia, lymphangiomatosis Cystic Simple cyst, hydatid cyst, pyogenic abscess Other lesions Focal fatty infiltration, inflammatory pseudotumor Primary malignant lesions Hepatocellular carcinoma, Hepatocellular fibrolamellar carcinoma, hepatocholangiocarcinoma, hepatoblastoma Biliary Cholangiocarcinoma, cystadenocarcinoma Mesenchymal Fibrosarcoma, leiomyosarcoma, liposarcoma, undifferentiated sarcoma, carcinosarcoma Vascular Angiosarcoma, epithelioid hemangioendothelioma Other lesions Lymphoma, sarcoma Metastatic Colon, lung, breast, stomach, Adenocarcinoma pancreases, prostate, ovary, thyroid, urinary tract Squamous cell Lung, esophagus, larynx, perineal Other Sarcomas, lymphomas, melanomas, neuroendocrine

Hepatocellular

underlying chronic liver disease/cirrhosis or a primary malignancy site signals cases of hepatocellular carcinoma (HCC) or metastatic disease, respectively. Background clinical information and associated clinical circumstances may be helpful in narrowing the differential diagnosis and help select the appropriate diagnostic test. Past medical history of viral hepatitis, alcohol history,

6

metabolic issues, or family history of liver disease should raise the suspicion of chronic liver disease leading to HCC. In such cases, the presence of signs and stigmata of chronic liver disease should be searched actively to rule out hepatocellular carcinoma (HCC). Similarly, in a patient with a history of primary sclerosing cholangitis, cholangiocarcinoma should be considered as the most probable diagnosis of a liver mass. On the other hand, hepatocellular adenoma (HCA) is a vascular liver mass frequent among healthy young women with history of oral contraceptives (OCs) use. When present, constitutional symptoms including anorexia, unexplained weight loss, fatigue and fever should point possibility of malignancy or infection. In most cases, solid liver lesions are identified based on ultrasound as a first diagnostic imaging study. Ultrasound is a simple and safe examination method but generally yields a poor sensitivity and specificity for diagnosis. Various dynamic diagnostic imaging modalities including contrast-enhanced ultrasound (CEUS), computer tomography (CT), and magnetic resonance imaging (MRI) have improved the ability to characterize the vascularization profile of solid liver lesions and make a qualitative diagnosis. No biochemical laboratory alterations are pathognomonic of specific solid liver mass, and the diagnosis should be made at the end of a complete workup, and in some cases, after excluding other causes. Generally, characterization of the lesion using dynamic imaging study is needed to establish the diagnosis. Finally, it is not infrequent that biopsy is included in the diagnostic workup for pathological analysis in atypical cases and if diagnosis could not be made radiologically. Conservative management approach is suggested for asymptomatic patients with smallsize solitary solid liver mass (e.g., lifestyle modification and discontinuation of OCs). It is clear that a malignant (primary or metastatic) lesion requires specific therapy. Even in cases of benign pathology, several factors must be considered to recommend specific treatment/management. Certain patients are at risk of progression of disease, and some benign lesions carry oncogenic

E. Feyssa and S. J. Munoz

potential. The size, number, and location of highly vascular liver mass determine the risk of symptoms and bleeding. For example, life-threatening intrabdominal bleeding could be a presenting clinical scenario of a ruptured HCA, which will require immediate resuscitation and transcatheter arterial embolization (TAE)  surgical resection. Local pressure symptoms from large hepatic mass may cause debilitating symptoms that needs to be surgically addressed. The efficacy and safety of specific management option and the general health/comorbidities that may affect postprocedural outcome of patient should be considered during counseling and managing a specific patient. Appropriate referral of cases to experienced centers and engaging multidisciplinary team (MDT) early for diagnosis and treatment recommendations is important to improve patient outcome. In this chapter, the prevalence, epidemiology, presenting symptoms, imaging characteristics, and recommended therapeutic options of frequently encountered benign solid liver masses, including hepatocellular adenoma (HCA), focal nodular hyperplasia (FNH), hepatic hemangioma, and nodular regenerative nodules are discussed. Approach to managing malignant solid liver lesions include hepatocellular carcinoma, cholangiocarcinoma, and metastatic diseases is addressed in separate chapters.

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Hepatic Hemangioma

Hepatic hemangioma (also referred as cavernous hemangioma) is the most common benign solid tumor of the liver. These are vascular lesions and result of hamartomatous proliferations of a vascular endothelial cell. Hepatic hemangioma lesions are characterized by blood-filled large vascular spaces, fed by hepatic arterial circulation and lined by a single layer of endothelial cells. The estimated prevalence of hepatic hemangioma in the general population ranges from 0.7% to 1.5% [1]. However, higher prevalence rate has been reported in necropsy studies (prevalence range from 0.4–7.3%) [2]. In majority of cases, hemangiomas are diagnosed in individuals

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Approach to the Patient with a Solid Liver Mass

between the ages of 30 and 50 years. Both men and women are affected, but the reported female to male ratio ranges from 1.2:1 to 6:1 [1, 3]. Hepatic hemangiomas are usually discovered incidentally on imaging study done for evaluation of nonspecific gastrointestinal ailments or unrelated symptoms. At the time of presentation, most cases of hepatic hemangioma are solitary and small in size; however, it is not infrequent that abdominal symptoms or symptoms related to complication may be the presenting clinical scenario(s) for large hemangiomas. Generally, it is accepted that giant hepatic hemangiomas are those with size larger than 10 cm in diameter. Several centers have reported symptomatic cases of giant hepatic hemangioma size greater than 20 cm in diameter including a case report of an extremely large hepatic hemangioma measuring ~50 cm [4]. Finally, symptomatic hepatic hemangioma patients also tend to have multiple lesions. Overall, in 10% of cases, hepatic hemangiomas are multiple [5].

3

Pathogenesis and Pathology

The pathogenesis of hepatic hemangioma is not clearly understood. Hepatic hemangiomas are more common in women than men. The role of hormone in the pathogenesis and progression of hepatic hemangioma has been mentioned but not clearly established. In their small case control study, Gomer et al did not see association between hepatic hemangioma and menstrual, reproductive, or OCs use history [6]. Large and symptomatic hepatic hemangioma has been described in women exposed to hormonal therapy, and growth of hepatic hemangiomas were also linked with OCs use and pregnancy. However, the direct relation between hormonal replacement and hepatic hemangioma development and growth is not well understood. Hence, there is no contraindication to the use of hormonal supplements in women with hepatic hemangioma, and women may continue OCs if clinically indicated. Hepatic hemangioma arises from vascular malformations composed of blood-filled vascular endothelial-lined channels supported by a fibrous

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Fig. 1 Cavernous hemangioma of the liver. A spongy network of blood-filled dilated vascular spaces separated by fibrous septa. Vascular spaces are lined by flat endothelial cells which are characteristics of this benign tumor (H&E X 4). (Illustration courtesy of Manju Balasubramanian, MD.)

stroma (Fig. 1). The abnormal vascular growth with dilatation in some cases led to the hypothesis that abnormal angiogenesis plays a role in the pathogenesis of hepatic hemangioma. This hypothesis was further supported by findings of increased expression of VEGF-A in hepatic hemangioma cells compared to normal liver endothelial cells. Similarly, anti-VEGF therapy has been tried to shrink the size of hemangioma. The role of anti-VEGF and resulting reduction in the size of giant hepatic hemangiomas were reported in two case reports [7, 8]. However, a recent retrospective study failed to show change in hepatic hemangioma tumor volume in patients who received anti-VEGF therapy for their non-hepatic oncologic issues [9].

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Clinical Presentation

Most cases and diagnosis of hepatic hemangiomas are asymptomatic and diagnosed incidentally on imaging study performed for other reasons or evaluation of abdominal pain or discomfort. When symptomatic, clinical presentation can range from vague nonspecific abdominal discomfort to severe life-threatening intra-abdominal hemorrhage from a ruptured lesion. Abdominal

8

discomfort and pain could be the result of stretching of the Gleason’s capsule and/or associated inflammation from large or enlarging hepatic hemangioma. In addition, compression of local organs such as the stomach could explain nonspecific symptoms including early satiety and postprandial bloating [3]. In most cases, bleeding of hepatic hemangioma could be either spontaneous from exophytic located mass or secondary to trauma. Bleeding as a presenting symptom for hepatic hemangioma is extremely infrequent. However, if present, it is a serious complication requiring resuscitation and urgent intervention. Giant hemangiomas may also become symptomatic in the event of infarction or thrombosis. Kasabach–Merritt syndrome is a rare but wellcharacterized syndrome presenting with coagulative disorder, including severe thrombocytopenia, consumptive coagulopathy, systemic bleeding, and microangiopathic hemolytic anemia. It is more common in giant hepatic hemangioma and could be the first presenting clinical symptom. Other uncommon but potential complications of a giant hepatic hemangioma includes gastric outlet obstruction syndrome, Budd-Chiari syndrome, and high-output congestive heart failure (CHF).

Fig. 2 Small hemangioma – Ultrasound of liver shows a 11  10  11 mm welldemarcated and homogeneously hyperechoic right lobe hepatic lesion

E. Feyssa and S. J. Munoz

5

Ultrasound

Ultrasound study is usually the first and most commonly done imaging modality to evaluate hemangiomas. Hepatic hemangioma appears as well-demarcated hyperechoic lesion with posterior acoustic enhancement (Fig. 2). Overall sensitivity of US in identifying a solid liver mass is good; however, it lacks specificity. In patients with hepatic steatosis, hepatic hemangioma may be hypoechoic or isoechoic given liver with steatosis. In such cases, contrast-enhanced CT or MRI can be used for better characterization of the lesion. Color Doppler Ultrasonography shows no flow within most hepatic hemangiomas. However, in the presence of intralesional arterio-portal shunt, a color Doppler ultrasound study may show blood flow within hemangioma. Generally, this imaging modality is not necessary to make a diagnosis of hepatic hemangioma nor improves the accuracy of a regular US study and may not add specificity to diagnosis [10, 11]. Despite better availability, the accuracy of US in differentiating hepatic hemangioma from solid malignant tumor is low, and further evaluation with dynamic contrast enhancement is required (Table 2).

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Approach to the Patient with a Solid Liver Mass

Table 2 Sensitivity and specificity of diagnostic methods in hepatic hemangioma Diagnostic method Ultrasonography Contrast enhanced ultrasonography Computed tomography Magnetic resonance imaging Tc-99m RBC blood pool scintigraphy

Sensitivity (%) 96.9 90.4

Specificity (%) 60.3 98.8

98.3 100

55.0 95

75

100

Contrast-enhanced ultrasound (CEUS) of the liver uses gas-filled microbubbles to better visualize and outline blood vessels in liver. On CEUS, hepatic hemangioma appears as a wellcircumscribed lesion and after contrast administration shows a nodular peripheral enhancement with a progressive centripetal fill-in. This radiologic feature is useful in differentiating hemangiomas from malignant tumors. CEUS performance versus other imaging modalities has been evaluated by Fang et al. and found CEUS to be as accurate as MRI in correctly diagnosing hepatic hemangiomas [12]. On CT scan, hepatic hemangioma is a welldemarcated hypodense lesion. The typical characteristics of a hepatic hemangioma on contrastenhanced CT scan of liver is a peripheral nodular enhancement, which is followed by a progressive centripetal homogeneous filling of the whole lesion. Small hepatic hemangioma may only show complete early fill-in of the nodule [13]. In the presence of intralesional arterioportal shunts, early arterial enhancement followed by isoattenuation or slight hyperattenuation in the portal phase can be appreciated. Perhaps the best radiologic technique to establish the diagnosis of hepatic hemangioma is MRI of liver (100% sensitivity, 95% specificity). The classic appearance is that of a well-defined, homogeneous, hypointense lesion on T1-weighted sequences and hyperintense on T2-weighted sequences. Gadolinium administration will show a typical globular peripheral enhancement with progressive hyperintense filling. Hyperintensity on T2-weighted images is an important imaging

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characteristic that helps differentiate hepatic hemangioma from solid malignant nodules. The presence of thrombosis, necrosis, or scarring within the hemangioma may give a nonenhancing focus on gadolinium-enhanced MRI. Other useful but less commonly used diagnostic imaging modalities includes Technetium-99m pertechnetate-labeled red blood cell pool scintigraphy, angiography, and single photon emission computed tomography (SPECT)/positron emission tomography (PET) scan. These diagnostic modalities appear to be helpful in cases of atypical hepatic hemangioma. Diagnostic biopsy in hepatic hemangioma is not appropriate. Biopsy of a highly vascular lesion carries a very high risk of bleeding and procedurerelated mortality. The accuracy of available advanced diagnostic imaging methods makes the need for liver biopsy a rarity, and in practice, biopsy is generally performed for atypical lesions or when the diagnosis is in question.

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Treatment

Recommendation for treatment of hepatic hemangioma is based on symptoms and possible risk of complication including compression, bleeding, or coagulopathy. More than half of cases with hepatic hemangioma report abdominal pain at the time of referral for evaluation; however symptoms could be attributed to hepatic hemangioma in only 12.6% of cases [14]. Abdominal pain is more likely to be related to other gastrointestinal ailments than hepatic hemangioma and not all patients experience resolution after surgical removal of the hemangioma. Despite lack of evidence linking abdominal pain and hepatic hemangioma, abdominal pain remains the indication for surgery in majority (48% to 86%) of cases [3, 15, 16]. Some recommend conservative follow-up with 6–12 months interval imaging study in hepatic hemangioma, which is less than 5 cm in size to assess for rapid growth. Generally, it is recommended that the imaging modality used to diagnose hepatic hemangioma also be used for follow-ups. Chance of progression in size and increase in size varies but was clearly documented

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in multiple studies that followed hepatic hemangioma cases [17, 18]. In a study of 163 hepatic hemangioma patients, Hasan et al. documented an average annual growth rate of 0.03 cm and found a correlation with increased annual growth in large hemangioma (>5 cm at initial size) [18]. When treatment is indicated, surgical (resection or enucleation) approach is the most commonly chosen procedure depending on size, location, number of lesions, patient’s surgical candidacy, and operator’s experience. Multiple studies reported comparable success and patient outcome comparing resection versus enucleation [19, 20]. Enucleation offers less risk of blood loss, fewer complications, and lower morbidity and short operative time. Enucleation also preserves maximum amount of normal liver tissue. However, in hepatic hemangioma larger in size (larger than 10 cm), Zhag et al. documented no difference in patient outcomes between enucleation and liver resection [21]. Furthermore, for hemangioma located deep in the liver parenchyma, resection may be a preferred surgical option than enucleation to lower risk of bleeding, complications, and reduce operation time. Both resection surgery and enucleation can be performed either using conventional open approach or laparoscopically. Liu et al. reported their observation that in selected patients laparoscopic approach offers superior short-term surgical outcomes and superior patient quality of life [22]. There is increasing trend with the use of laparoscopic approach for benign liver tumor resection in recent years. However, some of the limitations with this approach includes the need for skilled operator, challenges in controlling intraoperative bleeding, and lack of ability to assess for the presence of additional hepatic lesions. There is a significant increased risk of intraoperative hemorrhage associated with surgical resection or enucleation of giant hepatic hemangiomas. To reduce this bleeding risk, preoperative Radio Frequency Ablation (RFA) and Transcatheter Arterial Embolization (TAE) have been attempted with success [23, 24]. Transcatheter arterial embolization may also be used to control bleeding of a ruptured giant hemangioma or to stabilize patient before surgical resection.

E. Feyssa and S. J. Munoz

Moreover, for patients who are poor surgical candidates, RFA offers good treatment outcome. Laparoscopic RF ablation therapy is also a safe, feasible, and effective procedure for large subcapsular hepatic hemangiomas, even in the hepatic hemangiomas when size is 10 cm. Finally, RFA therapy for hepatic hemangioma can be performed safely and effectively using a laparoscopic approach with comparable result versus surgical resection [25]. In one series of 124 hepatic hemangioma cases treated with laparoscopic RFA, Gao et al reported achieving a complete ablation of hepatic hemangioma in 95.2% of their cases (including 92% in cases with lesions 10 cm) [26]. In general, liver transplantation for benign solid hepatic tumors, including hepatic hemangiomas, is extremely rare [27]. Almost always, the indications for liver transplantation in cases of hepatic hemangioma is an extreme and lifethreatening giant hemangioma complicated by Kasabach-Merritt syndrome [28]. Overall, posttransplant patient survival in those selected hepatic hemangioma cases is comparable to recipients of liver transplantation for other indications [27].

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Hepatocellular Adenoma

Hepatocellular Adenoma (HCA) is a rare benign hepatocellular tumor predominantly affecting women 30–40 years of age. The reported prevalence of HCA ranges between 0.001% to 0.004%. HCA is less common than FNA, with HCA to FNH ratio of 1:10 [29]. Perhaps, the most strongly linked risk factor in the development of HCA is the role of sex hormones. HCA most commonly occurs in young women, particularly those who have been exposed to estrogen-based oral contraceptives (OCs). This association is dose-dependent and the relative risk of HCA is as high as 25 to 40 times higher for women on long-term oral contraceptives (OCs) use compared with those who did not use OCs or used contraceptives for less than 12 months. On the other hand, HCA is

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Approach to the Patient with a Solid Liver Mass

known to regress following the withdrawal of OCs further supporting the strong relation between hormonal use and development or progression of HCA. Finally, a decrease in prevalence of HCA in recent times also corelates with decrease in estrogen content in modern OCs. HCA is more prevalent in females, with male to female ratio of 1:4; however, the widespread misuse of anabolic steroids by athletes and body builders resulted in the increased incidence of HCA in men [30]. The association between exogenous anabolic steroids and development of HCA was further supported by the reported incidence of HCA in patients receiving anabolic steroid therapy in aplastic anemia and Fanconi’s anemia. The potential imbalance in endogenous sex hormones was also implicated as risk factor for development of HCA in patients with Klinefelter’s syndrome and polycystic ovarian syndrome. The recent increase in the reported cases of HCA in women without history of hormonal supplement therapy has also been linked with the increased rate of obesity and metabolic syndrome seen in the general population [31, 32]. Obesity and metabolic syndrome are frequently found in patient with HCA, and the risk is even higher in obese women who also use OCs. Moreover, metabolic syndrome is the most frequently associated risk factor in men for malignant transformation of HCA to HCC [33]. HCA in men has a significant risk of malignant transformation, and surgical resection is indicated in men to mitigate this risk of oncogenic potential. Finally, HCA also has been associated with underlying other metabolic syndromes, including Type I and Type III glycogen storage disease, hemochromatosis, iron overload related to β-thalassemia, and maturity onset diabetes of the young type 3 (MODY3).

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Pathophysiology

Pathophysiology of HCA is not fully elucidated. HCAs are defined as monoclonal proliferation of hepatocytes without portal tract elements or bile ductules, which is a key feature in the histologic

11

distinction of HCA from focal nodular hyperplasia (FNH). Recent understanding of genetic heterogeneity in HCA and ability to detect molecular signature led to the identification of three distinct subtypes of HCA. Based on specific genotypic and phenotypic characteristics, HCA are classified into inflammatory (I-HCA), hepatocyte nuclear factor (HNF)-1α-inactivated (H-HCA), and β-catenin-activated types (β-HCA). The fourth group, which accounts for 5–10% of all HCA, remains poorly characterized with no identifiable clinicopathologic or immunochemical characteristics and is designated as unclassified HCA. The specific clinical, histologic, immunochemical markers, and radiologic features of each subtype are summarized in Table 3. HNF1A-Mutation HCA (H-HCA) encompassing 30–40% of all HCA cases is defined by mutations of the HNF1α gene. The HNF-1α is a transcription factor involved in the differentiation and glucose and lipid metabolism control. Inactivation of this factor leads to metabolic and pro-proliferative disorders. Inhibition of gluconeogenesis is coordinated with an activation of glycolysis citrate shuttle and fatty acid synthesis. One example of expression controlled by HNF1α gene is a cytoplasmic protein liver fatty acid-binding protein (LFABP). LFABP binds free fatty acids and their coenzyme A derivative, bilirubin, and other hydrophobic ligands. It has a role in lipid transport, uptake, and metabolism. The absence of expression in hepatocytes (LFABP ve on immunochemistry) leads to high rates of lipogenesis and the characteristic extensive intratumoral steatosis on histologic examination. This characteristic of H-HCA is useful in diagnosis. On MRI, a diffuse and homogeneous signal dropout may be appreciated on T1-weighted chemical shift sequence images on MRI of this type of HCA. Finally, LFABP staining is now available at some centers as a panel of immunohistological markers offering a 100% sensitivity and specificity for classifying H-HCAs if tissue is available [34]. Inflammatory adenomas (I-HCA) account for 35–45% of all HCAs. It is characterized by increased expression of members of the acute-

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E. Feyssa and S. J. Munoz

Table 3 Hepatocellular adenoma molecular classification HCA subtype (prevalence) HHCA (30–40%)

I-HCA (35-45%)

β-catenin exon 3 mutated HCA (5–10%) β-cateninmutated HCA exon 7/8 (5–10%) Unclassified HCA (5–10%)

Genetic mutation HNF1-A

Risk factors Adenomatosis MODY3

Specific MRI features Diffuse and homogenous signal dropout on chemical shift T1-weighted sequence (Fat) Strong hyperintense signal on T2-weighted MRI (Telangiectatic)

Histopathology Prominent steatosis

Immunohistochemistry LFABP –ve

Clusters of vessels with inflammatory infiltration and foci of sinusoidal dilatation Cell atypia, pseudoglandular formations and cholestasis

LFABP +ve SAA ( CRP) +ve

IL6ST, GNAS, STAT3, FRK or JAK1 CTNNB1 in exon 3

Obesity Alcohol Consumption

Male Liver vascular disease

No specific features

CTNNB1 in exons 7/8

No specific risk factor

No specific features

No typical features

GS +ve (faint and patchy); β-catenin nuclear –ve

No genetic alterations

No specific risk factor

No specific features

No typical features

LFABP +ve SAA/CRP –ve β-catenin nuclear –ve

LFABP +ve GS +ve (diffuse) β-catenin nuclear +ve

LFABP, Liver fatty acid-binding protein; SAA, serum amyloid A; CRP, C-reactive protein; I-HCA, inflammatory HCA; HNF1-A, hepatocyte nuclear factor-1α–inactivated; H-HCA, HNF1-A-inactivated HCA; β-HCA, β-catenin-activated HCA types; IL6ST, interleukin 6 signal transducer; STAT3, signal transducer and activator of transcription 3; JAK1, Janus kinase 1; CTNNB1, Catenin Beta 1

phase inflammatory response such as serum amyloid A (SAA) protein, C-reactive protein (CRP), and the interleukin 6 (IL-6) signaling pathway as a result of variety of gene mutations. These mutations are almost mutually exclusive and reported to result in activation of JAK/STAT pathways [35]. Elevated serum markers, including C-reactive protein and fibrinogen, indicate the presence of systemic inflammatory syndrome. Immunochemistry studies of I-HCA exhibit cytoplasmic expression of serum amyloid A (SAA) and CRP. Macroscopically, I-HCA exhibits clusters of small arteries with surrounding inflammatory infiltrates (hence, telangiectatic form). Telangiectatic form of I-HCA is frequently associated with use of oral contraceptives, hormonal therapy, and obesity, and the presence of other benign focal lesions of the liver. These HCAs are considered at high risk of bleeding and neoplastic transformation.

About 10% of HCAs are characterized by mutations of β-catenin. These HCAs are pathogenetically linked with a subgroup of HCCs, characterized by mutations of β-catenin. In a series of patients with HCA, those with β-catenin activation were shown to be at risk of malignant transformation [36]. The fact that no case of HCA with both β-catenin and biallelic inactivation of HNF1α was identified suggests that these two signaling pathways are mutually exclusive. About half of β-catenin-mutated HCA also displays inflammatory phenotype.

9

Pathology

Macroscopically, HCAs are well-defined, soft, fleshy appearing yellow-brown in color, sometimes encapsulated and often with highly vascularized surface and large subcapsular

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Approach to the Patient with a Solid Liver Mass

13

vessels. Focal areas of necrosis and/or hemorrhage in the parenchyma may give the heterogeneous appearance of the tumor macroscopically. Microscopically, the cells of HCA closely resemble normal hepatocytes. The histologic features are sheets of hepatocytes two or more cells thick without cellular atypia (to differentiate them from adenocarcinoma), portal tracts (to differentiate them from liver cell regeneration), and biliary ductules and fibrosis unlike FNH. Histologically, HCAs are classified as steatotic HCAs (overlapping with the HNF1α mutation subgroup of the molecular classification), telangiectatic HCAs (overlapping with the inflammatory subgroup of the molecular classification), and unclassified HCAs [33, 37]. Steatotic HCAs are characterized by prominent steatosis (>60%)

without other specific features (Fig. 3). Telangiectatic HCA is characterized by the presence of portal tract remnants associated with vascular changes and/or inflammatory infiltrates (Fig. 4). When no specific histologic features are present, HCAs are considered unclassified. Foci of malignant transformation have been described that may escape detection in small specimens obtained with a thin-needle liver biopsy. In the appropriate clinical setting, high-quality dynamic imaging studies lead to accurate diagnosis of majority of solid liver mass. The risk of bleeding related to biopsy attempt of a vascularized liver lesion is high. Hence, the role of percutaneous biopsy is limited to few atypical cases or when radiologic findings are nondiagnostic. If available, immunohistological

Fig. 3 Histological features of HNF-1a inactivated hepatocellular adenoma (H-HCA). (a) H-HCA with steatosis and (b) loss of LFABP expression (H&E and IHC X 20). (c) higher magnification showing marked steatosis (H&E x100). Margolskee et al., [38]. This is an open access

article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https:// creativecommons.org/licenses/by/4.0/

Fig. 4 Histological features of inflammatory hepatocellular adenoma (IHCA). (a) IHCA with telangiectasia and focal inflammation (H&E X 20). (b) Diffuse serum amyloid-A expression within the tumor (IHC X 20). (c) Higher magnification micrograph highlighting inflammation (lower right) and telangiectasia (upper left) (H&E X

100). Margolskee et al. [38]. This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/ licenses/by/4.0/

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E. Feyssa and S. J. Munoz

classification of HCAs may be helpful in defining the risk of malignant transformation and formulate management recommendation. However, the molecular subtyping of HCA is not yet part of clinical management guidelines.

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pathologic or immunohistochemistry evidence is required for diagnosis and management, it is recommended to get core biopsies instead of fine-needle aspiration.

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Imaging Findings

11.1

Ultrasonography and Contrast-Enhanced Ultrasonography

Clinical Features

HCAs has a varied pattern of clinical presentation. It is more likely for a patient with HCA to present with symptoms compared to that of patients with either FNH or hemangiomas; however, nearly half of the cases of HCA still are discovered incidentally on imaging studies performed for unrelated symptoms. In the remaining cases, presenting symptoms may range from abdominal pain and abdominal mass to extreme symptoms associated with life-threatening intra-abdominal bleeding resulting from adenoma rupture [39]. The risk of hemorrhage is higher in patient with multiple HCAs and in those patients who were taking oral contraceptives [40]. Physical examination is usually not helpful and may be normal. Hepatomegaly and/or abdominal mass could be appreciated when large HCA is present or in the presence of multiple lesions. Jaundice is rare but has been reported as presenting symptom due to compression of the intrahepatic bile ducts by the lesion. Abnormality of laboratory tests is generally uncommon in HCA. Elevated alkaline phosphatase and gamma-glutamyl transpeptidase (GGT) might be seen in large HCAs or multiple lesions or those HCAs complicated by bleeding [40]. Inflammatory HCAs are more often associated with an increased level of serum inflammatory biomarkers, including C-reactive protein [41]. Percutaneous liver biopsy has been considered of little value because of the possible lack of specific features in a small specimen. HCA is a hypervascular lesion, and risk of bleeding with biopsy is high. A small sample could also miss a malignant focus. However, recent data raised the possibility of using liver biopsies for the identification of the various HCA subtypes (Table 3). If

On ultrasound, HCA has variable sonographic appearances, and none are specific for diagnosis. In most cases, these lesions appear as a welldemarcated hyperechoic lesion given the presence of high fat content in adenomatous hepatocytes. HCA may appear as large complex lesion as a result of hemorrhage and necrotic changes. On color or power Doppler ultrasonography, identification of peripheral vascularity peritumoral vessels in HCA is a useful finding, and could help differentiate the lesion from FNH which exhibits intratumoral vessels radiating from the center to the periphery [42]. On contrast-enhanced ultrasonography (CEUS), adenoma shows intense enhancement pattern during the arterial phase except when areas of hemorrhage are present. During the portal venous and equilibrium phases, adenomas may appear as an isoechoic or slightly hyperechoic mass.

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Computed Tomography

Baseline computed tomography (CT) scans can easily detect the presence of fat or recent hemorrhage within HCA lesion, features that can suggest the diagnosis of adenoma. During the noncontrast-enhanced CT, HCA tend to be hypodense due to the presence of fat and hyperdense in the presence of intratumoral hemorrhage. In patients with hepatic steatosis, HCA are hyperattenuating during noncontrast-enhanced CT and all phases of contrast enhancement. During dynamic contrast-enhanced CT scanning, the

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Approach to the Patient with a Solid Liver Mass

lesion may demonstrate peripheral enhancement during the early phase with subsequent centripetal flow during the portal venous phase, which is characteristic of HCA. Presence of intratumoral hemorrhage and necrotic areas gives the lesion heterogeneous pattern. This is commonly seen in large or complicated lesions.

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Magnetic Resonance Imaging (MRI)

Perhaps the most preferred and comprehensive imaging modality to evaluate HCA is MRI. HCAs are usually well-demarcated lesions that have variable appearance on T1-weighted images, with up to 77% of cases appearing hyperintense on T1-weighted images [43]. HCAs show arterial phase enhancement on MRI, with varied enhancement patterns in the subsequent phases depending upon the lesion subtype. Furthermore, a gadobenate dimeglumine(Gd-BOPTA)enhanced MRI offers the possibility to evaluate both the delayed and the hepatobiliary phases, hence improving the diagnostic accuracy and the ease to differentiate HCA from FNH. Most HCA appears hypointense during the hepatobiliary sequences; however, some inflammatory HCA may be iso- or hyperintense on these sequences. The clinical usefulness of specific MRI features and applicable subtyping of HCA has been studied recently. The two most frequently identified subtypes of HCA, based on MRI appearance, are HNF1α-inactivated HCA and inflammatory HCA [44]. A diffuse and homogeneous signal dropout on chemical T1-weighted sequence marks the presence of marked fat distribution seen in HNF1α-inactivated HCA subtype (Fig. 5). Inflammatory HCA cases also displayed specific MRI features (Fig. 6). A combination of strong hyperintense signal on T2-weighted MRI and the persistent enhancement on delayed phases are found to be sensitive (85.2%) and specific (87.5%) for the radiologic diagnosis of inflammatory HCA subtypes [44]. Finally, similar to the typical enhancement pattern of HCC, HCA with

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β-catenin activation may display strong arterial enhancement with marked washout in the portal venous phase [44].

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Treatment

HCAs are usually solitary lesions and vary in size from few millimeters to several centimeters at presentation. HCAs have a risk of hemorrhage and some risk of malignant transformation. With improved understanding of predisposing factors and risks associated with complications, it is now possible to stratify cases for invasive surgical resection versus conservative management [46]. The overall size and number of lesions were used to stratify complication risks. In addition, HCA has molecular signatures that correlated with specific imaging findings that help to classify the tumor based on risk of malignant transformation. In general, hemorrhage occurs in 21% to 40% of HCAs [31, 46–48]. In most cases hemorrhage is intratumoral; however, intraperitoneal bleeding or subcapsular rupture is not infrequent. There is a direct association between size of HCA and risk of bleeding. Generally, HCAs with tumors greater than 5 cm have high risk of hemorrhage. Due to increased vascular component, I-HCA is also cited as risk factor for bleeding [34]. Other factors associated with risk of bleeding or rupture in HCA includes increasing tumor size, hormone use within the past 6 months and pregnancy [46]. Rupture of HCA may present with severe abdominal pain, hemodynamic instability and free intraperitoneal hemorrhage. Management of ruptured HCA may require initial stabilization of the patient, resuscitation, admission for close observation, and getting a contrast-enhanced imaging, preferably contrast-enhanced CT scan [31, 47, 48]. It is recommended patients be observed at or transferred to a center where transcatheter arterial embolization (TAE) can be performed to control bleeding. Emergent surgery of ruptured HCA carries a mortality rate of 5% to 10%. An initial stabilization with selective

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E. Feyssa and S. J. Munoz

Fig. 5 Adenoma (HNF1A subtype). (a) T1-weighted in-phase GRE image demonstrates a very large mass in a young woman. The mass is inhomogeneous and shows bright spots. (b) There is typical signal intensity drop on the opposed-phase image indicative of intratumoral fat. (c)

The T2-weighted TSE shows moderate hyperintensity. (d) On the gadoxetic acid-enhanced images in the hepatobiliary phase, there is little to no enhancement. (Adopted with permission Wolfgang Schima and RB Dow-Mu Koh.) [45]

transcatheter arterial embolization (TAE) may be required, and it may also lower the surgical risks including blood loss, postoperative complications, and is associated with a shorter length of hospital stay [31, 46, 47]. The estimated risk of malignant transformation in HCA is between 4% and 8% [33, 49]. Frequently associated factors with increased risk of malignant transformation are male gender, HCA tumor size greater than 5 cm, and β-catenin

mutation HCA subtype. HCA in men carries a tenfold higher incidence of malignant transformation to HCC [33], and curative therapy with surgical resection is recommended irrespective of HCA size [50]. Those patients who are poor candidates for surgery should be offered arterial embolization or ablative therapy. Similarly, β-catenin mutations are strongly associated with an increased risk of malignant transformation. Previous reviews showed up to 46% of

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Approach to the Patient with a Solid Liver Mass

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Fig. 6 Adenoma (inflammatory type) in a young female presenting with vague upper quadrant pain. (a) In- and (b) opposed-phase T1-weighted imaging shows no significant intralesional fat. The nodule is (c) mildly hyperintense on T2-weighted imaging. (d–f) Pre-contrast, post-contrast

arterial phase, and delayed phase images show avid arterial enhancement, which persists. Surgical resection confirmed an inflammatory adenoma. (Adopted with permission Wolfgang Schima and RB Dow-Mu Koh.) [45]

β-catenin-mutation HCAs may show the presence of HCC, and about 10% of inflammatory HCA show a mutated β-catenin gene and malignant transformation [36, 39]. Finally, it should be remembered that β-catenin mutations HCA subtype is overrepresented in men and yield higher risk for malignant transformation. The oncogenic potential of β-catenin-mutated HCA is inherently high, and there is strong indication to remove it. HCA subtyping is a useful tool that may offer additional information to guide treatment decision-making; however, the HCA subtyping using immunohistochemistry still requires validation in different population, and molecular classification is not widely used in clinical practice. Furthermore, immunohistochemical diagnosis is usually made on already surgically resection samples, and no further intervention is warranted.

In summary, the potential for hemorrhage and malignant transformation dictates the general treatment recommendation for HCA. Contrastenhanced MRI is recommended as baseline imaging study to document size and location of HCA (and possibly subtype). The risk of bleeding is tumor size-dependent, and a size cutoff of 5 cm separates tumors with low risk of bleeding from tumors with high risk of bleeding [51]. In women, HCA 20% of diameter) or is >5 cm at 6 months interval MRI should prompt evaluation for surgical resection to avoid risk of hemorrhage or malignant transformation [31, 51]. Similarly, exophytic location of an HCA of any size is also an indication for surgical resection or ablation therapy. Furthermore, tumor ablation should also be considered for women who for medical reasons cannot stop using oral contraceptives or for those who plan to become pregnant. In patients with HCA showing interval regression or stable size, surgical treatment or locoregional ablation may be avoided or delayed. Recommendations on the frequency, imaging modality and duration of follow-up of a stable HCA is still evolving. For lesions stable after 12 months, annual ultrasound is a preferred and cost-effective method to follow cases. There is no consensus regarding follow-up of HCA which is stable after 5-years; however, biannual ultrasound should be considered. HCA discovered in a pregnant woman presents a management challenge. It requires a close follow-up with frequent ultrasonography every 6–12 weeks interval. Pregnancy is not contraindicated in women with HCA smaller than 5 cm [53]. For a growing lesion, surgery is preferred prior to the 24 weeks of gestation to avoid risk of contrast and ionizing radiation associated with transcatheter arterial embolization that could harm the fetus. In the presence of small HCA that is not exophytic or growing, there is no data supporting benefit of cesarean section over vaginal delivery; therefore, mode of delivery should be dictated by obstetric indication. Approximately 30% of the patients have multiple nodules, and the presence of 10 or more adenomas defines liver adenomatosis [40]. The management of liver adenomatosis is problematic. A unilocular multiple nodule could be treated with hepatic resection. For patients with liver adenomatosis, surgical resection of the largest or of the complicated adenomas is an option. This is because it often is impossible to resect all tumors in patients with multiple HCAs. Liver

E. Feyssa and S. J. Munoz

transplantation has been proposed in rare cases of patients with more than 10 HCAs.

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Focal Nodular Hyperplasia (FNH)

15.1

Epidemiology

FNH is the second most common benign tumor of the liver. It usually is identified incidentally on imaging study of an asymptomatic patient. The estimated prevalence is about 2.5% in the general population but can vary between 0.4% and 3% in unselected autopsy studies [2, 51]. Overall, the prevalence of clinically relevant FNH is only 0.03% [51]. FNH is predominantly diagnosed in young women, with the average age at diagnosis between 35 years and 50 years. The tumor has a female to male prevalence ratio of 8:1 [54]. When FNH is identified in men, it is usually diagnosed later in life, and it displays more serve morphological atypia on histology. Furthermore, FNH in men is more likely to require surgical intervention compared to the need for surgical intervention in women. In the majority of cases, FNH is a solitary lesion and frequently small in size (less than 3 cm). Approximately, 20–30% of FNH cases present as multiple lesions. Several centers reported concomitant diagnosis of hemangioma in 20% of FNH cases [54, 55]. Association of FNH with hepatocellular adenomas (HCA) is less common and could be coincidental. However, it has been suggested that both FNH and HCA may share common underlying causal promotor including vascular anomalies, thrombotic events and/or localized arteriovenous shunts.

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Pathogenesis

FNH is thought to represent a hyperplastic response to a vascular malformation. The tumor is the result of polyclonal hepatocellular hyperplastic proliferation to an arterial lesion and/or

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Approach to the Patient with a Solid Liver Mass

portal venous malformation. With congenital or acquired localized vascular malformation, there is associated formation and enlargement of compensatory arterial to venous shunts. The altered distribution of oxygenated blood within the hepatic parenchyma then creates oxidative stress that triggers the hyperplastic reaction that leads to the formation of FNH nodule nucleus. Hepatic atrophy and nodular hyperplastic changes particularly bile-duct proliferation in response to chronic ischemia in human liver supports this hypothesis. Immunochemistry studies have also demonstrated that the extracellular matrix of FNH retains the overall organization of the normal liver. Similarly, studies have shown the matrix of central scar shown resembles that of the portal tracts [56]. Furthermore, a vascular malformation hypothesis in FNH development is further supported by the association of FNH with other conditions characterized by arterial damage, such as hereditary hemorrhagic telangiectasia [57], or previously treated solid tumors in children [58]. In the past, the observed higher frequency of FNH among women led to the speculation that there may be an association between OCs use and development of FNH. Also, OCs use has been associated with an increase in size and vascularity of FNH nodes. On the other hand, OCs withdrawal was believed to be associated with regression of nodules. The hypothesis that pregnancy and OCs play a role in development or progression of FNH was negated by a more recent longitudinal study from France [59]. In this 9-year longitudinal study following 216 women with FNH, Mathieu et al. found no FNH changes or complications associated with pregnancy [59].

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Pathology

FNH is a reactive hyperplastic response to polyclonal hepatocytes, fibrous stroma, and bile ductules resulting from arterial malformation. It develops within hepatic parenchymal tissue that is otherwise histologically normal. Macroscopically, FNH is typically a solitary mass, pale in color with well-defined margins, and mostly

19

unencapsulated. In about 50% of all FNH, it also shows a grayish-white central fibrous scar that contains dystrophic arterial vessels. Its presence is regarded as a pathognomonic finding. In about 80% of cases, FNH macroscopically shows multiple pseudolobules with fibrovascular and ductular areas that radiates from the perilobular septa. Histologically, FNH is composed of normalappearing hepatocytes and Kupffer cells arranged in nodules that are usually partially delineated by fibrous septa originating from the central scar. The dense fibrous septa contain large thick-walled arterioles and bile duct structures. In FNH lesion, the hypertrophic feeding artery develops centripetally and terminates in the central scar. This vascular feature gives a unique clue to diagnose FNH on ultrasound color Doppler study. Several degrees of ductular proliferation and intense inflammatory infiltrates may be seen in the fibrous septa. The bile duct structures, if seen, are very good evidence to differentiate FNH from HCC. The most common atypical form of FNH which poses diagnostic challenge is FNH nodule without recognizable central scar. A central scar is mostly absent in lesions 3 cm) nodules. When central scar is missing, especially in smaller lesions, combination of MRI

and CEUS might yield a higher diagnostic accuracy [64]. Finally, the hepatobiliary phase of MRI using hepatobiliary contrast GD-BOPTA or gadoxetic acid improves the diagnostic accuracy in FNH and most importantly in differentiating FNH from HCA (sensitivity and specificity up to 97% and 100%, respectively) [65]. During the late phase of GD-

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BOPTA-enhanced MRI, hyper- or isointensity of a lesion is considered typical for FNH.

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Treatment

Compared to other neoplastic disorders, the size of FNH is stable over time in the vast majority of cases and that complications are extremely rare. A slow incidental increase in size is not cause for concern in cases with a solid diagnosis. Uncommon and rare complications of FNH lesion includes intralesional hemorrhage, compression or obstruction of hepatic vein and KasabachMerritt syndrome. The presence of one or more of these complications may provide enough evidence to support elective surgery for FNH. However, even in symptomatic cases, symptoms are usually vague and nonspecific. In the absence of symptoms and complications, no specific treatment is required. Similarly, once a firm diagnosis is made, no long-term follow-up is recommended in asymptomatic cases. Surgical resection should be considered if treatment is considered in exceptional cases (e.g., in pedunculated FNH, lesion showing progressive growth, exophytic FNH, or FNH with compression symptoms). Subcapsular nodules can safely be resected laparoscopically. Transcatheter arterial embolization or radiofrequency ablation should be reserved for patients who are unfit for surgical resection. There is no indication for discontinuing OCs, and follow-up during pregnancy is not necessary.

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Nodular Regenerative Hyperplasia

Nodular regenerative hyperplasia (NRH) is a benign condition characterized by transformation of normal hepatic parenchyma into small regenerative nodules distributed throughout the liver with minimal or no fibrosis. NRH affects both men and women equally. There is no systematic

population-based study to accurately estimate the prevalence of NRH in the general population. Autopsy studies have found the prevalence of NRH to be 2.6% (6% in those older than 80 years of age) [66]. On the other hand, clinical significance NRH prevalence is 4.4% based on liver biopsy data [67]. Higher prevalence was reported in older patients; however, it is assumed to be reflective of the association of NRH with other diseases. Several disease conditions are associated with NRH, including drug injuries, toxin exposures, lymphoproliferative disorders, autoimmune disorders, rheumatoid arthritis, systemic sclerosis, primary biliary cirrhosis, transplantation (bone marrow, liver and/or kidney), anabolic steroids, hereditary hemorrhagic telangiectasia, polyarteritis nodosa, Budd-Chiari syndrome, amyloidosis, Felty’s syndrome, and primary liver cancer [52, 68].

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Pathophysiology and Pathology

The vascular theory describes NRH to be a result of an adaptive hyperplastic reaction of hepatocytes secondary to mechanical or functional obstruction in the portal blood venous system [68, 69]. The hemodynamic disturbance in the hepatic microvasculature leads to thrombosis, ischemia, and subsequent atrophy of the hepatocytes. Compensatory proliferation in the portal region ensues, thus forming the small regenerative nodules. These regenerating nodules compress intrahepatic portal radicles, which may lead to portal hypertension. Several chemotherapeutic agents and immunosuppressants have been implicated to cause NRH, possibly through a direct injury to endothelial cells of small hepatic veins. Similarly, antibody-mediated vasculopathy and associated hypercoagulable state in patients with autoimmune disorders may induce generalized proliferative disorder of the liver resulting in NRH.

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Approach to the Patient with a Solid Liver Mass

Fig. 9 Nodular regenerative hyperplasia (NRH). (a). Abnormal nodular growth pattern without fibrosis which is different from cirrhosis (H&E X 2). (b) Flattened and

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Clinical Presentation and Diagnosis

Symptomatic cases of NRH are rare, and most cases are discovered incidentally during evaluation for associated diseases. However, patients may present with clinical symptoms and signs of portal hypertension including splenomegaly, ascites, and esophageal varices [68]. In rare cases, NRH has also been noted to cause liver failure necessitating liver transplantation. On liver biochemical tests, transaminases are generally normal or may show mildly elevated alkaline phosphatase. Diagnostic imaging studies are not helpful to make definitive diagnosis in NRH given nonspecific findings. On ultrasound, nodules are usually not visible because of their small sizes. Well-delineated tiny isoechoic or hyperechoic lesion may be seen. On CT scans, nodules appear isodense or hypodense to the normal liver on both arterial and portal venous phases and could easily be differentiated from FNH or hepatocellular adenoma. Similarly, on MRI studies, nodules usually appear hyperintense on T1-weighted images and iso- or hypointense on T2-weighted images.

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compressed liver-cell plates between nodules (N). (Illustration courtesy of Manju Balasubramanian, MD.)

In majority of cases, liver biopsy is unavoidable to make a definitive diagnosis of NRH. Adequate tissue sampling with core or wedge biopsy is critical to improve diagnostic yield. Macroscopically, diffuse fine nodularity of the liver may mimic micronodular cirrhosis; however, microscopic examination shows no or only minimal fibrous scar between NRH nodules (Fig. 9). Additional histologic features in NRH includes regenerating hepatocytes and curvilinear compression of the central lobule. Treatment of NRH is directed at the nature and severity of the underlying disease and depends on the presence or absence of portal hypertension complications. In most cases, management of the underlying medical condition and elimination of causative factor (e.g., drugs toxicity) might be sufficient intervention. Patients who suffer from portal hypertension may require prevention or treatment of complications including variceal hemorrhage and ascites. Variceal bleeding is the main cause of mortality and may require endoscopic therapy or a surgically created portosystemic shunt or transjugular intrahepatic portosystemic shunts (TIPS). The prognosis of NRH correlates with the severity of the underlying illness. Prevention of secondary complications of portal hypertension

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confers very good survival in NRH cases. Generally, associated hepatocellular dysfunction is rare in NRH; however, if present, it may require liver transplantation.

References 1. Gandolfi L, Leo P, Solmi L, Vitelli E, Verros G, Colecchia A. Natural history of hepatic haemangiomas: clinical and ultrasound study. Gut. 1991;32(6):677–80. 2. Rubin RA, Mitchell DG. Evaluation of the solid hepatic mass. Med Clin N Am. 1996;80(5):907–28. 3. Farges O, Daradkeh S, Bismuth H. Cavernous hemangiomas of the liver: are there any indications for resection? World J Surg. 1995;19(1):19–24. 4. Yang Z, Tan H, Liu X, Sun Y. Extremely giant liver hemangioma (50 cm) with Kasabach-Merritt syndrome. J Gastrointest Surg. 2017;21(10):1748–9. 5. Ishak KG, Rabin L. Benign tumors of the liver. Med Clin N Am. 1975;59(4):995–1013. 6. Gemer O, Moscovici O, Ben-Horin CL, Linov L, Peled R, Segal S. Oral contraceptives and liver hemangioma: a case-control study. Acta Obstet Gynecol Scand. 2004;83(12):1199–201. 7. Yamashita S, Okita K, Harada K, Hirano A, Kimura T, Kato A. Giant cavernous hepatic hemangioma shrunk by use of sorafenib. Clin J Gastroenterol. 2013;6(1):55–62. 8. Ono M, Sawada K, Okumura T. A case of liver hemangioma with markedly reduced tumor size after metformin treatment: a case report. Clin J Gastroenterol. 2017;10(1):63–7. 9. Lee M, Choi JY, Lim JS, Park MS, Kim MJ, Kim H. Lack of anti-tumor activity by anti-VEGF treatments in hepatic hemangiomas. Angiogenesis. 2016;19(2):147–53. 10. Lim KJ, Kim KW, Jeong WK, Kim SY, Jang YJ, Yang S, et al. Colour Doppler sonography of hepatic haemangiomas with arterioportal shunts. Br J Radiol. 2012;85(1010):142–6. 11. Perkins AB, Imam K, Smith WJ, Cronan JJ. Color and power Doppler sonography of liver hemangiomas: a dream unfulfilled? J Clin Ultrasound. 2000;28(4):159–65. 12. Fang L, Zhu Z, Huang B, Ding H, Mao F, Li C, et al. A comparative study of contrast enhanced ultrasound and contrast enhanced magnetic resonance imaging for the detection and characterization of hepatic hemangiomas. Biosci Trends. 2015;9(2):104–10. 13. Caseiro-Alves F, Brito J, Araujo AE, Belo-Soares P, Rodrigues H, Cipriano A, et al. Liver haemangioma: common and uncommon findings and how to improve the differential diagnosis. Eur Radiol. 2007;17(6): 1544–54. 14. Etemadi A, Golozar A, Ghassabian A, Zarei M, Hashemi Taheri AP, Dawsey SM, et al. Cavernous

E. Feyssa and S. J. Munoz hemangioma of the liver: factors affecting disease progression in general hepatology practice. Eur J Gastroenterol Hepatol. 2011;23(4):354–8. 15. Herman P, Costa ML, Machado MA, Pugliese V, D'Albuquerque LA, Machado MC, et al. Management of hepatic hemangiomas: a 14-year experience. J Gastrointest Surg. 2005;9(6):853–9. 16. Yoon SS, Charny CK, Fong Y, Jarnagin WR, Schwartz LH, Blumgart LH, et al. Diagnosis, management, and outcomes of 115 patients with hepatic hemangioma. J Am Coll Surg. 2003;197(3):392–402. 17. Jing L, Liang H, Caifeng L, Jianjun Y, Feng X, Mengchao W, et al. New recognition of the natural history and growth pattern of hepatic hemangioma in adults. Hepatol Res. 2016;46(8):727–33. 18. Hasan HY, Hinshaw JL, Borman EJ, Gegios A, Leverson G, Winslow ER. Assessing normal growth of hepatic hemangiomas during long-term follow-up. JAMA Surg. 2014;149(12):1266–71. 19. Liu Y, Wei X, Wang K, Shan Q, Dai H, Xie H, et al. Enucleation versus anatomic resection for giant hepatic hemangioma: a meta-analysis. Gastrointest Tumors. 2017;3(3-4):153–62. 20. Giuliante F, Ardito F, Vellone M, Giordano M, Ranucci G, Piccoli M, et al. Reappraisal of surgical indications and approach for liver hemangioma: singlecenter experience on 74 patients. Am J Surg. 2011;201 (6):741–8. 21. Zhang W, Huang ZY, Ke CS, Wu C, Zhang ZW, Zhang BX, et al. Surgical treatment of giant liver hemangioma larger than 10cm: a single center’s experience with 86 patients. Medicine (Baltimore). 2015;94(34):e1420. 22. Liu Q, Liu F, Ding J, Wei Y, Li B. Surgical outcomes and quality of life between laparoscopic and open approach for hepatic hemangioma: a propensity score matching analysis. Medicine (Baltimore). 2019;98(6):e14485. 23. Wang S, Gao J, Yang M, Ke S, Ding X, Kong J, et al. Intratumoral coagulation by radiofrequency ablation facilitated the laparoscopic resection of giant hepatic hemangioma: a surgical technique report of two cases. Oncotarget. 2017;8(31):52006–11. 24. Bailey J, Di Carlo S, Blackwell J, Gomez D. Same day arterial embolisation followed by hepatic resection for treatment of giant haemangioma. BMJ Case Rep. 2016;2016 25. Zhang X, Yan L, Li B, Wen T, Wang W, Xu M, et al. Comparison of laparoscopic radiofrequency ablation versus open resection in the treatment of symptomatic-enlarging hepatic hemangiomas: a prospective study. Surg Endosc. 2016;30(2):756–63. 26. Gao J, Ji JS, Ding XM, Ke S, Xin ZH, Ning CM, et al. Laparoscopic radiofrequency ablation for large subcapsular hepatic hemangiomas: technical and clinical outcomes. PLoS One. 2016;11(2):e0149755. 27. Sundar Alagusundaramoorthy S, Vilchez V, Zanni A, Sourianarayanane A, Maynard E, Shah M, et al. Role of transplantation in the treatment of benign solid

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tumors of the liver: a review of the United Network of Organ Sharing data set. JAMA Surg. 2015;150(4): 337–42. 28. Prodromidou A, Machairas N, Garoufalia Z, Kostakis ID, Tsaparas P, Paspala A, et al. Liver transplantation for giant hepatic hemangioma: a systematic review. Transplant Proc. 2019;51(2):440–2. 29. Bonder A, Afdhal N. Evaluation of liver lesions. Clin Liver Dis. 2012;16(2):271–83. 30. Socas L, Zumbado M, Pérez-Luzardo O, Ramos A, Pérez C, Hernández JR, et al. Hepatocellular adenomas associated with anabolic androgenic steroid abuse in bodybuilders: a report of two cases and a review of the literature. Br J Sports Med. 2005;39(5):e27. 31. Dokmak S, Paradis V, Vilgrain V, Sauvanet A, Farges O, Valla D, et al. A single-center surgical experience of 122 patients with single and multiple hepatocellular adenomas. Gastroenterology. 2009;137(5):1698–705. 32. Chang CY, Hernandez-Prera JC, Roayaie S, Schwartz M, Thung SN. Changing epidemiology of hepatocellular adenoma in the United States: review of the literature. Int J Hepatol. 2013;2013:604860. 33. Farges O, Ferreira N, Dokmak S, Belghiti J, Bedossa P, Paradis V. Changing trends in malignant transformation of hepatocellular adenoma. Gut. 2011;60(1):85–9. 34. Bioulac-Sage P, Rebouissou S, Thomas C, Blanc JF, Saric J, Sa Cunha A, et al. Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry. Hepatology. 2007;46(3):740–8. 35. Nault JC, Bioulac-Sage P, Zucman-Rossi J. Hepatocellular benign tumors-from molecular classification to personalized clinical care. Gastroenterology. 2013;144(5):888–902. 36. Zucman-Rossi J, Jeannot E, Nhieu JT, Scoazec JY, Guettier C, Rebouissou S, et al. Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. Hepatology. 2006;43 (3):515–24. 37. Thomeer MG, Willemssen FE, Biermann KK, El Addouli H, de Man RA, Ijzermans JN, et al. MRI features of inflammatory hepatocellular adenomas on hepatocyte phase imaging with liver-specific contrast agents. J Magn Reson Imaging. 2014;39(5):1259–64. 38. Margolskee E, Bao F, de Gonzalez AK, Moreira RK, Lagana S, Sireci AN, et al. Hepatocellular adenoma classification: a comparative evaluation of immunohistochemistry and targeted mutational analysis. Diagn Pathol. 2016;11:27. 39. Bioulac-Sage P, Laumonier H, Couchy G, Le Bail B, Sa Cunha A, Rullier A, et al. Hepatocellular adenoma management and phenotypic classification: the Bordeaux experience. Hepatology. 2009;50(2):481–9. 40. Chiche L, Dao T, Salamé E, Galais MP, Bouvard N, Schmutz G, et al. Liver adenomatosis: reappraisal, diagnosis, and surgical management: eight new cases and review of the literature. Ann Surg. 2000;231(1): 74–81.

25 41. Paradis V, Champault A, Ronot M, Deschamps L, Valla DC, Vidaud D, et al. Telangiectatic adenoma: an entity associated with increased body mass index and inflammation. Hepatology. 2007;46(1):140–6. 42. Nicolau C, Brú C. Focal liver lesions: evaluation with contrast-enhanced ultrasonography. Abdom Imaging. 2004;29(3):348–59. 43. Paulson EK, McClellan JS, Washington K, Spritzer CE, Meyers WC, Baker ME. Hepatic adenoma: MR characteristics and correlation with pathologic findings. AJR Am J Roentgenol. 1994;163(1):113–6. 44. Laumonier H, Bioulac-Sage P, Laurent C, ZucmanRossi J, Balabaud C, Trillaud H. Hepatocellular adenomas: magnetic resonance imaging features as a function of molecular pathological classification. Hepatology. 2008;48(3):808–18. 45. Hodler J, Kubik-Huch RA, von Schulthess GK. Diseases of the abdomen and pelvis 2018–2021: diagnostic imaging. IDKD Book; 2018. 46. Deneve JL, Pawlik TM, Cunningham S, Clary B, Reddy S, Scoggins CR, et al. Liver cell adenoma: a multicenter analysis of risk factors for rupture and malignancy. Ann Surg Oncol. 2009;16(3):640–8. 47. Marini P, Vilgrain V, Belghiti J. Management of spontaneous rupture of liver tumours. Dig Surg. 2002;19(2): 109–13. 48. van Aalten SM, de Man RA, IJzermans JN, Terkivatan T. Systematic review of haemorrhage and rupture of hepatocellular adenomas. Br J Surg. 2012;99(7):911–6. 49. Stoot JH, Coelen RJ, De Jong MC, Dejong CH. Malignant transformation of hepatocellular adenomas into hepatocellular carcinomas: a systematic review including more than 1600 adenoma cases. HPB (Oxford). 2010;12(8):509–22. 50. Nault JC, Paradis V, Cherqui D, Vilgrain V, ZucmanRossi J. Molecular classification of hepatocellular adenoma in clinical practice. J Hepatol. 2017;67(5): 1074–83. 51. Marrero JA, Ahn J, Rajender Reddy K. Gastroenterology ACo. ACG clinical guideline: the diagnosis and management of focal liver lesions. Am J Gastroenterol. 2014;109(9):1328–47. quiz 48 52. Trotter JF, Everson GT. Benign focal lesions of the liver. Clin Liver Dis. 2001;5(1):17–42. v 53. Bröker ME, Ijzermans JN, van Aalten SM, de Man RA, Terkivatan T. The management of pregnancy in women with hepatocellular adenoma: a plea for an individualized approach. Int J Hepatol. 2012;2012:725735. 54. Nguyen BN, Fléjou JF, Terris B, Belghiti J, Degott C. Focal nodular hyperplasia of the liver: a comprehensive pathologic study of 305 lesions and recognition of new histologic forms. Am J Surg Pathol. 1999;23(12):1441–54. 55. Brancatelli G, Federle MP, Grazioli L, Blachar A, Peterson MS, Thaete L. Focal nodular hyperplasia: CT findings with emphasis on multiphasic helical CT in 78 patients. Radiology. 2001;219(1):61–8.

26 56. Scoazec JY, Flejou JF, D'Errico A, Couvelard A, Kozyraki R, Fiorentino M, et al. Focal nodular hyperplasia of the liver: composition of the extracellular matrix and expression of cell-cell and cell-matrix adhesion molecules. Hum Pathol. 1995;26(10):1114–25. 57. Buscarini E, Danesino C, Plauchu H, de Fazio C, Olivieri C, Brambilla G, et al. High prevalence of hepatic focal nodular hyperplasia in subjects with hereditary hemorrhagic telangiectasia. Ultrasound Med Biol. 2004;30(9):1089–97. 58. Bouyn CI, Leclere J, Raimondo G, Le Pointe HD, Couanet D, Valteau-Couanet D, et al. Hepatic focal nodular hyperplasia in children previously treated for a solid tumor. Incidence, risk factors, and outcome. Cancer. 2003;97(12):3107–13. 59. Mathieu D, Kobeiter H, Maison P, Rahmouni A, Cherqui D, Zafrani ES, et al. Oral contraceptive use and focal nodular hyperplasia of the liver. Gastroenterology. 2000;118(3):560–4. 60. Ronot M, Paradis V, Duran R, Kerbaol A, Vullierme MP, Belghiti J, et al. MR findings of steatotic focal nodular hyperplasia and comparison with other fatty tumours. Eur Radiol. 2013;23(4):914–23. 61. Paradis V, Bièche I, Dargère D, Laurendeau I, Nectoux J, Degott C, et al. A quantitative gene expression study suggests a role for angiopoietins in focal nodular hyperplasia. Gastroenterology. 2003;124(3):651–9. 62. Rebouissou S, Bioulac-Sage P, Zucman-Rossi J. Molecular pathogenesis of focal nodular hyperplasia

E. Feyssa and S. J. Munoz and hepatocellular adenoma. J Hepatol. 2008;48(1): 163–70. 63. Ungermann L, Eliás P, Zizka J, Ryska P, Klzo L. Focal nodular hyperplasia: spoke-wheel arterial pattern and other signs on dynamic contrast-enhanced ultrasonography. Eur J Radiol. 2007;63(2):290–4. 64. Bertin C, Egels S, Wagner M, Huynh-Charlier I, Vilgrain V, Lucidarme O. Contrast-enhanced ultrasound of focal nodular hyperplasia: a matter of size. Eur Radiol. 2014;24(10):2561–71. 65. McInnes MD, Hibbert RM, Inácio JR, Schieda N. Focal nodular hyperplasia and hepatocellular adenoma: accuracy of gadoxetic acid-enhanced MR imaging – a systematic review. Radiology. 2015;277(2): 413–23. 66. Nakanuma Y. Nodular regenerative hyperplasia of the liver: retrospective survey in autopsy series. J Clin Gastroenterol. 1990;12(4):460–5. 67. Barge S, Grando V, Nault JC, Broudin C, Beaugrand M, Ganne-Carrié N, et al. Prevalence and clinical significance of nodular regenerative hyperplasia in liver biopsies. Liver Int. 2016;36(7):1059–66. 68. Reshamwala PA, Kleiner DE, Heller T. Nodular regenerative hyperplasia: not all nodules are created equal. Hepatology. 2006;44(1):7–14. 69. Ibarrola C, Colina F. Clinicopathological features of nine cases of non-cirrhotic portal hypertension: current definitions and criteria are inadequate. Histopathology. 2003;42(3):251–64.

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Diagnosis and Evaluation of Hepatocellular Carcinoma Naemat Sandhu and Simona Rossi

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

2 HCC Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 2.1 Target Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 3 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 3.1 Diagnosis via Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 3.2 Pathological Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 4 4.1 4.2 4.3

Staging HCC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evaluation of Disease Extension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Staging Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patient Selection for Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

40 40 41 43

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Multidisciplinary Approach to Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Abstract

Hepatocellular carcinoma (HCC) is the fastest growing malignancy in the USA with a steady uptrend in the incidence and its associated mortality. This poses a significant burden to public healthcare. It is essential to have efficient and accurate tools to establish a diagnosis

N. Sandhu University Hospitals, Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA e-mail: [email protected] S. Rossi (*) Division of Digestive Disease and Transplantation, Einstein Medical Center, Philadelphia, PA, USA e-mail: [email protected]

of HCC in a timely manner. As a result of surveillance protocols for patients at high risk for HCC, diagnostic algorithms can be initiated to allow for earlier confirmation of an HCC diagnosis. This in turn ensures the timely implementation of therapeutic strategies with the ultimate goal to improve patient centered outcomes and overall survival. In this chapter we discuss the measures for HCC surveillance which opens the door to diagnostic evaluation. We detail the diagnostic tools and approach favored, staging of diagnosed HCCs, and the importance of having a multidisciplinary approach at the center of this process of diagnosis and evaluation.

© Springer Nature Switzerland AG 2022 C. Doria, J. N. Rogart (eds.), Hepato-Pancreato-Biliary Malignancies, https://doi.org/10.1007/978-3-030-41683-6_4

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TACE TIV TNM UCSF

Keywords

Hepatocellular carcinoma/HCC · Diagnosis · LI-RADS · Milan criteria · UCSF criteria · BCLC

UNOS US USA WHO

Abbreviations

AASLD American Association for the Study of Liver Diseases ACR American College of Radiology AFP Alpha fetoprotein BCLC Barcelona Clinic Liver Cancer bm-JIS Biomarker combined Japan Integrated Staging CEUS Contrast enhanced ultrasound CHB Chronic hepatitis B CK19 Cytokeratin 19 CLIP Cancer of the Liver Italian Program CT Computed tomography CUPI Chinese University Prognostic Index DAA Direct acting antivirals DCP Des gamma carboxy prothrombin EASL European Association for the Study of the Liver ECOG Eastern Cooperative Group FDA Food and Drug Administration FDG Fluorodeoxyglucose GPC3 Glypican 3 GS Glutamine synthetase HBV Hepatitis B virus HCC Hepatocellular carcinoma HCV Hepatitis C virus HSP70 Heat shock protein 70 LILiver Imaging Reporting and Data RADS System MELD Model for end-stage liver disease MRI Magnetic resonance imaging NAFLD Nonalcoholic fatty liver disease NASH Nonalcoholic steatohepatitis OATP Organic anion transporting polypeptides OLT Orthotopic liver transplantation OPTN Organ Procurement and Transplantation Network PET Positron emission tomography PS Performance status SVR Sustained virologic response

1

Transarterial chemoembolization Tumor in vein Tumor node metastasis University of California San Francisco United Network for Organ Sharing Ultrasound United States World Health Organization

Introduction

As of 2018, liver cancer is the fifth most common cancer and the third most common cause of cancer-related deaths globally, accounting for 4.7% and 8.2% of all cancers, respectively [1]. It is the fifth leading cause of cancer deaths in the USA [2]. Hepatocellular carcinoma (HCC) accounts for 90% of the primary liver cancer. In the USA, there continues to be an uptrend in the incidence and mortality attributed to HCC [3]. Over the last decade the incidence of liver cancer has risen by 2–3% annually, although this pace is noted to have slowed down recently [2]. Some projections indicate that by the next decade, liver cancer may surpass breast, colorectal, and prostate cancer to become the third leading cause of cancer-related deaths in the USA [4, 5]. This poses a significant burden to public healthcare. It is essential to have efficient and accurate tools in place to establish a diagnosis of HCC that in turn paves the way for a streamlined management plan of such identified cases, the ultimate goal being to improve patient survival. In this chapter, we discuss the tools and approach to diagnosis and evaluation of HCC.

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HCC Surveillance

The use of a diagnostic test over a period of time in at-risk individuals for a specific disease is the core principle of a surveillance program. The main goal of surveillance is reduction of disease-related mortality. A robust surveillance protocol will in turn lead to detection of disease at an early stage, allow application of available therapeutics, and improve disease-related mortality. The initiation of surveillance

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for HCC is dependent on identification of at-risk individuals while also accounting for the patient’s age, functional status, comorbidities, and compliance to the surveillance protocol. Hence, a decision to initiate HCC surveillance is not one that should be assumed but rather should be taken after careful consideration with the patient. This necessary consideration plays an important part in ensuring that the surveillance remains cost-effective. Most agencies identify an intervention to be effective if it either provides an increase in longevity of around 3 months or can be achieved at a cost of less than approximately US $50,000/year of life gained [6, 7].

2.1

Target Populations

2.1.1 Individuals with Cirrhosis Over 80–90% of those diagnosed with HCC have chronic liver disease with established cirrhosis [8]. In cirrhotic patients, a 1996 cost-effective analysis study demonstrated a need for HCC surveillance when the incidence was at or exceeded 1.5%/year [9]. Incidence rates for HCC in cirrhosis in the population range from 1 to 8%/year [10]. Hence, regardless of the etiology of liver disease whether it be viral hepatitis, alcohol related, autoimmune hepatitis, genetic disorders, or nonalcoholic fatty liver disease (NAFLD), once the disease progresses to the stage of advanced fibrosis and cirrhosis, the risk of HCC is considered significant. It is imperative to identify HCC in patients with compensated liver disease as the management of HCC is significantly hindered in an advanced or decompensated state. 2.1.2 Non-Cirrhotic Individuals The risk of developing HCC is not impacted by the presence of cirrhosis alone. Additional factors including hepatitis B (HBV) viremia, chronic hepatitis C (HCV), metabolic syndrome, active inflammation, age, gender, and tobacco and alcohol consumption also play an important role. The annual 1.5% risk of HCC however cannot be extrapolated to non-cirrhotic patients. For example, surveillance in patients with chronic hepatitis B (CHB) without cirrhosis has been noted to be cost-effective when the incidence exceeds 0.2%

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per year [10, 11]. HCC incidence in HBV without cirrhosis ranges from 0.1 to 0.8 per 100 personyears [10]. The natural progression of HBV varies depending on the age of viral acquisition, viral levels, and treatment with viral suppressive therapies. The unique risk of HCC in HBV in the absence of cirrhosis is in part due to the ability of HBV DNA to incorporate itself in the hepatocyte DNA. Additional factors that have been found to be associated with development of HCC in HBV infection include increasing age, male gender, family history of HCC, HBV e antigen serostatus, presence of active inflammation, genotype C, and increasing levels of HBV DNA, with the latter being the strongest risk predictor [12, 13]. As such, long-term data has shown a positive impact in the progression to both cirrhosis and development of HCC with the use of antiviral therapy and vaccination against HBV [14]. HCV infection is the most common cause of HCC in the Western world. The majority of HCC cases from HCV result in the setting of cirrhosis, but one cannot ignore the risk of those with moderate to severe fibrosis from chronic hepatitis C. Those with bridging fibrosis without cirrhosis, Metavir F3, are also at significant risk for HCC and should be considered for surveillance [15]. The advent and success of direct acting antiviral agents (DAA) has exposed the uncertainty of whether surveillance can be stopped after sustained virologic response (SVR) in HCV. Currently there is no concrete evidence to stop surveillance after achieving SVR for those who were enrolled based on their pretreatment parameters. This holds true regardless of the treatment agent used, whether it be an interferon-based regimen or DAA therapy. Data on patients at risk for HCC after SVR of HCV show that the risk is not eliminated; hence, surveillance should continue as is [16–18]. This is in line with the current recommendation by the American Association for the Study of Liver Diseases (AASLD). The increasing prevalence of NAFLD in the world has drawn attention to this type of liver disease as a relevant risk for the development of HCC. Worldwide, it is estimated that fatty liver disease has a prevalence of 25% which is expected to increase with increased prevalence of metabolic

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syndrome as a whole [19]. The incidence of HCC from NAFLD-related cirrhosis is significant but remains lower than that from HCV-related cirrhosis. A recent retrospective review using a large veterans affairs cohort, followed longitudinally over a median period of 9 years, showed that patients with NAFLD are at higher risk for development of HCC but that the largest risk in this population is still in the presence of cirrhosis, with an annual risk of 0.8%–2.3%. The authors also identified that 20% of NAFLD-related HCC developed in NALFD patients who did not have cirrhosis [20]. Similar findings of HCC in non-cirrhotic patients with NAFLD have been reported [21, 22]. Confounding risk factors including presence of diabetes mellitus, older age, and alcohol intake are associated with increased risk of HCC occurrence in NAFLD. However, the incidence of HCC in NAFLD patients without cirrhosis remains under a significant level to justify universal surveillance especially given the high prevalence of NAFLD. As a result, the current recommendation is that only patients with nonalcoholic steatohepatitis (NASH)-related severe fibrosis or cirrhosis should be enrolled in a surveillance program. The risk of HCC remains to be established for those without severe fibrosis or cirrhosis to warrant universal surveillance at this time.

2.1.3 Surveillance Methodology Currently the AASLD, EASL, and Asia-Pacific guidelines all recommend that patients with cirrhosis undergo surveillance for HCC on an every 6 months’ basis with or without the addition of the alpha fetoprotein (AFP) tumor marker. Exceptions to this recommendation include certain HBV patients who should undergo screening even in the absence of cirrhosis and consideration of exclusion of advanced-stage Child-Pugh class C patients not eligible for liver transplant, given the low life expectancy as result of their decompensated disease [5, 10, 23]. Mortality associated with HCC is significantly impacted by the stage at which it is diagnosed. Advancedstage HCC portends a very poor prognosis with a 5-year mortality less than 10%. On the other hand, if HCC is diagnosed at its early stages, the

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prognosis is significantly better with a 5-year survival in excess of 60–80%. This is especially true for tumors which are resectable or in patients who undergo a successful liver transplant [24]. Early detection outcome studies from which these guidelines arose, however, have been suboptimal in their retrospective designs, lead time biases, and short-term follow-up among other shortcomings. An effort to overcome this limitation was tackled in a large meta-analysis, concluding that HCC surveillance resulted in early tumor detection which in turn offered the option for early treatment leading to improvement in overall survival [25]. There seems to be a mortality benefit from HCC surveillance regardless of the treatment modality used [26].

2.1.4 Surveillance Tools Imaging and serological tests are used for HCC surveillance. Ultrasound (US) is generally accepted as the first-line modality for HCC surveillance. US is relatively cheap, noninvasive, and easily tolerated by patients without the need for any exposure to radiation or contrast dyes. For these reasons, US is commonly used as first-line surveillance tool for HCC. However, inherent limitations exist with US. These limitations are both patient-dependent such as body habitus, disease state of the liver especially in the case of severely coarse hepatic echotexture, as well as operator-dependent such as radiologist expertise. As a result, the reliability of US in detecting HCC is quite variable. Reported sensitivities range from 40% to 80% and specificities range from 80% to 100% [27]. A pooled meta-analysis of 19 studies showed a pooled sensitivity of 94% for US to detect majority of HCC before they presented clinically. However, this sensitivity dropped to 63% for detection of early-stage HCC highlighting the limitations of US [28]. Taking into consideration its modest cost and noninvasiveness, absence of potential toxicities associated with contrast enhanced imaging, and added benefit of evaluating other complications of cirrhosis like subclinical ascites or portal vein thrombosis, US is a popular and reasonable surveillance tool. Even though multiphase, cross-sectional contrast enhanced imaging in the form of computed

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Diagnosis and Evaluation of Hepatocellular Carcinoma

tomography (CT) or magnetic resonance imaging (MRI) has superior performance over US, they are not cost-effective tools for HCC surveillance even in high-risk populations. The potential risks of using contrast agents and high false-positivity rates ensuing increased diagnostic work-up makes these an impractical modality for primary surveillance [29]. They are useful in scenarios where US imaging is suboptimal in quality whether that be related to patient’s body habitus, background liver disease, obscured field as a result of bowel gas, or other factors. In such cases, it is important to pursue cross-sectional imaging modalities. However, the utility of longterm HCC surveillance with these techniques is questioned, given the risk of exposure to radiation with CT, contrast related adverse events, and the elevated costs. Serologic testing for clinical purposes consists of checking AFP levels. An AFP of >20 ng/mL is considered to be positive, with a sensitivity of 60% and specificity of 90% at this cutoff [30]. However, this cutoff should be interpreted with caution in certain clinical scenarios, as is the case in the setting of active hepatitis which can lead to elevations in the AFP in the absence of HCC. Conversely one has to be mindful that only a small proportion of tumors (10–20%) at an early stage present with abnormal serum AFP levels [5]. Therefore, AFP alone is not recommended for use for surveillance or diagnosis of HCC. While AFP in conjunction with biannual US is shown to improve overall survival, the added benefit of AFP is yet to be quantified [25]. AFP interpretation is also more reliable and useful in the form of a longitudinal trend rather than an isolated result at a point in time. Given the gaps in knowledge regarding the addition of AFP for HCC surveillance, AASLD released a conditional recommendation regarding the consideration of use of US with or without AFP every 6 months for surveillance. EASL continues to recommend against the use of AFP as a surveillance measure after weighing the large number of false positive results against a small improvement in detection rate by 6–8% [5]. The use of other serologic markers, lectinbinding subfraction of AFP (AFP-L3), and des

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gamma carboxy prothrombin (DCP) is restricted for risk stratification and prognostication rather than surveillance [31]. There continues to be ongoing development of novel cancer biomarkers that have not been validated for surveillance.

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Diagnosis

The diagnosis of HCC can be made noninvasively on the basis of specific imaging findings, with the caveat that the patient has a high risk of developing HCC or, in other words, a high pretest probability. However, in case of non-cirrhotic patients, it is imperative to obtain a histologic diagnosis. Given that majority of HCC occurs in the context of cirrhosis, for the remainder of this chapter, we will refer to the setting of HCC in the background of chronic liver disease with cirrhosis. It is one of the few malignancies where the diagnosis, staging, and treatment approach can be determined based on noninvasive evaluation and where the tissue diagnosis is confirmed either at the time of resection of amenable lesions or on explants after undergoing liver transplantation.

3.1

Diagnosis via Imaging

Based on results of surveillance testing, the need for further diagnostic evaluation may arise. US is currently the preferred surveillance imaging modality. Since 2017, categorization of US findings are based on the US Liver Imaging Reporting and Data System (LI-RADS) [32, 33]. A US-1 category is considered “negative,” which means there is absence of any focal abnormality or the observation identified is characterized as benign. A US-2 category correlates to “subthreshold” meaning the identified observation(s) are 20 ng/mL in the right clinical scenario require further investigation [10]. The use of noninvasive imaging for diagnosing HCC in the setting of cirrhosis has been accepted since 2001 when the classic diagnostic pattern was

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Fig. 3 US LI-RADS Category 3 observation in a 67-yearmale with chronic hepatitis C related cirrhosis undergoing US surveillance. Findings: An area of architectural distortion (highlighted by arrows) in comparison with the background liver

noted on dynamic imaging modalities [5, 34]. Multiphase CT or MRI can be used to delineate a suspected lesion by taking advantage of the unique vascular derangements that take place in hepatocarcinogenesis. There is a progressive increase in unmatched hepatic arteries which ultimately become the dominant source of blood supply to tumor cells. Coincident to the arterial changes noted in the blood supply to the tumor, the drainage shifts away from the hepatic veins toward the sinusoids and eventually to the portal veins. As the tumor progresses, the classic fibrous septa encapsulating it form, not otherwise seen in non-tumor nodules. Additional changes noted with HCC formation include the accumulation of fat and iron as well as a reduction in organic anion transporting polypeptide (OATP) transporters [35]. As a result of these changes, the pattern of arterial phase hypervascularity and delayed portal venous phase washout is classically unique in HCC and as such can be used to diagnose HCC with significant accuracy in most cases, leaving the need for histologic confirmation of HCC as the exception rather than the rule.

3.1.1 LI-RADS Since 2011, a standardized technique of imaging interpretation and reporting for patients deemed to

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be at high risk for developing HCC or those with HCC has been developed by the American College of Radiology (ACR). This has been named the Liver Imaging Reporting and Data System (LI-RADS) [36]. This has streamlined the terminology used for HCC diagnosis by reducing variability in lesion interpretation and has most recently been updated in 2018 [37]. In addition, it continues to facilitate the decision-making process for diagnosis and management of HCC by improving communication between clinical provider teams. LI-RADS version 2017 introduced criteria for US surveillance referred to as US LI-RADS [38]. As discussed earlier, these criteria were developed to facilitate the interpretation and reporting of US findings in high-risk populations undergoing HCC surveillance with US. LI-RADS is applied to cross-sectional imaging modalities, CT/MRI LIRADS, as a standard of care for diagnostic purposes for HCC. LI-RADS defines eight unique diagnostic categories based on imaging appearance reflecting the probability of HCC or malignancy (Table 1). Within the LI-RADS categorization, LI-RADS 1 and 2 are defined as “definitely benign” and “probably benign,” respectively. LI-RADS 1, for example, may refer to the identification of cysts and typical hemangiomas. LI-RADS 2 on the other hand may refer to observations like atypical hemangiomas and focal parenchymal abnormalities or nodules 3.25. HCV patients with established diagnosis of cirrhosis have a persistently high risk of HCC development despite SVR. However, the study demonstrated HCV cirrhotic patients who had pre-SVR FIB-4 score >3.25 had higher annual incidence of HCC at 3.66% compared to similar patients with pre-SVR FIB-4 score < 3.25 who had an annual HCC incidence of 1.16% [21]. HCC can also occur in non-cirrhotic HCV-infected individuals. One study found that non-cirrhotic HCV patients who had a pre-SVR FIB-4 >3.25 had an annual incidence of HCC of 1.22%. The annual incidence was even higher at 2.39% if the FIB-4 remained 30 has an increased relative risk of 1.56 for developing HCC [30]. Excessive adipose tissue is thought to create a chronic low-grade inflammatory response through increasing levels of leptin, a pro-inflammatory cytokine. Lipid accumulation in the liver may also lead to generation of reactive oxygen species and free fatty acids (FFAs). FFAs interfere with cell signaling and regulation of gene transcription [25]. In a study from the Mayo Clinic, diabetes was associated with increased risk of HCC (HR 4.22). Insulin resistance and increased insulin growth factors may promote primary liver cancer by activating several oncogenic pathways [25]. Overall, NAFLD-associated HCC can be seen in patients who have NASH with and without cirrhosis. Screening for HCC in NASH cirrhosis is mandatory. However, there are no current guidelines on HCC screening in non-cirrhotic NAFLD patients. There are some data as noted above which suggest an association between HCC and non-cirrhotic NAFLD. However, further research should focus on NAFLD and independent risk factors for HCC. As NAFLD is better understood, the incidence rates, epidemiology, and pathogenesis can continue to drive preventative and screening/surveillance recommendations.

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Alcoholic Liver Disease, ALD

Globally, alcohol is the seventh leading risk factor for both disability and death. Alcohol abuse is the most common etiology of cirrhosis in the developed world [31]. In the United States, ALD is a leading cause of liver transplant and cirrhosis. It accounts for 48% of liver--related deaths exceeding HCV-related deaths. Chronic alcohol abuse leads to a clinical spectrum of the disease ranging from steatosis, alcoholic hepatitis, and cirrhosis to HCC. It is thought that ALD accounts for 30% of HCC cases worldwide with an annual incidence of 2.9% [32]. Though the prevalence of ALD-associated cirrhosis is high, the incidence of ALD-associated HCC is lower than incidence associated with viral and hereditary forms of cirrhosis. To understand the relationship between HCC and ALD, several studies have evaluated alcohol both as an independent factor and cofactor for carcinogenesis in liver disease. Ethanol and its byproducts have proven to have toxic, carcinogenic effects on the liver. It has been identified as an independent risk factor for multiple malignancies including HCC [32]. According to WHO reports, 4.1% of the world’s population meets criteria for having alcohol use disorder. Studies from several countries have evaluated the relationship between HCC and alcohol. Case-control studies in countries with high prevalence of alcohol use, the United States and Italy, as well as those with lower prevalence, South Africa, report that heavy long-term alcohol use is independently associated with approximately twofold increase rates of HCC in heavy drinkers compared to nondrinkers. When ethanol use exceeds 80 g/day for a duration of 10 years or more, the odds ratio increases 5–7-fold [33]. Chronic alcohol use can lead to cirrhosis, which is itself a premalignant state. However, there are also factors specific to alcohol-mediated carcinogenesis. Ethanol is broken down to acetaldehyde by alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1). CYP2E1 is typically upregulated by higher exposure to ethanol. ADH and CYP2E1 convert ethanol to acetaldehyde. In turn, acetaldehyde has been shown to be carcinogenic in multiple animal models. Due to its electrophilic nature, acetaldehyde forms covalent

bonds with proteins, lipids, and DNA leading to damage and mutation [34]. Furthermore, ethanolpromoted CYP2E1 induction leads to increased levels of reactive oxidative species (ROS) and 4-hydroxynonenal (4HNE). ROS have mutagenic effects on DNA as well as play an important role in tumor angiogenesis. 4HNE can cause a mutation of codon in p53 gene commonly found in HCC. Lastly, alcohol inhibits synthesis of a universal methyl donor called S-adenosyl-L-methionine (SAMe) ultimately altering DNA and protein methylation [34]. Not all patients who chronically consume large amounts of alcohol develop cirrhosis or HCC. Multiple risk factors including ethnicity, gender, and genetics are also involved in the progression of ALD. Population surveys suggest men and women usually need to consume 40–80 g/day and 20–40 g/day, respectively, to achieve risk for development of liver disease. In addition, women progress to cirrhosis after 20 years of heavy alcohol use, compared with 35 years in men [35]. Multiple theories shed light as to why women may be more susceptible to the effects of alcohol. Women have less first-pass metabolism of alcohol compared to men due to lower levels of gastric alcohol dehydrogenase (ADH) leading to higher serum concentration of alcohol. Furthermore, estrogen increases sensitivity of Kupffer cells to lipopolysaccharides (LPS) ultimately leading to more severe liver injury [34]. In addition to gender, other risk factors alter the carcinogenic nature of alcohol. The coexistence of viral hepatitis in a patient with establish ALD is associated with higher rates of disease progression with increased rates of fibrosis and development of HCC. A prospective cohort study had found chronic HCV-alcohol cirrhosis patients had 2.5 times higher risk of developing HCC compared to patients with chronic HCV or alcoholic cirrhosis alone [33]. Limited evidence seems to suggest ALD has a propensity for South Asian males; however, more studies need to be conducted in order to evaluate confounding factors such as access to medical care, cultural differences, and drinking patterns. Several studies have found genetic associations with ALD. The most widely known genetic

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polymorphisms occur in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene. Though function is unknown, there is evidence suggesting a predisposition to ALD in patients with a single-nucleotide polymorphism (SNPs) in the PNPLA3 gene [36]. Some studies have demonstrated heavy alcohol use in non-cirrhotic patients with HCC. However, in most studies, the association was not statistically significant. The absolute risk of HCC in non-cirrhotic ALD is unknown. The ideal way to reduce HCC risk in ALD is alcohol cessation. An analysis of four studies shows decrease risk of HCC of about 6–7% per a year among those who stopped drinking. However, the effect of abstinence is largely dependent on extent of liver damage at the time of cessation. Studies suggest a prolonged elevated risk of HCC decade after alcohol cessation [37]. Despite societies’ attempt to destigmatize ALD, it remains a mental illness that many patients are unwilling to admit to or seek help for. This subsequently leads to downstream effects with poor patient compliance and decreased contact with healthcare profession. Thus, these patients are often subject to impaired or delayed cancer surveillance, leading to worse prognosis when HCC is found. HCC in ALD is often found outside of surveillance windows and at late-stage liver disease, precluding curative treatment.

mechanism to explain the gender disparity is still unknown but is thought to be related to DNA synthesis activities being higher in male cirrhotics than in female cirrhotics [38]. The increased mitotic activity causing tumor promotion may be from instability of chromosomes and an increased rate of random mutations. Newer studies looking at the underlying molecular mechanisms of HCC showed that the androgen receptor is involved in signaling pathways for carcinogenesis in HCC which may explain why males are more likely to develop HCC than females [39]. The overall incidence of HCC across all ethnic groups and gender continues to be highest in individuals over the age of 65. Racial and ethnic variation exists in the incidence of HCC in the United States with Asians having the highest incidence due in large part to HBV infection, especially in foreign-born citizens. HCC is thought to develop in Asian patients with chronic hepatitis B with or without cirrhosis because they usually acquire the infection early in infancy. It is important to recognize and address this as a health disparity because foreign-born individuals have a 24% higher risk of liver cancer mortality than US-born individuals [40]. Recommendations for routine HCC screening and surveillance therefore are aimed at young Asian and African patients with chronic hepatitis B. Certain coinfections in the setting of preexisting hepatitis B or C demonstrate that they could play a role in increasing the risk for developing HCC. The theory behind the increased risk is there being an increased severity of the liver disease – specifically more inflammation and possibly synergistic carcinogenic interaction between the two viruses [20]. Hepatitis delta virus relies on hepatitis B infection in the host to reproduce and accelerates the process of cirrhosis. A retrospective study of cirrhotic individuals in Western Europe that were followed for a median period of 6.6 years concluded that HBV cirrhotics coinfected with HDV had a threefold risk for developing HCC [41]. A small communitybased prospective cohort study done in South Korea evaluated HCC risk according to HBV and HCV mono- and coinfection. Hepatitis B and hepatitis C coinfection appeared to have a synergistic effect on HCC risk [20]. Hepatitis B and hepatitis C

6

Other Risk Factors

It is important to recognize and understand that there are other risk factors that lead to the development of hepatocellular carcinoma. Many can be considered modifiable by changes to lifestyle habits, potentially preventable, or currently treatable. The ability to modify some of these risk factors highlights the ability to decrease the global burden of HCC through the education of lifestyle changes. There are many studies that have examined gender in the context of HCC development, and most have concluded that males with chronic liver disease are more likely to develop HCC than females with chronic liver disease. The exact

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coinfection with HIV has also been shown to accelerate the process of HCC development. A recent study done in South Africa showed that HIV patients with HBV cirrhosis presented with HCC at a younger age [42]. Conversely, a study done in France showed that HCV/HIV-infected patients with cirrhosis on combination antiretroviral therapy did not have a higher risk for HCC compared to HCV mono-infected cirrhotics [43]. Still, more research needs to be done to understand the molecular mechanisms in patients coinfected with HIV and how it plays a role in accelerating the development of HCC. Tobacco use is a risk factor for HCC development and is thought to be due to carcinogens metabolized in the liver along with oxidative stress. A recent study was done by the Liver Cancer Pooling Project which looked at the tobacco use and risk for developing HCC. The study found that smoking more than 25 cigarettes per day was associated with a 55% increased HCC risk even in the absence of chronic liver disease. The study also found that people who stopped smoking >30 years ago had an HCC risk similar to people who never smoked [44]. A meta-analysis looked at nine studies that evaluated the interaction of HBV infection and cigarette smoking on leading to the development of HCC; there was an additive interaction between HBV infection and cigarette use on the risk for HCC. That same meta-analysis also assessed six studies that evaluated the combined effect of HCV infection and cigarette smoking on the risk of HCC. They found that smoking in patients with HCV had a multiplicative scaled effect on HCC risk [45]. Aflatoxin B1 (AFB1) is a mycotoxin produced by Aspergillus species that grows on food in warm and damp conditions. It is a known hepatocarcinogen. Aflatoxin toxicity is mediated by the oxidative stress and intermediate metabolite AFB1 exo-8,9-epoxide (AFBO) which leads to downstream DNA instability and damage [46]. The carcinogenic effect is augmented in patients with chronic liver disease. Studies have shown up to a 30 times increased risk of HCC in patients exposed to chronic HBVand aflatoxin than aflatoxin alone. There also appears to be a synergistic relationship between aflatoxin and HCV-related

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HCC [47]. A study done in China showed that AFB1 was an independent risk factor in patients with HCV-cirrhosis for development of HCC. There have been many public health interventions done worldwide to educate the agricultural industry about interventions that can be performed preharvest along with proper storage techniques and transportation efforts to reduce aflatoxin in crops. Alcohol use is also a significant risk factor for development of HCC and increases the relative risk of HCC by threefold to tenfold. A retrospective study was performed and found a 2.6% annual incidence of HCC in alcoholic cirrhotics [34]. A linear dose-response relationship between consumption and development of HCC has been established from a Japanese study. Additionally, alcohol use synergistically raises the risk for HCC with a twofold increase in the odds ratio in patients with either HBV or HCV who drank >60 grams of alcohol per day [48]. Obesity is a risk factor for nonalcoholic fatty liver disease (NAFLD) and hence a potential risk factor for HCC. A meta-analysis of cohort studies looking at the incidence of HCC compared persons of normal weight to those that were overweight and obese. The results showed that there was a 17% and 89% increased risk of HCC in those who were overweight and obese, respectively, compared to those of normal weight. The relationship was also stronger in men who were overweight and obese compared to women [49]. Obesity is also a risk cofactor of HCC development in patients with chronic liver diseases. A Taiwanese populationbased study showed that obese patients had a fourfold risk of HCC in HCV-positive subjects and 1.36-fold risk in HBV-infected subjects [50]. Another Taiwanese population-based prospective cohort study demonstrated that there was a synergistic interaction between obesity and alcohol use that increased the risk of HCC. The risk was the highest among those with extreme obesity which was defined as BMI 30 and those that had 20 or more years of alcohol use [51]. A family history of HCC also is a risk factor for development of HCC especially when there is clustering of HBV and HCV among family members [52]. A large case-control study observed that 6.1% of patients with HCC reported having

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first-degree family members with HCC. Their study concluded that a first-degree relative history of HCC yielded a fourfold increase in HCC risk, particularly in relatives of case subjects diagnosed before age 50 years. This makes routine HCC screening and surveillance important for chronic hepatitis B patients without cirrhosis with a family history of HCC. Environmental elements within the home also appear to be a risk factor including alcohol use, tobacco use, and consumption of aflatoxin-contaminated foods. Hepatocellular adenomas (HCA) are uncommon and mostly benign tumors in the liver that are caused by benign monoclonal proliferation of hepatocytes with high glycogen and fat content. They are associated with type I and type III glycogen storage disease (GSD). These adenomas are usually incidentally found solitary nodules but have the risk for malignant transformation to HCC, especially in patients with GSD. In a systematic review, the overall risk of malignant transformation from HCA to HCC was 4.2%. The risk for HCC is higher in lesions that are greater than 5 cm, male sex, and mutation of beta-catenin gene [53]. Men with HCA of any size should be considered for surgical resection due to the high risk for malignant transformation. Women with HCA greater than 5 cm should be considered for surgical resection as first-line therapy due to the higher risk for malignant transformation. Embolization of large lesions or ablation of smaller lesions can be considered if the patient is a poor surgical candidate. If the lesions are small and indeterminant on imaging, biopsy may need to be performed in order to assess for high-risk genetic alterations that could help guide management and HCC surveillance. For example, HCA less than 5 cm with HNF-1a subtype or those with inflammatory or activated beta-catenin negativity on biopsy may be managed conservatively with surveillance imaging [54]. Management of HCA includes discontinuing estrogen-containing medications such as oral contraceptives, discontinuing anabolic androgen use, and losing weight through dietary modifications and exercise. Hereditary hemochromatosis, primary biliary cholangitis, Wilson’s disease, and alpha-1 antitrypsin deficiency are other causes of chronic liver disease that are risk factors for hepatocellular

carcinoma. Excess hepatic iron is thought to be a direct carcinogen, and in a patient with hereditary hemochromatosis, length of disease portends a greater the risk of HCC. HCC develops in 45% of untreated hemochromatosis patients [36]. The degree of portal hypertension correlates with the development of HCC in patients with cirrhosis. Patients who had a hepatic venous pressure gradient above 10 mmHg had a sixfold increase of HCC risk. The incidence increases in parallel to increases in portal pressure [55].

7

Defining Prevention

Disease prevention and detection have been defined on three levels. Primary prevention is focused on preventing the disease from ever occurring in a population. An example of this would be initiation of a hepatitis B vaccination program to prevent a population from contracting hepatitis B and in turn preventing them from developing hepatocellular carcinoma. Other examples include screening food for aflatoxin B1 and educating populations about the health hazards of excessive iron consumption. Secondary prevention is focused on early disease detection even in healthy-appearing individuals. For example, the United States Preventive Services Task Force (USPSTF) recommends hepatitis C screening for all adults aged 18–79 years [56]. Tertiary prevention aims to reduce the morbidity from complications of a disease when the disease has already been established in a patient. These preventative aims can be costly. An example would be treating patients with hepatitis C with direct-acting antivirals to prevent further necroinflammation which could lead to cirrhosis and HCC.

8

Hepatitis B Prevention

Hepatitis B virus, originally known as the “Australia Antigen” was discovered in the 1960s by Dr. Baruch Blumberg. The discovery of hepatitis B virus was followed by the development of the first hepatitis B vaccination using active immunization. Further iterations of the hepatitis B vaccination came with the discovery of cloning HBV

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DNA, HBsAg and hepatitis B core antigen (HBcAg using gene technology in the 1980s. We now have recombinant DNA hepatitis B vaccinations that are synthetically prepared and do not contain any blood products. Taiwan was one of the first countries to begin universal childhood vaccination in 1984. At the time that the vaccination program was instituted, there was a high perinatal rate of transmission which led to an HBsAg carrier rate of 10%. The carrier rate 20 years later was only 1.2%, and the incidence had dropped from 0.57 to 0.17 in 100,000 person-years in children and adolescents [57]. The WHO started the Expanded Program on Immunization (EPI) in 1991 as a national immunization program to immunize all infants in countries with >8% carrier prevalence of HCC. The program was thought to take some time to realize an impact, and studies now are showing similar findings to that seen in Taiwan. Screening of blood donors for HBsAg which commenced in 1969 decreased the risk of hepatitis B infection from blood transfusion. The WHO now suggests screening with both HBsAg and hepatitis B core antibody which has further reduced the risk of contracting HBV from a blood transfusion. In the United States, HBV DNA screening was added in 2009 to HBsAg and hepatitis B core antibody (HBcAb) . The addition of HBV DNA lowered the risk of HBV transmission to 1:1,000,000 transfusions [58].

9

Surveillance and Screening Goals

The goals of surveillance and screening depend on the knowledge of the natural history of chronic liver disease and understanding the risk factors in the development of HCC. Screening programs should identify early disease symptoms or processes to implement early treatment or interventions to reduce morbidity and mortality. The value of a screening test is determined by its ability to distinguish a diseased from non-diseased state. Screening tests should be relatively inexpensive, easily available, and accurate; provide clinical value; and offer quick results [78]. When screening tests are performed at regular intervals, they are called surveillance [59].

Hepatocellular carcinoma has features which make it amenable to screening and surveillance. Screening modalities are noninvasive, and if malignancy is found early, it can often lead to curative treatment. Early HCC has a subclinical phase where individuals are asymptomatic making it difficult to detect without imaging. Once cirrhosis has been diagnosed, patients have a lifetime risk of developing HCC of about 30% [66]. Without screening and surveillance by the time a diagnosis has been made, a majority of the tumors are often too large and are unresectable. There have been a few large, randomized controlled trials that have shown that patients are more likely to have potentially curative treatment with early-stage HCC found on routine HCC surveillance than those patients who presented with symptoms [60]. One study in particular was a randomized controlled trial performed in China where 17,820 subjects were divided into a control group and a screening group. The screening group received serum alphafetoprotein (AFP) and ultrasound every 6 months, while the control group had no screening. In the screening group, HCC was detected at higher rates, and 76.8% of the HCC that was found was at a subclinical stage. Of the HCC tumors detected in this group, 70.6% was resected. On the other hand, no cases of HCC found in the control group were at subclinical stage. Overall, the 1-year survival rate of the screening group was 88.1%, while none of the patients diagnosed with HCC in the control group survived over a year. This study highlights the clear benefit of screening [61]. The primary risk factor for development of HCC is cirrhosis, which is a well-defined risk population. High-risk groups that lead to HCC have been identified in the population – hepatitis B, hepatitis C, alcoholic and nonalcoholic fatty liver disease, and other diseases that cause chronic liver injury. When considering initiating high-risk individuals into the HCC surveillance program, it is important to take a patientcentered approach with shared decision-making. This may involve understanding any social determinants of health that may prevent the patient from undergoing routine surveillance, educating the patient about their disease process at their literacy level, and talking to the patient about

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their wishes should a cancer be found. The patient should understand what to expect if HCC is detected and be willing and able to tolerate HCC-related treatments, whether those treatments be surgery, local treatment, or transplantation. Their age, health, functional status, and compliance should be taken into account as well. Ordering additional lab work and imaging on patients with underlying chronic liver disease come with added costs especially if the screening tests are performed a few times per year. It becomes important to be cost-effective with HCC screening and to detect HCC early in its course when tumors are small and curative therapies are possible. The screening test itself should be the least costly but also the most sensitive and specific. It is vital for screening tests to have a low false-positive rate since this will potentially lead to patient anxiety in addition to further testing and economic costs. Screening tests can also come with harm to the patient such as radiation exposure and risks from subsequent biopsies. An intervention is said to be cost-effective if it extends life expectancy by at least 3 months with a cost below an established threshold of US$50,000 per year of life saved [62]. The incremental costeffectiveness of biannual AFP and ultrasound is estimated to be around US$26,000 to US$74,000 per quality-adjusted life years in individuals eligible for routine surveillance. This is cost-effective when the yearly incidence rate is higher than 1.5–3% [63]. The yearly incidence rate of HCC varies between 1% and 7% depending on the underlying cause of the chronic liver disease and presence of cirrhosis. A cost-effectiveness study looked at the combination of earlier detection and use of curative first-line therapy. There was a 0.37-year gain in life expectancy as a result of routine surveillance and early detection of HCC [64]. This gain in life expectancy may seem modest but is actually excellent compared to most other cancer screening programs.

determine their ability to comply to screening intervals and willingness to undergo subsequent required interventions. There is no well-defined threshold to initiate HCC surveillance. However, in general, it is thought that screening should be initiated when screening is cost-effective. HCC screening is thought to be cost-effective in cirrhotic patients when HCC incidence rate is >1.5%/year. In concordance with the American Association for the Study of Liver Diseases (AASLD) guidelines, cirrhotic patients of varying etiologies with annual HCC risk of >1.5% should undergo screening [65]. Cirrhosis is the strongest risk factor for development of HCC. Overall, about 85–95% of HCCs develop in a cirrhotic liver. However, the risk varies with etiology of cirrhosis. In the western world, HCV cirrhosis is thought to have a 17% 5-year cumulative risk of development of HCC, followed by HBV cirrhosis at 15%, and finally alcoholic cirrhosis by 8%–12% [66]. When considering screening, it is imperative to remember presence of risk factors including coinfections (HCV/HBV), alcohol use, and metabolic syndrome which can further increase HCC risk in the cirrhotic patient. Currently, AASLD guidelines recommend screening all Child-Pugh A and Child-Pugh B cirrhotic patients regardless of etiology of cirrhosis or SVR (in HCV patients) [65]. Cost-effectiveness analysis has shown hepatitis B carriers, irrespective of degree of fibrosis, represent a separate subset, and HCC screening becomes cost-effective once incidence of HCC exceeds 0.2%/year. In the majority of patients, HBV DNA integrates into the cellular genome inciting genetic damage and fostering the development of tumor. In this way, HBV infection alone may increase HCC rates in the absence of cirrhosis. Furthermore, there is strong evidence that a persistent HBV e antigen and high levels of HBV DNA increase risk of HCC as well [65]. Many models created in the eastern world have been developed to determine individual risk for HBV-infected patients. These include the individual prediction model (IPM) and the modified Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B (REACH-B) score (mREACH-B). These models take into account various individual factors such as age, gender, HBeAg

10

Who Should Be Screened?

The decision to screen a patient for HCC is determined by their risk for HCC per a year as well as their individual health and social factors that

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status, HBV DNA level, and alcohol history. Unfortunately, almost all scores were created from treatment-naïve Asian chronic hepatitis B (CHB) patients. Thus, scores were only validated in the Asian CHB population, and models were less predicative in European Caucasian and American patients. AASLD guidelines do not take these models into account when advising on when to screen HBV patients. Another model, platelet count, age, gender, and hepatitis B (PAGE-B), stratifies risk of HCC in patients with chronic HBV and has been validated in Caucasian and Asian patients who have been treated with antiviral therapy and who are HBeAg negative. However, PAGE-B has not been validated in patients of African descent. European Association for the Study of the Liver (EASL) guidelines use this model to help determine need for HCC screening in chronic HBV patients; a PAGE-B score >10 prompts HCC screening [54]. In regard to chronic hepatitis B, spontaneous HBsAg loss occurs at a rate of about 1% per a year. Progression to cirrhosis and decompensation appears to stop with the loss of HBsAg; however, according to a multivariant analysis, the risk of HCC persists [67]. This is thought to be especially true in patients who are older than 50 years old. Per AASLD guidelines, patients with sustained HBsAg seroclearance should continue to undergo HCC screening if they have cirrhosis, a first-degree family member with HCC, or prolonged duration of infection (>40 years for men and >50 years for women) [65].

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In Whom Is Screening of Uncertain Benefit?

At this time, there is insufficient data to determine surveillance benefit of certain groups. Given the unknown cost-effectiveness and benefit to the patient, currently, AASLD 2018 HCC guidelines do not recommend HCC screening in noncirrhotic patients without HBV [65]. There is an ongoing debate of utility in HCC screening in patients with fibrosis without cirrhosis. Specifically, in non-cirrhotic HCV patients, it has been demonstrated that increased fibrosis increases annual rate of HCC. A study had found that

non-cirrhotic HCV patients who had a pre-SVR FIB-4 >3.25 had an HCC annual incidence of 1.22% [68]. This rate is less than the rate thought to be cost-effective for screening; thus, it is uncertain if patients with hepatitis C with stage 3 fibrosis benefit from surveillance. Similarly, non-cirrhotic NAFLD patients have an HCC annual rate of 0.08 per 1000 person-years [27]. However, the true incidence rate has not been determined which confounds the recommendation for screening. Thus, HCC surveillance in non-cirrhotic NAFLD patient is of uncertain benefit. Regardless, EASL HCC guidelines recommend screening in all patients with known F3 scores regardless of etiology as it can be difficult to define the transition from advanced fibrosis to cirrhosis. The AASLD 2018 guidelines have not to date adopted this practice.

12

Who Should Not Be Screened?

HCC screening is performed in order to improve survival and so should only be performed in patients who are eligible and can tolerate HCC-related treatment. Most treatment options including local resection, ablation, embolization, and systemic treatment are reserved for ChildPugh A and B patients. In a retrospective analysis of 821 cirrhotic patients who underwent surveillance, survival benefit was seen in patients with Child-Pugh A or B. There was no observed survival benefit of screening in patients with ChildPugh C cirrhosis given the high risk of dying from liver-related complications [69]. Therefore, in accordance with AASLD HCC guidelines, it is not beneficial to screen ChildPugh C cirrhotic patients who are not liver transplant candidates as anticipated survival rate of this patient population is low.

13

Screening Modalities

13.1

Imaging

All liver societies recommend screening for HCC using liver ultrasound (US) with or without alphafetoprotein (AFP) every 6 months [54, 65]. US is

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inexpensive, readily available, and generally well tolerated by patients. However, among all imaging modalities, liver US is the least sensitive for detection of HCC. Overall, sensitivity for detecting HCC at any stage is 78% (95% CI 67–86%), and for early stage, HCC is 45% (95% CI, 30–62%) [70]. The sensitivity of detecting HCC via ultrasound varies widely depending on the patient and the operator. From the operator perspective, imaging technique and operator experience may play a role in enhancing detection of HCC. Furthermore, certain areas of the liver such as the hepatic dome may be difficult to examine with US. Quality of the images can also be affected by patient characteristics. Studies may be limited by patient’s inability to momentarily hold their breath to capture adequate imaging. It can also be altered by the degree of cirrhosis, as a multinodular liver increases the parenchymal heterogeneity, thus obscuring small lesion. Lastly, patients’ BMI can affect US ability to detect HCC. In a retrospective study of 116 patient, a BMI > 30 showed a statistically significant decrease in sensitivity of HCC detection via US compared to patients with BMI < 30. However, computed tomography (CT) was able to detect HCC in 98% of the obese patients with negative US [71]. In specific patient populations, such as an obese patient or one with known multinodular cirrhosis, US may be inadequate. It has been estimated that about 20% of liver US performed for HCC screening is deemed inadequate for surveillance [65]. And so, contrast-enhanced CT or magnetic resonance imaging (MRI) should be considered in specific patients based on their characteristics. Currently, CT and MRI are not routinely used for HCC screening and initial imaging test due to high costs, radiation exposure, potential contrast injury, and lack of proven efficacy and cost-effectiveness in real-world scenarios. Exams are considered nondiagnostic if US detects lesions 10 mm or noted to have AFP > 20. Subsequently, positive screening tests should then be followed with imaging such as dynamic contrast-enhanced CT or MRI [65].

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13.2

Biomarkers

Given the limitations of US, there is a need for improvement in screening. Several biomarkers have been evaluated in attempt to improve sensitivity for HCC detection. The best studied biomarker is alpha-fetoprotein (AFP). It is commonly used for HCC surveillance as it is relatively inexpensive, widely available, and easy to perform. However, AFP alone should not be used as an HCC screening modality as it can lead to high rate of false positives and negatives with low sensitivity rate between 25% and 65%. Patients with chronic liver disease can express high levels of AFP in the absence of malignancy. In addition, about one-third of HCC patients have normal AFP [72]. Though AFP is not a sensitive screening test, in conjunction with US, results increase likelihood of diagnosis of HCC and serve as a prognostic marker. It is thought to increase sensitivity of surveillance US, though exact impact has not been studied. Use of AFP is shown to help predict overall mortality in HCC and prognosis after resection [72]. At this time, the utility of AFP is still debated, and AASLD HCC guidelines recommend US with or without AFP [65]. This allows providers to consider pros and cons of using AFP in conjunction with imaging study.

13.3

Screening Intervals

Per AASLD 2018 HCC guidelines, HCC screening should be performed every 6 months. This recommendation is based on the median doubling time of HCC which is thought to be between 4 and 6 months. Meta-analysis of surveillance studies has shown patients with cirrhosis who have had routine screening had earlier-stage HCC. A retrospective study compared 6-month screening interval to yearly screening and no screening. HCC patients who had appropriate 6-month screening had smaller lesions with 70% within Milan criteria. In patients who were screened yearly, only 58% of diagnosed HCC was within Milan criteria (P < 0.001). Increased screening intervals (3 months versus 6 months) increased detection of small lesions but not of HCC [73].

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Table 1 Recommended screening policies from international guidelines Guideline High-risk patient populations

EASL [54] • Child-Pugh A • Child-Pugh B • Child-Pugh C awaiting liver transplant • HBV without cirrhosis but intermediate risk of HCC (PAGE-B scores >10) • Bridging fibrosis

Interval Imaging modality Biomarkers

• Every 6 months • US • Not recommended

13.4

Screening Algorithm

Current guidelines from multiple associations recommend varying details encompassing HCC screening. Table 1 outlines the similarities and differences among EASL and AASLD. Below is a proposed algorithm for HCC screening. All patients with Child-Pugh A and Child-Pugh B cirrhosis as well as patients with chronic HBV infection regardless of diagnosis of established cirrhosis should be screened. Screening should be conducted initially with US as well as AFP testing and occur every 6 months for life [54, 65]. Proposed algorithm is outlined in Fig. 1.

14

Limitations of Surveillance

Studies have shown that HCC surveillance is associated with early tumor detection as well as improved survival. The goal of screening is to decrease mortality. The largest trial verifying the efficacy of HCC screening was a study performed in China. In this trial, over 19,000 patients with chronic HBV were followed for 5 years. Patients who underwent HCC surveillance with US and AFP had a 37% reduction in HCC-related mortality compared to patients without any form of HCC screening [74]. However, despite the known benefit for HCC screening, the majority of patients at risk do not receive appropriate surveillance. According to a systematic review of nine studies, surveillance rates were close to 50% among

AASLD [65] • Child-Pugh A • Child-Pugh B • Child-Pugh C awaiting liver transplant • HBV without cirrhosis and one of the following: Family history of HCC Asian males over the age of 40 years Asian females over the age of 50 years African descent • Every 6 months • US • AFP can be used in conjunction with US at providers discretion

patients that followed in gastroenterology subspecialty clinics versus 16.9% among patients that followed in primary care clinics [75]. The pooled surveillance rate was roughly 20% which is a relatively low rate for a screening tool. A study done with the Veterans Affairs (VA) patients with hepatitis C-related chronic liver disease showed that subsequent HCC surveillance follow-up actually dropped from 42% of their cirrhotic population receiving HCC screening in the first year to 12% receiving routine surveillance. The patients that came for routine surveillance had less comorbid conditions and lower incidence of varices and did not have any other decompensation events from their liver disease [76]. Provider and patient adherence to surveillance intervals may be disjointed for many reasons that need to be addressed when initiating surveillance programs. First, providers need to recognize which patients are at most risk for developing chronic liver disease and cirrhosis. Early recognition of chronic liver disease can lead to early screenings for cirrhosis which in turn should prompt initiation of screening for HCC. A survey of primary care physicians assessed provider barriers and practice patterns of HCC surveillance. A third of primary care physicians were more likely to defer HCC surveillance and referred the patients to subspecialists. Many physicians reported that they were not up to date on HCC surveillance recommendations and did not feel comfortable offering advice on screening [77]. HCC surveillance rates have increased with electronic health

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Fig. 1 Proposed screening algorithm for patients at high risk for HCC based on AASLD and EASL guidelines

HCC screening reminders, mailed outreach programs, and nursing quality improvement initiatives in the clinic. The screening tests themselves also come with the limitations of missing lesions and overcalling lesions as being malignant leading to more diagnostic testing. It is important to understand the different imaging modalities that can be used to screen for HCC. The most widely used is US, which is operator and equipment dependent. This accounts for the wide range in sensitivity in addition to patient characteristics such as obesity, male sex, alcohol or NASH cirrhosis, and advanced Child-Pugh B cirrhosis [70]. Detecting HCC in the background of cirrhosis can be difficult to discern from HCC detection due to the presence of fibrous septa and regenerative nodules which can mask a small tumor. If small lesions 80 years), or additional warm ischemia, as in the case of donation after circulatory death (DCD), has led to a

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Fig. 7 Surgical specimen after deceased donor liver transplantation in a cirrhotic patient with HCC beyond the Milan criteria of the right hemi-liver previously treated with 90Y-selective internal bridging radiotherapy, whereas

it met University of California, San Francisco (UCSF); up-to-seven; French model; and Hazard Associated with Liver Transplantation hepatocellular carcinoma low-risk score requirements

growing interest in machine perfusion (MP) [72, 73]. This offers three main advantages over prolonged static cold storage (SCS): a high-quality preservation, the ability to optimize graft function (reconditioning), and the possibility of testing the graft’s viability before implantation [72, 73]. ECDs are more vulnerable to ischemia/reperfusion injury (IRI) related to the interval between graft procurement and implantation during orthotopic LT but are a primary chance for HCC recipients with an optimal performance status and poor clinical symptoms related to basic cirrhotic liver disease [74]. After effective and sustained downstaging of eligible hepatocellular carcinomas beyond the Milan criteria, liver transplantation improved tumor event-free survival and overall survival compared with non-transplantation therapies Post-downstaging tumor response could contribute to the expansion of hepatocellular carcinoma transplantation criteria (Fig. 7) [75].

The modification of the temperature necessary for the destruction of cancer cells can be obtained through radio frequency, microwave (MWTA), laser, and cryotherapy. In recent years, numerous clinical studies have been published that are able to compare the various methods with a percutaneous approach, but MWTA has been found to be significantly more effective in lesions of diameter > 2 cm [76]. The best outcomes have been achieved in patients in Child-Pugh class A with a single lesion of a diameter < 3 cm. Independent predictors of survival are complete initial response, the ChildPugh class, the number and size of nodules, and baseline serum AFP. In highly specialized and skilled centers for MILS hepatobiliary surgery, MWTA can be performed with laparoscopic technique in order to guarantee a possible aspiration of peri-hepatic ascites and eventually reach the insertion site of the needle for MWTA and optimize hemostasis after the track ablation [16, 77–80].

4.3

5

Hepatic Thermal Ablation

Thermal surgical ablation is the treatment of choice in patients with early-stage HCC not candidates for either the LT or LR and only in cases that are approaching the insertion on the waiting list for LT.

Conclusion

LT and LR have become routine treatment modalities for HCC in patients with ESLD. Optimization of surgical technique may even further reduce morbidity.

142

It is known, for example, that the best results in terms of prognostic and efficacious treatment are obtained when the HCC lesion is detected early. When HCCs are unfit for LR and/or associated with ESLD, a complex clinical condition might require LT or possibly even interventional radiological procedures as neoadjuvant bridging options, such as MWTA.

References 1. Razavi H. Global epidemiology of viral hepatitis. Gastroenterol Clin North Am. 2020;49(2):179–89. https://doi.org/10.1016/j.gtc.2020.01.001. 2. De A, Duseja A. Natural history of simple steatosis or nonalcoholic fatty liver. J Clin Exp Hepatol. 2020;10(3): 255–62. https://doi.org/10.1016/j.jceh.2019.09.005. 3. Mazzaferro V, Citterio D, Bhoori S, et al. Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial. Lancet Oncol. 2020;21(7):947–56. https:// doi.org/10.1016/S1470-2045(20)30224-2. 4. Gruttadauria S, di Francesco F, Vizzini GB, et al. Early graft dysfunction following adult-to-adult livingrelated liver transplantation: predictive factors and outcomes. World J Gastroenterol. 2009;15(36):4556–60. https://doi.org/10.3748/wjg.15.4556. 5. Tomas K, Oguz S, Topaloglu S, et al. Is it rational to perform liver resection for patients with intermediate and advanced stages of hepatocellular carcinoma? Am Surg. 2020;86(4):313–23. 6. Kudo A, Shinoda M, Ariizumi S, et al. Des-gammacarboxy prothrombin affects the survival of HCC patients with marginal liver function and curative treatment: ACRoS1402 [published online ahead of print, 2020 May 27]. J Cancer Res Clin Oncol. 2020: 10.1007/s00432-020-03270-2. https://doi.org/10. 1007/s00432-020-03270-2. 7. Barabino M, Gurgitano M, Fochesato C, et al. LI-RADS to categorize liver nodules in patients at risk of HCC: tool or a gadget in daily practice? [published online ahead of print, 2020 May 26]. Radiol Med. 2020:10.1007/s11547-020-01225-8. https://doi. org/10.1007/s11547-020-01225-8. 8. Tian H, Cao S, Hu M, et al. Identification of predictive factors in hepatocellular carcinoma outcome: a longitudinal study. Oncol Lett. 2020;20(1):765–73. https:// doi.org/10.3892/ol.2020.11581. 9. Petta S, Sebastiani G, Viganò M, et al. Monitoring occurrence of liver-related events and survival by transient elastography in patients with nonalcoholic fatty liver disease and compensated advanced chronic liver disease [published online ahead of print, 2020 Jul 1]. Clin Gastroenterol Hepatol. 2020:S1542-3565(20) 30908-3. https://doi.org/10.1016/j.cgh.2020.06.045.

D. Pagano et al. 10. Rich NE, Murphy CC, Yopp AC, Tiro J, Marrero JA, Singal AG. Sex disparities in presentation and prognosis of 1110 patients with hepatocellular carcinoma [published online ahead of print, 2020 Jun 29]. Aliment Pharmacol Ther. 2020:10.1111/apt.15917. https://doi. org/10.1111/apt.15917. 11. McIntyre CA, Chou JF, Gonen M, et al. Hepatocellular carcinoma in patients with no identifiable risk factors [published online ahead of print, 2020 Jun 23]. HPB (Oxford). 2020:S1365-182X(20)31020-0. https://doi. org/10.1016/j.hpb.2020.05.005. 12. Rinaldi L, Nevola R, Franci G, et al. Risk of hepatocellular carcinoma after HCV clearance by directacting antivirals treatment predictive factors and role of epigenetics. Cancers (Basel). 2020;12(6):1351. Published 2020 May 26. https://doi.org/10.3390/ cancers12061351. 13. Lin Y, Pan XB. Differences in survival between firstline radiofrequency ablation versus surgery for earlystage hepatocellular carcinoma: a population study using the surveillance, epidemiology, and end results database. Med Sci Monit. 2020;26:e921782. Published 2020 May 28. https://doi.org/10.12659/MSM.921782. 14. Marasco G, Colecchia A, Silva G, et al. Non-invasive tests for the prediction of primary hepatocellular carcinoma. World J Gastroenterol. 2020;26(24):3326–43. https://doi.org/10.3748/wjg.v26.i24.3326. 15. Pagano D, Spada M, Cintorino D, et al. Evolution of surgical technique in conventional open hepatectomy for living liver donation over a 12-year period in a single center. Transplant Proc. 2014;46(7):2269–71. https://doi.org/10.1016/j.transproceed.2014.07.034. 16. Gruttadauria S, Pagano D, Tropea A, et al. Laparoscopic approach for thermoablation microwave in the treatment of hepatocellular carcinoma: a single Center experience. J Laparoendosc Adv Surg Tech A. 2016;26 (10):808–11. https://doi.org/10.1089/lap.2016.0373. 17. Zhou H, Zhang C, Du L, et al. Contrast-enhanced ultrasound liver imaging reporting and data system in diagnosing hepatocellular carcinoma: diagnostic performance and interobserver agreement [published online ahead of print, 2020 Jul 8]. Berichts- und DatensystemfürkontrastverstärktenUltraschall in der Leberbildgebung (CEUS-LI-RADS) für die Diagnose des hepatozellulärenKarzinoms: DiagnostischeLeistung und Interobserver-Übereinstimmung [published online ahead of print, 2020 Jul 8]. Ultraschall Med. 2020: 10.1055/a-1168-6321. https://doi.org/10.1055/a1168-6321. 18. Luca A, Caruso S, Milazzo M, et al. Multidetector-row computed tomography (MDCT) for the diagnosis of hepatocellular carcinoma in cirrhotic candidates for liver transplantation: prevalence of radiological vascular patterns and histological correlation with liver explants [published correction appears in EurRadiol. 2011 Jul;21(7):1574. Gruttadauria, Salvatore [corrected to Gruttadauria, Salvatore]]. EurRadiol. 2010;20(4):898–907. https://doi.org/10.1007/s00330009-1622-0.

7

Surgical Management of Hepatocellular Carcinoma

19. American College of Radiology. Liver imaging reporting and data system. https://www.acr.org/Clini cal-Resources/Reporting-and-Data-Systems/LI-RADS/ CT-MRI-LI-RADS-v2018. Accessed 9 Nov 2020. 20. Marrero JA, Kulik LM, Sirlin C, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68 (2):723–50. 21. Chernyak V, Fowler KJ, Kamaya A, Kielar AZ, Elsayes KM, Bashir MR, Kono Y, Do RK, Mitchell DG, Singal AG, Tang A, Sirlin CB. Liver Imaging Reporting and DataSystem (LI-RADS) Version 2018: imaging of hepatocellular carcinoma in at-risk patients. Radiology. 2018;289(3):816–30. https://doi.org/10. 1148/radiol.2018181494. Epub 2018 Sep 25. PMID: 30251931; PMCID: PMC6677371. 22. Elsayes KM, Kielar AZ, Elmohr MM, Chernyak V, Masch WR, Furlan A, Marks RM, Cruite I, Fowler KJ, Tang A, Bashir MR, Hecht EM, Kamaya A, Jambhekar K, Kamath A, Arora S, Bijan B, Ash R, Kassam Z, Chaudhry H, McGahan JP, Yacoub JH, McInnes M, Fung AW, Shanbhogue K, Lee J, Deshmukh S, Horvat N, Mitchell DG, Do RKG, Surabhi VR, Szklaruk J, Sirlin CB. White paper of the society of abdominal. Radiology hepatocellular carcinoma diagnosis disease-focused panel on LI-RADS v2018 for CT and MRI. Abdom Radiol (NY). 2018;43(10):2625–42. https://doi.org/10.1007/ s00261-018-1744-4. PMID: 30155697. 23. van der Pol CB, Lim CS, Sirlin CB, McGrath TA, Salameh JP, Bashir MR, Tang A, Singal AG, Costa AF, Fowler K, McInnes MDF. Accuracy of the liver imaging Reporting and data system in computed tomography and magnetic resonance image analysis of hepatocellular carcinoma or overall malignancy-a systematic review. Gastroenterology. 2019;156(4): 976–86. https://doi.org/10.1053/j.gastro.2018.11.020. Epub 2018 Nov 13. PMID: 30445016. 24. Ludwig DR, Fraum TJ, Cannella R, Ballard DH, Tsai R, Naeem M, LeBlanc M, Salter A, Tsung A, Shetty AS, Borhani AA, Furlan A, Fowler KJ. Hepatocellular carcinoma (HCC) versus non-HCC: accuracy and reliability of Liver Imaging Reporting and Data System v2018. Abdom Radiol (NY). 2019;44(6):2116–32. https://doi.org/10.1007/ s00261-019-01948-x. PMID: 30798397; PMCID: PMC6538452. 25. Lee S, Kim YY, Shin J, Hwang SH, Roh YH, Chung YE, Choi JY. CT and MRI liver imaging Reporting and data system version 2018 for hepatocellular carcinoma: a systematic review with meta-analysis. J Am Coll Radiol. 2020;17(10):1199–206. https://doi.org/10.1016/j.jacr. 2020.06.005. Epub 2020 Jul 5. PMID:32640250. 26. Sherman M. Alphafetoprotein: an obituary. J Hepatol. 2001;34(4):603–5. https://doi.org/10.1016/s01688278(01)00025-3. 27. Harding JJ, Khalil DN, Abou-Alfa GK. Biomarkers: what role do they play (if any) for diagnosis, prognosis

143 and tumor response prediction for hepatocellular carcinoma? Dig Dis Sci. 2019;64(4):918–27. https://doi. org/10.1007/s10620-019-05517-6. 28. Liu Z, Wu M, Lin D, Li N. Des-gamma-carboxyprothrombin is a favorable biomarker for the early diagnosis of alfa-fetoprotein-negative hepatitis B virusrelated hepatocellular carcinoma. J Int Med Res. 2020;48(2):300060520902575. https://doi.org/10. 1177/0300060520902575. 29. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379(9822):1245–55. https://doi. org/10.1016/S0140-6736(11)61347-0. 30. Cho HJ, Kim SS, Kang SY, et al. A proposal for modification of the Barcelona clinic liver cancer staging system considering the prognostic implication of performance status. Gut Liver. 2019;13(5):557–68. https://doi.org/10.5009/gnl18444. 31. Korean Liver Cancer Association, National Cancer Center. 2018 Korean liver cancer association-National Cancer Center Korea practice guidelines for the Management of Hepatocellular Carcinoma. Gut Liver. 2019;13(3):227–99. https://doi.org/10.5009/gnl19024. 32. Omata M, Cheng AL, Kokudo N, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int. 2017;11(4):317–70. https://doi.org/10.1007/s12072017-9799-9. 33. Nomura A, Ishigami M, Honda T, et al. Limitation of non-transplant treatment and proper timing for liver transplantation in patients with hepatocellular carcinoma considering long-term survival. Medicine (Baltimore). 2020;99(28):e21161. https://doi.org/10.1097/ MD.0000000000021161. 34. Finotti M, Vitale A, Volk M, Cillo U. A 2020 update on liver transplant for hepatocellular carcinoma [published online ahead of print, 2020 Jul 14]. Expert Rev Gastroenterol Hepatol. 2020:10.1080/ 17474124.2020.1791704. https://doi.org/10.1080/ 17474124.2020.1791704. 35. Levi Sandri GB, Lai Q, Ravaioli M, et al. The role of salvage transplantation in patients initially treated with open versus minimally invasive liver surgery: an intention-to-treat analysis. Liver Transpl. 2020;26(7): 878–87. https://doi.org/10.1002/lt.25768. 36. Hartley-Blossom Z, Alam M, Stone J, Iannuccilli J. Microwave ablation in the liver: an update [published online ahead of print, 2020 Jun 17]. Surg Technol Int. 2020;37:sti37/1321. 37. Zheng YJ, Li DL, Luo D, et al. Early versus delayed hepatectomy for spontaneously ruptured hepatocellular carcinoma: a systematic review and meta-analysis [published online ahead of print, 2020 Jul 13]. J Investig Surg. 2020:1–9. https://doi.org/10.1080/ 08941939.2020.1792009. 38. Kudo M, Han KH, Ye SL, et al. A changing paradigm for the treatment of intermediate-stage hepatocellular carcinoma: Asia-Pacific primary liver cancer expert consensus statements. Liver Cancer. 2020;9(3): 245–60. https://doi.org/10.1159/000507370.

144 39. Celsa C, Cabibbo G, Pagano D, di Marco V, Cammà C, Gruttadauria S. Sicily network for liver cancer: a multidisciplinary network model for the management of primary liver tumors [published online ahead of print, 2020 Jul 13]. J Laparoendosc Adv Surg Tech A. 2020: 10.1089/lap.2020.0471. https://doi.org/10.1089/lap. 2020.0471. 40. Llovet JM, Bruix J. Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol. 2008;48(Suppl 1):S20–37. 41. Reiberger T, Schwabl P, Trauner M, PeckRadosavljevic M, Mandorfer M. Measurement of the hepatic venous pressure gradient and transjugular liver biopsy. J Vis Exp. 2020;160:10.3791/58819. Published 2020 Jun 18. https://doi.org/10.3791/58819. 42. Torzilli G, Belghiti J, Kokudo N, et al. A snapshot of the effective indications and results of surgery for hepatocellular carcinoma in tertiary referral centers: is it adherent to the EASL/AASLD recommendations?: an observational study of the HCC East-West study group. Ann Surg. 2013;257(5):929–37. https://doi. org/10.1097/SLA.0b013e31828329b8. 43. Pagano D, Spada M, Parikh V, et al. Liver regeneration after liver resection: clinical aspects and correlation with infective complications. World J Gastroenterol. 2014;20(22):6953–60. https://doi.org/10.3748/wjg. v20.i22.6953. 44. Park S, Joo I, Lee DH, et al. Diagnostic performance of LI-RADS treatment response algorithm for hepatocellular carcinoma: adding ancillary features to MRI compared with enhancement patterns at CT and MRI [published online ahead of print, 2020 Jul 21]. Radiology. 2020;296:192797. https://doi.org/10.1148/radiol. 2020192797. 45. Zhao ZL, Wei Y, Wang TL, Peng LL, Li Y, Yu MA. Imaging and pathological features of idiopathic portal hypertension and differential diagnosis from liver cirrhosis [published correction appears in Sci Rep. 2020;10(1):7586]. Sci Rep. 2020;10(1):2473. Published 2020 Feb 12. https://doi.org/10.1038/ s41598-020-59286-8. 46. Gruttadauria S, Parikh V, Pagano D, et al. Early regeneration of the remnant liver volume after right hepatectomy for living donation: a multiple regression analysis. Liver Transpl. 2012;18(8):907–13. https:// doi.org/10.1002/lt.23450. 47. Gruttadauria S, di Francesco F, Wallis Marsh J, Marcos A, Gridelli B. Beyond the body surface area vauthey formula to identify the minimal donor volume for right-lobe living-donor liver transplantation. Liver Transpl. 2009;15(8):997–8. https://doi.org/10.1002/lt. 21779. 48. Gruttadauria S, Vasta F, Minervini MI, Piazza T, Arcadipane A, Marcos A, Gridelli B. Significance of the effective remnant liver volume in major hepatectomies. Am Surg. 2005;71(3):235–40. PMID: 15869140. 49. Gruttadauria S, Pagano D, Liotta R, et al. Liver volume restoration and hepatic microarchitecture in small-forsize syndrome. Ann Transplant. 2015;20:381–9.

D. Pagano et al. Published 2015 Jul 7. https://doi.org/10.12659/AOT. 894082. 50. Kim DK, Choi JI, Choi MH, et al. Prediction of Posthepatectomy liver failure: MRI with hepatocytespecific contrast agent versus Indocyanine green clearance test. AJR Am J Roentgenol. 2018;211(3):580–7. https://doi.org/10.2214/AJR.17.19206. 51. Gruttadauria S, Tropea A, Pagano D, et al. Miniinvasive approach contributes to expand the indication for liver resection for hepatocellular carcinoma without increasing the incidence of Posthepatectomy liver failure and other perioperative complications: a singleCenter analysis. J Laparoendosc Adv Surg Tech A. 2016;26(6):439–46. https://doi.org/10.1089/lap. 2016.0134. 52. Levi Sandri GB, Ettorre GM, Aldrighetti L, et al. Laparoscopic liver resection of hepatocellular carcinoma located in unfavorable segments: a propensity scorematched analysis from the I Go MILS (Italian Group of Minimally Invasive Liver Surgery) registry. Surg Endosc. 2019;33(5):1451–8. https://doi.org/10.1007/ s00464-018-6426-3. 53. Gon H, Kido M, Tanaka M, et al. Laparoscopic repeat hepatectomy is a more favorable treatment than open repeat hepatectomy for contralateral recurrent hepatocellular carcinoma cases [published online ahead of print, 2020 Jun 16]. Surg Endosc. 2020:10.1007/ s00464-020-07728-9. https://doi.org/10.1007/s00464020-07728-9. 54. Gruttadauria S, Pagano D, Corsini LR, et al. Impact of margin status on long-term results of liver resection for hepatocellular carcinoma: single-center time-to-recurrence analysis. Updates Surg. 2020;72(1):109–17. https://doi.org/10.1007/s13304-019-00686-5. 55. Procopio F, Torzilli G, Franchi E, et al. Ultrasoundguided anatomical liver resection using a compression technique combined with indocyanine green fluorescence imaging [published online ahead of print, 2020 Jun 18]. HPB (Oxford). 2020:S1365-182X(20) 31024-8. https://doi.org/10.1016/j.hpb.2020.05.009. 56. Donadon M, Terrone A, Procopio F, et al. Is R1 vascular hepatectomy for hepatocellular carcinoma oncologically adequate? Analysis of 327 consecutive patients. Surgery. 2019;165(5):897–904. https://doi. org/10.1016/j.surg.2018.12.002. 57. Gruttadauria S, Tropea A, Di Francesco F. Near infrared technology to evaluate segment IV in Split liver transplantation. J Gastrointest Surg. 2020;24:2702. https://doi.org/10.1007/s11605-020-04647-x. 58. Pagano D, Ricotta C, Barbàra M, et al. ERAS protocol for perioperative care of patients treated with laparoscopic nonanatomic liver resection for hepatocellular carcinoma: the ISMETT experience [published online ahead of print, 2020 Jul 22]. J Laparoendosc Adv Surg Tech A. 2020:10.1089/lap.2020.0445. https://doi.org/ 10.1089/lap.2020.0445. 59. Ikai I, Arii S, Kojiro M, Ichida T, Makuuchi M, Matsuyama Y, et al. Reevaluation of prognostic factors for survival after liver resection in patients with

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Surgical Management of Hepatocellular Carcinoma

hepatocellular carcinoma in a Japanese nationwide survey. Cancer. 2004;101(4):796–802. 60. Torzilli G, Viganò L, Gatti A, Costa G, Cimino M, Procopio F, Donadon M, Del Fabbro D. Twelve-year experience of “radical but conservative” liver surgery for colorectal metastases: impact on surgical practice and oncologic efficacy. HPB (Oxford). 2017;19(9): 775–84. https://doi.org/10.1016/j.hpb.2017.05.006. 61. Bruix J, Sherman M. Practice guidelines committee. American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology. 2005;42(5):1208–36. 62. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693–9. 63. Khouzam S, Pagano D, Barbàra M, et al. Impact of Italian score for organ allocation system on deceased donor liver transplantation: a monocentric competing risk time-to-event analysis. Transplant Proc. 2019;51 (9):2860–4. https://doi.org/10.1016/j.transproceed. 2019.02.073. 64. Vitale A, Boccagni P, Brolese A, et al. Progression of hepatocellular carcinoma before liver transplantation: dropout or liver transplantation? Transplant Proc. 2009;41(4):1264–7. https://doi.org/10.1016/j.transproceed.2009.03.095. 65. Pagano D, Barbera F, Conaldi PG, et al. Role of allelic imbalance in predicting Hepatocellular Carcinoma (HCC) recurrence risk after liver transplant. Ann Transplant. 2019;24:223–33. Published 2019 Apr 24. https://doi.org/10.12659/AOT.913692. 66. Angelico R, Trapani S, Spada M, et al. A national mandatory-split liver policy: a report from the Italian experience. Am J Transplant. 2019;19(7):2029–43. https://doi.org/10.1111/ajt.15300. 67. Gruttadauria S, Pagano D. Exploring new trends in living related liver transplantation. Hepatobiliary Surg Nutr. 2018;7(3):229–30. https://doi.org/10.21037/hbsn. 2018.03.15. 68. Lauterio A, Di Sandro S, Gruttadauria S, et al. Donor safety in living donor liver donation: an Italian multicenter survey. Liver Transpl. 2017;23(2):184–93. https://doi.org/10.1002/lt.24651. 69. Gruttadauria S, Tropea A, Di Francesco F. Near infrared technology to evaluate segment IV in split liver transplantation [published online ahead of print, 2020 Jun 23]. J Gastrointest Surg. 2020:10.1007/s11605-02004647-x. https://doi.org/10.1007/s11605-020-04647-x. 70. di Francesco F, de Ville de Goyet J, Pagano D, Mamone G, Gruttadauria S. Novel arterial reconstruction with donor femoral artery in Split-liver transplantation. Liver Transpl. 2020;26(5):729–30. https://doi. org/10.1002/lt.25736. 71. Gruttadauria S, Pagano D, Echeverri GJ, Cintorino D, Spada M, Gridelli BG. How to face organ shortage in liver transplantation in an area with low rate of deceased donation. Updat Surg. 2010;62(3–4):149–52. https:// doi.org/10.1007/s13304-010-0030-y.

145 72. di Francesco F, Pagano D, Martucci G, Gruttadauria S. Normothermic machine perfusion using an air/oxygen mixer for reconditioning a liver from a marginal brain death donor. Artif Organs. 2017;41(7): E66–8. https://doi.org/10.1111/aor.12964. 73. di Francesco F, Pagano D, Martucci G, Cintorino D, Gruttadauria S. Normothermic machine perfusion in liver transplantation: feasibility and promise of avoiding recooling before engrafting. Liver Transpl. 2019;25(7):1113–7. https://doi.org/10.1002/lt.25473. 74. Pagano D, Barbàra M, Seidita A, et al. Impact of extended-criteria donor liver grafts on benchmark metrics of clinical outcome after liver transplantation: a single Center experience. Transplant Proc. 2020;52(5):1588– 92. https://doi.org/10.1016/j.transproceed.2020.02.050. 75. Mazzaferro V, Citterio D, Bhoori S, Bongini M, Miceli R, De Carlis L, Colledan M, Salizzoni M, Romagnoli R, Antonelli B, Vivarelli M, Tisone G, Rossi M, Gruttadauria S, Di Sandro S, De Carlis R, Lucà MG, De Giorgio M, Mirabella S, Belli L, Fagiuoli S, Martini S, Iavarone M, Svegliati Baroni G, Angelico M, Ginanni Corradini S, Volpes R, Mariani L, Regalia E, Flores M, Droz Dit Busset M, Sposito C. Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial. Lancet Oncol. 2020;21(7):947–56. https://doi.org/10.1016/S14702045(20)30224-2. Erratum in: Lancet Oncol. 2020;21 (8):e373. PMID: 32615109. 76. Izzo F, Granata V, Grassi R, et al. Radiofrequency ablation and microwave ablation in liver tumors: an update. Oncologist. 2019;24(10):e990–e1005. https:// doi.org/10.1634/theoncologist.2018-0337. 77. Altman AM, Coughlan A, Shukla DM, et al. Minimally invasive microwave ablation provides excellent longterm outcomes for otherwise inaccessible hepatocellular cancer. J Surg Oncol. 2020;121(8):1218–24. https:// doi.org/10.1002/jso.25924. 78. Maruzzelli L, Miraglia R, Caruso S, Milazzo M, Mamone G, Gruttadauria S, Spada M, Luca A, Gridelli B. Percutaneous endovascular treatment of hepatic artery stenosis in adult and pediatric patients after liver transplantation. Cardiovasc Intervent Radiol. 2010;33(6):1111–9. https://doi.org/10.1007/ s00270-010-9848-4. Epub 2010 Apr 17. PMID: 20401610. 79. Marrone G, Crino’ F, Caruso S, Mamone G, Carollo V, Milazzo M, Gruttadauria S, Luca A, Gridelli B. Multidisciplinary imaging of liver hydatidosis. World J Gastroenterol. 2012;18(13):1438–47. https:// doi.org/10.3748/wjg.v18.i13.1438. PMID: 22509075; PMCID: PMC3319939. 80. Gruttadauria S, Saint Georges Chaumet M, Pagano D, Marsh JW, Bartoccelli C, Cintorino D, Arcadipane A, Vizzini G, Spada M, Gridelli B. Impact of blood transfusion on early outcome of liver resection for colorectal hepatic metastases. J Surg Oncol. 2011;103(2):140–7. https://doi.org/10.1002/jso.21796. Epub 2010 Nov 23. PMID: 21259247.

8

IR Liver-Directed Therapies for HCC Ajay Choudhri

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

2 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9

Directed Energy Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radiofrequency Ablation (RFA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microwave Ablation (MWA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cryoablation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Irreversible Electroporation (IRE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vascular Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transarterial Chemoembolization (TACE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug-Eluting Beads (DEB-TACE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transarterial Embolization (Bland Embolization) (TAE) . . . . . . . . . . . . . . . . . . . . . . . . Transarterial Radioembolization (TARE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3

Combination Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156

4

Future Locoregional Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156

5

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156

148 148 149 150 151 152 152 154 154 155

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156

Abstract

Keywords

There are a number of noninvasive interventional therapies available for treatment of HCC for resectable and unresectable disease including directed energy and embolic techniques. Treatment via microwave, RF and cryoablation are discussed along with embolization treatments.

Hepatocellular carcinoma · Interventional radiology · Ablation · Chemoembolization · Radioembolization · Cryoablation · Liver · Surgical Resection · BCLC

1

A. Choudhri (*) Interventional Radiology, Capital Health, Pennington, NJ, USA e-mail: [email protected]

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the fourth most common cause of cancer-related death worldwide [1]. Treatment of HCC is a multidisciplinary process and depends on factors such as tumor stage,

© Springer Nature Switzerland AG 2022 C. Doria, J. N. Rogart (eds.), Hepato-Pancreato-Biliary Malignancies, https://doi.org/10.1007/978-3-030-41683-6_5

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location, liver function and Eastern Cooperative Oncology Group (ECOG) status. For patients who are eligible, surgical resection is considered the standard of care. Resection patients generally fall with Barcelona Clinic Liver Cancer (BCLC) stage 0 or stage A [2]. If not resectable, orthotopic liver transplant is considered in patients meeting the Milan criteria [2]. These patients have a solitary tumor less than 5 cm or 1–3 tumors all less than 3 cm without signs of vascular invasion or extrahepatic involvement [3]. For those patients with unresectable disease, within the American Association for the Study of Liver Diseases (AASLD) guidelines, there are a number of image-guided locoregional therapies (LRT) that provide for treatment with prolonged survival [4] (Fig. 1). These imaged-guided interventions are minimally invasive, well tolerated, and safe and have proven treatment benefit not only in survival but also in quality of life. Locoregional therapies include a number of technologies that fall within two categories: directed energy and vascular intervention.

Fig. 1 Hepatology, Vol. 68, No. 2, 2018

A. Choudhri

Directed energy utilizes locally defined volumes under imaging guidance to cause cell death and tumor destruction with the use of thermal injury or electrical current. These modalities are primarily radiofrequency (RF) ablation, microwave (MW) ablation, cryoablation, and irreversible electroporation (IRE). Vascular Intervention utilizes techniques that take advantage of tumor blood supply by directing the therapy via catheter within the hepatic artery branches. This includes chemoembolization, bland and drug-eluting bead embolization, and radioembolization.

2

Directed Energy Techniques

2.1

Radiofrequency Ablation (RFA)

RF ablation of hepatic tumors is a percutaneous image-guided procedure that utilizes an electrode (probe) that acts as the cathode of an electrical circuit. This creates a high energy flux at the

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IR Liver-Directed Therapies for HCC

electrode tip causing vibrational energy in dipole molecules like water to disperse heat resulting in coagulative necrosis [5]. RFA is a prototypical tumor ablation technology dating back to first reports in 1990 [6, 7]. There is a long clinical experience with RF ablation in the liver and other organs, and it remains one of the most studied thermal ablation modalities. Initial designs of RF ablation electrodes utilized single-tip monopolar technology that required current to flow from electrode tip to grounding pads on the patient. Newer technologies allow for bipolar electrodes with multi-tined tips allowing current to flow locally (Fig. 2). Additional improvements include pulsed RF frequency and internally cooled tip electrodes to decrease local charring and enhance slow heating enhancing ablation volume and shortening ablation time [5]. Advantages of RFA versus surgical resection include reduced cost, being less invasive, shorter hospital stay, percutaneous approach, and hemostasis effect via electrocautery [5]. There is a historically large number of RF ablations performed throughout the world, and it

149

remains a mainstay of ablative practice. The use of ablative therapy in the nonsurgical candidate is clear; however, there is controversy in patients who may be resection candidates versus RFA for solitary HCC. For tumors 30 mm, OS and DSS were worse than resection or transplant [9]. Limitations of RFA for HCC include limited ablation volume up to 5 cm requiring overlapping electrodes, technically infeasible tumors that may be too close to adjacent organs, exophytic tumors, needle track seeding, and heat sink effect from adjacent blood vessels [10].

2.2

Microwave Ablation (MWA)

Microwave ablation (MWA) uses dielectric hysteresis to produce heat and create lethal temperatures from an applied electromagnetic field. Polar molecules such as water release kinetic energy raising the temperature of the tissue [11]. Microwave

a

b

Fig. 2 Hong, K, Georgiades, C. Radiofrequency Ablation: Mechanism of Action and Devices. J Vasc Interv Radiol 2010; 21:S179–S186

150

differs from RF ablation in that it does not depend on current passing through the tissues but rather radiating heat from the probe/antenna. This allows for treating despite local tissue desiccation or charring. Additionally, multiple antennas can be group to create a custom volume of synergistic heat radiation without the need for current passing between probes [11]. MWA can produce larger ablation volumes at higher temperatures with less heat sink effect and benefits from multiple antennae [12]. While RF ablation is the oldest and most widely used thermal ablation, MWA is becoming more popular. The majority of HCC ablation literature has been focused on RF ablation. Meta-analysis by Huo and Eslick demonstrated that RFA and MWA of liver lesions had similar 1–5-year overall survival, disease-free survival, and local recurrence rates [13]. MWA however has been reported to be cheaper, requiring less treatment sessions and shorter treatment duration [14–16]. Since the safety profiles and long-term survival benefits are similar, both MWA and RFA are useful in HCC treatment in the inoperable patient. Well-powered randomized control trials would be necessary to differentiate MWA and RFA not only on clinical outcomes but also on a cost/benefit and patient satisfaction basis.

Fig. 3 Illustration of microwave antenna/probe. Lubner et al. (2010)

A. Choudhri

2.3

Cryoablation

In contrast to MWA and RFA, cryoablation uses a different mechanism for tumor ablation by creating a defined volume of lethal freezing and thawing. Cryoablation causes tumor and tissue destruction via direct cellular injury and vascular-related injury [17]. The mechanisms of cell death are a cascade resulting from direct injury to cells via intracellular ice crystal formation, failure of microcirculation following thawing, and induction of apoptosis and necrosis [17] (Fig. 3). Placement of cryoprobes is image guided and similar to both MWA and RFA. To obtain an ideal ablative margin of 5–10 mm, multiple cryoprobes are required to create a lethal zone of at least 20  C requiring the zone of freezing to exceed the margin of the tumor (Fig. 4). Under CT and MRI, a visible area of ice formation or iceball allows for visualization of coverage of the tumor. Cryoablation has some advantages to RFA and MWA including visualization of the lethal zone, being relatively painless, and lack of severe damage to large blood vessels and gallbladder [18]. While older comparative data demonstrated some differences between RFA and cryoablation, recent advances in cryoprobe design and cooling

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151

Fig. 4 Iceball formation and temperature at varying distances from probe (Galil Medical 2014)

have led to a better safety profile; recent comparative studies demonstrate lower local tumor progression than RFA with similar overall 5-year survival rates [19].

2.4

Irreversible Electroporation (IRE)

Electroporation refers to the mechanism of increasing cell membrane permeability after exposure to high-voltage, short-duration pulsed electric fields [20]. Reversible electroporation is a temporary increase in permeability and can be used to facilitate the passage of therapeutics and vectors into cells. Irreversible electroporation however is electroporation to the level of cell death. In contrast to thermal injury ablation techniques, IRE only affects the cell membrane, preserving the structure of the extracellular matrix which may allow rapid restoration of perfusion [21]. Similar to the previously mentioned ablative techniques, IRE utilizes probes that produce current between adjacent probes (Fig. 5). The defined volume however is not around a single probe but rather the space between probes. This requires more probes and longer procedure time. Additionally, the procedure is performed under general

Fig. 5 Three IRE probes positioned around ablation zone (AngioDynamics)

anesthesia with muscle blockade [22]. Energy is then deposited by using cardiac synchronization to prevent ventricular arrhythmia [23]. In patients who are inoperable and where thermal energy techniques may not be suitable due to hazardous location or heat sink effect from adjacent blood vessels, IRE can be an alternative treatment [23]. Chronologic imaging after IRE demonstrates that normal hepatic tissue repopulates faster than thermal ablation likely related to the preservation of extracellular matrix [24]. IRE has shown to cause blood vessel occlusion in vessels 1.2, and the presence of extrahepatic disease [44]. TARE provides alternative treatment options in patients who may be excluded from TACE due to portal vein thrombosis (PVT) with survival benefit although outcomes worsen with worsening liver function. TARE is also effective in maintaining tumor size in potential liver transplant patients and can be considered as a downstaging therapy in select patients before transplantation [45]. TARE has increasingly become a treatment option over the last two decades with an excellent safety profile, survival benefit, and applicability in

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A. Choudhri

intermediate- and advanced-stage disease. A meta-analysis by Zhang et al. demonstrated the overall survival, 3-year OS rates, time to progression, and hospitalization time days compared to TACE [46].

3

Combination Therapies

HCC usually at discovery has a poor prognosis in the unresectable patient. There is a range of treatment options that must be tailored to the patient’s biophysical parameters and tumor characteristics. Given the wide range of treatment options discussed above, combination therapies have been studied although in much smaller numbers than monotherapy options; additionally, patients may undergo multiple sessions of a monotherapy or a combination of the above adding to study complexity and comparison. Examples of combination therapy include TACE plus RFA or MWA. The combination of TACE plus directed energy therapy (MWA or RFA) induces larger areas of coagulative necrosis with lower possibility of revascularization [47]. Combination therapy with a liver-directed therapy and systemic therapy has been studied. Sorafenib with 90Y radioembolization versus sorafenib alone demonstrated a median OS of 19.4 months which was better than sorafenib alone [48]. Side effects from this combination therapy were primarily from sorafenib.

4

Future Locoregional Therapies

HCC usually at discovery has a poor prognosis in the unresectable patient. There is a range of treatment options that have been discussed previously. The overall 5-year survival of patients with HCC has increased from 5% in 1987–1989 to 18% in 2005–2011. This is likely due to development and establishment of locoregional therapy given the lack of systemic options [49]. Drug-eluting beads (DEB) allow for directed delivery of therapeutic agents for sustained period of time while limiting system drug escape and

increasing intra-tumoral drug concentration. This heralds the loading of novel agents on drugeluting beads. Sunitinib is a tyrosine kinase inhibitor (TKI) that targets VEGF and PDGF receptors, which are involved in tumor growth and angiogenesis. Intra-arterial delivery demonstrated relatively high levels of intrahepatic sunitinib concentration and tumor growth arrest within 2 weeks [50, 51]. Another TKI, vandetanib, involved in VEGF and EGFR receptor targeting has been loaded on DEBs showing persistent intrahepatic therapeutic concentrations with low systemic escape [52]. Additionally, there are advancements in drug delivery vehicles including temporary or degradable particles, antibody loading with bevacizumab [53], targeted drug compounds like SW43-Dox [54], oncolytic viruses [55], and combination therapy with immune checkpoint inhibitors such as nivolumab.

5

Conclusion

As evidenced by improvement in survival from 1989 to 2011 with no impactful systemic therapy, locoregional therapies have evolved to the present day with better delivery platforms, therapeutic agents, and patient stratification. The current rapid advancement of immunotherapy, antibodies, and receptor inhibitors along with refinement of current locoregional therapies will continue to improve overall survival of this protean disease promising to change the landscape of HCC treatment. Stay tuned.

References 1. Wang H, Naghavi M, et al. Global burden of disease liver cancer collaboration 2015 mortality and causes of death collaborators. Global, regional, and national life expectancy, all-cause mortality, and causespecific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1459– 544. 2. Forner A, Reig ME, de Lope CR, et al. Current strategy for staging and treatment: the BCLC update and future prospects. Semin Liver Dis. 2010;30(01):61–74.

8

IR Liver-Directed Therapies for HCC

3. Mazzaferro V, Bhoori S, Sposito C, et al. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience. Liver Transpl. 2011:S44–57. 4. Heimbach JK, Kulik LM, Finn R, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67:358–80. 5. Hong K, Georgiades C. Radiofrequency ablation: mechanism of action and devices. J Vasc Interv Radiol. 2010;21:S179–86. 6. McGahan JP, Browning PD, Brock JM, et al. Hepatic ablation using radiofrequency electrocautery. Investig Radiol. 1990;25:267–70. 7. Rossi S, Fornari F, Pathies C, et al. Thermal lesions induced by 480 KHzlocalized current in Guinea pig and pig liver. Tumori. 1990;76:54–7. 8. Zhou Y, Zhao Y, Li B, et al. Meta-analysis of radiofrequency ablation versus hepatic resection for small hepatocellular carcinoma. BMC Gastroenterol. 2010;10:78. 9. Kutlu OC, Chan JA, Aloia TA, Chun YS, Kaseb AO, Passot G, Yamashita S, Vauthey JN, Conrad C. Comparative effectiveness of first-line radiofrequency ablation versus surgical resection and transplantation for patents with early hepatocellular carcinoma. Cancer. 2017;123:1817–27. 10. Rhim H, Lim HK. Radiofrequency ablation of hepatocellular carcinoma: pros and cons. Gut Liver. 2010;4 (Suppl 1):S113–8. 11. Lubner MG, Brace CL, Hinshaw JL, Lee FT Jr. Microwave tumor ablation: mechanism of action, clinical results, and devices. J Vasc Interv Radiol. 2010;21(8 Suppl):S192–203. https://doi.org/10.1016/ j.jvir.2010.04.007. 12. Brace CL, Laeseke PF, Sampson LA, Frey TM, van der Weide DW, Lee FT Jr. Microwave ablation with multiple simultaneously powered small-gauge triaxial antennas: results from an in vivo swine liver model. Radiology. 2007;244:151–6. 13. Huo YR, Eslick GD. Microwave ablation compared to radiofrequency ablation for hepatic lesions: a metaanalysis. J Vasc Interv Radiol. 2015;26:1139–46. 14. Zhang XG, Zhang ZL, Hu SY, Wang YL. Ultrasoundguided ablative therapy for hepatic malignancies: a comparison of the therapeutic effects of microwave and radiofrequency ablation. Acta Chir Belg. 2014;114:40–5. 15. Ohmoto K, Yoshioka N, Tomiyama Y, et al. Comparison of therapeutic effects between radiofrequency ablation and percutaneous microwave coagulation therapy for small hepatocellular carcinomas. J Gastroenterol Hepatol. 2009;24(2):223–7. 16. Iida H, Aihara T, Ikuta S, Yamanaka N. A comparative study of therapeutic effect between laparoscopic microwave coagulation and laparoscopic radiofrequency ablation. Hepato-Gastroenterology. 2013;60:662–5. 17. Baust JG, Gage AA, Bjerklund Johansen TE, Baust JM. Mechanisms of cryoablation: clinical consequences on malignant tumors. Cryobiology. 2014;68(1):1–11. https://doi.org/10.1016/j.cryobiol.2013.11.001.

157 18. Song KD. Percutaneous cryoablation for hepatocellular carcinoma. Clin Mol Hepatol. 2016;22(4):509–15. 19. Wang C, Wang H, Yang W, Hu K, Xie H, Hu KQ, Bai W, Dong Z, Lu Y, Zeng Z, Lou M, Wang H, Gao X, Chang X, An L, Qu J, Li J, Yang Y. Multicenter randomized controlled trial of percutaneous cryoablation versus radiofrequency ablation in hepatocellular carcinoma. Hepatology. 2015;61(5):1579–90. 20. Miller L, Leor J, Rubinsky B. Cancer cells ablation with irreversible electroporation. Technol Cancer Res Treat. 2005;4:699–705. 21. Golberg A, Broelsch GF, Bohr S, et al. Non-thermal, pulsed electric field cell ablation: a novel tool for regenerative medicine and scarless skin regeneration. Technology (Singap World Sci). 2013;1:1–8. 22. Nielsen K, Scheffer HJ, Vieveen JM, et al. Anaesthetic management during open and percutaneous irreversible electroporation. Br J Anaesth. 2014;113(6):985–92. 23. Sutter O, Calvo J, N’Kontchou G, Nault J-C, Ourabia R, Nahon P, Ganne-Carrié N, et al. Safety and efficacy of irreversible electroporation for the treatment of hepatocellular carcinoma not amenable to thermal ablation techniques: a retrospective single-center case series. Radiology. 2017;284(3):877–86. 24. Scheck J, Bruners P, Schindler D, et al. Comparison of chronologic change in the size and contrastenhancement of ablation zones on CT images after irreversible electroporation and RF ablation. Korean J Radiol. 2018;19:560–7. 25. Tamura M, et al. Predictors of occlusion of hepatic blood vessels after irreversible electroporation of liver tumors. J Vasc Interv Radiol. 2020;31(12):2033–2042.e1. 26. Balogh J, Victor D 3rd, Asham EH, et al. Hepatocellular carcinoma: a review. J Hepatocell Carcinoma. 2016;3:41–53. 27. Llovet JM, Real MI, Montaña X, Planas R, Coll S, Aponte J, Bruix J. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002;359(9319): 1734–9. 28. Lencioni R, de Baere T, Soulen MC, Rilling WS, Geschwind J-FH. Lipiodol transarterial chemoembolization for hepatocellular carcinoma: a systematic review of efficacy and safety data. Hepatology. 2016;64(1):106–16. 29. Lencioni R. Loco-regional treatment of hepatocellular carcinoma. Hepatology. 2010;52:762–77. 30. Song JE, Kim DY. Conventional vs drug-eluting beads transarterial chemoembolization for hepatocellular carcinoma. World J Hepatol. 2017;9(18):808–14. 31. Camma C, Schepis F, Orlando A, Albanese M, Shahied L, Trevisani F, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology. 2002;224:47–54. 32. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology. 2003;37:429–42.

158 33. Raza A, Sood GK. Hepatocellular carcinoma review: current treatment, and evidence-based medicine. World J Gastroenterol. 2014;20(15):4115–27. 34. Golfieri R, Cappelli A, Cucchetti A, Piscaglia F, Carpenzano M, Peri E, Ravaioli M, D’ErricoGrigioni A, Pinna AD, Bolondi L. Efficacy of selective transarterial chemoembolization in inducing tumor necrosis in small (& lt; 5 cm) hepatocellular carcinomas. Hepatology. 2011;53:1580–9. 35. Song MJ, Chun HJ, Song do S, Kim HY, Yoo SH, Park CH, Bae SH, Choi JY, Chang UI, Yang JM. Comparative study between doxorubicin-eluting beads and conventional transarterial chemoembolization for treatment of hepatocellular carcinoma. J Hepatol. 2012;57:1244–50. 36. Lammer J, Malagari K, Vogl T, et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol. 2010;33(1):41–52. 37. Golfieri R, Giampalma E, Renzulli M, et al. Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma. Br J Cancer. 2014;111(2):255–64. 38. Schicho A, Hellerbrand C, Kruger K, et al. Impact of different embolic agents for transarterial chemoembolization (TACE) procedures on systemic vascular endothelial growth factor (VEGF) levels. J Clin Transl Hepatol. 2016;4(4):288–92. 39. Yamaguchi R, Yano H, Iemura A, Ogasawara S, Haramaki M, Kojiro M. Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology. 1998;28(1):68–77. 40. Wu X, et al. Comparison of drug-eluting embolics versus conventional transarterial chemoembolization for the treatment of patients with unresectable hepatocellular carcinoma: a cost-effectiveness analysis. J Vasc Interv Radiol. 2021;32(1):2–12.e1. 41. Lee KH, Liapi E, Vossen JA, et al. Distribution of iron oxide-containing Embosphere particles after transcatheter arterial embolization in an animal model of liver cancer: evaluation with MR imaging and implication for therapy. J Vasc Interv Radiol. 2008;19:1490–6. 42. Brown KT, Do RK, Gonen M, Covey AM, et al. Randomized trial of hepatic artery embolization for hepatocellular carcinoma using doxorubicin-eluting microspheres compared with embolization with microspheres alone. J Clin Oncol. 2016;34(17):2046–53. 43. Tong AK, Kao YH, Too CW, Chin KF, Ng DC, Chow PK. Yttrium-90 hepatic radioembolization: clinical review and current techniques in interventional radiology and personalized dosimetry. Br J Radiol. 2016;89

A. Choudhri (1062):20150943. https://doi.org/10.1259/bjr. 20150943. 44. Sangro B, Carpanese L, Cianni R, Golfieri R, Gasparini D, et al. Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology. 2011;54(3):868–78. 45. Tohme S, et al. Yttrium-90 radioembolization as a bridge to liver transplantation: a single-institution experience. J Vasc Interv Radiol. 2013;24(11):1632–8. 46. Zhang Y, Li Y, Ji H, Zhao X, Lu H. Transarterial Y90 radioembolization versus chemoembolization for patients with hepatocellular carcinoma: a metaanalysis. Biosci Trends. 2015;9(5):289–98. 47. Buscarini L, Buscarini E, Di Stasi M, et al. Percutaneous radiofrequency thermal ablation combined with transcatheter arterial embolization in the treatment of large hepatocellular carcinoma. Ultraschall Med. 1999;20(2): 47–53. 48. Mahvash A, Murthy R, Odisio BC, Raghav KP, Girard L, Cheung S, et al. Yttrium-90 resin microspheres as an adjunct to sorafenib in patients with unresectable hepatocellular carcinoma. J Hepatocell Carcinoma. 2016;3:1–7. 49. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30. 50. Fuchs K, Bize PE, Dormond O, Denys A, Doelker E, Borchard G, et al. Drug-eluting beads loaded with antiangiogenic agents for chemoembolization: in vitro sunitinib loading and release and in vivo pharmacokinetics in an animal model. J Vasc Interv Radiol. 2014;25 (3):379–87. 387.e1–2 51. Bize P, Duran R, Fuchs K, Dormond O, Namur J, Decosterd LA, et al. Antitumoral effect of sunitinibeluting beads in the rabbit VX2 tumor model. Radiology. 2016;280(2):425–35. 52. Denys A, Czuczman P, Grey D, Bascal Z, Whomsley R, Kilpatrick H, et al. Vandetanib-eluting radiopaque beads: in vivo pharmacokinetics, safety and toxicity evaluation following swine liver embolization. Theranostics. 2017;7(8):2164–76. 53. Sakr OS, Berndt S, Carpentier G, Cuendet M, Jordan O, Borchard G. Arming embolic beads with anti-VEGF antibodies and controlling their release using LbL technology. J Control Release. 2016;224:199–207. 54. Ludwig JM, Gai Y, Sun L, Xiang G, Zeng D, Kim HS. SW43-DOX  loading onto drug-eluting bead, a potential new targeted drug delivery platform for systemic and locoregional cancer treatment – an in vitro evaluation. Mol Oncol. 2016;10(7):1133–45. 55. Yoo SY, Badrinath N, Woo HY, Heo J. Oncolytic virusbased immunotherapies for hepatocellular carcinoma. Mediat Inflamm. 2017;2017:5198798.

9

Clinical Presentation, Diagnosis, and Management of Uncommon Liver Tumors Elizabeth Richardson, Scott Fink, and Jessica Fried

Contents 1 1.1 1.2 1.3

Primary Hepatic Angiosarcoma (PHA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

160 160 161 162

2 2.1 2.2 2.3

Hepatic Epithelioid Hemangioendothelioma (HEH) . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

163 163 163 164

3 3.1 3.2 3.3

Undifferentiated Embryonal Sarcoma (UESL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

165 165 165 165

4 4.1 4.2 4.3

Combined Hepatocellular and Cholangiocarcinoma (CHC) . . . . . . . . . . . . . . . . Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

165 165 166 166

5 5.1 5.2 5.3

Hepatic Liposarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

168 168 168 168

E. Richardson (*) CT Gastroenterology Associates, Hartford, CT, USA Connecticut GI, Hartford, CT, USA e-mail: [email protected] S. Fink Main Line Gastroenterology Associates, Collegeville, PA, USA e-mail: sfi[email protected] J. Fried University of Michigan, Ann Arbor, MI, USA e-mail: [email protected] © Springer Nature Switzerland AG 2022 C. Doria, J. N. Rogart (eds.), Hepato-Pancreato-Biliary Malignancies, https://doi.org/10.1007/978-3-030-41683-6_11

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Primary Hepatic Lymphoma (PHL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

168 168 169 169

7 7.1 7.2 7.3

Hepatic Rhabdomyosarcoma (RMS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

169 169 170 172

8 8.1 8.2 8.3

Fibrolamellar HCC (FL-HCC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

172 172 172 173

9 9.1 9.2 9.3

Adult Hepatoblastoma (HB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

175 175 175 175

10 10.1 10.2 10.3

Hepatic Angiomyolipoma (AML) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

176 176 176 176

11 11.1 11.2 11.3

Bile Duct Adenoma (BDA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

176 176 177 177

12 12.1 12.2 12.3

Biliary Cystadenoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

177 177 177 177

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

Abstract

Aside from hepatocellular carcinoma, cholangiocarcinoma, or hepatic metastases, some hepatic lesions are exceedingly rare. Given the rarity of some hepatic lesions, arriving at a definitive diagnosis and management plan can be particularly challenging. In this chapter, we present an overview of clinical presentations, diagnosis, and management of uncommon hepatic tumors derived from available literature. Keywords

Rare liver tumors · Malignancy · Angiosarcoma · Hemangioendothelioma · Liposarcoma · Fibrolemellar · Lymphoma

1

Primary Hepatic Angiosarcoma (PHA)

1.1

Clinical Presentation

The most common symptoms of primary hepatic angiosarcoma (PHA) are vague and may include abdominal pain, weakness, fatigue, mild fever, and weight loss [1]. Clinical findings include hepatosplenomegaly, ascites, jaundice, and anemia [1]. Less common extrahepatic manifestations may be present and include thrombotic microangiopathy and Kasabach-Merritt syndrome (consumptive thrombocytopenia) [2]. Bone marrow fibrosis presenting as cytopenia is also associated with HA [2]. In cases of severe advanced disease, tumor rupture and fulminant hepatic failure may be present [3].

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PHA have varied appearance on cross-sectional imaging which reflects its varied histological components [4]. Imaging studies may show an appearance with multifocal lesions or a dominant mass [6]. Ultrasound (US) imaging may be nonspecific showing multiple or single mass with heterogeneous echogenicity, necrosis, and hemorrhagic areas [6]. US study is also useful in detecting hemoperitoneum if present [6]. Unenhanced computed tomographic (CT) images of PHA demonstrate the tumor to be predominantly hypoattenuating compared with normal liver tissue [4, 6]. On contrastenhanced CT images, most lesions are

hypoattenuating compared with normal surrounding hepatic parenchyma, but lesions can be hyperattenuating in some instances [4]. CT angiography may have diagnostic utility and demonstrate multiple or sometimes solitary hypervascular masses with heterogeneous early and progressive contrast enhancement as demonstrated in Fig. 1 [6]. Magnetic resonance (MR) images can demonstrate a heterogeneous appearance with hemorrhagic components, especially if lesions are large in size shown in Fig. 2 [4]. There is limited data regarding the usefulness of positron emission tomography (PET), but this technique may be a helpful method to assess tumor staging and to identify metastases [6]. Histological confirmation is recommended for definitive diagnosis as imaging findings may be equivocal [6]. There are case reports of bleeding complications in patients undergoing transcutaneous biopsy for PHA, and this approach is not the preferred method for biopsy 1, [4, 7]. Several studies recommend the use of fine-needle aspiration cytology (FNAC), but there is conflicting data regarding the safety and efficacy of this approach [6]. Cytological features of PHA include pencillate nucleoli, erythrophagocytosis, and other vasoformative features; however, these

Fig. 1 Primary hepatic angiosarcoma: A 51-year-old male presenting with abdominal pain. Subsequent resection and pathology consistent with well-differentiated angiosarcoma (CD31 and CD34 positive). Imaging: CT Abdomen and

Pelvis performed with intravenous contrast, axial post-contrast images (a), and coronal post-contrast images (b) demonstrate nodular enhancement of a lobulated irregular right hepatic lobe mass

Approximately 15% of patients suffer from acute abdomen and hemoperitoneum as a result of tumor rupture [3]. Fulminant hepatic failure is marked by the presence of encephalopathy and coagulopathy typically within 2 weeks after the development of jaundice [3]. Many patients will present with metastatic lesions at the time of presentation with most common sites of metastases being the lung, followed by the spleen [4, 5].

1.2

Diagnosis

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Fig. 2 Primary hepatic angiosarcoma. A 63-year-old male presenting with low energy and right upper quadrant pain. Ultimately, the patient passed away after palliative radiation treatment. Imaging: MR Abdomen without and with intravenous contrast at 3 T. Axial fat-saturated T2weighted images (a) show a large mass occupying the majority of the right lobe of the liver with numerous

small surrounding satellite nodules. Axial T1-weighted pre-contrast imaging (b) shows heterogeneity of the tumor, with high signal areas reflecting internal hemorrhage. Axial post-contrast images at 80 s post-injection (c) and delayed 5-min post-injection (d) show heterogeneous enhancement of the mass with progressive internal enhancement

features overlap with other nonvascular neoplasms [8]. Tissue specimens obtained by biopsy or resection may demonstrate tumor composed of spindle cells with vascular channels infiltrating surrounding hepatic parenchyma with local tissue destruction and infiltration on histology [9, 10]. Endothelial cells with enlarged hyperchromatic nuclei may be seen lining vascular channels [9]. Immunohistochemical markers include CD31, CD34, and vimentin, a mesenchymal marker [9, 10].

1.3

Management

Due to the low incidence of PHA with current literature based primarily on case reports, the treatment for PHA is not well defined [11]. In cases where tumors are solitary with evidence of normal, non-cirrhotic surrounding liver parenchyma, tumor resection is the treatment of choice [5]. Radical surgical resection (R0) in the appropriately selected patient is reported to offer the best survival advantage [11]. In a meta-analysis by Zheng et al.

9

Clinical Presentation, Diagnosis, and Management of Uncommon Liver Tumors

analyzing 64 cases of PHA, median survival for all patients was 5 months where 30 out of 64 patients that underwent complete surgical resection in combination or without adjuvant chemotherapy had a median overall survival (OS) of 17 months [1]. By comparison, liver transplant (LT) has been associated with poor outcomes [1, 11]. Orlando et al. reported in the European Liver Transplant Registry a high recurrence rate at 6 months and no patient survived after 23 months [12]. Due to poor outcomes, PHA is considered a contraindication to LT [1, 11]. Chemotherapy is a consideration for patients with metastatic or unresectable disease. Penel et al. in the ANGIOTAX phase II trial of weekly paclitaxel for angiosarcoma reported median OS of 8 months [13]. Bevacizumab, a recombinant humanized antibody against vascular endothelial growth factor (VEGF), has been reported by Agulnik et al. to be a well-tolerated in a small study with some promise as a potential target for angiosarcomas [14]. The use of neoadjuvant chemotherapy is not fully defined. Sorafenib has been shown to have some limited antitumor activity in patients previously treated for a short duration [15]. Transarterial embolization (TAE) is useful for control of hemoperitoneum [1]. Transarterial chemoembolization (TACE) offers a potential palliative intervention with reported survival time ranging between 2 and 12 months [1, 11].

2

Hepatic Epithelioid Hemangioendothelioma (HEH)

2.1

Clinical Presentation

Patients may present with nonspecific symptoms including right upper quadrant pain, hepatosplenomegaly, and weight loss [16]. Other common clinical presentations include weakness, epigastric mass, ascites, nausea, emesis, and jaundice [17]. Few patients have presented with the extremely rare complication of hepatic rupture manifesting as abrupt onset of severe abdominal pain and shock [18]. There is a case report of a patient presenting with stroke as initial presenting symptom attributed to underlying hypercoagulable state

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associated with this disease [19]. Approximately 25% of patients can present with no symptoms with an incidental finding of tumor on imaging [20].

2.2

Diagnosis

The most common laboratory findings in HEH are elevation of alkaline phosphatase and g-glutamyl transpeptidase followed by elevation of aspartate aminotransferase, alanine aminotransferase, and bilirubin [17]. Approximately 15% of patients can have normal laboratory parameters [20]. Tumor markers such as a-fetoprotein, carcinoembryonic antigen, and CA 19-9 tend to be within reference range [17]. Radiological studies demonstrate that imaging of HEH has a variable number of lesions and amount of liver involved [21]. HEH can generally be divided into two subtypes based on imaging [20, 21]. The nodular subtype presents with multifocal lesions present earlier in disease course [20, 21]. Over time with disease progression nodules grow and coalesce, forming large confluent masses typically in the periphery of the liver referred to as the diffuse subtype [20, 21]. CT or MRI studies may exhibit the “lollipop sign” defined as a hypodense well-defined tumor mass on enhanced images with a hepatic or portal occluded vein rendering the appearance of a lollipop [22, 23]. Additional imaging characteristics may include focal calcifications, capsular retraction, central hypodensity, and peripheral enhancement as shown in Fig. 3 [23]. The diagnosis of HEH requires histologic examination of tissue obtained by biopsy. Histological findings of HEH are marked by vascular invasion and include cords of epithelioid endothelial cells spreading within sinusoids and intracellular vascular lumina that may contain red blood cells [20]. HEH may have histologic findings like other hepatic malignancies, and immunohistochemistry for endothelial markers is usually required to establish the diagnosis of HEH. Well-known endothelial markers used in the diagnosis of HEH include CD31, CD34, and Factor VIII [23]. Podoplanin has also been reported as an immunohistochemical marker used to diagnose HEH [20, 23].

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Fig. 3 Hepatic epithelioid hemangioendothelioma. A 56year-old woman with incidental liver lesions on ultrasound for abnormal liver function tests. Imaging: MR of the Abdomen without and with intravenous contrast at 1.5 T. Axial pre-contrast T1 fat-saturated images (a) demonstrate multiple hepatic masses which are T1 hypointense relative to surrounding normal pancreatic parenchyma. Axial fat-

saturated T2-weighted images (b) show heterogeneous increased T2 signal intensity. Axial T1-weighted post-contrast images (c) show peripheral halo/targetoid enhancement pattern of the lesions. While not seen on this case, occasionally lesions can be associated with a thin peripheral hypointense rim

2.3

only about 9.4% of patients are reported to undergo resection [17]. Data regarding tumor recurrence following liver resection is inconsistent with success reported with major hepatic resection and aggressive recurrence after resection of localized lesions [25]. LT is reported to be the most common treatment modality used in patients with HEH [17]. In a review of 434 patients with HEH, 44% underwent LT [17]. According to a study of the United Network for Organ Sharing (UNOS) database between 1987 and 2005, 110 patients underwent 126 LTs for the indication of HEH [25]. Patient survival rates at 1 and 5 years were

Management

Therapeutic strategies for HEH have not been well established given the rarity of this malignancy and variable clinical presentation [17]. Current treatment options for HEH include liver transplantation, chemotherapy, radiotherapy, liver resection, and monitoring without intervention [24]. Surgical therapy with either local resection or LT comprises the mainstay of treatment for HEH [24]. Liver resection is considered the best first option; however, given the vast majority of patients presenting with multifocal lesions at the time of diagnosis,

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80% and 64%, respectively [25]. The presence of extrahepatic disease is not considered to significantly impact survival in LT undertaken for HEH and is not a contraindication to LT [17, 25, 26]. HEH appears to be unresponsive to chemotherapy. Chemotherapeutic agents employed include doxorubicin, vincristine, interferon-a, 5-fluorouricil, thalidomide, and monoclonal antibodies against vascular endothelial growth factor (VEGF) [27]. There is a case report of interferon-a2b used in the setting of adjuvant chemotherapy following LT [17]. The patient reported improvement in HEH symptoms and tumor regression but died of graft rejection caused by interferon [17]. TACE is a reasonable temporizing intervention in patients with advanced HEH awaiting transplant [17].

tumor rim and internal septations enhance [34]. A pseudo-capsule may be appreciated MRI [33, 34]. The definitive diagnosis of UESL requires pathological examination. Macroscopic tumor appearance is described as a large, wellcircumscribed mass with areas of hemorrhage, necrosis, and cystic degeneration [32]. Microscopically, UESL is sarcomatous appearing composed of loosely arranged spindle cells, stellate pleomorphic cells with poorly defined cell borders, and atypical giant cells [32]. PAS-positive, diastaseresistant eosinophilic globules within the cytoplasm are a reported observation [33, 35]. Immunohistochemical staining has shown variable reactivity to desmin, CD56, CD68, and vimentin, cytokeratin, alpha1 antitrypsin, and alpha 1 antichymotrypsin [35].

3

Undifferentiated Embryonal Sarcoma (UESL)

3.3

3.1

Clinical Presentation

The most common presentation of undifferentiated embryonal sarcoma (UESL) is a child patient between the ages of 6 and 10 years [28, 29]. Clinical complaints found in UESL are nonspecific and include upper abdominal pain, palpable mass, nausea, anorexia, fever, and headache [29]. There are case reports of hepatic rupture in adult patients related to UESL [30, 31].

3.2

Diagnosis

The diagnosis of UESL may be difficult because it has a nonspecific clinical presentation and diagnostic features that overlap with several other tumors and other hepatic lesions. Laboratory findings usually have normal or mildly elevated liver function [28, 32]. Tumor markers such as AFP, CEA, and CA19-9 are typically within normal range [28, 32]. On imaging studies, CT and MRI typical reveal a large solitary space occupying lesion varying in size ranging from 10 to 35 cm with mixed solid-cystic features [33]. Radiographic appearance can mimic complicated hydatid cyst or an abscess [34]. Most do not show enhancement on CT; however, the

Management

The standard treatment for UESL has not been defined due to the scarcity of this disease. Most patients with UESL have unresectable disease at the time of diagnosis because UESL often presents as a large lesion near major vascular structures [35]. The use of neoadjuvant chemotherapy has been utilized to reduce the size of a tumor and enable tumor resection. Adjuvant systemic chemotherapy following surgical resection has also led to improved outcomes [33, 36]. Chemotherapeutic regimens reported to provide some survival benefit include sarcoma-directed therapy and varied use of doxorubicin, cisplatin, vincristine, and cyclophosphamide [33]. The role of LT in the management of UESL is not well established with very few cases of LT for unresectable UESL reported in literature [37].

4

Combined Hepatocellular and Cholangiocarcinoma (CHC)

4.1

Clinical Presentation

Patients diagnosed with CHC can present without symptoms with tumor found incidentally on imaging or as part of hepatocellular carcinoma (HCC) screening in the setting of cirrhosis [38].

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Symptomatic patients may present with a range of clinical complaints including abdominal pain, jaundice, fever, weight loss, and palpable mass [38, 39]. Common risk factors for the development of HCC including the presence of cirrhosis may be present [40]. A history of alcohol abuse, HBV, HCV, and hemochromatosis among other causes of chronic liver disease may be present [40].

4.2

Diagnosis

Patients diagnosed with CHC have clinicopathologic features that overlap with cholangiocarcinoma (CCA) and HCC [41]. Prior studies have demonstrated HCC will have higher levels of AFP whereas CCA will have higher elevations in Ca19–9 [39]. Analysis of tumor markers for CHC demonstrates that AFP and CA19-9 levels likely reflect the degree of glandular differentiation and the histologic proportion of the predominant component of the CHC lesions [41]. HCC predominant CHC lesions may have higher AFP, whereas CCA predominant lesions will have higher CA19–9 [41]. Overall, tumor markers alone have a low specificity for the definite diagnosis of CHC. CHC can be challenging to diagnose based on imaging features. The imaging findings of CHC commonly share features of both HCC and CCA as shown in Fig. 4 [39]. According to a study by Fowler et al., CHC more commonly share radiographic findings similar to CCA as opposed to HCC [39]. In particular capsular retraction, pattern of enhancement and biliary ductal dilation are all findings that should raise concern for either CHC or CCA and less likely HCC [39]. Peripheral arterial enhancement was the most common feature of CHC tumors but was also observed in CCA as well in this study [39]. On dynamic CT, enhancement in a target-like pattern with peripheral hyperattenuation in arterial phase with hypoattenuated appearance on portal venous and delayed phase has also been described a characteristic imaging finding of CHC [40, 42]. Enhancement patterns of CHC on contrast-enhanced US (CEUS) imaging findings have also been studied and shown to be dependent on size characteristics as well as

proportion of HCC and CCA present [43]. Peripheral, irregular ringlike enhancement pattern corresponded with CCA predominant CHC lesions, whereas diffuse heterogeneous enhancement corresponded with HCC predominant CHC lesions [43]. Overall, tumor markers combined with imaging findings may improve diagnosis. The diagnosis of CHC can be considered when imaging findings and tumor marker elevation are incongruous [39]. Pathologic findings of CHC have features of HCC and ICC. Histological classification was first described in 1949 as three subtypes with further adjustment in classification in 1985 [44] which are type 1 collision tumor with separate and colliding areas of HCC and CC in the same liver, type 2 or transitional tumor with transitional intermingling of two components, and type 3 or mucin producing fibrolamellar tumor [44]. WHO classification describes two main types of CHC as classical type and CHC with stem cell features. The stem cell feature type is further divided into three subtypes: typical subtype, intermediate cell subtype, and cholangiolocellular subtype [44]. The diagnosis of CHC can be established by histology findings with immunohistochemistry stains [44]. Hepatocyte differentiation can be characterized by the presence of bile, Mallory-Denk bodies, alpha-1 antitrypsin globules, and trabecular arrangement of tumor cells [44]. The cholangiocarcinoma component can be established by the presence of mucin, desmoplastic stroma, and glandular structures [44]. By immunohistochemical stains, hepatocellular components will stain positive for HepPar1, pCEA, CD10, and glypican [44]. CCA components will stain positive for CK7, CK19, and mucin [44].

4.3

Management

The treatment of choice is surgical resection of tumor via major hepatectomy, if possible, to improve the prognosis in patients with CHC [43, 44]. For patients with unresectable lesions, curative or palliative locoregional therapy, including TACE or radiofrequency ablation (RFA), can be considered [45]. The therapeutic effect of

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167

Fig. 4 Combined hepatocellular carcinoma (HCC) and cholangiocarcinoma. A 71-year-old male with history of hepatitis C virus cirrhosis. Patient had undergone antiviral therapy with SVR. Atypical liver lesion discovered at MRI, biopsied with pathology finding mixed HCC/cholangiocarcinoma (cholangiohepatoma). Subsequent microwave ablation with excellent treatment response. Imaging: MR Abdomen without and with intravenous contrast at 1.5 T. Axial fat-saturated T2-weighted images (a) show a 1.7 cm

mass in segment V/VIII with intrinsic high T2 signal intensity (white arrow). Axial T1-weighted pre-contrast imaging (b) shows low signal intensity of the mass (white arrow). High B-value diffusion-weighted imaging (c) shows marked impeded diffusion of the mass (white arrow). This mass demonstrated a targetoid enhancement pattern on arterial phase imaging, with slightly delayed central enhancement (not shown)

TACE for CHC is less clear compared to that of HCC [45]. According to a series by Yin et al., six patients who underwent TACE for unresectable CHC had a median survival of only 6 months [45]. By comparison, in the same study 30 patients with tumor recurrence after surgical resection had a median survival time of 17 months [45]. Therefore, TACE may be more beneficial in patients who have undergone resection with recurrence as opposed to patients with unresectable disease.

Although data is sparse, LT has been shown in small studies to be a curative option in highly select patients with cirrhosis and CHC who are otherwise poor candidates for resection [41]. According to Panjala et al., 1-, 3-, and 5-year survival rates in 12 patients with CHC undergoing LT were 79%, 66%, and 16%, respectively [41]. The role of systemic chemotherapy for the treatment of CHC is limited to a few case reports [46]. Most available reports include patients

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treated with systemic chemotherapy with recurrence after surgical resection [46]. Adjuvant chemotherapy has not been widely reported in CHC. The most frequently chosen chemotherapeutic agents include platinum, gemcitabine, and fluorouracil [46]. Further prospective studies are needed to further assess the utility of chemotherapy in this patient population.

5

Hepatic Liposarcoma

5.1

Clinical Presentation

Common symptoms and clinical findings of primary hepatic liposarcoma include nausea, vomiting, fever, jaundice, abdominal fullness, right upper quadrant pain, and weight loss [47]. In large tumors, compression and displacement of extrahepatic organs such as the intestines can precipitate symptoms [47].

5.2

Diagnosis

Laboratory studies may reveal mild increases in the serum levels of liver transaminases, alkaline phosphatase, gamma glutamyl transferase, and CA19–9, although serologic studies may also be normal [48]. Histologically liposarcomas have been sub-characterized based on the stage of differentiation of the lipoblasts and overall degree of cellularity and pleomorphism [49]. Five major histological categories of liposarcomas are recognized: myxoid, round cell, well-differentiated, dedifferentiated, and pleomorphic. More than half of the hepatic liposarcomas are of myxoid type [48]. Histological examination is utilized to confirm the diagnosis and differentiate between each subtype. FNA biopsy makes a definite diagnosis in 58–82% of cases [48]. On radiologic studies, lipid-containing tumors are characterized as fat-containing masses; however, differentiating between a malignant and benign tumor may not be feasible with imaging studies alone [48]. On CT imaging, contrast enhancement depends on the level of

tumor differentiation [47]. Well-differentiated liposarcomas will show little enhancement compared to dedifferentiated subtypes [47]. Other imaging findings of liposarcoma include thick septae, nodularity, hemorrhage, and necrosis [47]. Metastatic spread may also be identified on imaging due to the aggressive nature of this tumor with sites including the brain, pleura, thyroid, pancreas, and spinal cord [47]. The MRI findings of hepatic liposarcomas may include findings consistent with fat-containing components and signal loss with fat suppression [50]. Positron emission tomography (PET)/CT evaluation for primary hepatic myxoid liposarcomas may show a metabolic tumor with little fat [50].

5.3

Management

Aggressive surgical resection with clear margins is the mainstay of treatment in patients with resectable hepatic liposarcoma [47]. There is a high rate of reoccurrence, especially in the pleomorphic variety, even in patients that have complete tumor resection [47]. In cases of advanced liposarcoma with metastasis, palliative therapy can be given. The role of radiotherapy is not well defined [47]. Given hepatic liposarcomas, generally large lesions and the total volume of the liver have a limited radiation dose tolerance, and radiation therapy in theory may be harmful [48]. Attempts of treatment with systemic chemotherapy for highgrade liposarcoma have been tried with low reported success rates [47]. The 5-year survival rate of patients who have undergone curative resection or radiation therapy is approximately 50% [47]. Liposarcoma is an absolute contraindication to LT [48].

6

Primary Hepatic Lymphoma (PHL)

6.1

Clinical Presentation

PHL may present with nonspecific symptoms such as right upper quadrant pain, fatigue, anorexia, nausea, weight loss, or fever [51].

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B symptoms which include fever, drenching sweats, and weight loss appear in 37–86% of patients [52]. It can rarely present with fulminant hepatic failure if diffuse liver involvement is present [51]. Palpable hepatomegaly is a common physical exam finding in PHL [53]. Patients with hepatitis C are more commonly affected which is found in 40–60% of patients with PHL, with significantly higher prevalence to the diffuse B cell non-Hodgkin’s subtype [53].

6.2

Diagnosis

Laboratory findings include elevated alkaline phosphatase, lactate dehydrogenase, and b-microglobulin [53]. Aminotransferases may be elevated or normal [52, 53]. Hypercalcemia is found in 40% of the patients [52]. Tumor markers AFP and Ca19-9 are typically not found to be elevated [53, 54]. Radiographic findings may demonstrate three possible patterns of PHL on imaging [55]: a solitary lesion, multiple lesions, or diffuse infiltration of the liver [55]. The most common presentation in the literature is a solitary lesion, which occurs in 55–60% of patients as seen in Fig. 5 [55]. Ultrasound findings are nonspecific and include a hypoechoic lesion to the surrounding normal liver parenchyma, typically with irregular margins [53]. Contrastenhanced CT may show slight rim enhancement of the lesion in the arterial phase and hypoenhancement in the remaining phases [53, 56]. MRI when performed will typically show a hypointense mass on T1-weighted images and hyperintense T2-weighted images which can be appreciated in Fig. 6 [56]. For histological examination, tissue sampling by FNA is typically nondiagnostic [56]. Core biopsy performed in conjunction with flow cytometry is usually diagnostic [56]. Non-Hodgkin lymphoma is the major histological subtype identified in PHL [53]. PHL with Hodgkin’s histology is limited to case reports and a rare occurrence [53]. Similar to different patterns of liver involvement on radiology studies, PHL can present as nodular or diffuse growth in which lymphoma cells expand into the surrounding hepatic

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parenchyma on pathology [53, 55]. The pattern of liver infiltration does not affect prognosis [53]. Additionally, PHL may be of T-cell or B-cell origin with the most common type being diffuse large B-cell lymphoma [53]. Other histologic subtypes of PHL include diffuse histiocytic lymphoma of the mucosa-associated lymphoid tissue, Burkitt lymphoma, follicular lymphoma, and mantle cell lymphoma [53, 55]. Immunohistochemical findings will aid in the diagnosis of specific histological subtype [53]. Diffuse large B-cell lymphoma will test positive for CD10, Bcl2, Bcl6, MUM1, and CD25 on immunohistochemical studies [53].

6.3

Management

Treatment options for PHL include surgery, chemotherapy, radiation therapy, or combination of these modalities [51, 55]. Optimal therapy is not fully defined; however, the gold standard largely includes use of CHOP-based chemotherapeutic regimens as either a single therapy or an adjunct to surgery [51]. The addition of rituximab to CHOP-based regimen has been demonstrated to improve response rate [55]. Surgical therapies including resection of localized disease or debulking prior to chemotherapy have been previously utilized [55].

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Hepatic Rhabdomyosarcoma (RMS)

7.1

Clinical Presentation

Clinically, hepatic RMS are usually asymptomatic until they become large in size and produce nonspecific symptoms. The patient may present with right upper quadrant or epigastric abdominal pain, anorexia, vomiting, weight loss, and fatigue [57]. Severe pain with tenderness may be present in large tumors that have ruptures and subsequently hemorrhaged [58]. If biliary obstruction is present, the patient will present jaundice with possible cholangitis [57]. Fever and a palpable mass are possible findings on physical examination [58].

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Fig. 5 Primary hepatic lymphoma: A 59-year-old man presenting for surveillance ultrasound for history of hepatitis C virus without overt cirrhosis. Subsequent biopsy proven primary hepatic lymphoma. Patient responded well to chemotherapy and HCV was treated with SVR. Imaging: Contrast-enhanced CT of the abdomen/pelvis and MR of the Abdomen without and with intravenous contrast at 1.5 T (examination is degraded by respiration motion artifact). Coronal contrast-enhanced CT of the abdomen (a) shows massive enlargement of the left lobe

of the liver. Color Doppler ultrasound images of the left lobe of the liver (b) demonstrate diffuse enlargement and hypoechogenicity of the left lobe of the liver. Axial T1weighted out-of-phase imaging (c) demonstrate infiltrative hypointense masses replacing the left lobe of the liver and a smaller similar lesion in segment VIII of the right lobe (white arrows). High B-value diffusion-weighted imaging (d) shows marked impeded diffusion of the mass in the left lobe of the liver. Massive enlargement of the spleen and enlarged porta hepatis lymph nodes are also seen

7.2

There are no reported descriptions of expected radiographic characteristics in hepatic RMS [59]. CT examination of hepatic RMS has been described in one case description by Yin et al. as a heterogeneous-appearing cystic lesion [58]. Most reported cases were detected as a large mass of >10 cm in diameter occupying a liver lobe [59]. The primary histological feature of RMS is a resemblance to developing muscle featuring rhabdomyoblasts [57]. Three major subtypes of rhabdomyosarcoma have been described based on

Diagnosis

According to available case studies, there are few biochemical abnormalities detected on laboratory studies. A review of all published cases of hepatic RMS by Schoofs et al. analyzed 13 cases identified between 1979 and 2011 [57]. Of the 13 cases analyzed, there were 3 patients with raised AFP, 6 with normal levels, and 4 with no data of the AFP levels. Mild cholestasis may be present [57]. Overall, most laboratory studies showed no abnormality.

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Fig. 6 (continued)

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cytologic features and histologic pattern: embryonal RMS, the alveolar RMS, and the pleomorphic type [57]. The pleomorphic type is relatively more frequent in adults and tends to have a poorer prognosis [57]. Most tumors are composed of undifferentiated cells with round to oval nuclei with minimal cytoplasm [57]. Immunostaining facilitates assessment of myogenic potential [57]. Hepatic RMS tumors are typically positive for muscle-specific markers, such as myogenin, myogenic determination factor, desmin, actin, myoglobin, and vimentin [57].

7.3

Management

Hepatic RMS is an extremely rare malignancy in adults, and therapeutic regimens used are based on evidence derived from pediatric therapies [60]. The standard treatment protocol for children as proposed by the Intergroup Rhabdomyosarcoma Study Group (IRSG) includes total surgical resection with negative margins and radiotherapy for the primary tumor site, with systemic chemotherapy to prevent metastases [60]. Chemotherapy regimens have included vincristine, actinomycinD, cyclophosphamide doxorubicin, ifosfamide, etoposide, and topotecan [60].

8

Fibrolamellar HCC (FL-HCC)

8.1

Clinical Presentation

Most patients diagnosed with FL-HCC are asymptomatic young patients with no prior history of liver disease [61]. Symptoms are usually present in patients with advanced disease and

include abdominal pain, weight loss, fever, jaundice, and nausea [61, 62]. Rare clinical presentations reported include male gynecomastia, fulminant liver failure, deep vein thrombosis, encephalopathy, thrombophlebitis of the lower extremity, and hypoglycemia caused by glucose utilization by growing tumor cells [61].

8.2

Diagnosis

Laboratory studies at presentation such as aminotransferases and alkaline phosphatase are normal or minimally elevated [61]. Serum markers found to be elevated in FL-HCC include vitamin B12 binding capacity and haptocorrin [63]. AFP is rarely elevated in these patients, unlike in typical HCC [63]. Imaging features of FL-HCC include a large, heterogeneous enhancing, well-defined mass that may contain a central scar and calcifications on imaging [64]. CT imaging may demonstrate hypervascularity and lymphadenopathy if present as shown in Fig. 7 [64]. By comparison, MRI demonstrates the central scar in FL-HCC better than CT but does not typically capture calcification [64]. In general on MRI, FL-HCC shows a heterogeneous hypervascular enhancement that is hyperattenuating on the arterial phase and in venous phase hypo-, iso-, or hyperattenuating demonstrated in Fig. 8 [64]. Histologically FL-HCC was first described by Edmonson et al. as large polygonal hepatocytes with eosinophilic and granular cytoplasm surrounded by thick fibrous bands, arranged in a parallel or lamellar distribution [65]. Further subclassification into two groups as described by Malouf et al. include pure FL-HCC meeting the

ä Fig. 6 Hepatic fibrolamellar HCC. A 32-year-old woman presenting with non-specific abdominal pain. Subsequent left hepatic tri-segmentectomy. Unfortunately, the patient presented with distant nodal metastases with progression after both radiation, chemotherapy, and immunotherapy. The patient passed away 3 years after initial diagnosis. Imaging: Contrast-enhanced CT of the abdomen and MR Abdomen without and with intravenous contrast (hepatobiliary specific contrast agent [Gadoxetate]) at 1.5 T. Axial contrast-enhanced CT of the abdomen (a) shows

heterogeneous enhancement of the large segment IVA mass. Axial T2 fat-saturated images (b) show a 7.0 cm mass centered in segment IVA that is slightly hyperintense relative to surrounding parenchyma. Axial T1-weighted pre-contrast imaging (c) shows that the mass is slightly hypointense relative to surrounding parenchyma. Postcontrast images demonstrate heterogeneous arterial hyperenhancement (d). Hepatobiliary phase (+20 min delay) shows “wash-out” of the mass relative to background liver (e)

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Fig. 7 Adult hepatoblastoma: A 23-year-old male originally presenting with abdominal pain. Subsequent left lobectomy with pathology consistent with adult hepatoblastoma. The patient ultimately had multifocal recurrence in the remaining lobe. Imaging: MR Abdomen without and with intravenous contrast performed at 1.5 T. Axial pre-contrast T1-weighted imaging (a) demonstrates

areas of high signal intensity compatible with internal hemorrhage (white arrow). Axial post-contrast T1weighted imaging (b) shows heterogeneous enhancement with areas of internal necrosis. Sagittal T1-weighted imaging (c) shows heterogeneous enhancement of the large mass centered in the left lobe of the liver with a large partially exophytic component extending caudally

diagnostic criteria of FL-HCC described by Edmondson) were present throughout the entire tumor; and mixed FL-HCC, in which conventional HCC is displayed in at least 1 distinct area of the tumor [65]. The diagnosis of FL-HCC is confirmed by demonstrating the presence of DNAJB1-PRKACA fusion gene which has been shown to be a sensitive marker for FL-HCC [61]. The fusion gene can be detected by RT-PCR or in situ hybridization [61].

8.3

Management

Complete surgical resection is the treatment of choice for FL-HCC [61]. The absence of cirrhosis in many patients diagnosed with FL-HCC makes this a viable option even in the presence of large tumors [61]. The median tumor size of patients undergoing resection is 10.5 cm [61]. LT has been described as a potential therapeutic option for select patients with FL-HCC. An analysis of the

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Fig. 8 Hepatic angiomyolipoma: Pregnant 24-year-old woman presenting with history of tuberous sclerosis, undergoing routine screening. Imaging: Contrastenhanced CT of the abdomen and pelvis and MR of the Abdomen without intravenous contrast at 1.5 T. Axial contrast-enhanced CT images (a) of the mass (white arrows) demonstrates attenuation similar to the subcutaneous fat. In addition to the dominant lesion in segment VII, a second small lesion (open white arrow) with similar imaging characteristics is seen in segment VI on coronal contrast-enhanced CT images (b). On axial T2-weighted

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fat-saturated images (c), the mass loses signal, indicating macroscopic fat content (white arrow). High B-value axial diffusion-weighted images (d) show no restricted diffusion associated with the mass. Note that this patient could not receive IV contrast due to her gravid state; however, vascular components of the AML would enhance avidly. T1weighted in-phase (e) and out-of-phase (f) imaging shows intrinsic high T1 signal intensity of the mass related to fat content. There is loss of signal on the out-of-phase images, compatible with intravoxel lipid

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Clinical Presentation, Diagnosis, and Management of Uncommon Liver Tumors

UNOS database by Atienza et al. evaluated outcomes in patients with FL-HCC undergoing LT between October 1988 and January 2013 [66]. Sixty-three patients with FL-HCC underwent LT for FL-HCC [66]. Overall survival at 1, 3, and 5 years was 96%, 80%, and 48% as compared to HCC patients whose rates were 89%, 77%, and 68% [66]. These findings suggest that transplant outcome for FL-HCC is comparable to that of LT for HCC [66]. The recurrence rate was 10% [66]. The role of systemic chemotherapy for the treatment of FL-HCC is not well defined. Given the rarity of this tumor, no randomized trials have been completed for systemic chemotherapy, and previously findings are limited to small case series [67]. There are prior reports of chemotherapy being used in both the neoadjuvant and adjuvant settings. Previously used regimens include gemcitabineoxaliplatin [68], cisplatin, and fluorouracil [61]. The checkpoint inhibitor pembrolizumab has been investigated in a small series of three patients with reported progression of disease [67].

9

Adult Hepatoblastoma (HB)

9.1

Clinical Presentation

HB is the most common primary malignant liver neoplasm in children with approximately 90% of the cases occurring in patients under 5 years of age [69]. Therefore, the most common clinical presentation will be in pediatric patients. Typical symptoms include weight loss, abdominal pain, fever, and vomiting [69]. A palpable mass of the RUQ or hepatomegaly may be found on physical exam [69].

9.2

Diagnosis

Liver function tests, hepatitis testing, and tumor markers, such as AFP, are not specific [70]. AFP elevation is reported to occur in approximately 90% of pediatric patients and is used as a marker for treatment response [71]. AFP elevation occurs less often in adult HB [71]. The initial diagnosis of HB is usually found on imaging given lack of specific laboratory findings. HB on US will appear as a

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hyperechoic, solid, intrahepatic mass [69]. CT imaging findings characteristic of HB include calcifications, cystic changes, and hypervascularity [70]. MRI findings in Fig. 7 include heterogenous enhancement and areas of necrosis and hemorrhage. The final diagnosis of HB relies on pathology findings. A definitive diagnosis of HB may be difficult to make given the rarity of adult HB and the presence of significant morphological overlap between HB and HCC [72]. The most common cellular components are the hepatoblasts. These are progenitor bipotential cells that can differentiate into hepatocytes or cholangiocytes [71]. Ishak and Glunz classified hepatoblastoma into two groups: an epithelial type and a mixed epithelial and mesenchymal type [70]. Later two additional subtypes were later recognized as macrotrabecular pattern and small cell undifferentiated [72]. Each subtype has its own characteristic histology findings and is accepted to have a prognostic role in the pediatric population [72]. In a study of 40 adult patients with HB by Wang et al., the mixed type of HB was the most common histologic type of adult HB [70].

9.3

Management

There is no standardized approach in the management in adult HB [72]. Radical surgical resection is the most common approach to management [72]. In the pediatric population, cisplatin-based preoperative chemotherapy, followed by surgery, is the accepted standard treatment approach [72]. In a report by Rougemont et al., they suggest adult HB treatment follows the same pediatric regimen [72]. In adults, there are a few cases of pre- and postoperative chemotherapy [70]. Prior chemotherapy protocols used in reported cases of adult HB include platinum, adriamycin, irinotecan, and pirarubicin [70]. Many adult patients with HB present with unresectable disease or develop recurrent disease or extrahepatic metastases after resection [70]. Multimodal treatment with neoadjuvant chemotherapy, surgical resection followed by adjuvant chemotherapy, has been reported to improve outcomes in a few adult cases of HB [70]. The role of chemoembolization was reported by Di Benedetto

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et al. as a rescue treatment for resected HB with recurrence in a patient that survived 11 months after chemoembolization [73]. Standardized guidelines for the treatment of adult HB are still needed [70].

10

Hepatic Angiomyolipoma (AML)

10.1

Clinical Presentation

Hepatic AML is usually found incidentally in asymptomatic patients [74]. Abdominal pain, abdominal fullness, and fever may be present [75]. A palpable mass may be found in physical examination; however, in the majority of patients, physical examination is unrevealing [76]. Spontaneous rupture has been reported [77].

10.2

Histologically as the name indicates, there are three components to hepatic AML consisting of fat, vascular, and smooth muscle components [80]. Mature adipose cells make up the fat components and as mentioned previously occur in variable degrees [80]. The vascular components are usually formed by tortuous blood vessels and thick walled arteries that form islands [80]. The smooth muscle portions are described as spindle cells and epithelioid cells [80]. Tsui et al. proposed four subcategories of tumors based on the predominant tissue type as mixed, lipomatous (>70% fat), myomatous (5 cm. With one point assigned to each criterion, the CRS predicted 5-year survival ranging from 60% to 14% for patients with 0–5 points (R2 0.92, p < 0.01). At that time, the authors concluded that patients with CRS 0–2 have favorable outcomes and should be offered hepatectomy. Patients with CRS 3–4 should be offered hepatectomy in the context of other adjuvant therapies, while CRS 5 suggests a poor prognosis, and surgical therapy should be considered “highly questionable.” While systemic therapies have progressed in the years since its publication, the general stratification of CRS remains applicable when assessing patients with CRLM.

3

Preoperative Management

3.1

Imaging

Multidetector computed tomography (CT) is the most common imaging modality and usually adequate for the preoperative assessment of CRLM. Scans should be performed at a maximum slice thickness of 5 mm (thinner slices through the liver improve the detection of smaller lesions) and evaluate the entire chest, abdomen, and pelvis. An IV contrast bolus followed by pre-contrast, arterial, portal venous, and delayed-phase images helps improve the diagnostic accuracy of CT, as metastatic liver lesions are poorly vascularized and tend to appear more clearly on delayed or venous phases. Arterial phase images are useful

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for diagnosing other benign liver lesions rather than CRLM, as well as highlighting the relevant arterial anatomy. Axial, coronal, and sagittal reconstructions can all be helpful in delineating the anatomy and planning future resections. Magnetic resonance imaging (MRI) is more expensive and time-consuming and requires a significant amount of patient cooperation. While modern CTs are nearly equivalent to MRI in their diagnostic accuracy, in certain settings, MRI may have superior sensitivity and specificity, such as assessing small or indeterminate lesions. It may also be useful in the setting of excessive steatosis that obscures the resolution of CT. Positron-emission tomography with 18fluorodeoxyglucose (FDG-PET) is not routinely performed to assess CRLM. FDG-PET is limited in its sensitivity to detect metabolic activity in small tumors and those previously treated with chemotherapy. Moreover, it is expensive and requires expertise in execution and interpretation that is not available everywhere. While some have suggested FDG-PET can improve lesion detection and prevent futile surgery, a randomized, multiinstitutional trial found FDG-PET did not significantly alter management or change survival for patients with CRLM [5]. Despite this, there are certainly situations where this technology has an impact on clinical decision-making. FDG-PET is helpful in characterizing indeterminate nodal or other soft tissue masses identified on CT or MRI, as well as assessing patients with unremarkable scans and an unexplained rise in their CEA level. FDG-PET is also helpful in assessing the viability of CRLM that have undergone systemic and/or liver-directed therapies but persist as hypointense lesions on standard imaging.

3.2

Resectability

Determining the resectability of a patient with CRLM is a complex and multistep process. The first step in assessing any patient is to determine their cardiopulmonary reserve and overall appropriateness for surgery. Hepatectomy requires a sustained decrease in preload that is required to minimize blood loss during parenchymal

transection, and this can be exacerbated in laparoscopic cases by intra-abdominal insufflation. Mobilization and manipulation of the liver, along with intermittent portal occlusion (Pringle maneuver), can further decrease preload for these patients. Occasionally, surgical misadventure results in blood loss that can add stress to a patient as well. Postoperatively, sufficient overall stamina is required to overcome incisional pain and rehabilitate back to a baseline level of function. With these considerations, chronologic age is not necessarily a contraindication to surgery, but adequate assessment of physiologic age and frailty is paramount. It is also necessary to make a sound determination regarding the “oncologic resectability” of CRLM, in the sense that a benefit must be extended to the patient undergoing surgery. As previously discussed, extrahepatic metastases are not an absolute contraindication to hepatectomy. Such extrahepatic lesions may be addressed simultaneously, sequentially, nonsurgically, or not at all depending on the specific situation. The important distinction to be made is whether resection of the CRLM will extend or improve the patient’s life in a manner that makes accepting the surgical risk worthwhile. Finally, it is important to determine the physical resectability of a patient’s disease, which starts with an accurate assessment of the arterial and venous anatomy as well as identification of all likely malignant lesions. The size and number of lesions are no longer absolute contraindications for surgical resection and/or ablation. The decision to be made is whether all hepatic diseases can be resected with negative margins and preservation of an adequate future liver remnant (FLR). The FLR must have at least two contiguous segments with adequate inflow, outflow, and biliary drainage to survive and sufficient parenchymal volume to meet the patient’s metabolic demands. As a rough estimate, this requires the FLR/total liver volume to be 20–25% for normal livers, >30% for patients who have undergone greater than three months of systemic chemotherapy, and > 40% for patients with liver cirrhosis. As discussed, the process of assessing patients with CRLM and determining overall fitness resectability requires expertise in a variety of

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fields. As such, this is not a practice to be taken lightly and should be centralized in centers with institutional experience in managing this disease. These patients should be presented at a multidisciplinary conference and evaluated by specialists in radiology, pathology, medical oncology, and liver surgery. Moreover, liver surgery is performed by surgeons with various training, in general hepatobiliary, transplant, and oncologic surgeries. These different disciplines offer unique insight and approaches to complex liver disease, and collaboration is helpful in determining the best course for each individual patient scenario.

3.3

Systemic Chemotherapy

In general, patients with metastatic CRC to lymph nodes or other organs should receive systemic chemotherapy. The FOLFOX regimen (leucovorin, 5-fluorouracil, and oxaliplatin) has revolutionized treatment of CRC and greatly improved long-term survival as a standard adjuvant therapy for surgically resected patients with stage III disease. Patients with metastatic disease are often treated with fluorouracil-based combinations including drugs such as irinotecan, bevacizumab, and cetuximab. Decisions regarding perioperative systemic therapy and timing of surgery for CRLM can be complex and are best evaluated by a multidisciplinary team, as described above. There are generally three situations in which patients will present with CRLM that have different implications for systemic therapy: unresectable metastatic disease, synchronous resectable CRLM, and metachronous CRLM. Patients who are unresectable as a result of medical comorbidities are treated with definitive systemic chemotherapy. Surgically appropriate patients who present as initially unresectable due to intra- or extrahepatic tumor characteristics have the potential to be “downstaged” with systemic chemotherapy. Some patients will demonstrate an impressive response to therapy with tumors that shrink and/or disappear on imaging, often corresponding to a decrease in their CEA levels. This response to chemotherapy is perhaps the

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most important prognostic factor and should be considered when evaluating for surgical resectability. Patients who progress or are unchanged on chemotherapy should be spared potentially morbid operations that will not extend their survival. Patients who present with synchronous primary CRC and resectable liver metastases can present a conundrum with many options. Decisions regarding simultaneous versus staged resection are discussed later. Most commonly, these patients will be treated with up-front systemic chemotherapy given their metastatic presentation and often first assessment by a medical oncologist. This also allows time to assess the cancer biology and response to chemotherapy. Patients with stable or decreasing tumor burden on chemotherapy should be evaluated by a surgeon and multidisciplinary team to assess feasibility and timing of resection. Three months (six cycles) of fluorouracil-based chemotherapy are generally accepted as an acceptable preoperative regimen as it provides sufficient treatment for the cancer without excessive exposure to liver toxicity. Chemotherapy-induced liver injury can increase surgical risk and also necessitate a larger FLR, which will become an important topic depending on the size and/or number of liver metastases being addressed. For patients presenting with metachronous CRLM, assessing the tumor-free interval is the most important prognostic indicator. Patients presenting more than a year after their primary CRC resection have the most potential to benefit from resection of their liver metastases, whereas patients presenting with shorter disease-free interval likely have a more biologically aggressive cancer. In these latter patients, systemic therapy is an important first step to assess the response to treatment and overall prognosis of the disease. Patients with oligometastatic disease and a long disease-free interval may benefit more from up-front surgery, especially if they already received adjuvant chemotherapy. Most patients receive adjuvant chemotherapy following complete resection of CRLM. While there are no definitive studies on the topic, most point to the European Organisation for Research

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and Treatment of Cancer (EORTC) 40983 trial for guidance [6]. In this study, patients with resected/ resectable CRC and 1–4 resectable liver metastases were randomized to either surgery alone or surgery plus pre- and postoperative FOLFOX, six cycles each. While chemotherapy was generally well tolerated, this group has significantly more reversible postoperative complications (25% vs 16%, p ¼ 0.04), and one aborted surgery due to liver damage. There were no differences in mortality. When analyzing all randomized patients, there was a nonsignificant improvement in 3-year disease-free survival for the FOLFOX group (35.4% vs 28.1%, HR 0.79, p ¼ 0.058). However, when analyzing only patients who underwent liver resection, there was a significant improvement (42.4% vs 33.2%, HR 0.73, p ¼ 0.025). In the long-term analysis, there was no difference in overall survival (61.3 vs 54.3 months, p ¼ 0.340), but eligible patients did have improved progression-free survival (20.9 vs 12.5 months, p ¼ 0.035) [7]. This trial can be interpreted both ways. On the surface, surgery alone had fewer complications and equivalent survival. However, resected patients in this group had a median overall survival of 73.3 months, which is quite high and likely due to sophisticated imaging and workup (as a function of study participation) or limited tumor burden (52% had one CRLM; 26% had two). This makes it difficult to identify a survival benefit with chemotherapy, similar to other CRC trials. The authors maintain that perioperative chemotherapy for patients with CRLM is compatible with hepatectomy and reduces progression of disease among eligible patients. For patients with up-front surgery or 3 months of preoperative chemotherapy, postoperative chemotherapy should be given to a cumulative treatment of 6 months (12 cycles). Decision-making is less clear for patients who have already completed a full course of systemic chemotherapy prior to their presentation and resection of CRLM. Some practitioners will avoid chemotherapy in patients with long disease-free interval and limited metastatic lesions that are completely resected. For patients with more concerning tumor biology, it may be advisable to treat with a variation of the

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standard FOLFOX regimen, such as FOLFIRI (irinotecan) or FOLFIRINOX (irinotecan and oxaliplatin) with or without the addition of other targeted therapies. Bevacizumab is a humanized antibody to vascular endothelial growth factor (VEGF) that inhibits angiogenesis and is used for metastatic CRC. While potentially protective against liver injury seen with cytotoxic agents, bevacizumab is associated with wound-healing complications and thus requires consideration in surgical planning. Colorectal resections should be scheduled a minimum of 6 weeks after last dose of bevacizumab given the potential for anastomotic leak, while hepatectomy does not appear to be specifically affected. Cetuximab is a monoclonal antibody that inhibits tumor growth by blocking the transmembrane tyrosine kinase epidermal growth factor receptor (EGFR). When combined with standard cytotoxic regimens, cetuximab can improve outcomes for patients with KRAS wild-type tumors, but not KRAS mutants. KRAS testing is increasingly being tested on CRC biopsy and resection specimens to guide treatment. The exact role of bevacizumab, cetuximab, and other experimental therapies and immunotherapies for resectable metastatic CRC is poorly understood; they are generally given in an unresectable metastatic scenario, and some patients will respond well enough that they become potentially resectable. The role of any such agents in the neoadjuvant or adjuvant setting is unclear. These algorithms are continually evolving and, as with many of these decisions, benefit from evaluation by a team of experienced specialists. Certain chemotherapeutic agents can cause liver injury over time that may affect surgical decision-making. Classically, oxaliplatin is associated with a “blue liver” as a result of sinusoidal obstruction and liver congestion, while irinotecan is associated with “yellow liver” as a result of steatohepatitis. These liver changes can also be exacerbated by background fatty liver disease, obesity, metabolic syndrome, alcohol, and other drugs. Similar to other causes of steatohepatitis and cirrhosis, chemotherapy-related liver injury

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can lead to increases in liver-specific and overall morbidity following hepatectomy [8]. In the aforementioned EORTC trial [6], patients receiving six cycles of neoadjuvant FOLFOX prior to liver resection had increased rates of bile leaks and other complications, a finding which has been repeated in other studies. Surgeons also generally consider duration of systemic therapy when calculating the desired FLR, as discussed.

3.4

Locoregional Therapies

Metastatic liver tumors have a predominantly arterial blood supply compared to the native parenchyma which is preferentially supplied by the portal venous system. As a result, arterially directed therapies have a theoretical potential to treat CRLM while minimizing toxicity to the normal liver. A comprehensive review of liverdirected therapies is outside of the scope of this chapter, but we will summarize areas of investigation relevant to surgeons managing this disease. Several techniques for nonsurgical percutaneous treatments are practiced by interventional radiologists. Transarterial chemoembolization (TACE) involves the injection of either embolic agents meant to induce arterial ischemia (bland embolization) or chemotherapeutic drug-eluting beads (DEB-TACE). Transarterial radioembolization (TARE) is a similar technique utilizing microspheres loaded with radioactive yttrium90. These therapies have been shown to extend survival for patients with unresectable CRLM, but there is currently no evidence supporting either as curative or as a strategy for downstaging CRLM to surgically resectable. Select centers offer high-dose locally directed chemotherapy through the hepatic arterial infusion (HAI) pump. This is a surgically implanted subcutaneous port with a catheter that inserts into the hepatic artery via the gastroduodenal artery. The most common agent used in this setting is floxuridine (FUDR), a precursor to 5-fluorouracil with a short half-life and high rate of hepatic extraction. FUDR can be given in high doses via the HAI pump to maximize treatment effect on CRLM while limiting systemic toxicity. Reports from

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high-volume centers have demonstrated impressive treatment effects for these patients. Studies have shown HAI therapy can improve tumor response and extend hepatic progression-free survival, but the overall survival benefit compared to modern chemotherapy remains questionable [9]. Critics cite the primitive systemic therapy regimens used as comparison in early studies and the potential liver-related toxicities seen in some HAI pump patients. Moreover, HAI therapy requires pump filling every 2 weeks by specialized team members, which makes it challenging for many patients due to geographical and transportation issues. The HAI pump remains a potentially powerful tool in the treatment of CRLM with limited dispersion due to technical and logistic challenges.

4

Surgical Approach

4.1

Simultaneous Versus Staged Resection for Synchronous Disease

While there is no consensus definition, “synchronous” liver metastases are generally considered those that appear within 12 months of the primary CRC diagnosis, and there have been multiple proposed strategies for approaching these patients [3]. Some have advocated resecting the primary tumor first, initiating adjuvant systemic therapy, and then monitoring the metastatic disease. For patients with other high-risk features (i.e., high CEA, multiple or large CRLM), this allows the surgeon to assess the biologic nature of the disease. While the majority of patients will respond favorably to treatment, some will progress on systemic chemotherapy and be saved a potentially morbid liver resection that would add nothing to their survival. For patients with stable or improved metastatic disease, hepatectomy can be scheduled after 3 months of chemotherapy in an attempt at cure. Other scenarios where the colon- or rectum-first approach is particularly beneficial include symptomatic primary tumors or impending obstruction. A small proportion of patients with CRLM will have such a dramatic response to treatment that their liver tumors are no longer visual on imaging,

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including PET and MRI. Some advocate the use of fiducial markers to prevent such a situation, but this is not our standard practice. Options for these patients include operative exploration with ultrasound and possible resection or ablation compared to close follow-up with CEA and liver imaging. Intraoperative ultrasound is often able to identify lesions that are invisible on crosssectional imaging. Depending on the lesion size and location, resection based on anatomic location alone may be an option. However, blind major hepatectomy should not be performed for small, deep lesions that have disappeared with systemic therapy. Others have proposed a liver-first approach, with the goal of “controlling” metastatic disease while giving the patient a full course of systemic chemotherapy before definitively resecting their primary tumor. This approach usually starts with 3 months of systemic therapy followed by hepatectomy, continued chemotherapy, and ultimately resection of the primary tumor. There are multiple theoretical benefits to this approach, such as avoiding progression of liver metastases between two major surgeries with a necessary break in chemotherapy. Also, patients with borderline or potentially resectable liver disease have the opportunity to respond favorably to systemic therapy and become more technically resectable. This strategy is obviously contraindicated in the setting of primary tumors that are either bleeding or causing partial or complete obstructions. For asymptomatic primary tumors, there is little risk in developing symptoms during treatment. In fact, the liver-first approach may specifically benefit locally advanced rectal tumors by downstaging them to resectable. There is also a growing potential for organ preservation with a complete or near-complete response to chemotherapy and/or radiation. While a detailed discussion of chemoradiation regimens for these tumors is outside of the scope of this chapter, addressing liver disease up front theoretically prevents disease progression during these treatments. Perhaps the greatest advantage of the liver-first approach is the associated chemotherapy schedule. Longer courses of chemotherapy are associated with liver injury and increased complications after

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hepatectomy. Therefore, performing liver resection earlier in the treatment course may mitigate these risks. The same risks are not seen following colorectal resection. Conversely, anastomotic leaks and infectious complications are a greater risk following colorectal rather than liver surgery. These can lead to substantial delays in systemic treatment which put overall cancer survival at risk. A third option is to resect the primary tumor and liver metastases simultaneously with chemotherapy before and/or after the surgery. Simultaneous colectomy and minor hepatectomy are safe in appropriately selected patients and in the hands of trained experts. Much of the early experience with simultaneous resection involved right hemicolectomy with only minor liver resections. These studies demonstrated acceptable outcomes, and surgeons subsequently expanded indications for this simultaneous approach. Adequate comparison of the various trials on this topic is difficult given the heterogeneity of patients, procedures, and complication definitions [3]. Available data are all retrospective and are skewed toward patients requiring straightforward colon resections and hepatectomies of three or fewer segments. In this setting, the simultaneous approach has been found to carry acceptable risk and an overall shorter hospitalization than two separate procedures. The decision to approach more substantial resections must be made carefully and is most often limited by the extent of hepatectomy required. The mortality rate for right hepatectomy alone is less than 3%, and minor hepatectomy combined with colorectal resection is less than 2%. However, the mortality rate for combined colorectal resection and major hepatectomy can be as high as 5–8% [3]. Moreover, it should be understood that these procedures require contingency plans. If the first planned procedure is complicated by difficulties, extended operative time, or excessive blood loss, then the team should consider completing the case and addressing subsequent resections at a future time. The benefit of a combined procedure can only be realized in the setting of a reasonable anesthetic time with hemodynamic stability and no undue physiologic stress on the patient.

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Treatment of Liver Metastases from Colorectal Cancer

Recurrence rates and overall survival appear similar between patients undergoing staged and combined procedures in the available studies and meta-analyses. As such, it appears that the most significant benefit of combining these procedures is to minimize resource utilization and the amount of time patients spend in the hospital. This benefit must be weighed against the risk of prolonged or difficult combined cases or the higher rates of morbidity and mortality associated with certain combined cases. The laparoscopic approach to simultaneous resection has also been found to have acceptable outcomes for these patients, although several caveats are important to mention. These studies are all retrospective and include a significant selection bias, whereby hepatectomies tended to be minor and for small and/or solitary metastases and colorectal resections tended to be for rectal tumors. Frequently, surgeons will perform part of all of the colorectal mobilization in a minimally invasive fashion and convert to open to finish and perform the hepatectomy. Other cases involve a minimally invasive resection or ablation of a single small CRLM along with colon resection. The proposed benefits of minimally invasive surgery are decreased pain and improved recovery.

205

Performing an unnecessarily difficult laparoscopic resection, either due to tumor location or surgeon experience, may incur greater risk than reward. Based on available data, combined colorectal and liver resections for small or straightforward tumors can improve the patient’s overall experience, but such cases are infrequent and should only be performed by surgeons with extensive minimally invasive experience.

4.2

Minimally Invasive Surgery

Over the past 20 years, surgeons have been increasingly utilizing minimally invasive approaches to surgery for CRLM (Table 1). The proposed benefits were less pain and faster recovery for patients undergoing laparoscopic liver resection (LLR) when compared to the traditional open technique (OLR). However, there were several concerns with applying laparoscopy to such a technically difficult and high-risk operation, such as uncontrollable bleeding, air embolism, inadequate oncologic resection, and port site recurrence. Despite this, many centers began to experiment with laparoscopic and robotic hepatectomy, and we now have several retrospective

Table 1 List of studies comparing 5-year overall survival between robotic, laparoscopic, and open liver resection First author Castaing [10] Topal [11] Cannon [12] Iwahashi [13] Montalti [14] Beppu [15] Allard [16] de’Angelis [17] Hasegawa [18] Lin [19] Cipriani [20] Lewin [21] Goumard [22] Efanov [23] Beard [24]

No. of patients LLR/OLR 60/60 20/20 35/140 21/21 57/57 171/342 73/73 52/52 102/69 36/36 133/133 140/122 43/121 20/20 LLR/RLR 514/115

Year

Journal

2009 2012 2012 2014 2014 2015 2015 2015 2015 2015 2016 2016 2018 2020

Ann Surg Surg Endosc Surgery Surg Endosc E J Surg Oncol J HPB Sci Ann Surg J Lap Adv Surg Tech Surgery Int J Colorectal Dis Br J Surg HPB HPB Surg Endosc

2020

World J Surg

Overall survival, % LLR OLR 64 56 48 46 36 42 42 51 60 65 70 68 78 75 73 62 57 49 51 55 64 63 54 63 81 68 60 65 LLR RLR 60 61

LLR laparoscopic liver resection, NS not significant, OLR open liver resection, RLR robotic liver resection

P value NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS

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and prospective studies to assess the safety and efficacy of the technique. A 2011 review identified 31 studies that compared LLR to OLR with over 1000 patients in each group [25]. LLR was associated with equivalent operative time, less blood loss, fewer blood transfusions, less postoperative pain and narcotic use, faster return to oral intake, less overall morbidity, and shorter hospital length of stay. Most importantly, there were no oncologic disadvantages identified for the LLR group, a concern which had prevented many from adopting this approach. This analysis included all tumor types, of which 35% were CRLM. Bagante et al. [26] performed a propensity score matched analysis of 1218 patients undergoing LLR and OLR in the National Surgical Quality Improvement Program Database and found LLR to have lower rates of postoperative blood transfusion, surgical site infection, liver failure, bile leak, pulmonary embolism, and length of stay. Again, this was a heterogenous group of indications for hepatectomy. Specific to CRLM, Nguyen et al. [27] performed a retrospective review of 109 patients at six centers who underwent LLR for a combination of major (45%) and minor (55%) hepatectomies with a mortality rate of 0% and morbidity rate of 13%. With regard to oncologic outcomes, the observed margin negativity was 94%, and overall survival at 1, 3, and 5 years was 88%, 69%, and 50%, respectively. Castaing et al. [10] performed a matched analysis of 120 patients at two centers in France and found no difference between LLR and OLR with regard to overall or disease-free survival. In the years since these studies were published, multiple others have demonstrated oncologic adequacy of LLR for CRLM. A meta-analysis of case-matched studies by Schiffman et al. [28] found either equivalent or superior surgical outcomes for patients undergoing LLR compared to OLR. When analyzing oncologic outcomes at 5 years, LLR had statistically equivalent diseasefree survival (32% vs 26%) and overall survival (51% vs 46%). Importantly, the authors note that the median number of tumors in each group was 1.4 and 1.5, and thus, their findings may only be

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extrapolated to patients with “a limited number” of CRLM (one or two metastases). The authors suggest that the “ideal candidates” for LLR are those with a single tumor 30 ng/mL, greater than 3–5 tumors, tumor size >5 cm, unresponsiveness to chemotherapy). Some have advocated including surgical right portal vein ligation at the time of the first-stage hepatectomy in order to reduce overall time and opportunity for tumor progression. This can be done with surgical dissection and ligation of the necessary portal vein branch, but such technique may result in inflammation and adhesions that distort the anatomy and make the second-stage procedure unnecessarily difficult. A more preferable option may be percutaneous PVE in the immediate postoperative period prior to discharge. For hospitals with the technological capabilities, performing the first-stage hepatectomy in a hybrid operating room can allow interventional radiologists to perform the PVE immediately following and under the same anesthesia as the minor hepatectomy. All of these approaches eliminate the 3–4-week waiting period between first-stage hepatectomy and PVE and cut in half the overall time of the two-stage approach. Consideration of these techniques requires specific institutional capabilities and surgeon experience.

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Associated Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS)

A recent novel approach to the two-stage hepatectomy known as associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) has generated much controversy. In the first operation, FLR left lobe clearance is performed along with right portal vein ligation (with or without right hepatic duct division) and liver parenchymal transection. This liver transection dramatically enhances the FLR hypertrophy such that the second-stage hepatectomy can be performed 1–2 weeks later. However, this procedure was initially associated with high rates of morbidity and mortality that limited its widespread adoption. A 2016 French report compared patients undergoing ALPPS and conventional two-stage hepatectomy at a single center; patients had a median of ten liver lesions and median size 4–5 cm [43]. While 17/17 patients completed ALPPS, 15/41 patients did not complete the two-stage hepatectomy. There were no differences in major complications or 90-day mortality, but the ALPPS group had inferior 2-year survival (42% vs 77%, p < 0.01), more liver recurrence, and fewer salvage surgeries. An Italian study of 26 patients undergoing ALPPS demonstrated a 49% 3-year overall survival, with worse median overall survival among KRAS mutant (15 vs 38 months, p < 0.01) [44]. These patients had a median number of five lesions and median size of 6 cm, and 85% had bilobar disease. A recent study of an international ALPPS registry between 2012 and 2017 examined 403 patients who underwent either right hepatectomy or right trisectionectomy for CRLM [45]. There were no differences between groups in the number or volume of tumors in segments II/III, but the right hepatectomy group had larger total liver volume and FLR compared to the trisectionectomy group. Regarding indications for ALPPS, they found a large proportion of patients did not meet generally accepted criteria for needing a two-stage hepatectomy, even after controlling for chemotherapy-induced liver injury. While original

indications were based on a liver to bodyweight ratio of 0.5, given the associated high risk of ALPPS and two-stage hepatectomy, a ratio of 0.3 is more commonly accepted as an indication for staged hepatectomy. In this study, 19% of patients underwent ALPPS with a preoperative liver to bodyweight ratio of 0.5 and fewer than 12 cycles of preoperative chemotherapy. The authors concluded that, given the criticisms of high morbidity and mortality, more stringent indications based on objective criteria might prevent unnecessary ALPPS procedures and subsequent poor outcomes. At this time, ALPPS has been associated with considerable risk and no clear benefit over traditional two-stage hepatectomy. Future studies will be informative as centers continue to hone the indications and technique of this complicated procedure. Until then, widespread adoption will likely remain limited.

5

Surveillance and Follow-Up

Following surgery for CRLM, standard surveillance regimens should be applied. A single postoperative surgical follow-up appointment should be performed according to surgeon preference. Our typical surveillance is CEA level and contrast CT or MRI every 4 months in year 1 and then twice a year in years 2–5 post-op, followed by once a year in years 6–10. When a recurrence is identified, these patients are offered repeat hepatectomy whenever possible. They are also discussed in a multidisciplinary liver tumor board, as the treatment options are constantly evolving.

References 1. Kopetz S, Chang GJ, Overman MJ, Eng C, Sargent DJ, Larson DW, Grothey A, Vauthey JN, Nagorney DM, McWilliams RR. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol. 2009;27(22):3677–83. 2. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230(3):309–18; discussion 318–321

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3. Krell RW, D’Angelica MI. Treatment sequencing for simultaneous colorectal liver metastases. J Surg Oncol. 2019;119(5):583–93. 4. Vauthey JN, Kawaguchi Y. Innovation and future perspectives in the treatment of colorectal liver metastases. J Gastrointest Surg. 2020;24(2):492–6. 5. Moulton CA, Gu CS, Law CH, Tandan VR, Hart R, Quan D, Fairfull Smith RJ, Jalink DW, Husien M, Serrano PE, et al. Effect of pet before liver resection on surgical management for colorectal adenocarcinoma metastases: a randomized clinical trial. JAMA. 2014;311(18):1863–9. 6. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, et al. Perioperative chemotherapy with folfox4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (eortc intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371(9617):1007–16. 7. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, et al. Perioperative folfox4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (eortc 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14(12):1208–15. 8. Zhao J, van Mierlo KMC, Gómez-Ramírez J, Kim H, Pilgrim CHC, Pessaux P, Rensen SS, van der Stok EP, Schaap FG, Soubrane O, et al. Systematic review of the influence of chemotherapy-associated liver injury on outcome after partial hepatectomy for colorectal liver metastases. Br J Surg. 2017;104(8):990–1002. 9. Abdalla EK, Bauer TW, Chun YS, D’Angelica M, Kooby DA, Jarnagin WR. Locoregional surgical and interventional therapies for advanced colorectal cancer liver metastases: expert consensus statements. HPB (Oxford). 2013;15(2):119–30. 10. Castaing D, Vibert E, Ricca L, Azoulay D, Adam R, Gayet B. Oncologic results of laparoscopic versus open hepatectomy for colorectal liver metastases in two specialized centers. Ann Surg. 2009;250(5):849–55. 11. Topal H, Tiek J, Aerts R, Topal B. Outcome of laparoscopic major liver resection for colorectal metastases. Surg Endosc. 2012;26(9):2451–5. 12. Cannon RM, Scoggins CR, Callender GG, McMasters KM, Martin RC. Laparoscopic versus open resection of hepatic colorectal metastases. Surgery. 2012;152(4): 567–73; discussion 573–564 13. Iwahashi S, Shimada M, Utsunomiya T, Imura S, Morine Y, Ikemoto T, Arakawa Y, Mori H, Kanamoto M, Yamada S. Laparoscopic hepatic resection for metastatic liver tumor of colorectal cancer: comparative analysis of short- and long-term results. Surg Endosc. 2014;28(1):80–4. 14. Montalti R, Berardi G, Laurent S, Sebastiani S, Ferdinande L, Libbrecht LJ, Smeets P, Brescia A, Rogiers X, de Hemptinne B, et al. Laparoscopic liver resection compared to open approach in patients with colorectal liver metastases improves further

211 resectability: oncological outcomes of a case-control matched-pairs analysis. Eur J Surg Oncol. 2014;40(5): 536–44. 15. Beppu T, Wakabayashi G, Hasegawa K, Gotohda N, Mizuguchi T, Takahashi Y, Hirokawa F, Taniai N, Watanabe M, Katou M, et al. Long-term and perioperative outcomes of laparoscopic versus open liver resection for colorectal liver metastases with propensity score matching: a multi-institutional Japanese study. J Hepatobiliary Pancreat Sci. 2015;22(10):711–20. 16. Allard MA, Cunha AS, Gayet B, Adam R, Goere D, Bachellier P, Azoulay D, Ayav A, Navarro F, Pessaux P, et al. Early and long-term oncological outcomes after laparoscopic resection for colorectal liver metastases: a propensity score-based analysis. Ann Surg. 2015;262(5):794–802. 17. de’Angelis N, Eshkenazy R, Brunetti F, Valente R, Costa M, Disabato M, Salloum C, Compagnon P, Laurent A, Azoulay D. Laparoscopic versus open resection for colorectal liver metastases: a single-center study with propensity score analysis. J Laparoendosc Adv Surg Tech A. 2015;25(1):12–20. 18. Hasegawa Y, Nitta H, Sasaki A, Takahara T, Itabashi H, Katagiri H, Otsuka K, Nishizuka S, Wakabayashi G. Long-term outcomes of laparoscopic versus open liver resection for liver metastases from colorectal cancer: a comparative analysis of 168 consecutive cases at a single center. Surgery. 2015;157(6):1065–72. 19. Lin Q, Ye Q, Zhu D, Wei Y, Ren L, Zheng P, Xu P, Ye L, Lv M, Fan J, et al. Comparison of minimally invasive and open colorectal resections for patients undergoing simultaneous r0 resection for liver metastases: a propensity score analysis. Int J Color Dis. 2015;30(3):385–95. 20. Cipriani F, Rawashdeh M, Stanton L, Armstrong T, Takhar A, Pearce NW, Primrose J, Abu Hilal M. Propensity score-based analysis of outcomes of laparoscopic versus open liver resection for colorectal metastases. Br J Surg. 2016;103(11):1504–12. 21. Lewin JW, O’Rourke NA, Chiow AKH, Bryant R, Martin I, Nathanson LK, Cavallucci DJ. Long-term survival in laparoscopic vs open resection for colorectal liver metastases: inverse probability of treatment weighting using propensity scores. HPB (Oxford). 2016;18(2):183–91. 22. Goumard C, Nancy You Y, Okuno M, Kutlu O, Chen HC, Simoneau E, Vega EA, Chun YS, David Tzeng C, Eng C, et al. Minimally invasive management of the entire treatment sequence in patients with stage iv colorectal cancer: A propensity-score weighting analysis. HPB (Oxford). 2018;20(12):1150–6. 23. Efanov M, Granov D, Alikhanov R, Rutkin I, Tsvirkun V, Kazakov I, Vankovich A, Koroleva A, Kovalenko D. Expanding indications for laparoscopic parenchyma-sparing resection of posterosuperior liver segments in patients with colorectal metastases: comparison with open hepatectomy for immediate and long-term outcomes. Surg Endosc. 2020. 24. Beard RE, Khan S, Troisi RI, Montalti R, Vanlander A, Fong Y, Kingham TP, Boerner T, Berber E,

212 Kahramangil B, et al. Long-term and oncologic outcomes of robotic versus laparoscopic liver resection for metastatic colorectal cancer: a multicenter, propensity score matching analysis. World J Surg. 2020;44(3):887–95. 25. Nguyen KT, Marsh JW, Tsung A, Steel JJ, Gamblin TC, Geller DA. Comparative benefits of laparoscopic vs open hepatic resection: a critical appraisal. Arch Surg. 2011;146(3):348–56. 26. Bagante F, Spolverato G, Strasberg SM, Gani F, Thompson V, Hall BL, Bentrem DJ, Pitt HA, Pawlik TM. Minimally invasive vs. open hepatectomy: a comparative analysis of the national surgical quality improvement program database. J Gastrointest Surg. 2016;20(9):1608–17. 27. Nguyen KT, Laurent A, Dagher I, Geller DA, Steel J, Thomas MT, Marvin M, Ravindra KV, Mejia A, Lainas P, et al. Minimally invasive liver resection for metastatic colorectal cancer: a multi-institutional, international report of safety, feasibility, and early outcomes. Ann Surg. 2009;250(5):842–8. 28. Schiffman SC, Kim KH, Tsung A, Marsh JW, Geller DA. Laparoscopic versus open liver resection for metastatic colorectal cancer: a metaanalysis of 610 patients. Surgery. 2015;157(2):211–22. 29. Fretland Å, Dagenborg VJ, Bjørnelv GMW, Kazaryan AM, Kristiansen R, Fagerland MW, Hausken J, Tønnessen TI, Abildgaard A, Barkhatov L, et al. Laparoscopic versus open resection for colorectal liver metastases: the oslo-comet randomized controlled trial. Ann Surg. 2018;267(2):199–207. 30. Robles-Campos R, Lopez-Lopez V, Brusadin R, Lopez-Conesa A, Gil-Vazquez PJ, Navarro-Barrios Á, Parrilla P. Open versus minimally invasive liver surgery for colorectal liver metastases (lapophuva): a prospective randomized controlled trial. Surg Endosc. 2019;33(12):3926–36. 31. Ciria R, Ocaña S, Gomez-Luque I, Cipriani F, Halls M, Fretland Å, Okuda Y, Aroori S, Briceño J, Aldrighetti L, et al. A systematic review and metaanalysis comparing the short- and long-term outcomes for laparoscopic and open liver resections for liver metastases from colorectal cancer. Surg Endosc. 2020;34(1):349–60. 32. Syn NL, Kabir T, Koh YX, Tan HL, Wang LZ, Chin BZ, Wee I, Teo JY, Tai BC, Goh BKP. Survival advantage of laparoscopic versus open resection for colorectal liver metastases: a meta-analysis of individual patient data from randomized trials and propensityscore matched studies. Ann Surg. 2019. 33. Kawai T, Goumard C, Jeune F, Savier E, Vaillant JC, Scatton O. Laparoscopic liver resection for colorectal liver metastasis patients allows patients to start adjuvant chemotherapy without delay: a propensity score analysis. Surg Endosc. 2018;32(7):3273–81. 34. Mbah N, Agle SC, Philips P, Egger ME, Scoggins CR, McMasters KM, Martin RCG. Laparoscopic hepatectomy significantly shortens the time to postoperative

R. S. Hoehn et al. chemotherapy in patients undergoing major hepatectomies. Am J Surg. 2017;213(6):1060–4. 35. Tohme S, Goswami J, Han K, Chidi AP, Geller DA, Reddy S, Gleisner A, Tsung A. Minimally invasive resection of colorectal cancer liver metastases leads to an earlier initiation of chemotherapy compared to open surgery. J Gastrointest Surg. 2015;19(12):2199–206. 36. Montalti R, Scuderi V, Patriti A, Vivarelli M, Troisi RI. Robotic versus laparoscopic resections of posterosuperior segments of the liver: a propensity scorematched comparison. Surg Endosc. 2016;30(3): 1004–13. 37. Tsung A, Geller DA, Sukato DC, Sabbaghian S, Tohme S, Steel J, Marsh W, Reddy SK, Bartlett DL. Robotic versus laparoscopic hepatectomy: a matched comparison. Ann Surg. 2014;259(3):549–55. 38. Wakabayashi G, Cherqui D, Geller DA, Buell JF, Kaneko H, Han HS, Asbun H, OʼRourke N, Tanabe M, Koffron AJ, et al. Recommendations for laparoscopic liver resection: a report from the second international consensus conference held in Morioka. Ann Surg. 2015;261(4):619–29. 39. Sucandy I, Cheek S, Golas BJ, Tsung A, Geller DA, Marsh JW. Longterm survival outcomes of patients undergoing treatment with radiofrequency ablation for hepatocellular carcinoma and metastatic colorectal cancer liver tumors. HPB (Oxford). 2016;18(9):756–63. 40. Abdalla EK, Vauthey JN, Ellis LM, Ellis V, Pollock R, Broglio KR, Hess K, Curley SA. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg. 2004;239(6):818–25; discussion 825–817 41. Tinguely P, Dal G, Bottai M, Nilsson H, Freedman J, Engstrand J. Microwave ablation versus resection for colorectal cancer liver metastases – a propensity score analysis from a population-based nationwide registry. Eur J Surg Oncol. 2020;46(3):476–85. 42. Takahashi H, Berber E. Role of thermal ablation in the management of colorectal liver metastasis. Hepatobiliary Surg Nutr. 2020;9(1):49–58. 43. Adam R, Imai K, Castro Benitez C, Allard MA, Vibert E, Sa Cunha A, Cherqui D, Baba H, Castaing D. Outcome after associating liver partition and portal vein ligation for staged hepatectomy and conventional two-stage hepatectomy for colorectal liver metastases. Br J Surg. 2016;103(11):1521–9. 44. Serenari M, Alvarez FA, Ardiles V, de Santibañes M, Pekolj J, de Santibañes E. The alpps approach for colorectal liver metastases: impact of kras mutation status in survival. Dig Surg. 2018;35(4):303–10. 45. Schnitzbauer AA, Schadde E, Linecker M, Machado MA, Adam R, Malago M, Clavien PA, de Santibanes E, Bechstein WO. Indicating alpps for colorectal liver metastases: a critical analysis of patients in the international alpps registry. Surgery. 2018;164(3): 387–94.

Treatment of Isolated Liver Metastasis from Non-colorectal Cancer

12

John B. Martinie, Benjamin M. Motz, and Jordan N. Robinson

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214

2 2.1 2.2 2.3

Neuroendocrine Liver Metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Perioperative Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management of Metastatic Neuroendocrine Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

215 215 215 215

Non-Colorectal Non-Neuroendocrine Liver Metastases . . . . . . . . . . . . . . . . . . . . . . Series Evaluating Multiple Metastatic Tumor Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Series Evaluating Single Metastatic Tumor Type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Minimally Invasive Liver Surgery for Non-Colorectal Non-Neuroendocrine Liver Metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Thermal Ablation for Non-Colorectal Non-Neuroendocrine Liver Metastases . . .

219 219 221

3 3.1 3.2 3.3

4

229 230

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

Abstract

Liver metastases from a wide variety of malignancies are a major source of cancer-related morbidity and mortality, and because they are so common, they contribute to a substantial portion of the modern hepatobiliary surgeon’s practice. Traditionally, metastatic liver lesions have portended a poor long-term prognosis. However, with advances in multimodal

J. B. Martinie (*) · B. M. Motz · J. N. Robinson Atrium Health, Charlotte, NC, USA e-mail: [email protected]; [email protected]; [email protected]

treatment of colorectal cancer, the most common primary site for metastatic liver lesions, as well as advances in the operative and perioperative care of patients undergoing liver resection, there have been dramatic improvements in long-term outcomes for patients with colorectal liver metastases. More recently, a similar approach has been used in non-colorectal liver metastases with apparent long-term survival benefits. The wide variety of primary tumor sites has complicated the study of these lesions, and their management therefore remains unclear. However, numerous studies over the last decade evaluating grouped cohorts of miscellaneous non-colorectal liver metastases, and several focused studies evaluating metastases from

© Springer Nature Switzerland AG 2022 C. Doria, J. N. Rogart (eds.), Hepato-Pancreato-Biliary Malignancies, https://doi.org/10.1007/978-3-030-41683-6_9

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single primary sites, have shown a benefit to liver-directed therapy in the setting of isolated liver metastases from non-colorectal primaries. This chapter will review the current literature on this topic. Keywords

Liver metastases · Non-colorectal · Hepatectomy · Laparoscopic liver surgery · Liver ablation

1

Introduction

Due to the liver’s role as a filtration organ and with dual blood supply from portal venous and systemic arterial circulations, it is a common site of distant metastasis for numerous malignancies. In fact, large autopsy series have shown that 50% of all cancer patients and up to 65% of patients with colon cancer have evidence of metastatic liver lesions [58]. Many of these metastases come from gastrointestinal (such as colorectal, gastric, pancreatic, etc.), lung, and breast cancer primaries, though any cancer that spreads hematogenously may metastasize to the liver. Often, hepatic involvement is the proximate cause of death for patients with metastatic cancer. Without treatment, long-term survival rates are expectedly poor, making the directed management of liver metastases an important component of cancer care in the twenty-first century. The management of metastatic cancer has changed dramatically over the last several decades. Chemotherapeutic regimens are continually improving, with improved response rates and prolonged survival seen for multiple cancers. Numerous genetic markers have been identified which now serve as targets for some of these regimens and allow for a personalized approach to each patient’s particular tumor biology. Even more recently, immunotherapy has arisen as a promising new approach for which new applications are under widespread investigation. Regardless, for many cancers, surgical resection has classically been considered the only opportunity for cure, but high perioperative morbidity has

limited the ability of surgeons to offer metastasectomy until recent decades. As surgical techniques and postoperative morbidity and mortality have improved, the opportunity for a cure has become available, even to patients with metastatic cancer. Management of colorectal liver metastases (CRLM) will be covered in detail in another chapter; however, the management of these lesions has certainly informed the management of other, noncolorectal liver metastases (NCRLM). Experience with liver resection for metastatic colorectal cancer over the last two decades has shown a significant improvement in oncologic outcomes, with median survival up to 74 months and 5-year overall survival of 58% in one large series published in 2005 [47]. Improvements in perioperative anesthesia care, operative technique, and postoperative management of patients undergoing hepatectomy have resulted in decreased morbidity and mortality of liver surgery [2, 30], making this an attractive option for patients with isolated liver metastases from an array of non-colorectal primary sites. Further advancements in the field of thermal ablation using radiofrequency, and more recently, microwave technologies have further decreased morbidity and allow for treatment of lesions that may be unresectable [1]. Despite these advancements, the role of liver-directed therapy in patients with NCRLM remains unclear. It is evident that patients with extrahepatic sites of metastasis and with shorter disease-free intervals between treatment of their primary tumor and development of hepatic metastasis benefit less from liver-directed therapy [4, 31], though for selected patients, liver resection is associated with long-term survival [4]. Despite the apparent benefits, liver-directed therapy for NCRLM remains fairly uncommon, and most series in this area include multiple disparate tumor types due to relatively low case numbers [2, 12, 63]. The exception to this is for patients with liver metastases from neuroendocrine tumors (NETs) who clearly are a unique group with a better prognosis than other patients with NRCLM [10, 54]. This distinction has allowed for the development of specific recommendations regarding the management of patient with

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Treatment of Isolated Liver Metastasis from Non-colorectal Cancer

metastatic NETs [45, 46]. Because of these differences, it is informative to divide NCRLM into two distinct categories: neuroendocrine liver metastases (NELM) and non-colorectal non-neuroendocrine liver metastases (NCNNLM).

2

Neuroendocrine Liver Metastases

2.1

Background

Neuroendocrine tumors are a heterogenous clinical entity manifesting a variety of biological behaviors and clinical presentations. Consequentially, they produce disparate symptomatology and prognoses based on tumor differentiation and functionality. As previously noted, the liver is one of the most common sites of metastasis from gastrointestinal tract (GI) malignancies, and NETs conform to this pattern. Although NETs are not exclusively of GI origin, most NELMs are of GI or pancreatic origin [49]. Such tumors are termed gastroenteropancreatic (GEP) and are classically divided into carcinoid and non-carcinoid subtypes. Further categorization divides them based on functionality and site of origin (Fig. 1). Additionally, NETs can be benign or malignant, with malignant tumors stratified into low and intermediate grades (well-differentiated) or highgrade (poorly differentiated) classifications [9]. For NETs, the grade of the tumor followed by the presence of metastasis is the most important prognostic factor [44]. Functional NETs secrete a variety of peptides and hormones which, when manifested clinically, are termed endocrinopathies. Hepatic metastasis is required for these products to bypass hepatic degradation and become clinically evident. The presence of endocrinopathies and tumor grade are essential considerations informing management strategies [24]. Importantly, the natural history for progression of NELMs tends to be protracted compared to other malignancies, often leading to a more indolent clinical course with 5-year survival approaching 30% [37]. Consequentially, debulking and cytoreductive strategies are effective for palliation and prolonging survival [45, 46].

2.2

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Perioperative Considerations

2.2.1 Carcinoid Disease During preoperative evaluation for patients with GI carcinoids, consideration of carcinoid syndrome and carcinoid heart disease are essential. Individuals with carcinoid syndrome should receive a somatostatin analogue preoperatively and intraoperatively to prevent carcinoid crisis [43]. Evaluation of carcinoid heart disease requires a thorough cardiac evaluation [17], and following objective evaluation of cardiac function, patients may be candidates for hepatic resection [11, 32]. Once deemed an appropriate candidate for major surgery, survival is improved for patients who undergo hepatic resection, with liver resection serving as an independent predictor of decreased risk of progression of cardiac disease (OR ¼ 0.29; 95% CI ¼ 0.06–0.75; p ¼ 0.03) [38]. 2.2.2 Patient Selection Knowledge of the prognostic factors related to each patient’s disease is essential for patient selection and management strategy. Generally, resection is reserved for low to intermediate grade NETs that are well-differentiated, with Ki-67 >20% defining high-grade tumors. Additionally, the primary tumor should be resectable with minimal extrahepatic disease present [20]. Tumor location relative to vital structures should be considered in addition to the postoperative size of the liver remnant. Stratification of preoperative risk can further inform therapeutic options with numerous, effective liver-directed alternatives to hepatic resection available.

2.3

Management of Metastatic Neuroendocrine Tumors

Current recommendations and guidelines regarding hepatectomy for NELMs are primarily based on small retrospective studies as study populations are constrained by low disease incidence. To date, no randomized control trials evaluating liver-directed therapy for NELMs have shown improvement in survival. There are numerous studies, however, suggesting therapeutic

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Esophagus

Stomach Gastrinoma Foregut

Duodenum Insulinoma Biliary tree Glucagonoma Pancreas

VIPoma Small bowel (jejunum, ileum)

Gastrointestinal Tract

Somatostatinoma Midgut

Appendix Pancreatic polypeptidoma Cecum/proximal colon

Distal colon Hindgut Rectum

Fig. 1 Hierarchy of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), categorized by site of origin, organ subtype, and functional status

benefit for cytoreduction and debulking strategies for patients with NELMs.

2.3.1 Hepatic Resection One large, multicenter study examined outcomes for liver-directed surgery in the treatment of NELMs [35]. This study reviewed data from patients who underwent surgical intervention for NELMs from 1989 to 2009 using an international database comprised from eight major hepatobiliary centers. The cohort consisted of patients with primarily pancreatic and small

bowel neuroendocrine tumors, 40% and 25%, respectively. 84.7% had previously undergone resection of their primary tumor. Only 35.4% of patients underwent preoperative systemic therapy, with most of them receiving octreotide. 78% of patients underwent hepatic resection, 3% underwent ablation alone, and 19% underwent a combination of resection and ablation. Following liver-directed surgery, patients were followed for a median of 43.3 months. Median overall survival was 125.1 months, with 5-year and 10-year survival of 74% and 51%,

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Treatment of Isolated Liver Metastasis from Non-colorectal Cancer

respectively. On multivariable analysis, improved survival was associated with R1 or R0 resection and hormonally functional neuroendocrine tumors. The vast majority of patients ultimately developed a recurrence or progression of their disease, with the liver being the most common site for recurrence. One-year, 3-year, and 5-year progression/disease-free survival was 56.9%, 24.2%, and 5.9%, respectively. This is consistent with findings from numerous studies that have also found near universal recurrence following hepatic resection for NELMs [53]. Traditionally, the ability to address a minimum of 90% of the hepatic metastasis tumor volume via resection or ablation was used as the recommended threshold for operative intervention; however, more recent data suggest outcomes with as little as 70% resection/ablation [57]. A study by Scott et al. [55] identified patients who underwent hepatic cytoreductive surgery for GEP NELMs to assess overall survival and progression-free survival across stratified groups based on number of metastases. Imaging was used to determine the percentage of cytoreduction achieved. Cytoreduction of greater than 70% was associated with significantly better overall survival than less than 70% (134 months versus 38 months). There were no significant differences in survival based on number of metastases. Morgan and colleagues noted similar findings in their study with no significant difference in survival outcomes after 70%, 90%, and 100% resection of tumor volume [40].

2.3.2 Transcatheter Embolization For patients who are not candidates for surgical resection, several other liver-directed therapies can aid in locoregional control, palliation, and extension of progression-free survival (PFS). These modalities include bland hepatic artery embolization, transarterial chemoembolization (TACE) with the addition of chemotherapy, and radioembolization (TARE) with the addition of yttrium-90. Transarterial embolization is useful as palliation for patients with multifocal, bilobar disease who are not amenable to surgery. A recent multi-institutional analysis compared outcomes for TACE and TARE with yttrium-90 in the

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setting of NELMs. Long-term outcomes were comparable, with both deemed safe and effective in cases of unresectable NELMs; however, shorter hospital length of stay was observed in patients receiving TARE, and improved short-term disease control rate was noted for TACE [14].

2.3.3 Thermal Ablation Additionally, thermal ablation with radiofrequency ablation (RFA) and microwave ablation (MWA) may be used for the management of NELMs, either in conjunction with hepatic resection or alone (Fig. 2). A large, multi-institutional analysis noted its safety in application to 20% of the study population with similar rates of disease recurrence and survival as compared to patients undergoing hepatic resection [35]. RFA, performed either percutaneously or operatively, is the most commonly employed ablative technique with many studies noting its safety and efficacy [7, 59]. In one recent study evaluating outcomes following RFA for multiple tumor types, tumor size less than 3 cm is associated with decreased local recurrence, a major indicator of complete ablation [59]. In this series, local recurrence for neuroendocrine tumors following RFA was uncommon (3.3%), while local recurrence for other tumor types was significantly higher. 2.3.4 Hepatic Transplantation Orthotopic liver transplantation (OLT) theoretically offers similar benefits to hepatic resection with the added benefit of increased certainty of R0 resection. This is especially appealing considering the low rate of R0 resection achieved for NELMs (approximately 10–25%) [36]. Prior to consideration for hepatic transplantation, the primary tumor must be completely resected, and extrahepatic metastasis should be ruled out with appropriate imaging. In 2007, criteria from the National Cancer Institute in Milan, Italy, suggested criteria for OLT for patients with NELMs. These criteria included patient age less than 55 years, biopsy-confirmed well-differentiated low and intermediate grade neuroendocrine histology with Ki67 index 36 months, and R0 resection were associated with improved overall survival. Patients with metastatic gastrointestinal tumors had the worst survival. In general, patients with genitourinary tumors had the best outcomes, with 60% 5-year overall survival. More recent studies have largely corroborated these findings. A large, multi-institutional study evaluated 420 patients who underwent liver resection for NCNNLM in four high-volume hepatobiliary centers in the United States between 1990 and 2009 [22]. Seventy-four percent of patients presented with metachronous disease and 21.3% of patients had extrahepatic metastases that were resected at the time of hepatectomy, with mean disease-free interval after resection of primary of 43 months (range: 0–312 months). There were multiple tumor types evaluated: 115 patients with breast cancer, 98 with sarcoma, 92 with genitourinary cancer, and 31 with melanoma. There were 84 patients that comprised a miscellaneous group of cancer types, including gastrointestinal stromal tumors (GIST), gastrointestinal adenocarcinomas, and lung cancers, among others. As expected in a more modern series, minimally invasive approaches were utilized in some cases, although these were used infrequently. Thirty-six patients underwent RFA of additional liver lesions during hepatectomy, and despite

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Table 1 Summary of large series of patients undergoing hepatectomy for non-colorectal, non-neuroendocrine liver metastases First author, year Harrison, 1997 Groeschl, 2012 Adam, 2006 Weitz, 2005

No. of patients 96 420 1452 141

Median OS (mos) 32 49 35 42

3-year OS (%) 45 50 49 57

5-year OS (%) 37 31 36 NR

Median DFS (mos) 36 23 13 17

3-year DFS (%) NR NR 21 30

5-year DFS (%) NR NR 14 NR

DFS, disease-free survival; NR, not reported; OS, overall survival

Table 2 Overall and disease-free survival after hepatic metastasectomy for various tumor types

Median follow-up Median OS 1-year OS 3-year OS 5-year OS Median DFS Recurrence (n, %) Locoregional Distant

Breast (n ¼ 115) 31 mos 52 mos 79% 52% 27% 22 mos 66/103, 64% 43/103, 42% 48/103, 47%

Sarcoma (n ¼ 98) 32 mos 72 mos 82% 60% 32% 31 mos 55/89, 62% 32/89, 36% 42/89, 47%

GU (n ¼ 92) 23 mos 46 mos 66% 48% 32% 28 mos 47/44, 61% 26/77, 34% 41/77, 53%

Melanoma (n ¼ 31) 3g mos 39 mos 57% 36% 36% 12 mos 21/29, 72% 9/29, 31% 17/29, 59%

Other (n ¼ 84) 24 mos 39 mos 69% 46% 30% 19 mos 53/66, 80% 32/66, 48% 35/66, 53%

Overall (n ¼ 420) 30 mos 49 mos 73% 50% 31% 23 mos 242/364, 66% 142/364, 39% 183/364, 50%

Adapted from data from Groeschl et al. [22] DFS, disease-free survival; GU, genitourinary; OS, overall survival

most of these operations being performed open, 13 patients had a laparoscopic resection. Use of systemic chemotherapy prior to and following hepatectomy was the norm, at 66.4% and 52.1%, respectively. Regional therapy with TACE was used in three patients and radiation therapy (RT) was performed in 15 patients following hepatectomy. Median follow-up for this series was 30 months. Median overall survival was 49 months and disease-free survival was 23 months (Table 2). On multivariable analysis, predictors of worse overall survival included lymphovascular invasion and tumor size 5 cm. After controlling for other factors, there was no significant difference in survival between different tumor types. Survival was noted to be significantly better in the cohort of patients undergoing hepatectomy after the year 2000, comprising 76% of cases in this series, with patients in this cohort more likely to be treated with chemotherapy. Patients in this cohort, which is likely more representative in the era of modern multimodal therapy, had a median

survival of 66 months with 1-year, 3-year, and 5-year survival of 77%, 55%, and 38%, respectively. The largest study to date evaluating the management of NCNNLM evaluated 1452 patients who underwent liver resection at 41 centers from 1983 through 2004 [2]. Patients had a wide variety of tumor types, the most common of which were breast cancer in 460 patients (32%), gastrointestinal cancer in 230 patients (16%), urologic cancer in 206 patients (14%), and melanoma in 148 patients (10%). The most common histologies encountered were adenocarcinoma in 60%, sarcoma or other stromal tumors in 14%, and melanoma in 13%. Ninety percent of patients underwent resection of their primary tumor, and in 42% of cases were treated with adjuvant chemotherapy prior to liver resection. Size and number of liver lesions varied, with 17% of patients having four or more lesions, and a wide range of tumor sizes, from 7 to 270 mm. Twenty-two percent of patients had at least one extrahepatic site of disease.

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Treatment of Isolated Liver Metastasis from Non-colorectal Cancer

The mean follow-up for this broad cohort was 31 months (range: 0–258 months), with 5-year and 10-year overall survival of 36% and 23%, respectively, and a median overall survival of 35 months. Recurrence-free survival was 14% at 5 years and 10% at 10 years following primary liver resection, with a median recurrence-free survival of 11 months. During the follow-up period, 49% of patients developed intrahepatic recurrence, slightly over half of whom also developed extrahepatic metastases. Repeat hepatectomy was performed in 32% of patients with isolated hepatic recurrence, with several patients undergoing repeated resections, up to a total of five hepatectomies in two particular patients. Patient outcomes were analyzed based on tumor histology, showing that 5-year survival was highest in patients with stromal (mainly GIST) tumors (70%), followed by adenocarcinomas (36%), sarcomas, and stromal tumors (31%), melanoma (21%), and squamous cell tumors (19%). On multivariate analysis of other patient and disease factors associated, Adams et al. identified several factors associated with worse overall survival: age >30 years, tumors other than breast (in particular, choroid melanoma and squamous cell cancers), disease-free interval of 10 mg/dL) in pCC than the increase seen in cholestasis from benign causes such as choledocholithiasis (2 to 4 mg/dL) [39]. Elevation of alkaline phosphatase without a concomitant rise in bilirubin is suggestive of a partial obstruction of one hepatic duct. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) may be normal initially, but chronic cholestasis can cause liver dysfunction and hepatocellular damage resulting in a rise in aminotransferases and prolongation of the PT/INR. Additionally, longstanding biliary obstruction can interfere with fat-soluble vitamin absorption and may contribute to coagulopathy through a vitamin K-dependent process. Repletion of vitamin K will correct PT/INR if hepatocellular function is preserved. Tumor markers CA19–9 and CEA can be elevated in pCC but are not reliable diagnostic studies due to poor sensitivities and specificities. Their role in screening for cholangiocarcinoma is best defined in patients affected by primary sclerosing cholangitis. As mentioned before, elevations of these markers are seen in other hepatobiliary, gynecological gastrointestinal conditions.

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3.3

Imaging

Ultrasound is a non-invasive, imaging modality that is often the first line when patients present with jaundice and right upper quadrant pain concerning for hepatobiliary disease. Ultrasound can help localize the level of obstruction and may be useful in excluding benign hepatobiliary pathologies such as choledocholithiasis. For pCC, there is often intrahepatic biliary duct dilation with a normal caliber extrahepatic duct and a decompressed gallbladder [40]. The use of Doppler flow can help identify compression and tumor encasement of the main or segmental portal veins or the hepatic artery. In 1 study of 39 patients with hilar cholangiocarcinoma, Doppler ultrasound detected tumor, morphological patterns, and extent of bile duct involvement in 87% of patients [41]. Contrastenhanced US has been used in 1 study with 30 patients to correctly diagnose hilar cholangiocarcinoma in 93.8% of patients [42]. However, more often than not, intrahepatic ductal dilation is seen without a well-discerned mass on ultrasound, thereby limiting its role in the definite diagnosis of pCC. With its poor characterization of the tumor, reliance on operator experience, and inherent limitations such as in obese patients, other imaging modalities are typically pursued following initial ultrasound examination [39]. Because of its widespread availability, superb anatomic assessment, and fast results, CT is commonly used to evaluate complaints suspected to be attributed to hepatobiliary disease. Multidetectorrow computed tomography (MDCT) has enhanced capabilities of CT in the evaluation of pCC with its high-resolution capabilities. It is more sensitive than ultrasound in detecting ductal masses and can accurately detect vascular involvement of the portal veins and hepatic artery. For vascular assessment, three-dimensional vascular reconstruction can be performed. MDCT has been reported to underestimate the longitudinal extension of tumors [43]. On triple phase CT, pCC can appear as a hyperattenuating mass relative to the liver, focal thickening of the duct wall with or without obliteration the lumen, and dilation of intrahepatic ducts [44, 45]. The sensitivity of CT for the diagnosis of pCC has been reported

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as 90–100% [46, 47] with an accuracy of 92.3% [48]. CT may also be useful in detecting lobar atrophy when there is invasion of one portal branch or longstanding biliary obstruction. The findings of atrophy accompanied by segmental bile duct dilation strongly suggest cholangiocarcinoma. The ability to detect metastatic disease, bi-lobar involvement, or vascular involvement is crucial because these findings may preclude curative resection. One limitation of CT is that it frequently does not detect peritoneal metastasis [49] and has a low sensitivity for detecting lymph node involvement, with a wide range of sensitivities with reports ranging from 35% to 61% [50, 51]. Magnetic resonance imaging/cholangiopancreatography (MRI/MRCP) plays an important role in the diagnosis of pCC and is the best non-invasive study to delineate the anatomy of the biliary tree with its two-dimensional and three-dimensional reconstruction capabilities. Tumors are hypointense on T1-weighted imaging and hyperattenuating on T2-weighted imaging with pooling of contrast on delayed imaging [44]. Fig. 4 is a typical pCC MRCP image demonstrating a stricture of the biliary hilum involving the common hepatic duct and right anterior and

Fig. 4 MRCP demonstrating a stricture of the biliary hilum involving the common hepatic duct, right anterior and posterior segmental ducts, and left hepatic duct in a patient with cholangiocarcinoma

T. Boortalary and D. Loren

posterior segmental ducts resulting in upstream dilation along with obstruction of the left hepatic duct with proximal dilation in a patient with cholangiocarcinoma. MRCP shares the advantages of CT for the diagnosis of pCC, with greater sensitivity and an accuracy greater than 90% [52, 53]. Compared to percutaneous transhepatic cholangiography (PTC) and endoscopic retrograde cholangiopancreatography (ERCP), MRCP provides similar diagnostic biliary accuracy but has the advantages of non-invasiveness, visualization proximal to an area obstruction, and not needing contrast [45]. Moreover, correlation of stricture with cross-sectional images can be diagnostic. MRCP delineates occluded intrahepatic segments that are overlooked because of lack of opacification by direct cholangiography (ERCP or PTC), and because of the increased intraluminal pressure from contrast injection, subtle changes in the biliary lumen occur, a problem that does not occur with MRCP. Additionally, MRCP provides information about the extent of tumor invasion, metastatic spread, and the relation of a primary tumor to surrounding structures. The main drawback is that MRCP is solely diagnostic, whereas ERCP can be a therapeutic aid in tissue acquisition. Importantly, MRI with MRCP can provide a roadmap for the endoscopist to follow when planning biliary decompression with considerations of the anatomic locations of obstruction and volume of preserved hepatic parenchyma. These findings profoundly aid in performing successful endoscopic biliary decompression. Direct cholangiography by ERCP or PTC has the added benefit of direct diagnostic capabilities through tissue sampling and therapeutic options with endoprosthesis placement. The sensitivity and specificity of ERCP/PTC for the diagnosis of malignant biliary obstruction are 70–85% and 70–72%, respectively [54, 55]. Although it is often challenging to differentiate benign and malignant disease based upon cholangiography alone, there are certain differences that can help in the diagnosis. Features suggestive of malignancy in a hilar stricture include length greater than 1 cm, irregular contour, abrupt transition from normal caliber to stricture, and asymmetric narrowing. Figure 5 demonstrates an ERCP image

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cholangiocarcinoma [56]. However, one of the risks associated with EUS-FNA is tumor seeding when transversing a peritoneal surface for attaining a biopsy [57] which may preclude liver transplantation. Endosonographers should avoid performing direct FNA of the primary tumors of patients with suspected pCC but rather focus their attention on sites of regional metastasis such as lymphatic spread as the findings of cancer in regional lymph nodes may preclude resection and transplantation. Tissue sampling of primary tumors is better performed from intraductal routes for patients with suspected pCC.

3.4 Fig. 5 ERCP of a patient with a biliary stricture of the common hepatic duct; biopsies demonstrated cholangiocarcinoma

of a patient with a stricture of the common hepatic duct; biopsies demonstrated cholangiocarcinoma. With complete biliary obstruction, one limitation of ERCP and PTC is failure to delineate the full biliary system, either proximal or distal, respectively, depending upon the route of access. Furthermore, direct cholangiography is of limited value in assessing the extent of infiltrative growth along the duct and the degree of parenchymal involvement. Because of the nature of the invasive procedure, ERCP and PTC carry the risks of cholangitis, perforation, bile leaks, and pancreatitis [40]. Cholangitis and hepatic abscess formation are particularly vexing problems due to the multiple sites of biliary obstruction that are common in pCC and propensity for contamination of segments not amenable to biliary decompression. Endoscopic ultrasonography (EUS) has become an emerging tool for the diagnosis and staging of pCC. With the proximity of the duodenum to the biliary tract, EUS allows for fine needle aspiration or core needle biopsy of tumor tissue. It is particularly of use when assessing lymph node involvement for staging purposes. In 1 study of 44 patients, EUS-FNA was found to have sensitivity of 89% and specificity of 100% for the preoperative diagnosis of hilar

Tissue Acquisition

ERCP- or PTC-assisted brush cytology and forceps biopsy are routine techniques used to establish a definite diagnosis of pCC. The sensitivities are limited ranging from 18 to 60 due to the sparse cancerous cells in an abundant fibrous stroma% [53, 58–60] and challenges in acquisition technique. ERCP-assisted tissue acquisition is preferred to EUS due to the concern of tumor seeding. EUS has a higher sensitivity (77%) for the detection of pCC but has a low negative predictive value that does not allow for exclusion of malignancy after a negative biopsy [61]. Additionally, the ability of EUS to evaluate proximal lesions is limited and has a higher sensitivity when compared to detecting distal lesions [62]. When ERCP is performed, multiple sampling modalities should be performed including brush biopsy and if possible intraductal forceps biopsy. This latter technique may be performed under direct cholangioscopic direction and/or fluoroscopic guidance. Multimodal intraductal sampling carries a higher diagnostic yield compared to a single modality such as cytologic brushing [63].

4

Distal Cholangiocarcinoma

Distal cholangiocarcinoma (dCC) is a malignancy of the common bile duct, and tumors in this region extend from the cystic duct to the ampulla of Vater. They comprise about 20–30% of all

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cholangiocacinomas [11]. They are smaller and have better outcomes than pCC [64]or iCC.

4.1

Signs and Symptoms

DCC can present similarly to pancreatic and pCC with signs and symptoms of biliary obstruction: painless jaundice, pruritus, pale stools, fat malabsorption, and tea-colored urine. They cause biliary obstruction earlier than proximal tumors due to obstruction of bile flow. Nonspecific findings include abdominal pain, fevers, weight loss, and early satiety.

4.2

Laboratory Tests and Tumor Markers

A suspicion for cholangiocarcinoma should prompt further diagnostic workup including of complete blood count, electrolytes, liver function tests, tumor markers, and imaging studies. Patients with dCC will have elevation of gamma-glutamyl transferase (GGT) and alkaline phosphatase two- to tenfold higher than normal and a total bilirubin often above 10 mg/dL. Although transaminases may initially be normal, longstanding obstruction can lead to hepatocellular damage and elevations in AST, ALT, and INR. As discussed previously, CA19–9 and CEA are tumor markers that can suggest cholangiocarcinoma when elevated, but lack high sensitivity (53–89%) and specificity (80–91%) for dCC [65].

4.3

Imaging

For patients presenting with jaundice, transabdominal ultrasound is generally used as the initial imaging modality to identify the level of obstruction. However, ultrasound has limited utility in the diagnosis of dCC; it fails to identify small tumors and to delineate tumor extent. Ultrasound may be more useful in the diagnosis of iCC and pCC [66]. The presence of bowel gas may preclude adequate visualization of the distal bile

duct and ampulla, thereby limiting the diagnostic yield of transabdominal US. On cross-sectional imaging, dCC may be seen as an abrupt obstruction with proximal dilation of the bile duct. CT and MRI may show a nodular mass or a concentric or asymmetric thickening of the bile duct with enhancement of the transition zone [44]. On T1-weighted, fat-suppressed MRI, the tumor may appear as a polypoid mass or stricture invading into adjacent periductal tissues with or without nodal involvement [66]. It is not uncommon to identify a thickening or a stricture of the distal bile duct without a mass in cases of DCC. These cases are difficult to differentiate from benign strictures. Benign strictures may be suspected in a patient with predisposing conditions such as primary sclerosing cholangitis, autoimmune disease in which case IgG4-related sclerosing cholangitis may be considered, prior surgery during which an iatrogenic biliary injury may have occurred, or history of abdominal trauma. The index of suspicion for DCC should be elevated in a patient with an abrupt obstruction on imaging without an associated mass or calculus in the setting of a normal pancreas [64] and normal caliber main pancreatic duct. Traditionally, ERCP has been the mainstay in the workup of cholangiocarcinoma owing to tissue sampling for diagnosis and endoprosthesis placement for therapeutic biliary decompression. Findings that are suggestive of cholangiocarcinoma on ERCP include polypoid lesions, strictures, and marked biliary dilation, a shelflike appearance to a stricture, and luminal irregularity. However, the additional information from cholangiography compared to cross-sectional imaging rarely carries any significant impact. EUS is the preferred method to visualize and sample the distal biliary tree when dCC is suspected. The diagnostic yield is greater with EUS than with ERCP, and fewer complications occur. EUS is particularly useful for distal lesions because they are most accessible for visualization when the EUS probe enters the stomach or duodenum. There is a decreased risk for infection and pancreatitis with EUS compared with ERCP, as contrast is not injected into a bile duct with already impaired drainage and care can be taken

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Diagnosis and Evaluation of Cholangiocarcinoma

to avoid pancreatic injury. Additionally, EUS allows for imaging of the lymph nodes and gallbladder, which can identify alternative causes of biliary obstruction and aid in staging.

4.4

Tissue Acquisition

Cytological analyses of biliary tract brushings may help to distinguish benign from malignant strictures; however, the negative predictive value is poor. As discussed previously, cytology obtained during ERCP has an unacceptably low sensitivity of 15% to 60% for the detection of cancer; however, this can be improved to over 60% when multiple methods of sampling are utilized such as the combination of brush cytology with fluoroscopically directed biopsy and bile aspiration [63, 67]. EUS-FNA has been demonstrated to be superior to ERCP for assessment of malignant obstruction of the distal extrahepatic duct. Although studies have often focused on pancreatic cancer as an etiology, extrahepatic cholangiocarcinoma can be safely sampled by EUS with or without concomitant biliary stent placement as bile leak is rare following sampling. A small (25 g) gauge needle is recommended when performing direct biliary sampling. EUS is superior to ERCP with brush cytology and intraductal forceps biopsy in diagnosing malignant biliary strictures, especially in the assessment of extraductal lesions and in those larger than 1.5cm [68]. In contrast to pCC, EUS-guided sampling of dCC does not impact a patient’s options for surgical cure.

5

Primary Sclerosing Cholangitis and Cholangiocarcinoma

Primary sclerosing cholangitis (PSC) is an autoimmune inflammatory condition of the bile ducts. PSC is a dominant risk factor for the development of cholangiocarcinoma, an effect that exists independent of the risk of cirrhosis. PSC carries a 5–13% lifetime risk of cholangiocarcinoma and an annual risk of 0.5–1.5% [69–72]. In 1 Swedish study, patients with PSC were found to be 161 times

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more likely to have a hepatobiliary malignancy compared with the general population [72]. The majority of PSC-associated cholangiocarcinomas are in the perihilar region. Approximately 50% of PSC-associated cholangiocarcinomas are diagnosed within the first 2 years of PSC [72, 73] diagnoses, and a high index of suspicion is warranted. Differentiating between benign and malignant strictures in patients with PSC can be very challenging, and therefore, a thorough multidisciplinary approach is often needed for diagnosis including laboratory studies, cross-sectional imaging, cholangioscopy, and pathology. In patients with PSC, cholangiocarcinoma should be considered when there is clinical deterioration such as the development of jaundice, weight loss, and/or persistent abdominal pain. Clinical features differ based on the location of the tumor. Isolated intrahepatic PSC-associated cholangiocarcinoma is less common than extrahepatic tumors and presents with anorexia, weight loss, and abdominal pain in advanced malignant disease. Extrahepatic cholangiocarcinoma complicating PSC presents with obstructive symptoms such as jaundice, cholestasis, pruritus, and cholangitis. Ultrasound and cross-sectional imaging (MRI/MRCP and CT) can raise the suspicion for cholangiocarcinoma when used for surveillance or investigation of concerning symptoms. Worrisome features include the presence of or progression of a dominant stricture, marked biliary dilation above a stricture, or a polypoid ductal mass  1 cm in diameter [74]. A hallmark of an inflammatory stricture is variability of the cholangiographic appearance of biliary strictures, whereas a fixed stricture should raise suspicion for cancer. Although US is the first-line imaging modality for the investigation of obstructive biliary disease, it has a limited role in the setting of PSC due to biliary changes that are indistinguishable between inflammation and cancer on US imaging. MRCP should be the initial test when there is suspicion for cholangiocarcinoma in PSC. MRCP can help evaluate the extent of ductal involvement, presence of intrahepatic metastases, or aberrant ductal anatomy. If a dominant stricture is identified, ERCP with brush cytology followed by chromosomal analysis, where available, should be performed.

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The role of CA19–9 as a screening measure has not been well established in patients without PSC, but it has been extensively studied and implemented in patients with PSC. In 1 study with 208 patients, a cutoff value for CA19–9 of 129 U/ml was found to have a sensitivity of 78.6% and specificity of 98.5%. A change of 63.2 U/ml in CA19–9 had sensitivity of 90% and specificity of 98% [75]. CEA by itself has is of little use in the diagnosis of cholangiocarcinoma in patients with PSC. However, Ramage and colleagues presented a formula combining CEA and CA19–9 that demonstrated a sensitivity and specificity of 66% and 100%, respectively [76]. Although consensus guidelines have not been established for the screening of cholangiocarcinoma in patients with PSC, the American College of Gastroenterology recommends ultrasound or MRI with CA19–9 every 6–12 months [77]. Many providers routinely check liver chemistries in addition to MRI/MRCP with CA19–9 annually. It is important to note that 60–80% of patients with PSC also have inflammatory bowel disease, most commonly ulcerative colitis. When PSC coexists with IBD, there is an increased risk of colorectal cancer that warrants more aggressive screening [78]. All patients with PSC should have a colonoscopy at the time of PSC diagnosis to screen for IBD and colon cancer. Patients with concomitant IBD may have a unique pattern of IBD that is characterized by rectal sparing, mild pancolitis, and backwash ileitis. This phenotype carries a higher risk for colon cancer and requires more routine colonoscopies with biopsies taken every 1 to 2 years [79].

6

desmoplastic nature of cholangiocarcinomas, brush cytology and biopsies have low sensitivities ranging 23–56% and 33–65%, respectively. The sensitivities can be improved to 60–70% when both are combined [80–84]. Repeated brushing can increase diagnostic yield, but brush length or stricture dilation does not increase detection rate. Fluoroscopic forceps biopsy is a sampling technique that involves the introduction of closed forceps into the papilla and guided through the stricture under fluoroscopy. Forceps are not wire guided and have difficulties reaching lesions that are not accessible in the common bile duct or common hepatic duct. Forceps biopsy provides for a better diagnostic yield than brush cytology, with a sensitivity of 56% and specificity of 97% [84, 85]. Fig. 6 demonstrates an ERCP image of an intraductal biopsy forceps for tissue acquisition in a patient with suspected cholangiocarcinoma. There is debate about the specific forceps used for fluoroscopic guidance with some endoscopists preferring smaller biopsies without a tissue spike and others using standard or jumbo capacity biopsy forceps.

General Tissue Acquisition Techniques

Tissue sampling and pathological confirmation are essential for patients with biliary strictures concerning for malignancy. ERCP enables for tissue sampling methods such as mucosal brushing, fine needle aspiration, and mucosal biopsies. Cellular material is attained for cytological analysis during ERCP with the introduction of a brush across a lesion or stricture. Because of the

Fig. 6 ERCP of an intraductal biopsy forceps for tissue acquisition in a patient with suspected cholangiocarcinoma

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Diagnosis and Evaluation of Cholangiocarcinoma

Even though ERCP is frequently the initial method of evaluating suspected biliary malignancy, the low sensitivity and number of inclusive findings make EUS with fine needle aspiration another important alternative. EUS produces high-resolution imaging and can identify lesions of 3 mm or greater. EUS-FNA has been shown to be more sensitive for diagnosing distal tumors (81%) compared to proximal tumors (59%) [62]. One important limitation to EUS-FNA is the concern for peritoneal tumor seeding as discussed previously. It is important to note that EUS-FNA is contraindicated if a patient is a candidate for potential curative liver transplant. When deciding on the use of EUS-FNA, the choice of needle and use of the stylet and suction are all factors to consider. FNA needles come in three basic sizes, 19, 22, and 25G, and either a ball or bevel tip stylet which helps the needle get across the tissue. 25G needles have been shown to be equivalent to 22 G needles in their diagnostic accuracy. However, they are associated with less injury and bleeding which can make the cytology more difficult to interpret [86, 87]. The presence of a stylet or type of stylet has not been shown to impact the histological assessment of EUS-FNA obtained solid lesions [88, 89]. The use of suction on FNA samples has been shown to increase the quantity of the FNA samples, but increase bloodiness and diminish quality. Wet suction is a modified technique that involves flushing the needle with sterile saline prior to puncturing the lesion and applying suction [90]. Although this technique has been shown to increase cellularity in solid lesions, further studies are needed to determine superiority in biliary sampling. The single-operator cholangioscope (SOC) improved on earlier versions of cholangioscopes that required two endoscopies: one to manipulate the duodenoscope and another to operate the cholangioscope. Additionally, older versions were fragile, had poor visualization within the duct, and had difficulty passing instruments through the therapeutic channel [91]. SOC allows for direct biopsies that has been shown to have higher accuracy (84.6%) compared ERCP-based brush cytology (38.5) and forceps biopsies (53.8%) [92, 93]. Abnormal or tortuous

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Fig. 7 Cholangioscopy cholangiocarcinoma

and

visualization

of

vasculature, villous mucosal projections, irregular mucosal nodularity, and mass-like features are features that suggest malignancy as opposed to benign strictures [94]. Figure 7 demonstrates cholangiocarcinoma found on cholangioscopy. Innovations in imaging and technology have made cholangioscopic evaluation and biopsy an important tool for the diagnosis of cholangiocarcinoma.

7

Molecular Diagnosis

Fluorescence in situ hybridization (FISH) uses fluorescence-based polynucleotide probes complimentary to the DNA sequence of interest mainly attained from brush cytology. Aneuploidy of chromosomes 3, 7, and 17 or deletion of p16 tumor suppressor gene (9p21) is the bestcharacterized genetic abnormalities in biliary cancers. The assay is positive for malignancy when five or more cells show evidence of polysomy. Studies have shown that FISH testing in addition to brush cytology improves diagnostic yield while maintaining high specificity [95]. It is likely that multiple other genetic abnormalities are involved in cholangiocarcinoma that are not detected on 4-probe FISH testing. FISH testing is especially beneficial in patients with PSC when malignant strictures are difficult to discern given the baseline cytological atypical from inflammation.

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Digital image analysis (DIA) quantifies DNA and identifies aneuploidy by measuring the intensity of Feulgen dye that binds to DNA. It has been shown to increase the sensitivity of brushings from 18% to 39% compared with routine cytology [60]. This technique can be useful in specimens that have limited cellularity since it looks at the DNA content of individual cells [96]. A novel diagnostic modality for the diagnosis of cholangiocarcinoma is that of next-generation sequencing (NGS) from biliary brushings or the effluent of centrifuged specimens placed in cytologic fixative. There are emerging data that this technique can identify pathogenic mutations in tumor-associated genes. In one recent study, NGS identified genomic alterations and when added to cytology resulted in a sensitivity of 93% for malignant strictures. The role of NGS requires further investigation but appears to have testing characteristics that are similar to or superior to FISH and is a technique that carries promise for improving the detection of cholangiocarcinoma from biliary samples [97].

or a single lobe are important factors to consider when deciding surgical candidacy [33]. For pCC, resectability can be determined by the extent of ductal, portal venous, biliary radicle, and hepatic artery involvement and lobar atrophy [98]. Hilar cancer is thought to be unresectable with the presence of bilateral segmental ductal extension, unilateral atrophy with contralateral segmental ductal or inflow vascular involvement, or unilateral segmental ductal extension with contralateral inflow vascular involvement [99, 100]. In dCC, because of the intimate proximity to the duodenum and pancreas, the surgery of choice is typically pancreaticoduodenectomy (i.e., Whipple resection) [101]. Special attention has to be paid to the adjacent structures that dCCs can invade, including the portal vein, hepatic artery, and hepatoduodenal ligament. In 2018, the American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) created the most recent (eighth edition) staging criteria for distal, perihilar, and intrahepatic cholangiocarcinoma (Table 1) [102, 103].

8

9

Mimickers of Cholangiocarcinoma

9.1

Primary Sclerosing Cholangitis

Cholangiocarcinoma Staging

Because surgical therapy is the only curative treatment of CCA, accurate staging of the tumor is critical to identify surgical candidates and distinguish them from those who will benefit more from palliative approaches. The staging of cholangiocarcinoma is based upon the extension of the tumor according to extension of primary tumor (T), lymph node involvement (N), and metastasis (M) to other distant sites. While pathology specimens help with defining the T and N stages, radiographic findings can identify metastasis. Nodal involvement and distant metastasis portend a worse prognosis in iCC and pCC compared to dCC. Each anatomic location of cholangiocarcinoma has distinct local structures that can be invaded by tumor, and this anatomy and considerations of effective biliary drainage and preservation of hepatic function are the dominant surgical considerations. For intrahepatic cholangiocarcinoma, tumor size, vascular invasion, and involvement of fewer hepatic segments

Primary sclerosing cholangitis (PSC) is an autoimmune inflammatory disorder that causes fibrosis of the intrahepatic and extrahepatic biliary ducts. As discussed previously, PCS usually occurs in the fourth or fifth decade of life and has a propensity to occur in those with inflammatory bowel disease, especially ulcerative colitis. The most dreaded complication of PSC is the development of cholangiocarcinoma. Laboratory studies show a cholestatic pattern of disease with marked elevation of alkaline phosphatase. MRI/MRCP has detailed three-dimensional imaging of fluid-filled structures that can identify the location of strictures, segmental dilations, and the “bead-like” appearance of typical PSC. This makes it the best imaging modality for the diagnosis of PSC. Sometimes, PSC can cause focal stricturing of segments in a short fragment that

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Diagnosis and Evaluation of Cholangiocarcinoma

251

Table 1 8th edition of the AJCC TNM staging for cholangiocarcinoma [2] Intrahepatic cholangiocarcinoma T Primary tumor T0 No evidence of primary tumor

Perihilar cholangiocarcinoma

Distal cholangiocarcinoma

T0

No evidence of primary tumor

Tis

Carcinoma in situ (intraductal)

Tis

Carcinoma in situ (intraductal)

T1

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

T0 No evidence of primary tumor Tis Carcinoma in situ/highgrade dysplasia T1 Tumor invades the bile duct wall with a depth less than 5 mm T2 Tumor invades the bile duct wall with a depth of 5–12 mm

Tumor confined to bile duct, with extension up to the muscle layer or fibrous tissue T1a Solitary tumor 5 cm without T2 Tumor invades beyond the wall of vascular invasion the bile duct to surrounding adipose tissue, or adjacent hepatic parenchyma T1b Solitary tumor >5 cm without T2a Tumor invades beyond the wall of T3 Tumor invades the bile duct vascular invasion the bile duct to surrounding adipose wall with a depth greater tissue than 12 mm T2 Solitary tumor with intrahepatic T2b Tumor invades adjacent hepatic T4 Tumor involves the celiac vascular invasion or multiple parenchyma axis, superior mesenteric tumors, with or without vascular artery, and/or common invasion hepatic artery T3 Tumor perforating the visceral T3 Tumor invades unilateral branches of peritoneum the portal vein or hepatic artery T4 Tumor involving local T4 Tumor invades main portal vein or extrahepatic structures by direct its branches bilaterally, or common invasion hepatic artery; or unilateral secondorder biliary radicals bilaterally with contralateral portal vein or hepatic artery involvement N Regional lymph nodes Nx Regional lymph nodes cannot Nx Regional lymph nodes cannot be Nx Regional lymph nodes be assessed assessed cannot be assessed N0 No regional lymph node N0 No regional lymph node metastasis N0 No regional lymph node metastasis metastasis N1 Regional lymph node metastasis N1 One to three lymph nodes typically N1 Metastasis in one to three is present involving the hilar, cystic duct, regional lymph nodes common bile duct, hepatic artery, posterior pancreatoduodenal, and portal vein lymph nodes N2 Four or more positive lymph nodes N2 Metastasis in four or more from the sites described for N1 regional lymph nodes M Distant metastasis M0 No distant metastasis M1 Distant metastasis AJCC prognostic groups T N M T N M T N M Stage 0 Tis N0 M0 Stage 0 Tis N0 M0 Stage 0 Tis N0 M0 Stage IA T1a N0 M0 Stage I T1 N0 M0 Stage 1 T1 N0 M0 Stage IB T1b N0 M0 Stage II T2a-b N0 M0 Stage IIA T1 N1 M0 Stage II T2 N0 M0 Stage IIIA T3 N0 M0 T2 N0 M0 Stage IIA T3 M0 M0 Stage IIIB T4 N0 M0 Stage IIB T2 N1 M0 Stage IIIB T4 N0 M0 Stage IIIC Any T N1 M0 T3 N0 M0 Any T N1 M0 Stage IVA Any T N2 M0 T3 N1 M0 (continued)

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Table 1 (continued) AJCC prognostic groups T N Stage IV Any T Any N

M M1

Stage IVB

T Any T

N Any N

M Ml

Stage IIIA

Stage IIIB

Stage IV

T T1 T2 T3 T4 T4 T4 Any T

N N2 N2 N2 N0 N1 N2 Any N

M M0 M0 M0 M0 M0 M0 M1

Reprinted with permission from [Springer Nature Customer Service Centre GmbH]: [Springer Nature] [Annals of Surgical Oncology] (The Clinical Management of Cholangiocarcinoma in the United States and Europe: A Comprehensive and Evidence-Based Comparison of Guidelines, Fong et al), [2021]

may make it hard to distinguish from periductal infiltrating CCA [104, 105]. ERCP with brush cytology can be used to try and differentiate the two entities. The presence of multiple intrahepatic strictures is commonly seen in PSC but occurs in CCA only in the presence of multifocal intrahepatic spread. A biliary stricture whose appearance of cholangiography or MRCP changes over time is more likely to be benign as opposed to a fixed stricture or stricture associated with a mass. These latter findings are concerning for CCA complicating PSC.

9.2

IgG4-Related Sclerosing Cholangitis

IgG4-related sclerosing cholangitis is a benign inflammatory process that is associated with other IgG4-related disorders such as autoimmune pancreatitis, sclerosing sialadenitis, and tubulointerstitial disease [106]. Patients can present with an acute onset of painless jaundice that responds rapidly to steroids. It is this response to steroids that is paramount in diagnosing IgG4-related sclerosing cholangitis as serum IgG-4 may be normal. Segmental narrowing and thickening of the bile ducts is usually seen, often involving the common bile duct. Findings can be difficult to distinguish from PSC or CCA. Both can appear as focal or multifocal circumferential bile duct wall thickening with hyperenhancement on cross-sectional imaging [107, 108]. Fig. 8 demonstrates an ERCP cholangiogram from a patient with IgG4-related

autoimmune pancreatitis. The image shows a distal biliary stricture and normal caliber pancreatic duct which could be mistaken for an extrahepatic cholangiocarcinoma (Fig. 9). Figure 10 demonstrates ERCP image of a patient who presented with biliary obstruction, initially thought to be perihilar cholangiocarcinoma. However, the patient was treated with steroids and had resolution of the obstruction. The initial image (10A) shows non-opacification of the common hepatic duct (CHD) as well as the right hepatic duct (RHD) and left hepatic duct (LHD). This is compared to the latter image (10B) taken from her post-steroid treatment. Because IgG4 is a systemic disease, involvement of other organs on imaging can be highly specific for this disease. Pancreatitis is the most common manifestation of IgG4 disease occurring in 60% of people affected. It often develops in close association to IgG4 sclerosing cholangitis. On imaging, the pancreas can appear diffusely enlarged, encased in a capsule-like rim, and display ductal abnormalities. Other distinguishing features include involvement of other intra-abdominal structures such as finding a soft tissue mass in the retroperitoneum, lymphadenopathy, and wedgedshaped renal cortical lesions [109].

9.3

Inflammatory Pseudotumor

Inflammatory pseudotumor (IPT) is a rare, idiopathic disease process characterized by benign proliferation of chronic inflammatory cells (plasma cells, lymphocytes, and histiocytes) and

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Diagnosis and Evaluation of Cholangiocarcinoma

253

Fig. 8 ERCP from a patient with IgG4-related autoimmune pancreatitis demonstrating a distal biliary stricture (CBD) and normal caliber pancreatic duct (PD). This appearance may be similar to malignant extrahepatic cholangiocarcinoma as seen in Fig. 9

Fig. 9 MRCP with extrahepatic distal biliary stricture and non-dilated pancreatic duct. Biopsy of the stricture diagnosed adenocarcinoma

fibrosis involving multiple organs. The lungs are the primary location involved, appearing as a well-circumscribed mass or ill-defined, pneumonia-like density, but the liver is the second most common [110, 111]. IPT can mimic just about any hepatic mass due to its variable patterns of

echogenicity on imaging depending on the degree of hypercellularity, fibrosis, or necrosis in the lesion. IPT can cause biliary strictures similar to cholangiocarcinoma and produce delayed but persistent enhancement from its fibrous components. The extent of capillary proliferation can also

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Fig. 10 Patient with presented with biliary obstruction and suspected perihilar cholangiocarcinoma. Subsequent imaging with plasticity of the bile ducts, and she was treated with steroid. The initial image (a) shows non-opacification of the common hepatic duct (CHD) as

well as the right hepatic duct (RHD) and left hepatic duct (LHD). This compared to the second image (b) taken from her post-steroid treatment ERCP 10(A) Initial image pre-treatment. 10 (b) Post-treatment with steroids

influence the appearance on CT and MRI [112]. There is no specific presentation, laboratory findings, or imaging characteristics that can specifically point to a diagnosis of IPT, but it should be considered in a young patient with a wellcircumscribed liver mass [113]. The presence of a mass distinguishes it from PSC and IgG4-related sclerosing cholangitis; however, it can appear identical to malignancy with strictures typical of CCA. Treatment is with surgical resection.

9.5

9.4

Eosinophilic Cholangitis

Eosinophilic cholangitis (EC) is a rare inflammatory condition of the biliary tract that is characterized by a dense, transmural deposition of eosinophilic infiltrates in the bile ducts. It can cause fibrosis, stricturing, and obstruction. This disorder can be a component of a systemic eosinophilic disorder or as an isolated condition only involving the biliary tract. Peripheral eosinophilia, a history of asthma and allergies, and rapid response to steroids are typical features in a patient history, and the steroid is the dominant distinguishing factor [114].

Mirizzi Syndrome

Mirizzi syndrome is a phenomenon that occurs when an impacted stone lodges in the cystic duct or gallbladder neck and causes gallbladder distention and subsequent extrahepatic biliary obstruction. The obstruction can be caused by the stone itself or by secondary inflammation and edema. Those with a long, low insertion of the cystic duct that runs parallel to the common hepatic duct are at increased risk for the development of Mirizzi syndrome. Patients usually present with slowly progressive jaundice rather than acute cholecystitis or cholangitis, a clinical presentation that mimics cholangiocarcinoma. Biliary obstruction due to recurrent episodes of cholangitis and inflammation can cause strictures, which may resemble periductal-infiltrating cholangiocarcinoma. On CT, Mirizzi syndrome can be indistinguishable from malignancy when there is biliary ductal dilation and the radiolucent stones are not visible. The prominent inflammation can result in wall thickening and obscure stones on ultrasound [113]. Endoscopic sampling is benign, and surgery is ultimately required for diagnosis and treatment in the majority of cases.

13

9.6

Diagnosis and Evaluation of Cholangiocarcinoma

Ischemic Cholangiopathy

Ischemic cholangiopathy refers to decreased blood flow to the bile ducts resulting in biliary necrosis and fibrosis. Unlike the hepatic sinusoids that receive a dual blood supply from the hepatic artery and portal vein, the biliary system receives only arterial blood flow and is more sensitive to ischemic injury. Risk factors for ischemic cholangiopathy include prior abdominal surgery, hepatic intraarterial chemotherapy, history of liver transplant, thrombotic disorders, and vasculitis [114]. There is a rich vascular plexus derived from hepatic artery and retroduodenal arteries at the level of the common bile duct that can be interrupted during liver transplants or compromised in vasculitis. On imaging, ischemic cholangitis can appear as multifocal strictures, typically centrally located about the biliary hilum. Strictures tend to be static or locally progressive unlike PSC or IgG4-related sclerosing cholangitis. Distinguishing features from cholangiocarcinoma are the presence of a predisposing condition and the absence of a solid mass on CT or MRI [115]. On histology, the large ducts will be atrophied and eroded, and smaller interlobular ductules may demonstrate ductopenia [116].

9.7

AIDS Cholangiopathy

AIDS cholangiopathy is a form of infectious biliary tract inflammation that results in strictures and obstructions in those with HIVand advanced immunosuppression (CD4 count90 seconds) after injection of contrast is characteristic of hepatocellular carcinoma [136].

9.14

Adenomyosis of the Bile Ducts

An adenomyoma is a benign proliferation of epithelial cells most often encountered in the gallbladder. The condition is also termed adenomyomatosis [137]. When it occurs primarily in the extrahepatic bile ducts, it is an extremely rare lesion with only a handful of cases cited in literature [138]. In the biliary system, it involves the common bile duct and can present with obstructive jaundice, cholangitis, or abdominal pain [139]. Although no studies have shown how to distinguish adenomyosis from malignancy on imaging, it does appear to be a well-demarcated hypoattenuating lesion on CT scan [140]. Histological examination is necessary for diagnosis and

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Diagnosis and Evaluation of Cholangiocarcinoma

demonstrates a duct-like structure with interlacing hyperplasia of smooth muscle cells [137, 141].

9.15

Pancreatic Cancer

Pancreatic malignancies involving the head of the pancreas can cause biliary obstruction and can present similarly to distal cholangiocarcinoma or in the setting of an exophytic cancer of the superior head of the gland may appear as perihilar disease. Diagnosis is challenging as distal cholangiocarcinomas have a propensity to involve the ampullary regions and even metastasize to the pancreas [142] . Patients typically have jaundice, weight loss, and anorexia. Chronic pancreatitis may have a similar presentation as pancreatic cancer and is a risk factor for pancreatic cancer that can present with epigastric pain radiating to the back suggesting pancreatic duct obstruction [143]. Other risk factors include diabetes, smoking, and a family history of pancreatic cancer. MDCT is the initial imaging of choice when diagnosing pancreatic cancer and can demonstrate a hypodense lesion in the pancreas and ductal dilation to the level of the pancreatic head. EUS-FNA may identify a pancreas mass even when pre-procedure imaging is non-diagnostic and can confirm the diagnosis of pancreatic adenocarcinoma [144, 145].

9.16

257

images at the time of ERCP also show a stricture at the hilum (Fig. 10b). When biopsies were taken (Fig. 10c and d), immunohistochemical stains for p40 (nuclear, brown) and CK5/6 (cytoplasmic red) supported squamous differentiation. These two markers are negative in adenocarcinoma. Malignant lymphadenopathy leading to external compression can also cause biliary obstruction. Image findings of metastasis can involve any part of the biliary system and do not reliably distinguish metastatic disease from primary cancer. Therefore, histological examination and immunohistochemistry are necessary for diagnosis.

9.17

Carcinoma of the Gallbladder

Gallbladder cancer is a rare malignancy that can lead to hilar obstruction through either direct extension or metastasis [113, 128] and is easily confused for primary perihilar cholangiocarcinoma. It is more common in women in the sixth decade and is more prevalent in areas like Asia and South America [143]. Risk factors include chronic inflammation of the gallbladder including infections or and gallstones [147]. Patients present with jaundice, right upper quadrant pain, and weight loss. CT and ultrasound demonstrate a focal or diffuse gall bladder wall thickening, intraluminal lesion, or, in the case of large tumors, a mass in the liver [148].

Metastatic Disease 9.18

The biliary system is rarely affected by metastasis, but when it does occur, colorectal cancer is the most common culprit [104]. Other cancers that can metastasize to the biliary system include gastric, lung, breast, pancreas, and, less commonly, melanoma and renal cell carcinoma [145, 146]. It is often difficult to distinguish metastatic disease from cholangiocarcinoma, necessitating biopsies and review of pathology. An MRCP of a patient with biliary obstruction and a remote history squamous cell carcinoma (SCC) is shown in Fig. 11a. The infiltrating mass and obstruction are centered at the junction of the left and right hepatic ducts and are concerning for a malignancy. Fluoroscopic

Xanthogranulomatous Cholecystitis and Cholangitis

Xanthogranulomatous cholecystitis is a distinct type of chronic cholecystitis characterized by a destructive inflammatory process, with accumulation of foamy macrophages and fibrous tissue [149]. The disease process is associated with gallstones and can resemble gallbladder cancer [107]. Pathogenesis is believed to be due to mucosal injury and extravasation of bile into the gallbladder wall. This leads to macrophage phagocytosis of bile lipids and a subsequent inflammatory cascade and fibrosis [149]. Xanthogranulomatous cholecystitis can appear as focal or diffuse gallbladder wall

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Fig. 11 (a) MRI/MRCP of a patient with remote SCC showing an infiltrating mass at the hilum concerning for cholangiocarcinoma. (b) ERCP of the same patient showing a hilar stricture. (c) Bile duct biopsy shows pseudoglandular structures in a desmoplastic stroma (H&E,

100x). This can easily be confused with adenocarcinoma (cholangiocarcinoma). (d) Double immunohistochemical stain for p40 (nuclear, brown) and CK5/6 (cytoplasmic, red) supports squamous differentiation (400x). These two markers are negative in adenocarcinoma

thickening, occasionally extending to adjacent structures [150]. There can be associated biliary obstruction and inflammatory strictures that may resemble hilar cholangiocarcinoma [113].

on the constellation of patients’ clinical presentations, laboratory findings, and radiographic imaging to optimize their chance in making an early and correct diagnosis.

10

References

Conclusion

In conclusion, cholangiocarcinoma is a rare but aggressive malignancy with low rates of survival. Many patients are not candidates for surgical resection because they are identified at advanced stages at the time of diagnosis. This emphasizes the need for early detection. Physicians must rely

1. Clinic C. Current clinical medicine e-book: expert consult – online. Elsevier Health Sciences. Maryland Heights, MO; 2010. 2. Kirstein MM, Vogel A. Epidemiology and risk factors of cholangiocarcinoma. Visc Med. 2016;32:395–400. 3. Khan SA, Thomas HC, Davidson BR, TaylorRobinson SD. Cholangiocarcinoma. Lancet. 2005; 366:1303–14.

13

Diagnosis and Evaluation of Cholangiocarcinoma

4. Yamasaki S. Intrahepatic cholangiocarcinoma: macroscopic type and stage classification. J HepatoBiliary-Pancreat Surg. 2003;10:288–91. 5. Mafi P, Chu QD, Smith RR, Gibbs JF. Cholangiocarcinoma. In: Chu QD, Gibbs JF, Zibari GB, editors. Surgical oncology: a practical and comprehensive approach. New York: Springer; 2015. p. 257–82. 6. Rekman JF, Rocha FG. Staging and prognosis. In: Pawlik TM, Cloyd JM, Dillhoff M, editors. Intrahepatic cholangiocarcinoma: diagnosis and management. Cham: Springer International Publishing; 2019. p. 21–51. 7. Gamblin TC. Surgical oncology clinics, an issue of surgical oncology clinics of North America, ebook. Elsevier Health Sciences. Maryland Heights, MO; 2019. 8. Papafragkakis C, Lee J. Comprehensive management of cholangiocarcinoma: part I. Diagnosis. Int J Gastrointest Interv. 2017;6:85–93. 9. Yeh MM. Pathology of combined hepatocellularcholangiocarcinoma. J Gastroenterol Hepatol. 2010; 25:1485–92. 10. Banales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB, Invernizzi P, et al. Expert consensus document: cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European network for the study of cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 2016;13:261–80. 11. Nakeeb A, Pitt HA, Sohn TA, Coleman J, Abrams RA, Piantadosi S, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg. 1996;224:463–73; Discussion 473–465. 12. El Rassi ZE, Partensky C, Scoazec JY, Henry L, Lombard-Bohas C, Maddern G. Peripheral cholangiocarcinoma: presentation, diagnosis, pathology and management. Eur J Surg Oncol. 1999;25:375–80. 13. Yedibela S, Demir R, Zhang W, Meyer T, Hohenberger W, Schonleben F. Surgical treatment of mass-forming intrahepatic cholangiocarcinoma: an 11-year western single-center experience in 107 patients. Ann Surg Oncol. 2009;16:404–12. 14. Shimada K, Sano T, Sakamoto Y, Esaki M, Kosuge T, Ojima H. Surgical outcomes of the mass-forming plus periductal infiltrating types of intrahepatic cholangiocarcinoma: a comparative study with the typical mass-forming type of intrahepatic cholangiocarcinoma. World J Surg. 2007;31:2016–22. 15. Alvaro D, Bragazzi MC, Benedetti A, Fabris L, Fava G, Invernizzi P, et al. Cholangiocarcinoma in Italy: a national survey on clinical characteristics, diagnostic modalities and treatment. Results from the “cholangiocarcinoma” committee of the Italian association for the study of liver disease. Dig Liver Dis. 2011;43:60–5. 16. Singh S, Tang SJ, Sreenarasimhaiah J, Lara LF, Siddiqui A. The clinical utility and limitations of serum carbohydrate antigen (ca19-9) as a diagnostic

259 tool for pancreatic cancer and cholangiocarcinoma. Dig Dis Sci. 2011;56:2491–6. 17. Leelawat K, Narong S, Wannaprasert J, Ratanashu-ek T. Prospective study of MMP7 serum levels in the diagnosis of cholangiocarcinoma. World J Gastroenterol. 2010;16:4697–703. 18. Patel AH, Harnois DM, Klee GG, LaRusso NF, Gores GJ. The utility of ca 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis. Am J Gastroenterol. 2000;95:204–7. 19. Pawlik TM, Cloyd JM, Dillhoff M. Intrahepatic cholangiocarcinoma: diagnosis and management. Springer International Publishing. Columbus Ohio; 2019. 20. Xu HX, Chen LD, Liu LN, Zhang YF, Guo LH, Liu C. Contrast-enhanced ultrasound of intrahepatic cholangiocarcinoma: correlation with pathological examination. Br J Radiol. 2012;85:1029–37. 21. Colli A, Cocciolo M, Mumoli N, Cesarini L, Prisco A, Gaffuri I, et al. Peripheral intrahepatic cholangiocarcinoma: ultrasound findings and differential diagnosis from hepatocellular carcinoma. Eur J Ultrasound. 1998;7:93–9. 22. Fabrega-Foster K, Ghasabeh MA, Pawlik TM, Kamel IR. Multimodality imaging of intrahepatic cholangiocarcinoma. Hepatobiliary Surg Nutr. 2017;6:67–78. 23. Hamrick-Turner J, Abbitt PL, Ros PR. Intrahepatic cholangiocarcinoma: MR appearance. AJR Am J Roentgenol. 1992;158:77–9. 24. Suthar M, Purohit S, Bhargav V, Goyal P. Role of mrcp in differentiation of benign and malignant causes of biliary obstruction. J Clin Diagn Res. 2015;9:TC08–12. 25. Jhaveri KS, Hosseini-Nik H. MRI of cholangiocarcinoma. J Magn Reson Imaging. 2015;42:1165–79. 26. Khan SA, Davidson BR, Goldin RD, Heaton N, Karani J, Pereira SP, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update. Gut. 2012;61:1657–69. 27. Anderson CD, Rice MH, Pinson CW, Chapman WC, Chari RS, Delbeke D. Fluorodeoxyglucose pet imaging in the evaluation of gallbladder carcinoma and cholangiocarcinoma. J Gastrointest Surg. 2004;8:90–7. 28. Kim YJ, Yun M, Lee WJ, Kim KS, Lee JD. Usefulness of 18f-fdg pet in intrahepatic cholangiocarcinoma. Eur J Nucl Med Mol Imaging. 2003;30:1467–72. 29. Fevery J, Buchel O, Nevens F, Verslype C, Stroobants S, Van Steenbergen W. Positron emission tomography is not a reliable method for the early diagnosis of cholangiocarcinoma in patients with primary sclerosing cholangitis. J Hepatol. 2005;43:358–60. 30. Corvera CU, Blumgart LH, Akhurst T, DeMatteo RP, D’Angelica M, Fong Y, et al. 18f-fluorodeoxyglucose positron emission tomography influences management decisions in patients with biliary cancer. J Am Coll Surg. 2008;206:57–65. 31. Lee SW, Kim HJ, Park JH, Park DI, Cho YK, Sohn CI, et al. Clinical usefulness of 18f-fdg pet-ct for

260 patients with gallbladder cancer and cholangiocarcinoma. J Gastroenterol. 2010;45:560–6. 32. Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol. 2014;60:1268–89. 33. Weber SM, Ribero D, O’Reilly EM, Kokudo N, Miyazaki M, Pawlik TM. Intrahepatic cholangiocarcinoma: expert consensus statement. HPB (Oxford). 2015;17:669–80. 34. Bismuth H, Nakache R, Diamond T. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg. 1992;215:31–8. 35. Rizvi S, Gores GJ. Current diagnostic and management options in perihilar cholangiocarcinoma. Digestion. 2014;89:216–24. 36. Hadjis NS, Adam A, Gibson R, Blenkharn JI, Benjamin IS, Blumgart LH. Nonoperative approach to hilar cancer determined by the atrophy-hypertrophy complex. Am J Surg. 1989;157:395–9. 37. Blechacz B, Gores GJ. Cholangiocarcinoma: advances in pathogenesis, diagnosis, and treatment. Hepatology. 2008;48:308–21. 38. Fitzgerald JE, White MJ, Lobo DN. Courvoisier’s gallbladder: law or sign? World J Surg. 2009;33: 886–91. 39. Rahnemai-Azar AA, Collins KM, Fowler KJ, Chapman WC. Perihilar cholangiocarcinoma. In: Morita SY, Balch CM, Klimberg VS, Pawlik TM, Posner MC, Tanabe KK, editors. Textbook of complex general surgical oncology. New York: McGraw-Hill Education; 2018. 40. Weber A, Schmid RM, Prinz C. Diagnostic approaches for cholangiocarcinoma. World J Gastroenterol. 2008;14:4131–6. 41. Hann LE, Greatrex KV, Bach AM, Fong Y, Blumgart LH. Cholangiocarcinoma at the hepatic hilus: sonographic findings. AJR Am J Roentgenol. 1997;168: 985–9. 42. Xu HX, Chen LD, Xie XY, Xie XH, Xu ZF, Liu GJ, et al. Enhancement pattern of hilar cholangiocarcinoma: contrast-enhanced ultrasound versus contrast-enhanced computed tomography. Eur J Radiol. 2010;75:197–202. 43. Seo H, Lee JM, Kim IH, Han JK, Kim SH, Jang JY, et al. Evaluation of the gross type and longitudinal extent of extrahepatic cholangiocarcinomas on contrast-enhanced multidetector row computed tomography. J Comput Assist Tomogr. 2009;33: 376–82. 44. Gore RM, Levine MS. Neoplasms of the gallbladder and biliary tract. In: Textbook of gastrointestinal radiology e-book. 4th ed. Elsevier Health Sciences; 2014. p. 1402–26. 45. Yin XY. Diagnosis. In: Lau WY, editor. Hilar cholangiocarcinoma. Dordrecht: Springer Netherlands. Springer Dordrecht Heidelberg New York London; 2013. p. 91–8.

T. Boortalary and D. Loren 46. Aljiffry M, Walsh MJ, Molinari M. Advances in diagnosis, treatment and palliation of cholangiocarcinoma: 1990–2009. World J Gastroenterol. 2009;15:4240–62. 47. Feydy A, Vilgrain V, Denys A, Sibert A, Belghiti J, Vullierme MP, et al. Helical CT assessment in hilar cholangiocarcinoma: correlation with surgical and pathologic findings. AJR Am J Roentgenol. 1999; 172:73–7. 48. Watadani T, Akahane M, Yoshikawa T, Ohtomo K. Preoperative assessment of hilar cholangiocarcinoma using multidetector-row CT: correlation with histopathological findings. Radiat Med. 2008;26:402–7. 49. Vilgrain V. Staging cholangiocarcinoma by imaging studies. HPB (Oxford). 2008;10:106–9. 50. Choi JY, Kim MJ, Lee JM, Kim KW, Lee JY, Han JK, et al. Hilar cholangiocarcinoma: role of preoperative imaging with sonography, MDCT, MRI, and direct cholangiography. AJR Am J Roentgenol. 2008;191: 1448–57. 51. Ruys AT, van Beem BE, Engelbrecht MR, Bipat S, Stoker J, Van Gulik TM. Radiological staging in patients with hilar cholangiocarcinoma: a systematic review and meta-analysis. Br J Radiol. 2012;85: 1255–62. 52. Singh A, Mann HS, Thukral CL, Singh NR. Diagnostic accuracy of MRCP as compared to ultrasound/CT in patients with obstructive jaundice. J Clin Diagn Res. 2014;8:103–7. 53. Waxman I, Gonzalez-Haba M. Assessment of bile duct tumors: endoscopic vs radiographic. In: Millis JM, Matthews JB, editors. Difficult decisions in hepatobiliary and pancreatic surgery: an evidencebased approach. Cham: Springer International Publishing; 2016. p. 329–39. 54. Rosch T, Meining A, Fruhmorgen S, Zillinger C, Schusdziarra V, Hellerhoff K, et al. A prospective comparison of the diagnostic accuracy of ERCP, MRCP, CT, and EUS in biliary strictures. Gastrointest Endosc. 2002;55:870–6. 55. Park MS, Kim TK, Kim KW, Park SW, Lee JK, Kim JS, et al. Differentiation of extrahepatic bile duct cholangiocarcinoma from benign stricture: findings at MRCP versus ERCP. Radiology. 2004; 233:234–40. 56. Fritscher-Ravens A, Broering DC, Knoefel WT, Rogiers X, Swain P, Thonke F, et al. EUS-guided fine-needle aspiration of suspected hilar cholangiocarcinoma in potentially operable patients with negative brush cytology. Am J Gastroenterol. 2004;99:45–51. 57. Levy MJ, Heimbach JK, Gores GJ. Endoscopic ultrasound staging of cholangiocarcinoma. Curr Opin Gastroenterol. 2012;28:244–52. 58. Rosch T, Hofrichter K, Frimberger E, Meining A, Born P, Weigert N, et al. Ercp or eus for tissue diagnosis of biliary strictures? A prospective comparative study. Gastrointest Endosc. 2004;60:390–6.

13

Diagnosis and Evaluation of Cholangiocarcinoma

59. Weber A, von Weyhern C, Fend F, Schneider J, Neu B, Meining A, et al. Endoscopic transpapillary brush cytology and forceps biopsy in patients with hilar cholangiocarcinoma. World J Gastroenterol. 2008;14:1097–101. 60. Baron TH, Harewood GC, Rumalla A, Pochron NL, Stadheim LM, Gores GJ, et al. A prospective comparison of digital image analysis and routine cytology for the identification of malignancy in biliary tract strictures. Clin Gastroenterol Hepatol. 2004;2:214–9. 61. DeWitt J, Misra VL, Leblanc JK, McHenry L, Sherman S. EUS-guided FNA of proximal biliary strictures after negative ERCP brush cytology results. Gastrointest Endosc. 2006;64:325–33. 62. Mohamadnejad M, DeWitt JM, Sherman S, LeBlanc JK, Pitt HA, House MG, et al. Role of eus for preoperative evaluation of cholangiocarcinoma: a large single-center experience. Gastrointest Endosc. 2011; 73:71–8. 63. Korc P, Sherman S. ERCP tissue sampling. Gastrointest Endosc. 2016;84:557–71. 64. Gupta AK, Garg A, Khandelwal N. Diagnostic radiology: gastrointestinal and hepatobiliary imaging. Jaypee Brothers, Medical Publishers Pvt. Limited; 2017. 65. Hameed SM, Dixon E. Distal cholangiocarcinoma and periampullary cancer. In: Morita SY, Balch CM, Klimberg VS, Pawlik TM, Posner MC, Tanabe KK, editors. Textbook of complex general surgical oncology. New York: McGraw-Hill Education; 2018. 66. Lad N, Kooby DA. Distal cholangiocarcinoma. Surg Oncol Clin N Am. 2014;23:265–87. 67. Schoefl R, Haefner M, Wrba F, Pfeffel F, Stain C, Poetzi R, et al. Forceps biopsy and brush cytology during endoscopic retrograde cholangiopancreatography for the diagnosis of biliary stenoses. Scand J Gastroenterol. 1997;32:363–8. 68. Moura DTH, de Moura EGH, Matuguma SE, Dos Santos ME, Moura ETH, Baracat FI, et al. EUS-FNA versus ERCP for tissue diagnosis of suspect malignant biliary strictures: a prospective comparative study. Endosc Int Open. 2018;6:E769–77. 69. Burak K, Angulo P, Pasha TM, Egan K, Petz J, Lindor KD. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol. 2004;99:523–6. 70. Kornfeld D, Ekbom A, Ihre T. Survival and risk of cholangiocarcinoma in patients with primary sclerosing cholangitis. A population-based study. Scand J Gastroenterol. 1997;32:1042–5. 71. Razumilava N, Gores GJ. Classification, diagnosis, and management of cholangiocarcinoma. Clin Gastroenterol Hepatol. 2013;11:13–21. e11; quiz e13–14. 72. Bergquist A, Ekbom A, Olsson R, Kornfeldt D, Loof L, Danielsson A, et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol. 2002;36:321–7.

261 73. Boberg K, Bergquist A, Mitchell S, Pares A, Rosina F, Broome U, et al. Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical presentation. Scand J Gastroenterol. 2002;37:1205–11. 74. Jarnagin WR. Primary sclerosing cholangitis. In: Blumgart’s surgery of the liver, pancreas and biliary tract e-book. Elsevier Health Sciences; 2016. p. 603–14. 75. Levy C, Lymp J, Angulo P, Gores GJ, Larusso N, Lindor KD. The value of serum ca 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Springer Nature, Cham Switzerland: Dig Dis Sci. 2005;50:1734–40. 76. Ramage JK, Donaghy A, Farrant JM, Iorns R, Williams R. Serum tumor markers for the diagnosis of cholangiocarcinoma in primary sclerosing cholangitis. Gastroenterology. 1995;108:865–9. 77. Lindor KD, Kowdley KV, Harrison ME. American College of G: Acg clinical guideline: primary sclerosing cholangitis. Am J Gastroenterol. 2015;110:646– 59; quiz 660. 78. Sokol H, Cosnes J, Chazouilleres O, Beaugerie L, Tiret E, Poupon R, et al. Disease activity and cancer risk in inflammatory bowel disease associated with primary sclerosing cholangitis. World J Gastroenterol. 2008;14:3497–503. 79. Palmela C, Peerani F, Castaneda D, Torres J, Itzkowitz SH. Inflammatory bowel disease and primary sclerosing cholangitis: a review of the phenotype and associated specific features. Gut Liver. 2018;12:17–29. 80. Singh A, Siddiqui UD. The role of endoscopy in the diagnosis and management of cholangiocarcinoma. J Clin Gastroenterol. 2015;49:725–37. 81. Glasbrenner B, Ardan M, Boeck W, Preclik G, Moller P, Adler G. Prospective evaluation of brush cytology of biliary strictures during endoscopic retrograde cholangiopancreatography. Endoscopy. 1999;31:712–7. 82. Pugliese V, Conio M, Nicolo G, Saccomanno S, Gatteschi B. Endoscopic retrograde forceps biopsy and brush cytology of biliary strictures: a prospective study. Gastrointest Endosc. 1995;42:520–6. 83. Fogel EL, deBellis M, McHenry L, Watkins JL, Chappo J, Cramer H, et al. Effectiveness of a new long cytology brush in the evaluation of malignant biliary obstruction: a prospective study. Gastrointest Endosc. 2006;63:71–7. 84. de Bellis M, Sherman S, Fogel EL, Cramer H, Chappo J, McHenry L Jr, et al. Tissue sampling at ERCP in suspected malignant biliary strictures (part 2). Gastrointest Endosc. 2002;56:720–30. 85. Technology Assessment C, Barkun A, Liu J, Carpenter S, Chotiprasidhi P, Chuttani R, et al. Update on endoscopic tissue sampling devices. Gastrointest Endosc. 2006;63:741–5. 86. Siddiqui AA, Strongin A, Kistler A, Eloubeidi MA. Equipment and approach. In: Lee LS, editor. ERCP and EUS: a case-based approach. New York: Springer; 2015. p. 357–70.

262 87. Al-Haddad MA. Endoscopic ultrasound in bile duct, gallbladder, and ampullary lesions. In: Endosonography. 11th ed; 2019. p. 201–24. 88. Abe Y, Kawakami H, Oba K, Hayashi T, Yasuda I, Mukai T, et al. Effect of a stylet on a histological specimen in EUS-guided fine-needle tissue acquisition by using 22-gauge needles: a multicenter, prospective, randomized, controlled trial. Gastrointest Endosc. Robert H. Hawes Publisher: Elsevier Saunders, Philadelphia; 2015;82:837–44. e831 89. Wani S, Gupta N, Gaddam S, Singh V, Ulusarac O, Romanas M, et al. A comparative study of endoscopic ultrasound guided fine needle aspiration with and without a stylet. Dig Dis Sci. 2011;56:2409–14. 90. Attam R, Arain MA, Bloechl SJ, Trikudanathan G, Munigala S, Bakman Y, et al. “Wet suction technique (west)”: a novel way to enhance the quality of EUS-FNA aspirate. Results of a prospective, singleblind, randomized, controlled trial using a 22-gauge needle for EUS-FNA of solid lesions. Gastrointest Endosc. 2015;81:1401–7. 91. Karagyozov P, Boeva I, Tishkov I. Role of digital single-operator cholangioscopy in the diagnosis and treatment of biliary disorders. World J Gastrointest Endosc. 2019;11:31–40. 92. Huang W-H. ERCP for biliary-pancreatic tissue acquisition. In: Lai K-H, Mo L-R, Wang H-P, editors. Biliopancreatic endoscopy: practical application. Singapore: Springer; 2018. p. 107–15. 93. Draganov PV, Chauhan S, Wagh MS, Gupte AR, Lin T, Hou W, et al. Diagnostic accuracy of conventional and cholangioscopy-guided sampling of indeterminate biliary lesions at the time of ERCP: a prospective, long-term follow-up study. Gastrointest Endosc. 2012;75:347–53. 94. Laleman W, Verraes K, Van Steenbergen W, Cassiman D, Nevens F, Van der Merwe S, et al. Usefulness of the single-operator cholangioscopy system spyglass in biliary disease: a single-center prospective cohort study and aggregated review. Surg Endosc. 2017;31:2223–32. 95. Kipp BR, Stadheim LM, Halling SA, Pochron NL, Harmsen S, Nagorney DM, et al. A comparison of routine cytology and fluorescence in situ hybridization for the detection of malignant bile duct strictures. Am J Gastroenterol. 2004;99:1675–81. 96. Nguyen K, Sing JT Jr. Review of endoscopic techniques in the diagnosis and management of cholangiocarcinoma. World J Gastroenterol. 2008; 14:2995–9. 97. Harbhajanka A, Michael CW, Janaki N, Gokozan HN, Wasman J, Bomeisl P, et al. Tiny but mighty: use of next generation sequencing on discarded cytocentrifuged bile duct brushing specimens to increase sensitivity of cytological diagnosis. Mod Pathol. 2020:1–7. 98. Warner SG, Cho CS, Fong Y. Biliary tract tumors. Shackelford’s surgery of the alimentary tract, 2 volume set; 2019. 33:1323–39.

T. Boortalary and D. Loren 99. El-Khoueiry A. Uncommon hepatobiliary tumors. In: Textbook of uncommon cancer; 2017. pp. 444–57. 100. Kim SY. Preoperative radiologic evaluation of cholangiocarcinoma. Korean J Gastroenterol 2017;69:159–63. 101. Blechacz B, Komuta M, Roskams T, Gores GJ. Clinical diagnosis and staging of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol. 2011;8: 512–22. 102. Forner A, Vidili G, Rengo M, Bujanda L, PonzSarvise M, Lamarca A. Clinical presentation, diagnosis and staging of cholangiocarcinoma. Liver Int. 2019;39(Suppl 1):98–107. 103. Amin MB, Edge SB. AJCC cancer staging manual. Springer; 2017. 104. Menias CO, Surabhi VR, Prasad SR, Wang HL, Narra VR, Chintapalli KN. Oak Brook, IL: Mimics of cholangiocarcinoma: spectrum of disease. Radiographics. 2008;28:1115–29. 105. Tsunoda T, Eto T, Yamada M, Tajima Y, Matsuo S, Tsuchiya R, et al. Segmental primary sclerosing cholangitis mimicking bile duct cancer – report of a case and review of the Japanese literature. Jpn J Surg. 1991;21:329–34. 106. Stone JH, Zen Y, Deshpande V. Igg4-related disease. N Engl J Med. 2012;366:539–51. 107. Suriawinata A. Neoplastic mimics in gastrointestinal and liver pathology. New York: Demos Medical Publishing; 2014. 108. Lee JJ, Schindera ST, Jang H-J, Fung S, Kim TK. Cholangiocarcinoma and its mimickers in primary sclerosing cholangitis. Abdom Radiol. 2017;42:2898–908. 109. Zen Y, Kawakami H, Kim JH. Igg4-related sclerosing cholangitis: all we need to know. J Gastroenterol. 2016;51:295–312. 110. Zhang Y, Lu H, Ji H, Li Y. Inflammatory pseudotumor of the liver: a case report and literature review. Intractable Rare Dis Res. 2015;4:155–8. 111. Narla LD, Newman B, Spottswood SS, Narla S, Kolli R. Inflammatory pseudotumor. Radiographics. 2003; 23:719–29. 112. Matsuo Y, Sato M, Shibata T, Morimoto M, Tsuboi K, Shamoto T, et al. Inflammatory pseudotumor of the liver diagnosed as metastatic liver tumor in a patient with a gastrointestinal stromal tumor of the rectum: report of a case. World J Surg Oncol. 2014;12:140. 113. Kassahun W, Stumpp P, Hoffmeister A, Jonas S. Differential diagnosis. In: Lau WY, editor. Hilar cholangiocarcinoma. Dordrecht: Springer; 2013. p. 99–109. 114. Jessurun J, Pambuccian S. Infectious and inflammatory disorders of the gallbladder and extrahepatic biliary tract. In: Surgical pathology of the GI tract, liver, biliary tract, and pancreas. Elsevier; 2009. p. 823–43. 115. Giesbrandt KJ, Bulatao IG, Keaveny AP, Nguyen JH, Paz-Fumagalli R, Taner CB. Radiologic characterization of ischemic cholangiopathy in donation-after-

13

Diagnosis and Evaluation of Cholangiocarcinoma

cardiac-death liver transplants and correlation with clinical outcomes. Leesburg, VA: AJR Am J Roentgenol. 2015;205:976–84. 116. Abdalian R, Heathcote EJ. Sclerosing cholangitis: a focus on secondary causes. Hepatology. 2006;44: 1063–74. 117. Cappell MS. Hepatobiliary manifestations of the acquired immune deficiency syndrome. Am J Gastroenterol. 1991;86. 118. Margulis SJ, Honig CL, Soave R, Govoni AF, Mouradian JA, Jacobson IM. Biliary tract obstruction in the acquired immunodeficiency syndrome. Ann Intern Med. 1986;105:207–10. 119. Gao Y, Chin K, Mishriki YY. Aids cholangiopathy in an asymptomatic, previously undiagnosed late-stage hiv-positive patient from Kenya. Int J Hepatol. 2011;2011:465895. 120. Nash JA, Cohen SA. Gallbladder and biliary tract disease in aids. Gastroenterol Clin N Am. 1997;26: 323–35. 121. Bouche H, Housset C, Dumont J, Carnot F, Menu Y, Aveline B, et al. Aids-related cholangitis: diagnostic features and course in 15 patients. J Hepatol. 1993;17: 34–9. 122. Benhamou Y, Caumes E, Gerosa Y, Cadranel JF, Dohin E, Katlama C, et al. Aids-related cholangiopathy. Dig Dis Sci. 1993;38:1113–8. 123. Suzuki K, Morise Z, Furuta S, Tanahashi Y, Takeura C, Kagawa T, et al. Hepatic sarcoidosis mimicking hilar cholangiocarcinoma: case report and review of the literature. Case Rep Gastroenterol. 2011;5:152–8. 124. Alam I, Levenson SD, Ferrell LD, Bass NM. Diffuse intrahepatic biliary strictures in sarcoidosis resembling sclerosing cholangitis: case report and review of the literature. Dig Dis Sci. 1997;42:1295. 125. Allaire GS, Rabin L, Ishak KG, Sesterhenn IA. Bile duct adenoma. A study of 152 cases. Am J Surg Pathol. 1988;12:708–15. 126. Murray KF, Larson AM. Fibrocystic diseases of the liver. Humana Press; 2010. 127. Coakley FV. Pearls and pitfalls in abdominal imaging: pseudotumors, variants and other difficult diagnoses. Cambridge, UK: Cambridge University Press; 2010. 128. Gibson RN, Sutherland T. Biliary anatomy. In: Grainger & Allison’s diagnostic radiology: abdominal imaging; 2015. p. 193. 129. Salihefendić N, Licanin Z, Zildzić M. Cavernous transformation of portal vein. Med Arh. 2005;59: 132–4. 130. Majid Z, Tahir F, Bin Arif T, Ahmed J. Chronic non-cirrhotic portal vein thrombosis with cavernous transformation secondary to protein c and s deficiency. Cureus. 2020;12:e7142. 131. Altun E, El-Azzazi M, Semelka RC, Braga L, Altun E, El-Azzazi M, et al. Liver imaging: MRI with CT correlation. Wiley: Somerset; 2015. 132. Greiner L, Nuernberg D, Schmidt G, Nuernberg D. Differential diagnosis in ultrasound imaging.

263 New York: Thieme Medical Publishers, Incorporated; 2014. 133. Moomjian LN, Winks SG. Portal cavernoma cholangiopathy: diagnosis, imaging, and intervention. Abdom Radiol. 2017;42:57–68. 134. De Gaetano AM, Lafortune M, Patriquin H, De Franco A, Aubin B, Paradis K. Cavernous transformation of the portal vein: patterns of intrahepatic and splanchnic collateral circulation detected with doppler sonography. AJR Am J Roentgenol. 1995;165: 1151–5. 135. Bialecki ES, Di Bisceglie AM. Clinical presentation and natural course of hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 2005;17:485–9. 136. Kim TK, Lee E, Jang HJ. Imaging findings of mimickers of hepatocellular carcinoma. Clin Mol Hepatol. 2015;21:326–43. 137. Jang K-T, G-h A, Heo J-S, Choi D-I, Oh Y-L, Choi S-H, et al. Adenomyoma of ampulla of vater or the common bile duct-a report of three cases. Korean J Pathol. 2005;39:59–62. 138. Mulla M, Srivastava V, Hopper I, Klein J, Larvin M, Hall R. Diagnosis of biliary adenomyomatosis. Eur Surg. 2008;40:81–2. 139. Zimmermann A. Reactive bile duct alterations mimicking biliary cancer: Inflammatory conditions. In: Tumors and tumor-like lesions of the hepatobiliary tract: general and surgical pathology. Cham: Springer International Publishing; 2017. p. 2533–49. 140. Aoun N, Zafatayeff S, Smayra T, Haddad-Zebouni S, Tohme C, Ghossain M. Adenomyoma of the ampullary region: imaging findings in four patients. Abdom Imaging. 2004;30:86–9. 141. Handra-Luca A, Terris B, Couvelard A, Bonte H, Flejou J-F. Adenomyoma and adenomyomatous hyperplasia of the vaterian system: clinical, pathological, and new immunohistochemical features of 13 cases. Mod Pathol. 2003;16:530–6. 142. Zimmermann A. Extrahepatic cholangiocarcinoma: carcinoma of the middle and distal common bile duct (middle and lower bile duct carcinomas). In: Tumors and tumor-like lesions of the hepatobiliary tract. Cham: Springer International Publishing; 2016. p. 1–21. 143. Dumonceau J-M, Delhaye M, Charette N, Farina A. Challenging biliary strictures: pathophysiological features, differential diagnosis, diagnostic algorithms, and new clinically relevant biomarkers-part 1. Ther Adv Gastroenterol. 2020;13:1756284820927292. 144. Tummala P, Junaidi O, Agarwal B. Imaging of pancreatic cancer: an overview. J Gastrointest Oncol. 2011;2:168. 145. Mizrahi M, Cohen J, de Andrade Lima JGG, Pleskow D. Malignant biliary obstruction: distal. In: ERCP. Elsevier; 2019. p. 372–84. e374. 146. Coletta M, Montalti R, Pistelli M, Vincenzi P, Mocchegiani F, Vivarelli M. Metastatic breast cancer mimicking a hilar cholangiocarcinoma: case report and review of the literature. Springer Nature, Cham Switzerland: World J Surg Oncol. 2014;12:384.

264 147. Nemunaitis JM, Brown-Glabeman U, Soares H, Belmonte J, Liem B, Nir I, et al. Gallbladder cancer: review of a rare orphan gastrointestinal cancer with a focus on populations of New Mexico. BMC Cancer. 2018;18:665. 148. Barnes D. Gallbladder and biliary tract disease. Cleveland Clinic; 2010.

T. Boortalary and D. Loren 149. Goodman ZD, Ishak KG. Xanthogranulomatous cholecystitis. Philadelphia PA: Am J Surg Pathol. 1981;5: 653–9. 150. Singh VP, Rajesh S, Bihari C, Desai SN, Pargewar SS, Arora A. Xanthogranulomatous cholecystitis: what every radiologist should know. World J Radiol. 2016;8:183.

Cholangiocarcinoma: Epidemiology, Pathogenesis, and Prognosis

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Yunseok Namn and Juan Carlos Bucobo

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266

2 2.1 2.2 2.3 2.4

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gender . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Geographical Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Trends of Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cholangiocarcinoma and Misclassification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

266 267 267 267 268

3 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8

Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Parasitic Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hepatitis B, Hepatitis C, and Cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biliary Stone Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biliary Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Primary Sclerosing Cholangitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metabolic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Toxin Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

269 269 269 270 270 270 271 271 271

Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inflammation and Cholestasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inflammatory Mediators, Cytokines, and Growth Factors . . . . . . . . . . . . . . . . . . . . . . . Inducible Nitric Oxide Synthase (iNOS) and Reactive Nitrogen Oxygen Species (RNOS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4 Developmental Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5 Tumor Microenvironment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6 Genetic Alterations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

272 272 272

Staging and Classification System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bismuth-Corlette System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Memorial Sloan Kettering Cancer Center (MSKCC) Classification System . . . . AJCC/UICC TNM Staging System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

275 275 275 276

4 4.1 4.2 4.3

5 5.1 5.2 5.3

273 273 274 274

Y. Namn · J. C. Bucobo (*) Stony Brook Medicine, New York, NY, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2022 C. Doria, J. N. Rogart (eds.), Hepato-Pancreato-Biliary Malignancies, https://doi.org/10.1007/978-3-030-41683-6_13

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Y. Namn and J. C. Bucobo 6 Prognosis and Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 6.1 Surgical Outcome: Resection-Related Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 6.2 Tumor-Related Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291

Abstract

Cholangiocarcinoma is a malignancy arising from epithelial cells of the biliary tract characterized by its aggressive natural history, late diagnosis, and often fatal outcome. It is the most common biliary malignancy accounting for approximately 15–20% of all primary hepatobiliary cancers. Cholangiocarcinoma is classically subdivided based on anatomic location: intrahepatic, hilar, and distal. Each subtype is distinct in epidemiologic trend, natural history of progression, and prognosis. There are substantial geographical variations in incidence with the highest rates reported in Southeast Asia. Cholangiocarcinogenesis is driven by a complex multistep process beginning with chronic biliary tract inflammation followed by exposure to carcinogenic molecules and overexpression of proliferative growth factors. This results in stepwise accumulation of genetic mutations, ultimately leading to uncontrolled cell growth and metastasis. Patients with non-resectable advanced-stage cholangiocarcinoma have a dismal prognosis with a median survival of less than 24 months after diagnosis. If patients are diagnosed at an early stage, complete tumor resection is the only treatment that offers the best chance of cure and long-term survival. Unfortunately, despite R0 negative margin resections, long-term prognosis defined by survival and tumor recurrence remains poor in the presence of aggressive tumor-related factors. Keywords

Cholangiocarcinoma · Bile duct cancer

1

Introduction

Cholangiocarcinoma (CCA) represents a heterogeneous group of malignancies that can arise from anywhere along the biliary tree. Perihilar

cholangiocarcinoma (pCCA), also known as the Klatskin tumor, is the most common type with an incidence of 50–70%, followed by distal cholangiocarcinoma (dCCA) of 20–40% and intrahepatic cholangiocarcinoma (iCCA) of 5–10% [1, 2]. The hilar and distal forms comprise the broad classification group known as extrahepatic cholangiocarcinoma (EH-CCA). These three types are distinct in their epidemiologic trend, clinical presentation, natural history of progression, and prognosis. CCA is characterized by its aggressive and fatal nature as it is often diagnosed in advanced disease stages. Complete tumor resection is the only available treatment that offers the best opportunity for long-term survival. Despite progress in the standard of care and management, the 5-year overall survival (OS) across all CCA subtypes remains dismal at 5–18% [2, 3]. It is important to understand the epidemiology, pathogenesis, and prognostic factors of each cholangiocarcinoma type in order to better prognosticate, treat, and improve long-term oncologic and survival outcomes.

2

Epidemiology

Cholangiocarcinoma is the most common biliary malignancy accounting for approximately 15–20% of all primary hepatobiliary cancers worldwide [1, 4]. Approximately 5,000 new patients are diagnosed with cholangiocarcinoma in the United States each year. It is the 9th most common gastroenterological malignancy and the second most common hepatic malignancy after hepatocellular carcinoma. It represents nearly 3% of all gastrointestinal tumors with a peak age of incidence occurring within the seventh decade in Western populations. Globally, diagnosis is usually made after 50 years of age [4–7]. Hepatobiliary malignancies account for approximately 13% of cancerrelated deaths, of which 10–20% are attributable

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Cholangiocarcinoma: Epidemiology, Pathogenesis, and Prognosis

to cholangiocarcinoma [2, 4, 5]. When discussing epidemiologic trends and risk factors, it should be noted that there are no specific population-based studies that distinguish hilar and distal cholangiocarcinomas. These tumors are examined within the broad context of all cholangiocarcinomas or within the group of EH-CCA.

2.1

Gender

Based on the Surveillance, Epidemiology, and End Results (SEER) cancer registry, CCA affects both genders although males have a slightly higher incidence at a male/female ratio of approximately 1:1.2 in patients younger than 40 years of age. However, this ratio increases to 1:2.5 for patients in their 60s–70s. Males are also noted to have slightly higher incidence of mortality [6]. This trend is seen globally in both the Eastern and Western populations. The etiology behind this gender disparity is not entirely clear. Variations in biologic modifiers of tumor behavior such as male and female hormones have been discussed as potential attributing factors. For example, some studies have found that 17B-estradiol (E2) and estrogen receptor (ERα) levels were upregulated in males with CCA. Differences in socioeconomic factors such as insurance status or adherence to treatment regimens may be contributing factors as well.

2.2

Geographical Distribution

There is substantial heterogeneity of global incidences reported among various countries with the highest incidence reported in Southeast Asia. Australia reports one of the lowest agestandardized incidence rate of CCA at 0.1/ 100,000 person-years in women and 0.2/100,000 in men [1, 4, 8]. In Western Europe, agestandardized incidence rates range from 0.45/ 100,000 in Switzerland to 3.36/100,000 in Italy. Meanwhile, in Thailand, incidence is reported to be as high as 113/100,000 in men and 50/100,000 in women [1, 4]. This rate is nearly 100 times higher than that of the Western population where

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CCA incidence ranges between 0.5 and 1.5/ 100,000 person-years [1, 8]. In Thailand, cholangiocarcinomas account for 89% of primary hepatic cancers. The United States overall has an incidence rate of 1.18/100,000 and 1.02/100,000 for iCCA and EH-CCA, respectively [9]. Within the United States, Asian Pacific Islanders report the highest incidences of CCA at 1.87/100,000. In contrast, African Americans have the lowest reported rate at 1.17/100,000 [1, 6, 9]. The large disparities of global incidence are attributable to variations in genetic background and risk factors endemic to a particular region. For example, the hepatobiliary fluke infection and hepatolithiasis, which are well-established cholangiocarcinoma risk factors, are much more prevalent in Asia than in Western countries (see Sect. 3). Studies also show cholangiocarcinoma subtypes (iCCA and EH-CCA) have a geographically based distribution, which is likely a reflection of the spatial segregation of etiological factors. iCCA is the predominant form of cholangiocarcinoma over EH-CCA in Asian countries including China, Thailand, South Korea, Japan, Taiwan, and the Philippines [10]. On the other hand, countries in Western Europe such as Austria, Greece, Italy, and Germany have similar or greater incidence rates of EH-CCA compared to that of iCCA. In the United States, the overall distribution of iCCA and EH-CCA appears to be similar. The highest incidences of both iCCA and EH-CCA within the United States have been found in the Pacific region. Interestingly, 46% of Asians/Pacific Islanders in the United States live in the Pacific region which may account for the high rates of cancer seen here [10].

2.3

Trends of Incidence

Over the past few decades, many epidemiologic studies involving the World Health Organization (WHO) database, SEER database, and National Center for Health Statistics (NCHS) have reported a rise in incidence and mortality of iCCA worldwide, while EH-CCA has remained relatively stable [1, 4, 8, 9]. This trend was noted in both

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genders across several countries including the United States, the United Kingdom, Australia, Japan, and those of the European Union. An analysis of the last three decades using the US SEER database reported an increase in the incidence of iCCA from 0.44 to 1.18/100,000. This correlated to an annual percentage change (APC) of +2.30% with an accelerated increase to an APC of 4.36% within the past decade [9]. The incidence of EH-CCA remained relatively stable throughout this time with only a modest increase from 0.95/ 100,000 to 1.02/100,000, corresponding to an APC of 0.14%. The national iCCA-related mortality rate is reported to have nearly doubled across both genders between 1995 and 2015 [1, 9]. The etiology behind these recent trends is still unclear. The increasing incidence of iCCA may be related to improvements in diagnostic modalities or perhaps due to the overall aging population. Rising incidences of risk factors that may be associated with CCA such as metabolic syndrome, obesity, hepatic steatosis, diabetes, and cirrhosis may be playing a role as well.

2.4

Cholangiocarcinoma and Misclassification

Another potential explanation for the reported increase in incidence may be related to the inherent challenge of accurately classifying CCAs. First, it is often difficult to distinguish between intrahepatic and extrahepatic locations in advanced tumor states. Unfortunately, upon presentation, the majority of CCAs is found in advanced stages due to their aggressive natural history. Second, classifying CCAs appropriately has been historically difficult given the lack of a uniform, accurate, and consistent staging system. There have been significant coding inconsistencies in prior classification systems which have led to discrepant results across clinical studies and cancer registries. For example, in version one of the International Classification of Diseases for Oncology (ICD-O) which was implemented between 1973 and 1991, a unique code was not even designated for pCCAs. In the second version

of the International Classification Disease for Oncology (ICD-O-2) which was implemented between 1992 and 2000, although pCCAs were given a unique morphologic histology code, it was done so where it could have been mistakenly classified as iCCA instead [1, 4, 6, 9]. Under the ICD-O-2 classification system, a US SEER database analysis reported an increase in age-adjusted incidence rate from 0.59 to 0.91/100,000. During this time period, one post hoc study estimated that nearly 91% of pCCAs were incorrectly coded as iCCAs resulting in an overestimation of iCCA incidence by 13% and an underestimation of EH-CCA incidence by 15% [9–11]. In the currently used third iteration of the ICD-O (ICD-O-3), codes are based on anatomic location (topographical coding) and histology (morphologic coding) which better clarifies pCCA as a separate entity from iCCA. Since the implementation of ICD-O-3 in 2001, a US SEER database analysis demonstrated a subsequent decrease in iCCA incidence rate from 0.91/ 100,000 in 2001 to 0.6/100,000 in 2007 [1, 6, 9–11]. Other studies, however, did not reveal a similar trend despite the previous misclassification of hilar and intrahepatic tumors. Although improved compared to prior versions, the ICD-O3 still lacks clarity as it does not have an accurate morphologic coding system. For example, the ICD-O-3 has a morphologic code for pCCA but lacks specific codes for iCCA or dCCA. Hilar tumors can still potentially be incorrectly coded as iCCA or dCCA; therefore, the true incidence rates of each subtype are still likely unknown. The apparent rise in iCCA incidence may also be a result of intrahepatic tumors increasingly being recognized as a separate entity distinct from cancers of unknown primary (CUP). Clinically differentiating iCCA from CUP has previously been challenging as intrahepatic tumors may at times resemble metastatic disease to the liver. Subsequently, many iCCAs have been misdiagnosed as CUP in the past [4, 9]. Recent improvements in molecular diagnostics and histopathologic techniques have allowed clinicians to distinguish cancers with gene expression and histology consistent with cholangiocarcinoma from CUP. Since this distinction was made, the

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incidence of CUP has decreased by nearly 51% between 1973 and 2012, while the incidence of iCCA has risen during this time [9–11]. The ability to distinguish iCCA from CUP may be a contributory factor to the reported increase in iCCA trend. It is unknown if this trend represents a true increase in the iCCA disease burden or if it is a result of skewed data based on classification discrepancies and lack of a uniform and consistent coding system. In turn, the true incidence and mortality rates of CCA are still unclear at this time, and reported changes in epidemiologic trends should continue to be interpreted with caution.

factors commonly found in the region include a nitrite-rich diet through fish consumption, smoking, and alcohol use [4]. Opisthorchis viverrini is endemic to Thailand, Laos, and Cambodia, while C. sinensis is endemic to areas such as China, Taiwan, and Korea. Both parasites can inhabit the bile ducts, gallbladder, and pancreatic duct for many years causing chronic inflammation, cholangitis, obstructive jaundice, and fibrosis of the periportal system. These parasites increase the exposure of cholangiocytes to both endogenous and exogenous carcinogenic molecules. The International Agency for Research on Cancer (IARC) has since recognized both O. viverrini and C. sinensis as established carcinogens.

3

3.2

Risk Factors

There are several risk factors for cholangiocarcinoma that are well established including parasitic fluke infections, biliary cysts, primary sclerosing cholangitis, hepatolithiasis, and toxins such as thorotrast [1, 4]. Less established potential risk factors include the systemic viral and liverspecific infections, presence of cirrhosis, metabolic syndrome, diabetes, obesity, nonalcoholic fatty liver disease (NAFLD), smoking, alcohol use, and host genetic polymorphisms. Overall, most risk factors are broadly shared among all CCA types. However, some risk factors are more prevalent to a CCA subtype. Despite our advancements in knowledge of cholangiocarcinoma etiology, nearly 50% of cases in the Western countries still do not have an identifiable risk factor [1, 4, 5, 9]. Further studies need to be performed to evaluate for these causes.

3.1

Parasitic Infections

Regions of the Far East and Southeast Asia have one of the highest incidences of hepatobiliary fluke infections (Opisthorchis viverrini and Clonorchis sinensis) [1, 2, 4]. These parasitic infections occur through the ingestion of raw or undercooked fish and are regarded as one of the most significant risk factors of cholangiocarcinogenesis. Additional risk

Hepatitis B, Hepatitis C, and Cirrhosis

Hepatitis B virus (HBV), hepatitis C virus (HCV) infection, and liver cirrhosis have been recognized as less established risk factors for CCA. The HBV and HCV infections seem to have a stronger association with iCCA rather than EH-CCA. Viral hepatitis likely leads to chronic inflammation resulting in increased cell turnover and proliferation. However, studies have also shown that HBV and HCV in the absence of the chronic liver disease may be associated with CCA as well. It is postulated that the viruses may have a direct carcinogenic effect on cells. Overall, the association between HBV and HCV with CCA is not entirely clear as studies have differing conclusions. Depending on the study, there are variations of CCA incidence even in regions where HBV and HCV are endemic. For instance, a case control study performed in Korea demonstrated a significant association between HBV and iCCA (OR 2.3, 95% CI 1.6–3.3); however, other populationbased studies did not report these findings. Interestingly, in Asian countries where HBV is endemic, hepatitis B appears to have a strong association with iCCA compared to HCV. On the other hand, in Western nations including the United States where HCV is more prevalent, data suggests a significant association between HCV

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and iCCA rather than HBV [1, 2, 4, 5]. These geographical variations may be explained by the differences in genetic predispositions and environmental risks. Chronic liver disease or cirrhosis even in the absence of viral etiology may also be associated with intrahepatic cholangiocarcinoma [9, 12]. A large meta-analysis reported an odds ratio (OR) of 15.32 (95% CI 9.33–25.15) for nonspecific cirrhosis [2]. Chronic liver disease likely promotes a carcinogenic microenvironment though chronic inflammation, progressive fibrosis, and increased cell turnover.

3.3

Biliary Stone Disease

Hepatolithiasis is stones of the intrahepatic duct located proximal to the union of the right and left hepatic ducts. It is a well-established risk factor for predominantly iCCAs. Hepatolithiasis has a high prevalence in Asian countries with a cumulative incidence of 4–11%; however, it is rarely found in the West [1, 9, 12]. A case control study performed in Korea reported a near 50-fold increased risk of iCCA in patients with hepatolithiasis. It is thought that the chronic calculi burden leads to chronic biliary inflammation and recurrent infections with parasites such as C. sinensis and Ascaris lumbricoides. These infections can be found in 30% of patients with hepatholithiasis [1, 9, 12]. Other cholelithiasis entities such as choledocholithiasis and cholecystolithiasis are commonly found in the Western world. These stones are postulated to potentially increase the risk of developing EH-CCA although this relationship is not as well established.

3.4

Biliary Cysts

Fibropolycystic liver diseases (FPLD) represent a heterogenous group of conditions characterized by cystic lesions in the liver often association with fibrotic liver disease. The FPLD group includes congenital hepatic fibrosis and biliary choledochal cysts. Collectively, FPLD heralds approximately a 10–15% risk of developing

CCA [1, 4, 5, 9]. The association between biliary cysts and CCA is well established and is more commonly found in Asian compared to Western countries. Patients with biliary cysts have a lifetime incidence of CCA 6%–30% and are reported to have up to a 50-fold increased risk of CCA compared to the general population. There is also an accelerated incidence of CCA once after the age of 20 where the incidence is greater than 14% compared to an incidence of 0.7% in the first decade of life [1, 4, 9]. Cholangiocarcinoma can arise from cysts as well as the non-dilated portions of the biliary tree. Generally, the risk of cancer decreases after cyst excision, but malignancy risk can still remain elevated in certain biliary subtypes. Caroli’s disease which is characterized by saccular dilation of the large intrahepatic bile ducts particularly has a strong association with CCA [4, 9, 12].

3.5

Primary Sclerosing Cholangitis

Special consideration and surveillance should be given to patients with primary sclerosing cholangitis (PSC) who are considered a high-risk population. Primary sclerosing cholangitis (PSC) is an autoimmune disease characterized by progressive biliary duct destruction and stricturing of the extra- and/or intrahepatic biliary ductal system. Impaired biliary drainage and bile stasis are thought to be the driving force behind chronic inflammation, carcinogenic exposure, and cholangiocarcinogenesis. Patients with PSC are at an elevated risk for cholangiocarcinoma, predominantly located at the hilum. The mean age of CCA development in patients with PSC occurs much earlier than the general population at around the fourth decade of life [4, 6]. The annual risk of developing CCA is 0.5–1.5% with a lifetime incidence of 6–36%, which is equivalent to a near 398-fold increased risk compared to the general population. Nearly 30–50% of CCAs will be found within the first year of PSC diagnosis [1, 7]. In the Western population, although the majority of CCA occurs sporadically, PSC with or without ulcerative colitis (UC) is currently the most well-established predisposing condition. The overall prevalence

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Cholangiocarcinoma: Epidemiology, Pathogenesis, and Prognosis

rate of cholangiocarcinoma in PSC ranges between 5% and 15% [1, 7]. Cholangiocarcinoma still remains the leading cause of death in patients with PSC with a median survival of only 5 months. In non-resectable cancers, only 10% survive beyond 2 years [1, 6, 7]. The development of CCA in PSC patients is often heralded by symptoms such as rapid clinical deterioration, declining performance status, jaundice, weight loss, and abdominal discomfort. Nearly 50% of CCAs are diagnosed within the first year of PSC diagnosis and are mostly identified at the hilum. Smoking, alcohol use, elevated serum bilirubin, history of variceal bleeding, older age at PSC diagnosis, and coexisting colorectal neoplasia have been identified as potential additional risk factors of CCA [1, 7, 9, 12]. It is less clear if duration of PSC, distribution of biliary strictures, and history of colectomy are associated with an increased risk of cholangiocarcinoma. It is unclear if the presence of underlying inflammatory bowel disease has an impact on CCA risk; however, one study reported a 20-year CCA cumulative incidence rate of 31% in PSC patients with IBD compared to those without IBD at 2%. Some studies also report that CCA seems to occur more commonly in patients with UC (60–80%) than in patients with Crohn’s disease (7–21%) [5, 7, 12]. Earlier diagnosis through radiologic screening mechanisms and clinical awareness may improve the frequency and effectiveness of surgical resection; however, there are still currently no clinical or biochemical features that risk stratify and accurately identify patients at most risk for developing CCA.

3.6

Metabolic Disorders

From a lifestyle perspective, diabetes, obesity, alcohol consumption, and tobacco use are increasingly being recognized as risk factors although these are currently considered weaker associations [5, 9, 12]. Several US and UK populationbased case control studies have demonstrated that diabetes is associated with both iCCA and EH-CCA, while other studies have failed to show a significant association. The data on

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obesity is very limited. A UK-based study reported that a BMI
30 had a significant but weak association to CCA (OR 1.52, 95% CI 1.0–2.2). On the same spectrum, nonalcoholic fatty liver disease (NAFLD) is considered potential risk factors as well with some studies citing a threefold increased risk of both iCCA and EH-CCA. However, at this time, the data available on these factors is too inconsistent and limited to make any significant conclusions.

3.7

Toxin Exposure

Of the toxins, the most well-established risk factor is the radiographic contrast agent known as Thorotrast. This contrast was primarily used between 1930 and 1960 and was found to have a 300-fold increased risk of developing CCA [1, 12]. The use of this contrast agent is now banned. Several cohort and population-based studies have reported a strong association between heavy alcohol consumption (>80 grams/day) and CCA. A US SEER database analysis of Medicare patients found alcoholic liver disease to be significantly associated with both iCCA and EH-CCA with an OR of 7.4 (95% CI 4.3–12.8). Other population-based case control studies, however, did not find alcohol use to be a risk factor. It is thought that alcohol could potentially increase the risk of CCA through chronic hepatic injury and through direct carcinogenesis by inducing the cytochrome P450 family 2 subfamily E member 1 (CYP2E1) and releasing mutagenic reactive oxygen species [1, 4, 9, 12]. Smoking has also been postulated to increase both iCCA and EH-CCA although data is inconsistent. Several population-based studies including a SEER database case control study have demonstrated weak associations, while other studies have not reported any significant association [1, 7, 9, 12].

3.8

Genetic Diseases

A number of genetic polymorphisms responsible for regulation of DNA repair and inflammation

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have been identified with possible association with cholangiocarcinoma. Genes coding for enzymes responsible for metabolism of carcinogens, DNA repair, and inflammation have been evaluated for polymorphic variants that may predispose to CCA. However, given the lack of adequate studies at this time, no definitive conclusions can be made [9, 12]. Genetic disorders such as Lynch syndrome and biliary papillomatosis are considered potential risk factors for cholangiocarcinoma [1, 4, 5]. Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is an autosomal dominant disorder caused by germline mutations in one of the DNA mismatch repair genes. Alongside the widely recognized increased risk of colorectal, uterine, upper gastrointestinal tract, and urinary tract cancers, some studies report an increased risk in pancreatic and biliary tract cancers including cholangiocarcinoma. Biliary papillomatosis is a rare condition characterized by multiple adenomatous polyps distributed throughout the biliary tree. It is considered a premalignant condition with some studies citing up to an 80% rate of malignant transformation. Other genetic disorders associated with cholangiocarcinoma include the BRCA-associated protein (BAP) 1 tumor predisposition syndrome. Families that carry germline missense variants of the BAP1 gene potentially have increased risk for CCA [1, 18].

4

Pathogenesis

Despite the diverse range of risk factors identified, the recurring pathologic features are longstanding chronic inflammation and biliary cholestasis [1, 9, 13]. These two factors work hand in hand, triggering a complex cascade of pathways and molecular pathogenesis that promotes cholangiocarcinogenesis. Chronic inflammation provides a microenvironment that induces malignant transformation of bile duct-associated cells including cholangiocytes, biliary stem cells, and peribiliary gland epithelial cells. Given the varying cells of origin, the well-described adenomadysplasia-carcinoma sequence witnessed in other

cancers has not yet been fully characterized in CCA.

4.1

Inflammation and Cholestasis

Chronic liver or biliary inflammation and cholestasis are regarded as key components in the pathogenesis of CCA. Inflammation and cholestasis cause obstruction of bile flow and accumulation of bile acids. These events lead to high concentration of carcinogenic molecules and activation of signaling pathways, overexpression of inflammatory mediators, cytokines, and proliferative growth factors [9, 13]. Over a period of time, biliary epithelial cells will undergo stepwise progressive mutations in tumor suppressor genes, protooncogenes, and DNA mismatch repair genes resulting in uncontrolled cell proliferation. The combination of these tumorigenic factors can lead to irreversible changes in cell physiology resulting in the expansion of the tumor microenvironment, dysregulated cell growth, tumor neo-angiogenesis, and increased capacity for tumor invasion and metastasis [1, 9, 13, 14].

4.2

Inflammatory Mediators, Cytokines, and Growth Factors

Bile acids contain high concentrations of oxysterols (oxygenated cholesterol derivatives) which promote carcinogenesis by stimulating proliferative signaling molecules such as interleukin (IL)-6 cytokines and epidermal growth factor receptors (EGFR). Activation of the EGFR pathway then triggers a series of mitogen-activated protein kinase (MAPK) cascades resulting in overexpression of cytokines such as COX-2, which is a key contributor to cholangiocarcinogenesis. COX-2 propagates uncontrolled cell growth through the production of prostaglandin E2 (PGE2) which is a critical molecule in promoting tumor growth, survival, and invasion [9, 13–15]. The ErbB-2, an EGFR homolog, is another commonly overexpressed oncoprotein which not only directly stimulates COX-2 production but also forms a key complex with the IL-6/

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Cholangiocarcinoma: Epidemiology, Pathogenesis, and Prognosis

IL-6 receptor [1, 9, 13]. This process in turn stimulates the Raf/MAPK pathways, triggering a cascade for uncontrolled cell proliferation. IL-6 and TGF-B are the two major cytokines involved in the regulation of cholangiocarcinoma. IL-6 is produced at very high concentrations during chronic inflammation and plays a number of key roles in propagating the neoplastic process. IL-6 cytokines activate the p44/p42 and p38 MAPK cascade resulting in cell cycle deregulation and hypermethylation of the tumor suppressor gene p21. In normal cells, IL-6 is eventually turned off through a negative feedback loop by activating the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT-3) pathway and increasing the transcription of the suppressor of cytokine signaling 3 (SOCS3). However, in cholangiocarcinoma, SOCS3 is silenced, thereby inhibiting the negative feedback loop [1, 19, 13–16]. This leads to uncontrolled production of anti-apoptotic protein Myeloid cell leukemia 1 (Mcl-1) and induces resistance to the tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL), a potent stimulator for apoptosis. IL-6 is also able to downregulate certain microRNAs (miRNAs) which results in increased expression of the DNA Methyltransferase 1 (DNMT1) enzyme and subsequent suppression of tumor suppressor genes. Progranulin is another highly secreted growth factor commonly found in cholangiocarcinoma. It is stimulated by the IL-6 cytokine through the AKT signaling pathway leading to increased cell survival, uncontrolled mitosis, cell migration, and angiogenesis [13–16]. In normal physiologic conditions, TGF-B exerts antiproliferative effects. However, in cholangiocarcinoma, mutational changes to the TGF-B receptor, loss of the Smad4 tumor suppressor gene, and overexpression of cyclin D1 have been found to diminish the antiproliferative effects of TGF-B [9, 13–15]. There is a phenomenon known as the “E- to N-cadherin switch” which is a fundamental process that mediates cancer progression and involves transitioning cancer cells from a nonmotile epithelial phenotype to a migratory mesenchymal phenotype. TGF-B and EGFR activation play key roles in initiating the cadherin switch which leads to loss of cell to cell adhesion and increases the tumor’s ability to invade [9, 13].

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C-MET, also known as the hepatocyte growth factor (HGF) receptor (HGFR), is a receptor tyrosine kinase which is found in high concentrations in cholangiocarcinoma. Alongside its only known ligand hepatocyte growth factor (HGF), this complex activates the AKT, extracellular signal-regulated kinase (ERK), and MAPK cascade promoting tumor growth, cell invasiveness, and poor tumor differentiation [9, 13, 14]. A number of growth factors and cytokines including vascular endothelial growth factor (VEGF), C-MET, IL-6, and COX-2 have been found to interact with the ErbB receptor kinase family. This molecular interaction then activates the MAPK cascade and the AKT signaling pathway, thereby triggering the metastatic potential of cholangiocarcinoma [1, 13–15]. High concentrations of these inflammatory mediators will ultimately lead to progressive mutations in tumor suppressor genes, proto-oncogenes, and DNA mismatch repair (MMR) genes.

4.3

Inducible Nitric Oxide Synthase (iNOS) and Reactive Nitrogen Oxygen Species (RNOS)

During the course of inflammation, nitric oxide synthase (iNOS) is found in high concentrations resulting in the formation of reactive nitrogen oxide species (RNOS). RNOS enhances COX-2 expression and directly damages DNA mismatch repair proteins, proto-oncogenes, and tumor suppressor genes. It also plays an independent role in the stimulation of proliferative inflammatory cytokines, growth factors, and tyrosine kinases, such as IL-6 receptors, c-MET, EGFR, and VEGFR. iNOS, in conjunction with COX-2, plays a critical role in dysregulation of apoptosis by overexpressing the anti-apoptotic Bcl-2 protein and promoting mutation of the kirsten rat sarcoma virus (KRAS/p53) oncogenes [13, 15, 16].

4.4

Developmental Pathways

Deregulation of developmental pathways is involved in CCA pathophysiology. The Notch signaling pathway through the interaction

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between the Notch2 receptor and Notch ligand Jagged1 is a critical pathway for cholangiocarcinogenesis. Murine models have demonstrated that inhibition of Notch signaling almost completely eliminated CCA development. Expression of the Notch2 is found to upregulate genes that sustain dysplastic proliferation of cholangiocytes, makes cells more resistant to apoptosis, and enhances migration of CCA cells [9, 16]. Another developmental pathway involved in CCA is the hedgehog (Hh) signaling pathway. Studies show that the Hh ligand sonic hedgehog protein is overexpressed in CCA. Activation of the hedgehog pathway is critical in protecting CCA cells from TRAIL-induced apoptosis [16]. Targeting these developmental pathways may be a promising therapeutic tool.

4.5

Tumor Microenvironment

Recently, it has been discovered that carcinogenesis is a byproduct of dynamic cross talking between cells of tumor parenchyma and its microenvironment. The tumor microenvironment is made of neoplastic epithelial cells and a complex stroma consisting of inflammatory cells, vascular endothelial cells, fibroblasts, and an extracellular matrix, all of which play key roles in tumor growth. The invasiveness of cholangiocarcinoma has been associated with the expansion of the surrounding stroma and increased extracellular matrix deposition which is stimulated by proliferative cytokines such as IL-6 [1, 9, 13, 14]. Tumor-associated macrophages found in the microenvironment have even found to be able to confer resistance to both endogenous and chemotherapeutic cytotoxic insults. These macrophages prevent the degradation of intracellular B-catenin which results in increased cell viability and resistance to apoptosis. This bidirectional communication between the tumor parenchyma and its microenvironment determines the tumor phenotype and is critical in the development, invasiveness, and metastatic capacity of cholangiocarcinoma [1, 9]. Angiogenesis through vascular endothelial cell proliferation is critical in providing the tumor with the nutrient supply necessary for its growth and

metastasis. Alpha smooth muscle actin myofibroblasts, known as cancer-associated fibroblasts (CAF), are found in high concentration in the stromal microenvironment which drives the production of TGF-B and insulin growth factor (IGF). These growth factors induce VEGF expression which in turn stimulates angiogenesis, a key contributor to the malignant phenotype, maintenance, and growth of the tumor [13–16]. CAFs further induce cell invasion and metastasis by promoting the E- to N-cadherin transition and by overexpressing platelet-derived growth factor receptor B (PDGFR-B). PGDFR-B permits cell migration by upregulating matrix metalloproteinases MMP-7 and MMP-9, which break down extracellular matrices [1, 13–15]. The exact mechanisms through which tumor and its microenvironment communicate and how support cells of the stroma are recruited are still unclear. However, targeting the tumor microenvironment rather than the cholangiocarcinoma cells directly may potentially lead to effective therapeutic strategies.

4.6

Genetic Alterations

Genetic alterations play a key role in pathogenesis of CCA resulting in dysregulated replications, insensitivity to growth inhibition, and escape from cell apoptosis. There are a number of principal genes altered in the development of CCA including KRAS, p53, phosphatase and tensin homolog (PTEN), SMAD4, p14ARF, p16INK4a, and B-catenin. Studies also show that CCAs have different molecular genetic makeup and genetic anomalies based on their subtype. For example, iCCAs have more genetic mutations in the IDH1/ 2, PBMR1, and BAP1 genes, while EH-CCAs are more frequently found to have KRAS and TP53 mutations [1, 9, 17]. Epigenetic alterations, such as promoter hypermethylation and miRNA dysregulation, play an important role in the development and progression of CCAs. There is now growing evidence that miRNAs regulate various aspects of CCA formation including angiogenesis and lymphangiogenesis [1, 9, 17]. miRNAs are small noncoding RNA sequences that regulate

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Cholangiocarcinoma: Epidemiology, Pathogenesis, and Prognosis

posttranscriptional gene expression. These small sequences can be either upregulated or downregulated in CCA resulting in uncontrolled mitosis, increased cell survival, and metastasis [1, 14, 15]. However, whole epigenome analysis has not yet been conducted, and only a limited number of genes have been analyzed thus far. For example, miR-141, miR-21, miR-27a, and miR-200b are overexpressed, while tumor suppressors miR-29b, miR-128a, and miR-152 are downregulated in cholangiocarcinoma [1, 9, 14, 17]. Some miRNAs including miR-200a and miR-203 influence tumor grade, while miR-200c, miR-141, miR-223, and miR-204 have been associated with multifocal disease and vascular invasion [14, 17]. miR-192 is currently a very promising diagnostic biomarker for iCCA and is also associated with lymph node metastasis and poor survival. The IL-6 cytokine also appears to have a direct impact on cholangiocarcinogenesis by downregulating the expression of certain miRNAs, such as miR-370, which subsequently leads to the overexpression of oncogene mitogen-activated protein kinase kinase kinase 8 (MAP3K8) [1, 9, 14, 17]. Although many other miRNAs are either up- or downregulated in CCAs, it is unclear whether they are the cause or result of cholangiocarcinogenesis.

5

Staging and Classification System

Cholangiocarcinomas are classically subdivided into two groups based on anatomic location: intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (EH-CCA). iCCAs are anatomically distinguished from EH-CCAs by the second-order bile ducts. Eighty to ninety percent of tumors are EH-CCAs which can be further subclassified into perihilar CCA (pCCA) and distal CCA (dCCA). The cystic duct demarcates the boundary between hilar and distal tumors [18]. A number of different classification systems have been proposed to describe intrahepatic and extrahepatic cholangiocarcinomas. Unfortunately, a universally used staging criterion that provides

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accurate prognostication and survival stratification is not available at this time. An ideal staging system should take into account both the local and metastatic extent of the disease as well as its resectability. A reliable and consistent classification system that accurately predicts prognosis is important for assessing disease outcomes and optimizing treatment strategy.

5.1

Bismuth-Corlette System

The Bismuth-Corlette system has been commonly used to describe perihilar CCAs and is based on the anatomic location within the biliary tree [1, 18]. This staging system aids in preoperative assessment of local tumor spread by taking into account the extent and level of the tumor invasion along the biliary tree. However, it does not take into account critical prognostic factors such as vascular encasement, metastatic disease, lymph node involvement, and atrophy of the liver. It also does not take into account the extension of the tumor away from the biliary ductal system including the adjacent hepatic parenchyma, vascular structures, and perihilar soft tissues [1, 18]. This system is useful in describing the location of the tumor and assessing the extent of resection. However, because it does not account for important prognostic features, its use in evaluating prognosis is limited. Studies have failed to validate the Bismuth-Corlette system’s prognostic ability, reporting similar 5-year survival rates across all subtypes: type I (33.3%), type II (38.1%), type III (24%), and type IV (29.8%) [19]. Many centers no longer follow the Bismuth-Corlette system as variations in the anatomy of the branches often deter its applicability.

5.2

Memorial Sloan Kettering Cancer Center (MSKCC) Classification System

The Memorial Sloan Kettering Cancer Center (MSKCC) classification system has been utilized for preoperative staging of perihilar CCAs by characterizing the location and extent of local

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tumors. Similar to the Bismuth-Corlette system, it takes into account the bile duct involvement and assesses for local resectability. However, it also does not account for relevant prognostic factors such as nodal or metastatic disease. However, this classification system does account for three distinct parameters identified on imaging: (1) extent of tumor along biliary tract, (2) portal vein involvement, and (3) presence of hepatic atrophy [18]. The assessment of lobar atrophy is clinically important as long-standing biliary obstruction or lack of portal blood flow is a key determinant of resectability. Unilobar atrophy indicates the presence of unilateral biliary obstruction resulting in atrophy of the affected lobe and hypertrophy of the unaffected lobe, a phenomenon known as the “hypertrophy-atrophy complex.” Signs of lobar atrophy and portal vein invasion have been associated with worse prognosis [18]. Validation studies of the classification system’s prognostic ability have reported conflicting results. Some studies have demonstrated correlation of the MSKCC substages with tumor resectability and survivability, while others have failed to validate its use for prognostication.

5.3

AJCC/UICC TNM Staging System

The 8th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor node metastasis (TNM) staging criteria is currently the most widely accepted and implemented classification system. Unlike the Bismuth-Corlette and the MSKCC criteria, the AJCC system accounts for important prognostic features such as depth of ductal invasion, nodal invasion, distant metastasis, and vascular encasement of the portal vein and hepatic artery [20]. It has minimal utility in assessing preoperative resectability; however, it more accurately discriminates prognosis and stratifies survivability based on the tumors’ clinicopathologic features. Prior to the 7th edition, CCA was only classified into two entities: iCCA and EH-CCA. However, it is now recognized that each of the three subtypes has distinct differences in biologic

features and prognosis. In turn, subsequent editions have distinguished EH-CCA into separate entities, hilar and distal cholangiocarcinoma [20]. The current edition has introduced several changes to the staging system in attempt to reflect each subtype’s unique natural history.

5.3.1

Intrahepatic Cholangiocarcinoma and Validation of the AJCC Staging System Several notable changes have been made to the iCCA classification system. First, the T classification is now distinguished based on tumor size of 5 cm and is subclassified into T1a (5 cm) and T1b (>5 cm). Second, the T2 stage no longer distinguishes multiple tumors (with or without vascular invasion) from solitary tumors with vascular invasion to reflect the equivalent prognostic value of these two clinicopathologic features. Third, local direct invasion into extrahepatic structures is now upgraded from T3 to T4, and the periductal infiltration growth pattern has been excluded from T4 stage due to the equivocal nature of its prognostic significance. Finally, the overall TNM staging system has been reclassified where stage IV is defined by distant metastasis only (any T, any N,M1), and advanced locoregional cancer (any T, N1, M0) is downstaged from IVA to IIIB, thereby defining fewer patients as incurable distant metastatic disease [20]. These changes were made in part due to prior studies reporting that a subset of patients, including those with N1 disease, are potential candidates for R0 (negative microscopic margins)/R1 (residual microscopic tumor) resection. The available data regarding the prognostic accuracy of the current AJCC staging system is limited; however, it appears to have a comparable ability to prognosticate survival compared to prior editions. Based on an analysis of the US SEER registry between 1998 and 2013, the overall TNM classification system appears to appropriately stratify the 5-year OS: stage IA 57.8%, stage IB 44.5%, stage II 30.5%, stage IIIA 24.4%, stage IIIB 12.4%, and stage IV 8.6% [20]. When based on the T stage system, the prognostic accuracy is more variable although there is a general trend toward decreased survivability based on increasing severity of the T stage. A large validation

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Cholangiocarcinoma: Epidemiology, Pathogenesis, and Prognosis

study involving 14 hepatobiliary centers reported a median survival (months) and 5-year OS (%) of 61 months and 60.8% in T1a, 32 months and 36.7% in T1b, 25 months and 29.3% in T2, 27 months and 45.8% in T3, and 12 months and 14.7% in T4 disease. [21] A significant prognostic difference is seen between T1a and T1b suggesting the addition of tumor size provides enhanced prognostic discrimination. T1b, T2, and T4 stages all have significantly greater risk of death compared to T1a. However, validation studies consistently show that the new T3 stage, defined by peritoneal or serosal invasion, has a paradoxically higher survival compared to T1b and T2 tumors. This suggests that vascular involvement has a more significant prognostic impact than peritoneal invasion. The prognostic significance of serosal invasion is unclear, and some studies have even proposed removing this criteria from the classification system. The current characterization of the T3 stage is not truly reflective of the tumor biology and, therefore, needs to be further refined [20, 21].

5.3.2

Hilar Cholangiocarcinoma and Validation of the AJCC Staging System Several changes have been made in attempt to better discriminate prognosis in hilar cholangiocarcinomas. First, high-grade biliary intraepithelial neoplasia is now incorporated into carcinoma in situ (Tis), and Bismuth type IV tumors have been removed from T4 classification. This was based on studies citing that there was no significant difference in survival of Bismuth type IV tumors compared to other subtypes. Second, the AJCC now stratifies the N stage based on the number of nodes involved: N0, N1 (1–3 positive nodes), and N2 (
4 positive nodes). Third, T4 tumors have been downstaged from stage IVA to IIIB as some T4 tumors are now deemed to be resectable with combined vascular resection and reconstruction. Finally, N1 tumors have been upstaged from stage IIIB to IIIC (if 1–3 positive lymph nodes) or IVA (if
4 positive lymph nodes). T4 disease, previously classified under stage IVA, has subsequently been downstaged to IIIB (if negative nodes) or IIIC (if 1–3 positive lymph nodes) [19, 20]. This change

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is based on studies consistently citing lymph node invasion as one of the strongest adverse prognosticators of survival. The prognostic performance of the AJCC system is questionable at this time with studies reporting inaccuracies. Based on the overall TNM system, there appears to be a trend toward prognostic discrimination with 5-year OS rates of stages I (50.1%), II (40.3%), IIIA (23%), IIIB (29.4%), IIIC (13.2%), IVA (8.1%), and IVB (0%) [19, 20]. However, among all the stages compared, only comparisons between II and IIIA, IIIC and IVA, IVA and IVB were significant. The correlation between T stages and long-term survival is also unclear with 5-year OS rates of T1 (42.6%), T2 (31.2%), T3 (13.9%), and T4 (15.1%). Significant increased risk of death is noted for stages T2b and T3 compared to T1 but not for T2a tumors. Validations studies have also failed to show that the modified T4 stage which excludes Bismuth type IV tumors improves prognostic accuracy. Based on the three-tiered N staging system, studies report a stepwise ability to discriminate prognosis with 5-year OS rates of N0 (38.1%), N1(12.6%), and N2 (7.4%) [19, 20].

5.3.3

Distal Cholangiocarcinoma and Validation of the AJCC Staging System A few key changes have been made to the distal cholangiocarcinoma classification system. First, high-grade biliary intraepithelial neoplasia is now categorized under Tis. Second, the T classification is categorized based on objective markers of the tumor depth invasion defined as the distance from the basal lamina of normal epithelium to the deepest infiltration of tumor cells: (1) T1 12 mm. The degree of invasion was previously demarcated by an obscure anatomic landmark described as either “confined to the bile duct” or “beyond the wall of the bile duct.” This distinction has been problematic as the bile duct wall lacks discrete tissue boundaries and the duct wall is not uniformly concentric along its length. Third, the N stage is now categorized based on the number of positive metastatic nodes: N0, N1 (1–3 nodes), and N2 (
4 nodes) [23, 23].

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Validation studies performed so far demonstrate an enhanced ability to accurately predict prognosis based on the new T and N categories. Significant 5-year survival differences are noted across all T stages: T1: 59.3%, T2: 42.4%, and T3: 12.2%, suggesting depth of invasion has significant survival implications [22, 23]. Significant 5-year survival differences are also noted based on the three-tiered N system: N0 (47.3%), N1 (17%), and N2 (14.7%). Finally, based on the overall TNM staging system, there is a clear trend where higher-staged tumors are associated with significantly shorter 5-year survival: stages I (59.0%), II (35.4%), and III (14.7%) [22, 23].

6

Prognosis and Outcomes

Cholangiocarcinoma represents a heterogeneous group of malignancies. iCCA, pCCA, and dCCA each has its distinct clinical presentation, natural history of progression, and prognosis. Overall, cholangiocarcinomas are characterized by an aggressive clinical course, late diagnosis, and fatal outcome with a median survival of less than 24 months after diagnosis and a 5-year OS of 5– 18% [2, 3]. When stratified based on the subtype, the 5-year overall survival for iCCA, pCCA, and dCCA ranges between 20% and 32%, 10% and 30%, and 18% and 41% [3, 19–23]. Unfortunately, cholangiocarcinoma often remains clinically silent and is usually diagnosed in advanced stages. If the tumor is non-resectable, chemotherapy is often the only option with a median survival of only 13–15.2 months [24]. For patients treated with sole supportive care, the median survival is only 3–4 months [1, 19, 24]. A multitude of prognostic factors that influence long-term clinical and oncologic outcomes have been identified. These factors can be broadly categorized into two groups: (1) postsurgical resection margin status and (2) tumor-related prognostic factors. The prognostic impact of surgical resection margin status is dictated by whether complete gross and microscopic tumor (R0) resection (as opposed to R1 and R2 resection) can be achieved. The most common tumorrelated factors involve the biology, pathology,

histology, grade, and local and metastatic extent of the disease as classified under the AJCC system. The long-term prognostic outcomes measured by survival and disease recurrence will be discussed.

6.1

Surgical Outcome: ResectionRelated Prognosis

Only 10–40% of patients of all CCAs will have resectable disease. Resectability rates range between 50% and 66% in iCCA, 66.4–78.4% in pCCA, and 91–96% in dCCA with more distally located tumors displaying higher rates [2, 3, 25–29]. If the tumor is deemed resectable, the primary goal should always be to obtain negative microscopic margins (R0) regardless of site. Overall, complete tumor (R0) is the only treatment that offers the best chance for cure and post resection and is considered to be one of the most robust predictors of long-term survival. [2, 25] If R0 is obtained, studies cite an increase in the median survival to 28 months and 5-year OS to 24–40% [1, 3]. The overall R0 resection rate is variable with respect to each CCA type: iCCA (69–83%), pCCA (65.6–80.8%), and dCCA (78–90%) [25–29]. The variable rates of resection likely reflect differences in preoperative imaging modalities, surgeon expertise, and the volume of cases encountered at each respective institution. Based on recent literature, the 5-year OS generally increases across all tumors with curative resection: iCCA (30–63%), pCCA (30–40%), and dCCA (27–63%) [2, 3, 25]. R0 resection also appears to play a role in the overall reduction of tumor recurrence; however, despite R0 resections, studies cite recurrence rates as high at 80%, 76%, and 50% for iCCA, pCCA, and dCCA, respectively [25–29]. This high rate of recurrence and poor survival are likely driven by aggressive tumor-related prognostic factors which are strongly associated with residual microlesions and micrometastases that may not be detected by postsurgical surveillance imaging. Therefore, when prognosticating, it is critical to not just account for the R0 margin status but also tumorrelated factors. These factors most notably include

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Cholangiocarcinoma: Epidemiology, Pathogenesis, and Prognosis

lymph node metastases, which have significant impact on tumor recurrence and long-term survival.

6.1.1

Intrahepatic Cholangiocarcinoma

R0 Survival Attempting curative resection is still the only approach that can offer acceptable long-term results. However, among patients who undergo curative intent surgery, literature is conflicting regarding the long-term prognostic impact of R0 resection when compared to tumor-related prognostic factors. A large meta-analysis of 2132 patients demonstrated that positive margins do not appear to affect overall survival with an hazard ratio (HR) of 1.06 (95% CI 0.49–2.32) [30]. However, other studies have reported significantly greater 5-year survival rates of 36–54% for R0 compared to 5-year survival rates of 0–21% for R1. A possible explanation for the difference in results could be ascribed to the size of the negative resection margin. Larger widths of negative margins have been found to have increased survival compared to smaller R0 margin sizes. Compared to a
1 cm margin status, the risk mortality of 1– 4 mm R0 margins was greater than that of 5–9 mm R0 margins (HR 1.95 vs. 1.21) [31]. Aggressive resection to achieve negative margins of at least 1 cm should be pursued in order to maximize the chance of cure and for adequate oncologic clearance. Unfortunately, achieving wide negative margins is difficult due to rapid spreading of disease through intrahepatic metastases, diffusion through lymphatic and perineural structures, and early infiltration of vasculature. Other than achieving R0 margin, studies point to tumorrelated factors, namely, lymph node metastasis, to be the predominant driving force for iCCA prognosis, which further underscores the importance of earlier diagnosis. R0 Recurrence It is unclear how much of a prognostic impact R0 margins have on the tumor recurrence rate. A large meta-analysis demonstrated that the R margin status does not affect recurrence-free survival (RFS) with an HR of 0.89 (95% CI

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0.64–1.23) [30]. In contrast, other studies have reported that intrahepatic tumors with R1 resection were significantly more likely to have recurrence compared to R0 resections (28% vs. 3%) with an HR of 1.61 (95% CI 1.15–2.27). A possible rationale for the difference in these studies results could potentially be attributed to the size of the negative resection margin. Patients with wider negative margins are significantly less likely to have disease recurrence. In comparison to a
1 cm margin status, margin widths of 1–4 mm are reported to have a recurrence HR of 1.32 (95% CI 0.98–1.78), while margin widths of 5–9 mm have a recurrence HR of 1.21 (95% CI 0.89–1.66) [31]. Unfortunately, recurrence rates approach nearly 80% despite achieving R0 margins (5-years post resection), underscoring the significance of tumor-related factors on long-term clinical and oncologic outcomes.

6.1.2

Extrahepatic Cholangiocarcinoma

R0 Survival Achieving R0 margin status in patients undergoing curative intent surgical treatment is widely recognized as the most important prognostic factor in patients undergoing resection of EH-CCA tumors. In hilar tumors, the median survival is significantly greater in R0 resections than R1 resections (35.2 vs. 12.4 months). A large metaanalysis reported a mortality HR of 2.04 (95% CI 1.73–2.41) for positive resection margins. Similarly, in distal tumors, the median survival for R0 is 46 months compared to 21.3 months for R1 resections. A meta-analysis reported that patients with positive margins had a mortality HR of 2.36 (95% CI 1.89–2.93) compared to R0 resections. [25, 26, 27, 29] There is a strong association of survival based on the tumor’s location within the extrahepatic duct [25, 26]. Proximally located tumors near the hilum have significantly worse 5-year OS than distal tumors (24.5% vs. 51.7%) with a median survival of 9 months and 21 months, respectively [26]. The prognostic significance of location within the extrahepatic duct is likely related to

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the higher resectability and R0 rates achieved in distal compared to hilar tumors. R1 resection rates are reported to be significantly higher for hilar compared to distal CCAs (31.1% vs. 12.3%). The higher curative resection rate in distal CCA is likely related to the lower incidences of liver and major vessel invasion compared to that of hilar tumors. By virtue of their location, hilar tumors have a strong tendency to invade the adjacent liver and peri-hepatic structures, including the portal vein and hepatic artery, despite being a slow-growing and locally invasive disease [25, 26, 29, 32]. The location of hilar tumors often poses technical challenges in achieving curative resection as well. Therefore, smaller-sized and well-differentiated hilar tumors with negative nodal and vascular invasions correlate to a higher likelihood of obtaining tumor-free margins [25, 27]. The difference in anatomy and histology of pCCAs and dCCAs is another contributing factor regarding survivability. For example, in the hilar region, muscle fibers are scattered, while the distal bile duct is composed of bundles of smooth muscle. These structural variations may influence the tumors’ capacity to infiltrate the duct wall and metastasize to lymph nodes. Finally, earlier manifestations of symptoms for dCCAs (e.g., jaundice and cholangitis) lead to diagnoses in earlier stages, which is another potential factor in improved prognosis.

common for both hilar and distal tumors with rates approaching as high as 76% and 50%, respectively [26–29]. These findings are likely attributable to tumor-related prognostic factors, which are closely associated with tumor recurrence and overall survival. Even in the absence of clinical recurrence in the early follow-up period, long-term follow-up is needed before declaring cure.

R0 Recurrence Hilar tumors with R1 resection have a greater 5-year cumulative recurrence probability compared to R0 (86% vs. 57%). Similarly, in distal tumors, the 5-year RFS rate is significantly greater in R0 compared to R1 resections (39.1% vs. 22.5%) with a median recurrence-free survival time of 26.3 months and 13.7 months, respectively. The recurrence risk of extrahepatic tumors is influenced by the location within the bile duct with hilar CCAs exhibiting higher incidences of recurrence compared to distal CCAs [32, 35]. The 5-year RFS rates of hilar and distal tumors are 23.3% and 50.9%, respectively. The difference in rates reflects the higher resection and R0 rates that are achieved in distal lesions. However, despite R0 resections, recurrence is still very

Growth Patterns The Liver Cancer Study Group of Japan identifies intrahepatic cholangiocarcinoma as three distinct macroscopic types: (1) intraductal growth, (2) mass forming, and (3) periductal infiltrating. An additional subtype for periductal infiltrating and mass forming is also described [33]. Each of these growth types has a different natural history of progression and behavior. The intraductal growth (IG)-type tumors represent only 8–29% of iCCAs. They are mostly well differentiated and exhibit low rates of lymphovascular, lymph node, and perineural spread. In 31–36% of cases, invasion is limited to the walls of the duct without infiltration into the surrounding parenchyma [33]. Even in the presence of lymph node involvement, IG types

6.2

Tumor-Related Prognosis

6.2.1

Intrahepatic Cholangiocarcinoma and Survival Less than 1/3 of iCCA patients who undergo curative-intent surgical treatment survive beyond 5 years post resection. Even if R0 margins are obtained, the 5-year OS remains poor at 30–63% with a 5-year recurrence rates up to 80%. Based on conflicting data, the prognostic impact of R0 margins in patients who undergo curative intent resection remains unclear. Studies suggest tumorrelated factors, which also have a significant impact on risk of recurrence, are the predominant driving force of iCCA long-term prognosis. Significant clinicopathologic prognostic factors include lymph node metastasis, tumor size, multifocal disease, tumor differentiation, and vascular invasion [28, 30].

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Cholangiocarcinoma: Epidemiology, Pathogenesis, and Prognosis

demonstrate the best prognosis compared to the other growth types with a post-resection 5-year survival rate of 41–80%. The mass forming (MF) type occurs most frequently and represents 60–70% of iCCAs. MF types have a worse prognosis than IG tumors. They are associated with high incidences of vascular invasion (47%), lymph node metastases (31%), and intrahepatic spread (36%). The 5-year overall survival ranges between 25% and 51%. In the subgroup of patients (63%) who have histologic evidence of deep ductal wall invasion, the 5-year survival drops to 11% [33]. MF tumors with deep ductal invasion are more likely to have microscopic vascular, lymphatic, and perineural spread. The periductal infiltrating (PI) growth type has a poor prognosis and represents 15–35% of iCCAs. It exhibits more infiltrative features than MF tumors and is characterized by its preferential spread through Glisson’s capsule and into the lymph nodes of the hepatic hilum. Lymphovascular spread is not uncommon although the rates of portal invasion and intrahepatic metastases are lower compared to those of the MF tumors. The reported 5-year OS in patients with PI tumors is highly variable ranging between 0% and 49% [33]. Studies demonstrate conflicting results regarding their prognostic role on overall survival. Given the lack of clarity of its prognostic impact, the PI growth type has been removed from the T4 stage of the 8th edition of AJCC classification system. Tumors with mixed MF and PI growth types are observed in 25–46% of patients and represent the worst prognosis with a 5-year survival rate of 25.5%. This subtype is commonly found in advanced stages of disease and is associated with the highest incidence rates of lymph node spread (50–80%) as well as vascular invasion (80%) and intrahepatic metastases (46%) [33]. T Category-Based Prognostic Factors One of the new prognostic factors introduced to the AJCC staging system is tumor size. Most iCCAs on initial presentation are at least 2 cm. In advanced disease, the median size ranges between 5 and 8 cm. One study involving 1116

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patients who underwent resection reported that tumor sizes 5 cm had a significantly greater 5-year OS than tumors >5 cm (51.7% vs. 32.6%) [34]. Similarly, another study demonstrated a significantly greater 5-year OS for tumors 6 cm (0%). A large meta-analysis of 907 patients reported a shorter OS with each 1 cm increment increase in tumor size [30]. The optimal size cutoff is not universally defined at this time; however, the current AJCC staging system suggests 5 cm as the cutoff size for optimal prognostic discrimination. Tumors >5 cm are more significantly associated with lymph node spread, microscopic vascular invasion, and higher tumor grades compared to smaller tumors. Tumor multifocality remains a strong predictor of poor prognosis. Compared to solitary lesions, the median survival of multifocal tumors decreases significantly (87 vs. 18 months). The 5-year OS is significantly lower in multifocal tumors (0–7%) compared to solitary tumors (3–57%). A meta-analysis reports a mortality HR of 1.70 (95% CI 1.43–2.02). Based on several studies, the incidence of multifocal intrahepatic involvement ranges between 19% and 53% [28, 30]. Multifocal tumors tend to be associated with larger-sized tumors, lymph node metastasis, vascular invasion, poor cell differentiation, and the MF growth type. One study demonstrated that patients with a combination of multifocal tumors and lymph node metastases had an additive adverse effect on survival. The 5-year OS rate is 3.2%, which was significantly worse compared to either risk factor alone (12.8%) or in patients with unifocal disease without nodal metastasis (28.8%) [28, 30]. Based on recent validation studies, the presence of multifocal tumors and vascular invasion seem to have equivalent prognostic value. No significant difference in 3-year diseasespecific survival (DSS) has been found between solitary tumors with vascular invasion (70.2%) compared to multiple tumors with or without vascular invasion (56.5%). The current AJCC staging system has subsequently combined the previous T2a (solitary lesion with vascular invasion) and T2b (multiple tumors with or without vascular invasion) into a single T2 entity [20, 21]. At this

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time, whether the combination of multiple tumors and vascular invasion has a synergistic adverse effect is unclear given conflicting clinical research results. The presence of vascular invasion, namely, of the portal vein, is a significant independent negative prognostic factor of survival. One study reported a significantly worse 3-year survival rate in patients with portal invasion compared to those without (0% vs. 46.1%) with a median survival of 24 months and 57 months, respectively. A large meta-analysis cited a mortality HR of 1.87 (95% CI 1.44–2.42) [30]. Patients with vascular invasion are also noted to be associated with increased risk of nodal disease at HR 2.89 (95% CI 1.56–5.35). The type of vascular invasion appears to have a prognostic impact as well with 5-year survival rates found to be significantly higher in peripheral portal branches (25%) than the major branches or the main portal vein (0%) [33]. The prognostic significance of serosal or peritoneal invasion is unclear. As seen in several validation studies, the T3 tumors consistently have higher survival rates than T1b and T2 tumors suggesting that peritoneal invasion may not be prognostically relevant [21]. Other studies, however, have reported a significantly greater 5-year survival rate in patients with peritoneal invasion than those without (24% vs. 39%) [33]. N Category-Based Prognostic Factors Lymph node invasion is widely regarded as one of, if not, the most important factor of long-term prognosis. Studies cite a high but variable prevalence of nodal metastasis at 17–73%. A large multi-institutional study reported that among patients who underwent lymph node dissection, 30% had lymph node metastasis with a median positive node count of one [33, 35, 36]. Seventyfive percent of regional spread occurs at the hepatoduodenal, periduodenal, and peripancreatic lymph nodes. A large meta-analysis of 1661 patients cited a mortality HR of 2.09 (95% CI 1.80–2.43) in patients with lymph node disease [30]. The median survival in patients with nodal invasion is significantly worse compared to patients without (15 vs. 37 months). Patients

Y. Namn and J. C. Bucobo

with grossly positive porta hepatis lymph nodes are noted to have a particularly poor prognosis. In addition, nodal positive disease has been more frequently identified in larger centrally located tumors, higher T stages, multifocal disease, vascular invasion, and the MF and PI growth types. The number of positive nodes has an impact on survival as well. An analysis of 881 patients queried from the National Cancer Database (NCDB) revealed a 5-year OS of 34.7 in N0 disease, 5.8% in patients with 1–3 positive nodes, and 0% in patients with 4–11 positive nodes. Similarly, in a SEER database analysis of 475 patients who underwent lymphadenectomies, patients without nodal involvement had a significantly higher 3-year DSS of 71% compared to patients with 1– 3 (38.9%) and
4 (22.9%) positive lymph nodes [35, 36]. Patients with
4 positive lymph node in fact had a similar survival prognosis as patients with stage IV disease. Oncologic outcome appears to be dictated by nodal invasion more so than any other relevant clinicopathologic variable such as tumor size, number, vascular invasion, and even R margin status. For example, studies have reported greater survivability of T4N0M0 compared to TanyN1M0staged disease. When nodal disease is absent (N0), tumor number, vascular invasion, and R1 resections are each able to be identified as independent predictors of survival ( p < 0.001). However, when nodal disease is present (N1), the presence of multiple tumors, vascular invasion, and R1 resection failed to discriminate patients into discrete prognostic groups and were not associated with worse survival ( p ¼ 0.34). [28, 31, 35, 36] There is an inconsistent practice of lymph node sampling which can potentially lead to inaccurate estimation of survival and prognostication [35, 36]. According to a large multi-institutional study, approximately ½ of patients have undergone lymphadenectomies with a median nodal count of three. European and US studies report that approximately 57% of patients have had at least one node examined compared to 85% in Japanese literature. The current 8th edition of AJCC staging system recommends recovery of at least six lymph nodes for complete nodal staging [20]. This is important as lymph node

14

Cholangiocarcinoma: Epidemiology, Pathogenesis, and Prognosis

metastasis cannot be accurately predicted using preoperative imaging such as cross-sectional CT where the diagnostic accuracy is reported to be only 46.1%. Many studies now advocate for routine lymphadenectomy at the time of hepatic resection given the significant impact on outcomes caused by lymph node metastasis. M Category-Based Prognosis Advanced iCCA preferentially metastasizes to the liver and other extrahepatic organs including the lungs and bones. Patients with distant metastatic disease have a significantly worse 3-year OS compared to patients without (42% vs. 66.5%) and with a mortality HR of 3.92 [33]. Studies reveal that different metastatic sites may also have distinct impact on survival outcomes of patients with advanced iCCA. Patients with liver metastasis are noted to have a significantly greater 5-year OS than those with bone metastasis. No survival differences have been noted between patients with liver and lung metastases. Microscopic Features of Prognosis Patients with well-differentiated or moderately differentiated neoplasms have a significantly better 5-year OS rate than poorly differentiated tumors at 50%, 39%, and 0%, respectively. Moderately and poorly differentiated neoplasms have a reported mortality HR of 1.30 (95% CI 0.93–1.81) and 1.89 (95% CI 1.34–2.68), respectively, compared to well-differentiated tumors. [25, 28, 33] Spreading of disease through diffusion into the lymphatic and perineural structures often occurs even in the early stages. Therefore, lymphatic and perineural invasions are considered negative prognostics factors associated with poor survivability as well nodal metastases and vascular invasion. The 5-year OS is significantly greater in patients with perineural invasion compared to those without (7% vs. 50%) and with a median survival of 20 and 55 months, respectively. The 5-year OS is also noted to be significantly worse in patients with lymphatic invasion than those without (71% vs. 90%) [28, 30, 33]. The most common sites of lymphatic metastases involve the hepatic hilar, peripancreatic, retroperitoneal, paraaortic, and mediastinal regions. The periductal

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growth type, in particular, has a tendency to infiltrate and spread along Glisson’s sheath using lymphatic vessels, leading to the invasion of connective tissue and major vessels along the hilum and hepatoduodenal ligament [33]. Microvascular invasion (MVI) is another important prognostic factor of survival. Patients have a significantly worse median survival in the presence of microvascular invasion than in the absence of it (27 vs. 57 months) [28, 33]. High degree of MVI has been associated with a poorer survival compared to MVIs of low degree. When compared to patients without microvascular invasion, low-degree MVI had a reported mortality HR of 1.81 (95% CI 1.04–3.14), while high-degree MVI had an HR of 5.36 (95% CI 2.49–11.57). Tumor Location The 5-year OS is more favorable for peripheral (37–43%) compared to centrally located tumors (0–4%) [33]. MF growth types are more likely to be identified in peripheral lesions, while PI and mixed MF + PI tumors are more frequently found in central lesions. Overall, central tumors appear to have a more aggressive natural history than peripheral tumors with higher rates of portal invasion (66% vs. 37%) and nodal metastasis (75% vs. 45%). Molecular Factors Many genomic and transcriptomic biomarkers have been identified as potential adverse prognostic factors. TGF-B is critical for proliferation and tumor differentiation. High expressions of this cytokine have been associated with poor histologic differentiation, high clinical stage, metastasis to the liver/lymph nodes, and early tumor recurrence. SMAD4, a tumor suppressor protein which mediates TGF signaling, is another strong prognostic biomarker. Low expressions of SMAD4 is associated with poor tumor differentiation and increased incidence of lymph node involvement. In one study, SMAD4 was absent in 72% of patients with lymph node metastasis and in 73.3% of patients with intrahepatic metastasis [39, 43]. Overexpression of the MET or hepatocyte growth factor receptor (HGFR) has been

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identified in 15–28% of tumors and has been associated with increased ability for tumor invasion. VEGF, which is a critical factor in angiogenesis and cell migration, has been strongly associated with lymph node metastasis, positive resection margin, and decreased survivability. Alterations in expression patterns of E-cadherin, vimentin, and fibronectin have also been associated with loss of tumor differentiation and more aggressive behavior. [33, 37] A number of genetic mutations affecting signaling pathways have been identified as poor prognostic markers including EGFR, ErbB2, TP53, KRAS, and IDH1/2 mutations. High levels of EGFR are associated with shorter median survival compared to lower levels of expression (8.5 vs. 38.5 months). Overexpression of the ErbB protein, identified in 10–32% of iCCAs, is closely associated with disease progression. The inhibitory oncoprotein of p53 known as mouse double minute 2 (MDM2) is frequently seen in iCCA and may herald a more aggressive natural behavior and increased likelihood of metastasis. High expressions of the KRAS mutation are also regarded as independent predictor of worse postsurgical survival. Studies report a worse 3-year survival in tumors with the IDH gene mutation compared to tumors without (33% vs. 81%). IDH mutations are closely associated with poor histologic differentiation and are more frequently observed in iCCA than in EH-CCA [37]. The mucin proteins MUC1 and MUC2 which play a role in cell differentiation, turnover, and adhesion are also more commonly found in MF and PI rather than IG tumors. In MF growth types, the overexpression of MUC1 proteins has been associated with vascular invasion and poor postsurgical outcome. MUC4 proteins promote tumor cell progression by suppressing apoptosis signaling. The overexpression of matrix metalloproteinases (MMP), such as MMP-7 and MMP-9, has also been strongly associated with poor postsurgical survival by promoting tumor invasion through the degradation of the extracellular matrices [33, 37].

6.2.2

Intrahepatic Cholangiocarcinoma and Recurrence Despite curative resection, recurrence rates approach 32–80% within 5 years [28]. Most

Y. Namn and J. C. Bucobo

recurrences are within the first 2 years after surgery with a disease-free survival time of only 9–21 months. The liver remnant (40–70%) is the most common site of recurrence. Other extrahepatic manifestations include the lung (11%), lymph node (11%), and peritoneum (22%) [25, 28]. The mode of recurrence appears to be driven by the morphologic tumor type. The MF growth type, for example, is more frequently associated with intrahepatic recurrences, while mixed MF + PI and PI neoplasms are more frequently identified with lymph node recurrences [33]. The high rate of recurrence despite R0 resection is predominantly driven by aggressive tumor-related factors, most notably lymph node invasion. [25, 28, 30] Several studies identify positive lymph nodes as the most important prognostic factor of recurrence with an HR of 2.67 (95% CI 1.59–4.49) [28, 30, 31, 36]. The median recurrencefree survival of patients with positive nodes compared to patients with negative nodal invasion is 6.1 months and 21.2 months, respectively. Other identified risk factors of recurrence include the presence of non-intraductal growth type tumors, poor histologic differentiation, tumor size
5 cm, multifocal tumors, higher T stage (T3/T4), portal vein involvement, microvascular invasion, perineural invasion, and high postoperative carcinoma (CA) 19-9 levels
37 which may be suggestive of high tumor burden [28, 30, 31, 36].

6.2.3

Prognosis of Hilar Cholangiocarcinoma Several studies have demonstrated that among patients who have undergone curative intent surgery, achieving R0 resection was the most impactful factor and independent predictor of survival in both univariate and multivariate analysis. However, in spite of R0 negative margins, the 5-year OS still remains poor at 30–40% with 5-year recurrence rate as high as 76%. Alongside R margin status, this poor prognosis is driven by the frequency of disease recurrence and aggressive tumor-related factors. These factors include tumor growth type; histologic differentiation; depth of tumor invasion; distant metastasis; and invasion of vasculature, lymph nodes, lymphatic channels, and perineural structures [25, 26].

14

Cholangiocarcinoma: Epidemiology, Pathogenesis, and Prognosis

Macroscopic Growth Patterns Extrahepatic cholangiocarcinomas can be classified into three primary macroscopic forms of growth: (1) papillary, (2) sclerosing, and (3) nodular; however, many tumors have overlapping features. Papillary types represent only 4–5% of all EH-CCAs and have a 5-year OS of 55.6%. They are characterized by soft and friable lesions with a predominant intraductal growth pattern that expands the duct superficially without deep invasion into the fibromuscular wall layers. The papillary growth type represents the highest resectability and cure rate and is regarded as an independent predictor of survival [33]. This survival advantage of papillary tumors over other growth types is persistent across all stages of disease. The majority of papillary CCAs is also associated with early-stage disease with more than 70% of the tumors staged less than AJCC IIA. Papillary tumors rarely have an invasive carcinoma component and tend to be better differentiated than that of nodular-sclerosing lesions. Sclerosing types represent the majority (70%) of EH-CCA tumors and carry the worst prognosis with a 5-year OS of 30.6% [33]. Unlike papillary growths, these tumors are highly invasive characterized by extensive fibrosis, circumferential thickening, and diffuse invasion along the biliary wall. They have a greater tendency to invade the ductal wall which can potentially lead to metastatic spread. Subsequently, these tumors are associated with low resectability and cure rates. Sclerosing types have a strong association with poorly differentiated histology and advanced stages of disease. They are more likely to be identified in higher T stages (T2–T4), while papillary tumors are predominantly found in the T1 stage. Nodular CCAs are highly invasive tumors with low resectability and cure rates. Most patients with nodular growth types have advanced disease at the time of diagnosis and have a worse median survival compared to papillary types (33 vs. 55 months) [33]. Nodular tumors have a greater tendency to infiltrate bile duct and periductal tissues more extensively than the papillary types. They also more frequently invade the deep

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submucosa which may make resection more difficult. Even when compared to advanced-staged papillary tumors with nodal disease, nodular CCAs still have a worse prognosis with a 10-year survival rate of 12% and 5%, respectively. T Category-Based Prognosis The prognostic ability of the AJCC T staging scheme is unclear with several studies noting inaccuracies. Categorization into the current T stage subgroups is dependent on whether the tumor is confined to the bile duct histologically. This methodology of categorizing stages is imprecise as bile ducts lack discrete tissue boundaries and the duct wall is not uniformly concentric along its length with varying amount of fibrous and loose connective tissue [38]. In turn, several studies have advocated for depth-based rather than layer-based T stage prognostication. Several studies have demonstrated that greater depths of tumors are associated with worse overall survivability. One study involving 315 patients who underwent surgical resection reported a median survival of 29.7 months for tumor depths of 5 cm without vascular invasion Tumor with intrahepatic vascular invasion or multiple tumors with or without vascular invasion Tumor perforating the visceral peritoneum Tumor directly invading local extrahepatic structures Criteria No regional lymph nodes assessed No metastasis to regional lymph nodes Any regional lymph node metastasis Criteria No distant metastasis Distant metastasis present

for assessment. N0 is defined as no evidence of regional lymph node metastasis. N1 is defined as the presence of regional lymph node metastasis, regardless of the number of lymph nodes involved. For sufficient pathological staging, a minimum of six lymph nodes is recommended to assess lymph node involvement [16, 17]. The M classification characterizes the presence of distant metastasis (see Table 1). M0 is defined as no distant metastasis, and M1 is reserved for the presence of distant metastasis. Common distant metastatic sites include the peritoneum, bone, lungs, and pleura. Extra regional abdominal lymph node metastasis, including spread to celiac, periaortic, and pericaval lymph nodes, is also considered M1 [16, 17].

10

Prognosis

Intrahepatic cholangiocarcinomas are aggressive carcinomas with high mortality and poor survival rates. Patients with resectable tumors have a better prognosis. Macroscopic vascular invasion,

positive surgical margins, lymph node metastasis, and advanced TNM stage are associated with high recurrence rate and poor prognosis. Tumor recurrence after resection occurs in up to two-thirds of patients. Small duct ICC has a better 5-year postoperative survival rate than large duct ICC secondary to early stage at diagnosis; large duct ICC usually has a higher T stage and more frequently shows perineural infiltration [2, 13].

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Carcinoma of the Extrahepatic Bile Ducts

Carcinoma of the extrahepatic bile ducts (EHBD) are tumors of the biliary tract outside of the liver, including the common hepatic duct and common bile duct. EHBD can be further divided into perihilar, distal, or diffuse based on location. Perihilar EHBD are proximal or upstream from the origin of the cystic duct and account for 70–80% of EHBD carcinomas. Distal EHBD starts from the common bile duct, including the intrapancreatic portion and above the ampulla of Vater and accounts for 20–30% of EHBD carcinomas. Diffuse EHBD carcinoma involves both perihilar and distal EHBD and accounts for approximately ~2% of EHBD carcinomas [19–23].

12

Clinical Features

Carcinoma of the extrahepatic bile ducts (CEHBD) occurs primarily in the sixth and seventh decade of life and has no gender predominance. Unlike intrahepatic cholangiocarcinoma, CEHBD usually presents early on while the tumor is still small with obstructive jaundice, right upper quadrant pain, malaise, weight loss, pruritus, and fever and chills if cholangitis develops. If body habitus allows, a palpable mass or ascites usually indicates advanced disease. Laboratory findings are usually consistent with extrahepatic bile duct obstruction and include hyperbilirubinemia, bilirubinuria, and a moderate rise in serum alkaline phosphatase and glutamic transferase activity [19, 21].

15

The Pathophysiology and Pathology of Intrahepatic and Extrahepatic Cholangiocarcinomas

Risk factors for carcinoma of extrahepatic bile ducts are related to biliary conditions that lead to chronic inflammation, including primary sclerosing cholangitis, parasitic infections, and developmental conditions such as choledochal cyst and abnormal choledochopancreatic junction. Primary sclerosing cholangitis can occur in a small portion of patients with ulcerative colitis who develop bile duct involvement. These patients are usually younger and have a long history of extensive colitis (mean duration 15–20 years) [19, 21, 22].

13

Gross Appearance

Carcinomas of the extrahepatic bile ducts are grossly divided into papillary, nodular, sclerosing, and diffuse types. Sclerosing is the most common type, which causes annular constrictive thickening of the bile ducts. The diffuse type grows longitudinally along the bile duct and may cause focal constricting lesions (see Figs. 5 and 6). A combination of the different types is often seen. On the cut surface, the CEHBD is white-tan, firm, and gritty. Non-invasive carcinomas may appear as multiple polypoid lesions above the mucosal surface, while invasive carcinomas present as smooth solid nodules that may fill the entire ductal lumen [19, 21, 24].

14

Microscopic Description

The most common types of carcinomas of the extrahepatic bile ducts are pancreatobiliary-type adenocarcinoma and papillary adenocarcinoma, and their precursor lesions are biliary intraepithelial neoplasia and intraductal papillary neoplasm. Biliary intraepithelial neoplasia (BilIN), same as the described above, is also a precursor lesion to large duct-type intrahepatic cholangiocarcinoma. BilIN is formed by large, cuboidal, or columnar cells with enlarged hyperchromatic nuclei, loss of nuclear polarity, pseudostratification, and variable mitotic activity. Intraductal papillary neoplasm is characterized by fibrovascular stalks lined by biliary epithelium with cystically dilated bile ducts [1, 3]. It can be further categorized into low grade,

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intermediate grade, or high grade based on nuclear atypia. High-grade dysplasia and carcinoma in situ are terms often used interchangeably, and morphologic criteria for both the extrahepatic bile ducts are the same as those in similar lesions in the gallbladder. Both flat and papillary carcinoma in situ lesions are usually found adjacent to invasive carcinomas but rarely occur as an isolated lesion without evidence of invasive carcinoma [24, 25]. These lesions are often focal and multicentric. Pancreatobiliary-type adenocarcinomas are usually well-moderately differentiated with glands lined by either tall columnar, cuboidal, or flat biliary-type cells with mild to moderate nuclear atypia and eosinophilic cytoplasm. On occasion, cribriform glands and solid nests can be seen in association with moderately differentiated adenocarcinomas. Small cytoplasmic and intraluminal mucin is usually present (see Figs. 5 and 6) [19, 24]. As in the gallbladder, papillary carcinomas of EHBD are usually well-moderately differentiated with intraductal growth before invading the ductal wall. In addition to complex papillary architecture, these tumors will also have a glandular component, which can be of pancreatobiliary, intestinal, gastric, or oncocytic type. Pancreatobiliary type consists of columnar cells with eosinophilic cytoplasm and round nuclei. The intestinal type resembles villous neoplasms of the colon. The gastric type consists of foveolar epithelium. The oncocytic type consists of cells with abundant, intensely eosinophilic cytoplasm. Gastric and oncocytic types are rare, and biliary type is the most common. Papillary carcinomas can be non-invasive, but the invasive component is usually the glandular component and invades as a tubular, mucinous adenocarcinoma [19, 24]. Other histological variants include clear-cell adenocarcinoma and adenosquamous, squamous, signet ring cell, and small-cell carcinomas. EHBDC are graded as well differentiated, moderately differentiated, poorly differentiated, and undifferentiated using the same criteria as for carcinomas of the gallbladder. CEHBDs induce a stromal desmoplastic response and are often present with perineural infiltration and lymphovascular invasion. Metastasis of CEHBDs can be

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Fig. 5 Gross image of perihilar cholangiocarcinoma with red inset demonstrating low power (0.5x) of invasive moderately differentiated adenocarcinoma from red circled

C. Wang and N. Setia

area. Black inset: High power (10x) of invasive malignant glands involving adjacent liver parenchyma from black circled area

maintaining well-differentiated morphologic features [19, 24].

15

Fig. 6 Distal extrahepatic bile duct with invasive moderately differentiated adenocarcinoma (0.5x). Inset: High power (20x) of invasive malignant glands from circled area

through direct extension to adjacent tissues, spread through blood vessels and lymphatic spaces, and perineural invasion. CEHBDs commonly metastasis to regional lymph nodes while

Diagnostic Criteria and Differential Diagnosis

Similar to immunoprofile for intrahepatic cholangiocarcinoma, carcinoma of extrahepatic bile ducts is positive for CK-7, CK-19, CEA, MUC-1, and variably positive for CK-20 [12, 11]. These tumors contain endocrine cells that are immunoreactive for the general neuroendocrine markers, such as synaptophysin and chromogranin; however, their presence is not required for diagnosis. CEHBDs need to be differentiated from reactive periductal bile ducts; secondary involvement by pancreatic ductal adenocarcinoma also needs to be excluded. Reactive atypia in native ductular epithelium show enlarged vesicular nuclei with prominent nucleoli; associated polymorphonuclear leukocytes are also present. Typically, the lobular pattern of the

15

The Pathophysiology and Pathology of Intrahepatic and Extrahepatic Cholangiocarcinomas

glands is usually preserved in reactive atypia. Even though reactive atypia may present with a cribriform glandular pattern, hyperchromasia and pseudostratification can occur; however, overexpression of p53 protein is not present, and a low proliferative index as measured by Ki-67 immunostain is seen [19, 24]. CEHBD is nearly indistinguishable from pancreatic ductal adenocarcinoma by histology and immunostain profiles. Clinical and radiographic correlation is strongly recommended.

16

PRKACB fusions and ELF3 and ARID1B mutations are relatively specific for CEHBDs [19].

18

Pathological Classification and Staging (pTNM)

Staging of carcinoma of extrahepatic bile duct follows the American Joint Committee on Cancer (AJCC) eighth edition Staging Manual. These tumors are staged separately based on location: perihilar bile ducts and distal bile duct.

Cytology 18.1

Brush cytology is usually the primary sampling method since histological sampling is often not possible with a sensitivity of 43% and specificity of 97%. Features suggestive of malignancy include irregular nuclear contour, increased nuclear:cytoplasmic ratio, nuclear pleomorphism, prominent nucleoli, chromatin clumping, 3D cell clusters, and high mitotic activity. Commonly in these specimens, there is a duo population of benign and malignant cells [19]. There are several limitations to cytology specimens as the primary diagnostic method. Coexisting inflammation and reactive atypia can make a definitive diagnosis of malignancy difficult. Cytology cannot differentiate between carcinoma in situ and invasive carcinomas. Diagnosis can be impaired by the amount of material obtained for examination resulting in hypocellular or acellular smears. Furthermore, carcinomas that grow longitudinally beneath the mucosa will not be properly sampled for diagnosis. If a diagnosis of CEHBD is clinically suspected, and the cytologic brushings biopsy is negative, the procedure should be repeated. The sensitivity of brush cytology increases with repeated brushings [26].

17

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Molecular Pathology

Common mutations found in and shared by carcinomas of extrahepatic bile ducts and intrahepatic cholangiocarcinomas include TP53, KRAS, SMAD4, ARID1A, and GNAS. PRKACA/

Perihilar/Proximal Bile Ducts

Perihilar, also defined as proximal, bile ducts involve the area of convergence of the right and left hepatic ducts to just before the junction with the cystic duct, which accounts for the majority of CEHBDs. The depth of invasion defines the pT classification of these tumors (see Table 2). T0 is defined by the lack of evidence of a primary tumor in the specimen. Tis is defined as the presence of only carcinoma in situ, also known as high-grade dysplasia, without invasion through the basement membrane. Tumor that is confined to the bile duct with invasion up to the muscle layer or the fibrous tissue is classified as T1. T2 tumor invades through the wall of the bile duct and is further subcategorized into T2a when there is invasion into the surrounding adipose tissue and T2b when there is invasion into adjacent liver parenchyma. T3 tumor has involvement of unilateral branches of the portal vein or hepatic artery. Lastly, T4 tumor invades the main portal vein, its branches bilaterally, common hepatic artery, unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvement [28]. The N classification defines the presence of lymph node involvement (see Table 2). NX is defined as no regional lymph node is available for assessment. N0 is defined as no evidence of regional lymph node metastasis. N1 is defined as tumor metastasis to one to three regional lymph nodes. Regional lymph nodes include the hilar, cystic duct, common bile duct, hepatic artery, posterior pancreaticoduodenal, and portal vein

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Table 2 Definition of TMN categories for perihilar bile duct tumors. Regional lymph nodes include the hilar, cystic duct, common bile duct, hepatic artery, posterior pancreatoduodenal, and/or portal vein lymph nodes [31] T category TX T0 Tis T1 T2 T2a

T2b T3 T4

N category NX N0 N1 N2 M category M0 M1

Criteria Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ/high-grade dysplasia Tumor confined to bile duct, up to muscle layer or fibrous tissue Tumor invades beyond the bile duct wall Tumor invades beyond the wall of the bile duct to the surrounding adipose tissue Tumor invades beyond the wall of the bile duct to adjacent hepatic parenchyma Tumor invades unilateral branches of the portal vein or hepatic artery Tumor invades the main portal vein or its branches bilaterally, common hepatic artery, unilateral secondary biliary radicals with contralateral portal vein, or hepatic artery Criteria No regional lymph nodes assessed No metastasis to regional lymph nodes Metastasis to 1–3 regional lymph nodes Metastasis to >4 regional lymph nodes Criteria No distant metastasis Distant metastasis present

lymph nodes. When there are four or more regional lymph node metastases, the nodal stage is classified as N2 [28]. The M classification is defined by the presence or absence of distant metastasis, M1 and M0, respectively (see Table 2). The liver is the most common site for metastasis [28].

18.2

Distal Extrahepatic Bile Ducts

The distal bile duct is the stretch of common bile duct distal to the convergence of the cystic duct to the ampulla of Vater, including choledochal cysts and the intrapancreatic portion of common bile duct. The depth of invasion defines the pT classification of these tumors (see Table 3). T0 is

Table 3 Definition of TMN categories for distal bile duct tumors [32] T category TX Tis T1 T2 T3 T4

N category NX N0 N1 N2 M category M0 M1

Criteria Primary tumor cannot be assessed Carcinoma in situ/high-grade dysplasia Tumor invades bile duct wall 12 mm in depth Tumor involves celiac axis, superior mesenteric artery, and/or common hepatic artery Criteria No regional lymph nodes assessed No metastasis to regional lymph nodes Metastasis to 1–3 regional lymph nodes Metastasis to >4 regional lymph nodes Criteria No distant metastasis Distant metastasis present

defined by the lack of evidence of a primary tumor in the specimen. Tis is defined as the presence of only carcinoma in situ/high-grade dysplasia. Tumor invasion into the bile duct wall to a depth of less than 5 mm, depth of 5–12 mm, and greater than 12 mm is defined as T1, T2, and T3, respectively. Lastly, T4 tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic artery [29]. The N classification defines the presence of lymph node involvement (see Table 3). NX is defined as no regional lymph node is available for assessment. N0 is defined as no evidence of regional lymph node metastasis. N1 is defined as tumor metastasis to one to three regional lymph nodes, and involvement of four or more regional lymph nodes is classified as N2. Regional lymph nodes include common bile duct, hepatic artery, celiac trunk, pancreaticoduodenal, superior mesenteric vein, and right lateral wall of superior mesenteric artery lymph nodes [29]. The M classification is defined by the presence or absence of distant metastasis, M1 and M0, respectively (see Table 3). Common sites of distant metastasis include the liver, lungs, and peritoneum [29].

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The Pathophysiology and Pathology of Intrahepatic and Extrahepatic Cholangiocarcinomas

Prognosis

The 5-year overall survival rate for resectable tumors is 20–30% and is almost 0% for unresectable cases. Patients with papillary adenocarcinomas that grow into the bile duct lumen have a better prognosis. High histologic grade, positive resection margins, vascular invasion, and perineural infiltration are associated with a poor prognosis. Local recurrences that result from a residual tumor at the surgical margin is the most likely cause of mortality in these cases [21].

References 1. WHO Classification of Tumours Editorial Board. Digestive system tumours. Lyon: International Agency for Research on Cancer; 2019. p. 254–9. 2. Bridgewater J, Galle PR, Khan SA, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol. 2014;60:1268–89. 3. Torbenson MS. Biopsy interpretation of the liver. Philadelphia: Wolters Kluwer Health; 2015. 4. Saxena R. Practical hepatic pathology: a diagnostic approach. 2nd ed. Philadelphia: Elsevier; 2018. 34: Benign and Malignant Tumors of Bile Ducts; 545–554. 5. Zhang H, Yang T, Wu M, Shen F. Intrahepatic cholangiocarcinoma: epidemiology, risk factors, diagnosis and surgical management. Cancer Lett. 2016;379(2):198–205. 6. Krasinskas AM. Cholangiocarcinoma. Surg Pathol Clin. 2018;11(2):403–29. 7. Massarweh NN, El-Serag HB. Epidemiology of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Cancer Control. 2017;24(3): 1073274817729245. 8. Buettner S, van Vugt JL, IJzermans JN, Koerkamp BG. Intrahepatic cholangiocarcinoma: current perspectives. Onco Targets Ther. 2017;10:1131. 9. Chung YE, Kim MJ, Park YN, Choi JY, Pyo JY, Kim YC, Cho HJ, Kim KA, Choi SY. Varying appearances of cholangiocarcinoma: radiologic-pathologic correlation. Radiographics. 2009;29(3):683–700. 10. Kozaka K, Sasaki M, Fujii T, et al. A subgroup of intrahepatic cholangiocarcinoma with an infiltrating replacement growth pattern and a resemblance to reactive proliferating bile ductules: ‘bile ductular carcinoma’. Histopathology. 2007;51(3):390–400. 11. Lau SK, Prakash S, Geller SA, Alsabeh R. Comparative immunohistochemical profile of hepatocellular carcinoma, cholangiocarcinoma, and metastatic adenocarcinoma. Hum Pathol. 2002;33(12): 1175–81.

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12. Rullier A, Le Bail B, Fawaz R, et al. Cytokeratin 7 and 20 expression in cholangiocarcinomas varies along the biliary tract but still differs from that in colorectal carcinoma metastasis. Am J Surg Pathol. 2000;24(6):870–6. 13. Esnaola NF, Meyer JE, Karachristos A, Maranki JL, Camp ER, Denlinger CS. Evaluation and management of intrahepatic and extrahepatic cholangiocarcinoma. Cancer. 2016;122(9):1349–69. 14. Rahnemai-Azar AA, Weisbrod A, Dillhoff M, Schmidt C, Pawlik TM. Intrahepatic cholangiocarcinoma: molecular markers for diagnosis and prognosis. Surg Oncol. 2017;26(2):125–37. 15. McKay SC, Unger K, Pericleous S, Stamp G, Thomas G, Hutchins RR, Spalding DR. Array comparative genomic hybridization identifies novel potential therapeutic targets in cholangiocarcinoma. HPB. 2011;13(5):309–19. 16. Chun YS, Pawlik TM, Vauthey JN. 8th edition of the AJCC cancer staging manual: pancreas and hepatobiliary cancers. Ann Surg Oncol. 2018;25(4):845–7. 17. Aloia T, Pawlik T, Taouli B, Rubbia-Brandt L, Vauthey JN. Intrahepatic bile ducts. In: 8th ed. AJCC cancer staging manual. Springer International Publishing; 2017. p. 295–302. 18. Moeini A, Sia D, Bardeesy N, Mazzaferro V, Llovet JM. Molecular pathogenesis and targeted therapies for intrahepatic cholangiocarcinoma. Clin Cancer Res. 2016;22(2):291–300. 19. WHO classification of tumours editorial board: tumours of the gallbladder and extrahepatic bile ducts. In: WHO classification of tumours: digestive system tumours. 5th ed. Lyon: IARC Press; 2019. p. 289–91. 20. Roos E, Franken LC, Soer EC, van Hooft JE, Takkenberg RB, Klümpen HJ, Wilmink JW, van de Vijver MJ, van Gulik TM, Verheij J. Lost in translation: confusion on resection and dissection planes hampers the interpretation of pathology reports for perihilar cholangiocarcinoma. Virchows Arch. 2019;475(4):435–43. 21. Jarnagin WR. Cholangiocarcinoma of the extrahepatic bile ducts. In Seminars in surgical oncology 2000 Sep (Vol. 19, No. 2, pp. 156–176). New York: Wiley. 22. Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. In: Seminars in liver disease 2004 May (Vol. 24, No. 02, pp. 115–125). New York: Copyright© 2004 by Thieme Medical Publishers, Inc. 23. Welzel TM, McGlynn KA, Hsing AW, O’Brien TR, Pfeiffer RM. Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intraand extrahepatic cholangiocarcinoma in the United States. J Natl Cancer Inst. 2006;98(12):873–5. 24. Albores-Saavedra J, Henson DE, Klimstra DS. Tumors of the gallbladder, extrahepatic bile ducts, and vaterian system. American Registry of Pathology; 2015. 25. Funabiki T, Matsubara T, Miyakawa S, Ishihara S. Pancreaticobiliary maljunction and carcinogenesis to biliary and pancreatic malignancy. Langenbeck’s Arch Surg. 2009;394(1):159–69. 26. Rabinovitz M, Zajko AB, Hassanein T, Shetty B, Bron KM, Schade RR, Gavaler JS, Block G, van Thiel DH, Dekker A. Diagnostic value of brush cytology in the

306 diagnosis of bile duct carcinoma: a study in 65 patients with bile duct strictures. Hepatology. 1990;12(4): 747–52. 27. Higuchi R, Yazawa T, Uemura S, Izumo W, Furukawa T, Yamamoto M. High-grade dysplasia/carcinoma in situ of the bile duct margin in patients with surgically resected node-negative perihilar cholangiocarcinoma is associated with poor survival: a retrospective study. J Hepatobiliary Pancreat Sci. 2017;24(8): 456–65. 28. Nagorney DM, Pawlik TM, Chun YS, Ebata T, Vauthey JN. Perihilar bile ducts. In: 8th ed. AJCC cancer staging manual. Springer International Publishing; 2017. p. 311–6. 29. Krasinskas A, Pawlik TM, Kenudson MM, Vauthey JN. Distal bile ducts. In: 8th ed. AJCC cancer staging manual. Springer International Publishing; 2017. p. 317–26.

C. Wang and N. Setia 30. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, et al., editors. AJCC cancer staging manual (8th edition). Springer International Publishing: American Joint Commission on Cancer; 2017. [cited 2016 Dec 28]. p. 295–302. 31. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, et al., editors. AJCC cancer staging manual (8th edition). Springer International Publishing: American Joint Commission on Cancer; 2017. [cited 2016 Dec 28]. p. 311–6. 32. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, et al., editors. AJCC cancer staging manual (8th edition). Springer International Publishing: American Joint Commission on Cancer; 2017. [cited 2016 Dec 28]. p. 317–25.

Nonsurgical Management of Cholangiocarcinoma

16

Michael J. Breen, Osman S. Ahmed, Joshua Owen, and Chih-Yi Liao

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308

2 Locoregional Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308 2.1 Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308 2.2 Liver-Directed Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 3 Cytotoxic Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310 3.1 Adjuvant Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 3.2 Chemotherapy for Advanced Unresectable and Metastatic Disease . . . . . . . . . . . . . 313 4 4.1 4.2 4.3 4.4

Targeted Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genomic Profiling and Molecular Classification of Cholangiocarcinoma . . . . . . . IDH Mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . FGFR Rearrangements and Fusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BRAF V600E Mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

314 315 316 316 317

5

Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318

6

Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320

Abstract M. J. Breen · C.-Y. Liao (*) Section of Hematology/Oncology, Department of Medicine, University of Chicago Medical Center, Chicago, IL, USA e-mail: [email protected]; [email protected] O. S. Ahmed Section of Vascular and Interventional Radiology, Department of Radiology, University of Chicago Medical Center, Chicago, IL, USA e-mail: [email protected] J. Owen Department of Medicine, University of Minnesota, Minneapolis, MN, USA

Cholangiocarcinoma arises from the biliary tract epithelium, comprising intrahepatic and extrahepatic cholangiocarcinomas. Surgical resection can be curative, but few patients are resectable at diagnosis, and the majority of patients who undergo surgery eventually recur, highlighting the significant unmet need to develop effective nonsurgical treatment. For resected patients, adjuvant therapy can reduce the risk of disease recurrence and improve survival. Adjuvant capecitabine for 6 months is the standard of care, and patients

© Springer Nature Switzerland AG 2022 C. Doria, J. N. Rogart (eds.), Hepato-Pancreato-Biliary Malignancies, https://doi.org/10.1007/978-3-030-41683-6_16

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with extrahepatic cholangiocarcinoma and a microscopically positive (R1) surgical margin may be offered chemotherapy with chemoradiation. Patients with locally advanced, unresectable cholangiocarcinoma should undergo multimodality treatment to maximize the chances of downstaging to allow for eventual resection. Locoregional therapies, including radiotherapy and liver-directed therapy, are instrumental in this setting. Additional studies are underway to investigate how to best sequence or combine locoregional therapies with systemic therapies to optimize efficacy. For patients with advanced or metastatic cholangiocarcinoma, chemotherapy with gemcitabine and cisplatin is the standard firstline systemic therapy. Genomic profiling studies in cholangiocarcinoma have revealed many actionable genomic alterations. Clinical trials with targeted therapies against IDH mutations, FGFR fusions/rearrangements, and BRAF V600E mutations have provided promising results. The role of immunotherapy in cholangiocarcinoma continues to evolve. For patients with mismatch repair deficient or microsatellite unstable (MMRd/MSI-H) tumors, checkpoint inhibitor therapy with a PD-1 inhibitor produces high response rates and durable responses. For patients without MMRd/MSI-H tumors, additional studies are needed to further identify predictive biomarkers and develop novel immunotherapy strategies to enhance anti-tumor immunity and maximize clinical responses. Keywords

Cholangiocarcinoma · Liver-directed therapy · Systemic therapy · Targeted therapy · Immunotherapy

extrahepatic cholangiocarcinoma if they arise from the extrahepatic bile ducts. Extrahepatic cholangiocarcinomas are further subclassified into perihilar cholangiocarcinoma (if arising in the portion of the biliary tract from the right and left hepatic ducts to the common bile duct) and distal cholangiocarcinoma (if arising in the distal common bile duct). In addition to cholangiocarcinoma, other biliary tract cancers include gallbladder cancers and ampulla of Vater cancers, which are often also included in clinical trials investigating nonsurgical treatment options for cholangiocarcinoma. Surgical resection can be part of a potential curative treatment modality for cholangiocarcinoma patients, but only a minority of patients are surgical candidates at the time of presentation, with estimates of resectability ranging from 10% to 40% [7]. For patients with advanced and unresectable disease, potential locoregional treatment options include liver-directed therapy and radiotherapy, while potential systemic therapy options include cytotoxic chemotherapy, targeted therapy, and immunotherapy. Genomic profiling studies in cholangiocarcinoma have uncovered many potential therapeutic targets, and clinical trials with novel targeted agents against IDH1 (isocitrate dehydrogenase 1), FGFR2 (fibroblast growth factor receptor 2), and BRAF have produced promising preliminary results.

2

Patients with locally advanced and unresectable cholangiocarcinoma, without distant metastases, may be eligible for locoregional therapies including radiotherapy and liver-directed therapy.

2.1

1

Introduction

Cholangiocarcinomas are malignant tumors arising from the biliary tract. Clinically, these tumors are classified as intrahepatic cholangiocarcinoma if they arise from the intrahepatic bile ducts and

Locoregional Therapy

Radiotherapy

Advances in radiotherapy technology have allowed for delivery of more precise, highly conformal radiation treatment to intrahepatic cholangiocarcinomas, maximally sparing adjacent normal tissues. A retrospective study of 79 patients with unresectable intrahepatic cholangiocarcinoma

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undergoing ablative doses definitive radiotherapy showed that radiation dose was the most strongly correlated with overall survival (OS) [44]. Among the 19 patients treated with a biologic equivalent dose higher than the median 80.5 Gray, 3-year OS was 73% vs. 38% for those receiving lower doses (p ¼ 0.017). Additional studies are necessary to determine how best to sequence or combine radiotherapy with other modalities of therapy for patients with locally advanced, unresectable cholangiocarcinoma.

2.2

Liver-Directed Therapy

Liver-directed therapy for advanced and unresectable cholangiocarcinoma represent a collection of locoregional therapies that target the primary hepatic tumor for purposes of palliation or downstaging to resection [52]. These treatments provide the advantage of limiting systemic toxicity through selective administration of chemoembolic (i.e., transarterial chemoembolization) or radioactive microspheres (i.e., transarterial radioembolization) to tumor feeding vessels. Alternatively, percutaneous thermal ablation (i.e., radiofrequency or microwave ablation) may also be utilized to selectively target and ablate tumor tissue. Intrahepatic cholangiocarcinoma (as opposed to extrahepatic cholangiocarcinoma) is particularly advantageous for locoregional treatment given the ability to safely avoid critical hilar structures during intervention.

Fig. 1 Trans-arterial radioembolization (TARE). Transarterial radioembolization (TARE) is a form of selective internal radiation therapy that involves selective catheterization of tumor feeding vessels to deliver radioactive embolic particles approximately 25–35 microns in diameter to the tumor, which leads to free radical generation and subsequent cellular damage. (a) During TARE procedures,

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Intra-arterial therapies for hepatic malignancies rely on the physiologic principle that normal liver parenchymal perfusion is largely derived from the portal vein whereas tumoral supply is via the hepatic artery. Thus, direct hepatic arterial infusion allows for delivery of high concentrations of drug with relative sparing of normal liver tissue. In general, intra-arterial treatments are not limited by tumor burden or focality. Such treatments are validated as standard of care therapies in the management of hepatocellular carcinoma and liver-only or liver-dominant metastatic colorectal cancer [49]. The primary mechanism of action for transarterial chemoembolization (TACE) is to induce tumor ischemia and facilitate local chemotherapeutic administration through selective catheterization of tumor feeding vessels [8]. Similarly, transarterial radioembolization (TARE) is a form of selective internal radiation therapy that utilizes radioactive embolic particles approximately 25–35 microns in diameter that are delivered in the same manner as TACE (Fig. 1). As opposed to TACE, the primary mechanism of tumoricidal action with TARE is through beta emission of injected particles that result in free radical generation and subsequent cellular damage [8]. This mode of treatment is particularly useful for gastrointestinal tumors as combination therapy with radiosensitizing chemotherapy (such as capecitabine) given a potential to improve patient outcomes [20]. Intra-arterial therapy for cholangiocarcinoma specifically has been shown to be technically

catheter angiogram from the hepatic artery demonstrate tumor blush to delineate tumor blood supply. (b) Intraprocedural CT during angiography can further confirm tumor blood supply anatomy, allowing for delivery of radioactive embolic particles to these sites via the tumor feeding vessels

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feasible and associated with improved overall survival (OS) and time to progression compared with chemotherapy alone. A meta-analysis of cholangiocarcinoma patients treated by TACE (n ¼ 438) and TARE (n ¼ 127) demonstrated an OS of 13.9 months and 12.4 months, respectively [6]. Most studies reported similar outcomes in terms of OS regardless of trans-arterial modality utilized for intra-hepatic cholangiocarcinoma with occasional studies showing increased (albeit nonsignificant) survival and decreased toxicity outcomes for patients treated by TARE [6, 38, 52]. Of note, toxicities reported in TACE analyses identified WHO Grade III/IV toxicities in up to 30% of patients, with the majority of studies reporting rates closer to 15% (Ray et al. 2013). TARE appeared to be associated with less toxicity, with most studies reporting Grade III/IV events in the 10% range [38]. Recent literature has cited improved survival benefits from TARE for the treatment of intrahepatic cholangiocarcinoma. One review of 85 cholangiocarcinoma patients treated by TARE reported a median OS of 21.4 months from diagnosis and 12 months following TARE treatment [16]. A prospective, multicenter observational study of 61 patients with chemotherapy refractory intrahepatic cholangiocarcinoma treated by TARE reported 8.7 month median OS from treatment [50]. Additionally, a recent phase II trial studying TARE as an adjunct to first-line chemotherapy in 41 patients reported median OS of 22 months, median progression free survival (PFS) of 14 months, and 45% survival at 2 years. Further, 22% of patients (n ¼ 9) were subsequently downstaged to resection [14]. A follow-up phase III trial is ongoing. Figure 2 demonstrates an example of a patient with locally advanced intrahepatic cholangiocarcinoma who was treated with TARE and successfully downstaged to allow eventual resection. In contrast to transarterial therapies, percutaneous ablation therapy via radiofrequency or microwave ablation utilize heat-based thermal energy deposition to cause coagulative necrosis of tumor. Other ablative modalities such as cryoablation or irreversible electroporation are less studied [43]. Similar to arterial based

M. J. Breen et al.

treatments, the use of ablation has been adopted from the management algorithm of hepatocellular carcinoma in which it is recognized as a curative intent treatment for early-stage disease. A meta-analysis demonstrated that OS was improved in patients with intrahepatic cholangiocarcinoma treated by percutaneous ablation and ineligible for surgery [19]. While technical success rates neared 100% for tumors less than 3 cm, the risk for incomplete ablation or recurrent disease that negatively impacted overall survival and local time to progression was significantly worse as tumor size increased [54]. This is additionally compounded by the infiltrative growth pattern of intrahepatic cholangiocarcinoma, which limits accurate coverage of tumor during ablation. A review of 10 studies on percutaneous ablation reported variable OS ranging from 8.7 to 54.2 months, likely reflecting the limitations of this technology based on tumor size. In a comparison of thermal ablation to repeat surgical resection for recurrent intrahepatic cholangiocarcinoma, however, thermal ablation demonstrated comparable results in terms of disease-free survival (21.3 vs. 20.3 months) in addition to OS (6.8 vs. 9.1 months) [54]. In summary, locoregional therapies comprise a broad range of treatment strategies from palliation or downstaging to surgical resection for patients with primarily intrahepatic cholangiocarcinoma. These treatments include arterial based therapies such as TACE and TARE as well as percutaneous needle ablation. While ablative therapies are limited by tumor size, TACE and TARE can be utilized for larger, multifocal, or infiltrative lesions. Emerging data for TARE with first-line chemotherapy is encouraging with subsequent trials underway to explore its role in this setting.

3

Cytotoxic Chemotherapy

Cytotoxic chemotherapy has been the mainstay of systemic therapy for advanced cholangiocarcinoma. Historically, clinical practice had largely been informed by phase II clinical trials and retrospective analyses, though results of

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Nonsurgical Management of Cholangiocarcinoma

311

Fig. 2 Successful downstaging to resection with TARE. As a liver-directed therapy option for locally advanced intrahepatic cholangiocarcinoma, TARE can be used to downstage tumors to allow for eventual surgical resection. (a) Shown here are CT and PET scan images at initial diagnosis of a 68-year-old woman with locally advanced intrahepatic cholangiocarcinoma with a 5 cm FDG-avid tumor centered in segment IV of the liver, with extension into the right anterior liver segments. She was treated with neoadjuvant gemcitabine/cisplatin chemotherapy for three

cycles, followed by TARE. (b) One month post-TARE, contrast-enhanced CT showed necrotic tumor with lack of enhancement consistent with treatment effect. (c) Three months post-TARE, PET/CT showed no residual tumor metabolic activity, consistent with complete metabolic response. (d) The patient subsequently underwent right tri-segmentectomy with an R0 resection, and surveillance CT scan 15 months after surgery showed expected left lateral segment hypertrophy and no evidence of residual/ recurrent tumor

several landmark phase III clinical trials are now available, and several additional phase III clinical trials are currently ongoing to further delineate the role of cytotoxic chemotherapy in the nonsurgical management of cholangiocarcinoma.

Until recently, there had been no standard of care for adjuvant therapy in cholangiocarcinoma. A 2012 meta-analysis of 20 predominantly retrospective, single-institution studies found a trend toward improved OS with adjuvant therapy, though it was not statistically significant in the overall population [21]. Subgroup analysis showed potential benefit for adjuvant therapy for patients with pathologically involved nodes (stage pN1 or higher disease) or with microscopically positive surgical margins (R1 resection). Of note, in this metaanalysis, adjuvant therapy included cytotoxic chemotherapy alone, radiotherapy alone, or concomitant chemotherapy and radiotherapy (chemoradiation). The benefit of radiotherapy appeared to be limited to patients with R1 disease.

3.1

Adjuvant Chemotherapy

Surgical resection can be part of a potential curative treatment modality for cholangiocarcinoma patients, but unfortunately, many patients experience recurrent disease after surgery. Adjuvant therapy are treatments given after surgical resection to reduce recurrence risk, improve relapsefree survival (RFS), and potentially improve OS.

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Since then, adjuvant therapy with cytotoxic chemotherapy for cholangiocarcinoma has been investigated in several large clinical trials: 1. The Bile Duct Cancer Adjuvant Trial (BCAT) was an open-label, phase III clinical trial of adjuvant gemcitabine monotherapy in Japanese patients with extrahepatic cholangiocarcinoma [12]. The primary endpoint was OS. 226 patients were randomized 1:1 to adjuvant gemcitabine versus observation. There was no appreciable difference between the two arms, with median OS of 62.3 months in the gemcitabine arm and 63.8 months in the observation arm (p ¼ 0.96). 2. PRODIGE 12-ACCORD 18-UNICANCER GI (P12-A18) was an open-label, phase III clinical trial of adjuvant gemcitabine and oxaliplatin (GEMOX) versus surveillance for resected biliary tract cancers [13]. Co-primary endpoints were RFS and time to definitive deterioration of health-related quality of life (HRQOL). Median RFS was 30.4 months in the GEMOX arm and 18.5 months in the surveillance arm, though this was not statistically significant (p ¼ 0.48). Subgroup analysis showed that patients with gallbladder cancer (20% of the overall population) had statistically significant worse RFS with adjuvant GEMOX. There were no statistically significant differences in time to definitive deterioration of global HRQOL (log-rank p ¼ 0.39), though there were trends toward worse fatigue (p ¼ 0.07) with chemotherapy. 3. BILCAP was an open-label, phase III study of adjuvant capecitabine conducted in the United Kingdom [37]. 447 patients with resected biliary tract cancers were randomized 1:1 to adjuvant capecitabine for 6 months versus observation. The primary endpoint was

OS. In the intention-to-treat analysis, there was a nonsignificant increase in median OS (51.1 vs. 36.4 months; p ¼ 0.09). In the prespecified per protocol analysis, the primary endpoint was met (53 vs. 36 months; p ¼ 0.02). The difference between these analyses arises from 17 patients who were not eligible or were assigned to but did not receive capecitabine. The most common reason for failure to receive capecitabine was patient withdrawal after randomization. Thus, while this study did not meet its primary endpoint in the intention-to-treat population, the prespecified per protocol analysis suggests a potential benefit of adjuvant capecitabine in improving OS. The discrepancies between these study results could be potentially explained by different chemotherapy regimens and different patient populations (Table 1). Capecitabine is a fluoropyrimidine that inhibits thymidylate synthase, while gemcitabine is a pyrimidine antimetabolite that inhibits ribonucleotide reductase and DNA polymerase. BILCAP contained a greater proportion of patients with microscopically positive resection margins (R1 disease; 35% of patients) compared with either P12-A18 (13%) or BCAT (11%). There was also a greater proportion of pathologically lymph node-positive (pN1) patients in BILCAP (54%) versus the other two studies (35% in both). Finally, BILCAP and P12-A18 each had a minority of patients with gallbladder cancer (18% and 20%, respectively) while BCAT excluded both gallbladder and intrahepatic cholangiocarcinoma. Chemoradiation may also be potentially beneficial as adjuvant therapy for cholangiocarcinoma. SWOG S0809 was a phase II single-arm trial of adjuvant therapy with four cycles of capecitabine

Table 1 Patient characteristics in key adjuvant therapy clinical trials Study BILCAP P12-A18 BCAT

Regimen Capecitabine Gemcitabine GEMOX

R1 resection (%) 35 13 11

pN1 disease (%) 54 35 35

Gallbladder cancer (%) 18 20 0

GEMOX, gemcitabine/oxaliplatin chemotherapy; pN1 disease, pathologically involved lymph nodes; R1 resection, microscopically positive surgical margin

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Nonsurgical Management of Cholangiocarcinoma

and gemcitabine followed by chemoradiation with capecitabine [5]. 79 patients were included, of which 68% had extrahepatic cholangiocarcinoma and the remainder gallbladder cancer. 68% of all patients had a microscopically margin negative (R0) resection, and 78% of cholangiocarcinoma patients had involved lymph nodes. The primary endpoint was 2-year overall survival, stratified by resection status (R0 vs. R1). The study found 67% OS at 2 years in R0 patients and 60% in R1 patients. The most common grade 3–4 adverse event was neutropenia occurring in 44% of patients. Based on these results, chemotherapy and chemoradiation may be potentially beneficial as adjuvant therapy in patients with extrahepatic cholangiocarcinoma, especially in patients with pathologically involved lymph nodes (pN1+) or microscopically positive (R1) surgical resection margin. From these adjuvant therapy clinical trial results, the 2019 American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines recommend that all patients with resected biliary tract cancers be offered adjuvant capecitabine for 6 months. In addition, patients with extrahepatic cholangiocarcinoma or gallbladder cancer, and an R1 resection, may be offered chemoradiation therapy [41]. Additional phase III trials of adjuvant therapy with pending results include the ASCOT study (adjuvant oral fluoropyrimidine S-1) and the ACTICCA-1 study (adjuvant gemcitabine and cisplatin).

3.2

Chemotherapy for Advanced Unresectable and Metastatic Disease

For patients with advanced and unresectable and metastatic cholangiocarcinoma, gemcitabine and cisplatin is the current standard of care first-line systemic therapy, based on results of the Advanced Biliary Cancer-02 (ABC-02) clinical trial [46]. In this phase III study, 410 patients with locally advanced or metastatic biliary tract cancers (56% cholangiocarcinoma, 36% gallbladder cancer, and 5% ampullary cancer) were randomized to chemotherapy with gemcitabine and

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cisplatin versus gemcitabine alone. Compared to single-agent gemcitabine, gemcitabine and cisplatin improved median OS (11.7 vs. 8.1 months, hazard ratio [HR] 0.64, p < 0.001) and median PFS (8.0 months vs. 5.0 months, p < 0.001). Compared to single-agent gemcitabine, gemcitabine and cisplatin also improved objective response rate (ORR, 26% vs. 15%) and disease control rate (DCR, 81% vs. 72%, p ¼ 0.049). The most significant grade 3 adverse event for gemcitabine and cisplatin was neutropenia, seen in 25% of patients versus 16% with monotherapy. For patients who are ineligible for cisplatin, gemcitabine and oxaliplatin (a platinum chemotherapy agent like cisplatin) are a reasonable alternative regimen, based on data from several phase II clinical trials. To investigate whether adding an additional cytotoxic chemotherapy agent to the gemcitabine/ cisplatin backbone would be beneficial, a singlearm, phase II study of 62 patients examined the addition of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) to gemcitabine/cisplatin as first-line therapy [40]. In this study, gemcitabine/cisplatin/ nab-paclitaxel achieved a median PFS of 11.4 months and median OS of 19.2 months. ORR was 45%, and DCR was 84%. Numerically, these figures compare favorably to the ABC-02 results, though cross trial comparisons are not advisable given the distinct study designs and patient populations. In this regimen, nab-paclitaxel was initially dosed at 100 mg/m2 (combined with gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2). Hematologic toxicity was unacceptable with this dose, and subsequently, the protocol was amended to reduce the dose to nab-paclitaxel 80 mg/m2, gemcitabine 800 mg/m2, and cisplatin 25 mg/m2. The promising results of this phase II study have led to a confirmatory phase III study comparing gemcitabine/cisplatin/nab-paclitaxel to gemcitabine/cisplatin, and the high response rate makes this regimen an attractive one to downstage locally advanced and unresectable tumors to becoming potentially resectable. With the advent of targeted therapies, several studies sought to investigate the addition of epidermal growth factor (EGFR) inhibitors to the standard gemcitabine/platinum chemotherapy backbone:

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1. A South Korean phase III, open-label study evaluated the addition of the EGFR inhibitor erlotinib to a backbone of gemcitabine and oxaliplatin in patients with biliary tract cancers, 67% of which were cholangiocarcinoma [28]. The primary endpoint of PFS was nonsignificantly increased in the overall population (5.8 versus 4.2 months; p ¼ 0.087). A predefined subset of only cholangiocarcinoma, the improvement in PFS did reach statistical significance (5.9 vs. 3.0 months, HR p ¼ 0.049). Response rate was nearly double with the addition of erlotinib (40% vs. 21%). While there are problems with generalizability to a non-Asian population, this does suggest that addition of erlotinib may be beneficial in situations where an objective response is needed. 2. The BINGO trial was an open label, noncomparative, phase II trial that evaluated the addition of cetuximab (an EGFR inhibitor) to gemcitabine and oxaliplatin [32]. The study showed no difference in PFS or OS with the addition of cetuximab. Moreover, there appeared to be no difference in those with either KRAS or BRAF mutations. 3. Vecti-BIL was an open-label, phase II randomized trial conducted in Italy of 89 patients with KRAS wild-type biliary tract cancers treated with gemcitabine and oxaliplatin with or without panitumumab, an EGFR inhibitor [30]. The study did not meet its primary endpoint of increased PFS in the overall population. There was a suggestion of increased OS with the addition of panitumumab for patients with intrahepatic cholangiocarcinoma (47% of the overall study population) with an increase in median OS of 15.1 vs. 11.8 months; p ¼ 0.13. As with the above studies, any effect if present is modest and/or limited to an as-yet unidentified subset of patients. Other studies have sought to investigate the addition of vascular endothelial growth factor (VEGF) inhibitors to the standard gemcitabine and platinum chemotherapy backbone. In ABC-03, a multicenter, placebo-controlled, phase II trial, the addition of cediranib to gemcitabine and cisplatin did not improve PFS or OS [47]. Moreover, there were increased dose-limiting side

M. J. Breen et al.

effects including hypertension and diarrhea, consistent with this class of medication. Therefore, addition of EGFR and VEGF inhibitors to the gemcitabine and platinum chemotherapy backbone has not clearly proven to be beneficial in the biomarker-unselected population for patients with advanced and unresectable or metastatic cholangiocarcinoma. Unfortunately, for patients who derive clinical benefit from first-line gemcitabine and cisplatin, resistance to therapy invariable develops. Second-line cytotoxic chemotherapy may be of benefit, as suggested by the phase III ABC-06 trial [27]. This study compared addition of cytotoxic chemotherapy with modified FOLFOX (mFOLFOX) to active symptom control (ASC), versus ASC alone in patients that had progressed on first-line gemcitabine and cisplatin. Addition of mFOLFOX to ASC improved OS vs. ASC alone (6.2 months vs. 5.3 month, HR 0.69, p ¼ 0.031). Survival at 6 months was 50.6% vs. 35.5% and at 12 months 25.9% vs. 11.4%, all favoring the mFOLFOX arm. Retrospective analysis of two prospective multicenter cohorts showed similar overall survival with fluoropyrimidine monotherapy vs. doublets with either irinotecan or platinum chemotherapy [36]. Prospective validation of this data will be necessary to establish this as standard practice in all patients, though it provides support for fluoropyrimidine-based cytotoxic chemotherapy as second-line therapy after progression on first-line gemcitabine and cisplatin. In summary, gemcitabine and cisplatin are the current standard first-line cytotoxic chemotherapy regimen for patients with advanced and unresectable or metastatic cholangiocarcinoma. Fluoropyrimidine-based regimens such as mFOLFOX may be considered a second-line therapy, though with such modest results, there is a clear unmet need to develop novel therapeutic strategies and to investigate predictive biomarkers in cholangiocarcinoma.

4

Targeted Therapy

Genomic profiling studies of cholangiocarcinoma have revealed many recurring genomic alterations (Table 2) [22]. Targeted therapies are novel therapeutic agents directed against these

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Table 2 Targetable molecular alterations in cholangiocarcinomaa Alteration ERBB2 amplification BRAF mutation PIK3CA mutation FGFR fusions/amplification CDKN2A/CDKN2B loss IDH1/IDH2 mutation ARID1A alterations MET amplification a

Intrahepatic cholangiocarcinoma (%) 4 5 5 11 27 20 18 2

Extrahepatic cholangiocarcinoma (%) 11 3 7 0 17 0 12 0

Javle et al. [20]

actionable genomic alterations to interfere with tumor cell growth and survival. With the advent of next-generation sequencing, clinicians are now able to assess the genomic profile of cholangiocarcinoma patients in real-time to determine whether patients would benefit from targeted therapies.

4.1

Genomic Profiling and Molecular Classification of Cholangiocarcinoma

The Cancer Genome Atlas (TCGA), a landmark cancer genomics program, molecularly characterized cholangiocarcinoma by whole-exome sequencing, SNP (single nucleotide polymorphism) copy number array, RNA sequencing, DNA methylation, and reverse-phase protein array [15]. The TCGA analysis of cholangiocarcinoma examined 38 samples from a predominantly North American set, with 84% of samples from patients with intrahepatic cholangiocarcinoma. The analysis revealed four distinct molecular clusters: (1) extrahepatic cholangiocarcinoma-type, (2) IDH (isocitrate dehydrogenase)-mutant type, (3) METH2 cluster with highly hypermethylated profile, and (4) METH3 cluster with BAP1 (BRCA1 associated protein-1) mutation and FGFR2 fusions. Survival did not vary with the clusters, though sample size was small. There was a strong increase in mitochondria-related gene expression (i.e., mitochondrial ribosomal proteins, electron transport chain, mitochondrial structural components) in IDH mutant tumors and a strong inverse correlation with a chromatin modifier signature.

Another genomic profile study of extrahepatic cholangiocarcinoma shows a distinct mutational profile from that of intrahepatic cholangiocarcinoma [29]. This study used hybridization capture to sequence 315 genes with known cancer relevance. There were no genes that were altered in >50% of cases. The most frequently altered genes were TP53 (45%), KRAS (43%), CDKN2A (28%), CDKN2B (15%), SMAD4 (15%), and ARID1A (13%). ERBB2 (HER2/neu) was altered in 9% of patients. Mutations along the PI3KAKT pathway were found in 28% of patients. No IDH mutations or FGFR2 gene fusions were identified. A whole-exome and transcriptome sequencing study of biliary tract cancers molecularly characterized 260 cases of biliary tract cancers from Japan and identified 32 significantly altered genes, and nearly 40% of the cases included a potentially targetable genomic alteration [35]. Driver fusion genes in FGFR and PRKACA/PRKACB (catalytic subunits of cyclic AMP (cAMP)-dependent protein kinase) were identified in intrahepatic and extrahepatic cholangiocarcinomas, respectively. Genomic alterations were classified by pathways into five modules: (1) kinase-RAS module, (2) TGF-β-SWI/SNF/MYC module, (3) RB-cell cycle module, (4) TP53 module, and (5) epigenetic module. Gene expression analysis identified four molecular clusters of biliary tract cancers, each with different prognosis: the cluster with the best prognosis (mainly extrahepatic cholangiocarcinoma patients) had significant negative enrichment of the RAS and MAPK (mitogen-activated protein kinase) pathway activation signatures, while the cluster with the worst prognosis (including hypermutated cases)

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showed positive enrichment for genes involved in the immune system and antiapoptotic genes. The largest, international study of integrated whole-genome and epigenomic analysis of cholangiocarcinoma analyzed 489 cases from 10 countries, and identified 4 clusters of cholangiocarcinomas with distinct genomic, gene expression and epigenetic profiles, each with independent prognostic significance [24]. Cholangiocarcinomas associated with liver fluke infection (a common risk factor in Southeast Asia) are enriched in ERBB2 amplifications and TP53 mutations. Cholangiocarcinomas not associated with liver fluke infection exhibit high copy number alterations, PD-1 expression, and alterations in IDH1/IDH2, BAP1, and FGFR. This study highlights the interplay of genetics, epigenetics, and environmental exposures in the carcinogenesis of cholangiocarcinoma.

4.2

IDH Mutations

Isocitrate dehydrogenase 1 (IDH1) and IDH2 are metabolic enzymes expressed in the cytoplasm/ peroxisome and mitochondria, respectively. The normal function is regulation of interconversion between α-ketoglutarate and isocitrate. IDH mutations alter the enzymatic activity such that α-ketoglutarate is instead converted into an alternate metabolite, 2-hydroxyglutarate (2-HG). 2-HG accumulation interferes with the function of various epigenetic regulators including histone and DNA demethylases, leading to alterations in stem and progenitor cell differentiation [48]. Recurrent mutations are found in human leukemias, sarcomas, and glioblastomas. IDH1 and IDH2 mutations are found in 20% of intrahepatic cholangiocarcinoma patients, but not in extrahepatic cholangiocarcinoma patients. Among IDH mutations in cholangiocarcinoma, R132 mutations are commonly seen. Ivosidenib is an oral inhibitor of mutant IDH1 that is FDA-approved for treatment of acute myeloid leukemia with IDH1 mutation in patients who either cannot tolerate intensive chemotherapy or are in the relapsed/refractory setting. In cholangiocarcinoma, a phase I trial of ivosidenib in 73 patients with IDH1 mutation who have progressed

on first-line therapy demonstrated excellent safety profile and promising preliminary efficacy, with DCR of 61% [31]. Common toxicities included nausea, fatigue, diarrhea, and prolonged QT interval. Ivosidenib treatment led to dramatic reductions in 2-HG, demonstrating pharmacodynamic efficacy. On-treatment biopsies also demonstrated favorable histologic changes in cholangiocarcinoma tumors. The follow-up phase III study, ClarIDHy, was a randomized, double-blind, and placebo-controlled study of ivosidenib versus placebo for IDH1 mutant, chemotherapy refractory cholangiocarcinoma patients [1]. Compared to placebo, ivosidenib improved median PFS (2.7 months vs. 1.4 months, HR 0.37, p < 0.0001). Notably, PFS was 32% at 6 months and 22% at 12 months for ivosidenib, while all patients on placebo group had experienced disease progression or death by 6 months. Moreover, there was a trend toward improved OS (10.8 vs. 9.7 months, HR 0.69, p ¼ 0.060). The study allowed crossover from the placebo arm to the ivosidenib arm at the time of disease progression, so the effect of ivosidenib on OS is likely underestimated by these data. With ivosidenib, ORR was 2% while DCR was 53% (compared to 0% and 28%, respectively, in the placebo arm).

4.3

FGFR Rearrangements and Fusions

Fibroblast growth factor receptors (FGFRs) are a family of four transmembrane receptor tyrosine kinases (FGFR1–4). There are 18 ligands in the FGF family. Deregulation of this pathway has been implicated in tumor cell mitosis, angiogenesis, and therapy resistance through numerous downstream effectors including MAP kinases, PI3K-Akt, phospholipase C, and JAK-STAT signaling [4, 28, 51]. FGFR alterations are found primarily in intrahepatic cholangiocarcinomas (rather than in extrahepatic cholangiocarcinomas or gallbladder cancers) and comprise gene fusions, rearrangements, amplifications, and mutations. 10–15% of intrahepatic cholangiocarcinoma patients have FGFR fusions [3].

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Multiple FGFR inhibitors with various isoform selectivity and mechanisms of action are currently being evaluated in clinical trials. Infigratinib (BGJ398), a reversible FGFR1–4 inhibitor, demonstrated promising preliminary efficacy in a phase II study of 61 patients with advanced or metastatic cholangiocarcinoma with FGFR alterations who have progressed on standard chemotherapy, with ORR 15% (19% in patients with FGFR fusions) and median PFS 5.8 months [23]. Derazantinib (ARQ 087), another reversible FGFR 1–4 inhibitor, demonstrated ORR 21% and DCR 83% in a phase I/II study [34]. Pemigatinib, a reversible FGFR 1–3 inhibitor, is the first FDA-approved FGFR inhibitor for patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or rearrangement. The accelerated approval was based on the FIGHT-202 study, a single-arm, multicohort phase II study of patients with (1) FGFR2 fusions and rearrangements, (2) other FGFR alterations, or (3) no FGFR/FGF alterations who had progressed on at least one line of prior therapy [2]. For patients with FGFR2 fusions/rearrangements, pemigatinib led to an ORR of 35.5% (including 2.8% complete response) and DCR of 82%. Median duration of response was 9.1 months. Median PFS was 6.9 months and median OS was 21.1 months. Interestingly, of 107 FGFR2 fusions, there were 56 different fusion partner genes identified, of which 42 were unique to single patients. The most common fusion was FGFR2-BICC1 (29% of patients), while 5% of patients had no fusion partner identified. Objective responses to pemigatinib were seen regardless of fusion partner. Notably, for patients with other FGFR alterations (such as mutations or amplifications) and for patients without FGFR/ FGF alterations, no objective responses were seen. Based on these promising results for pemigatinib in advanced or metastatic cholangiocarcinoma patients with FGFR2 fusions or rearrangements, a follow-up phase III study is currently being conducted in this population comparing first-line pemigatinib therapy to standard gemcitabine and cisplatin chemotherapy. Finally, futibatinib (TAS-120) is an irreversible inhibitor of FGFR1–4 that covalently binds to a

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conserved cysteine residue in the ATP binding pocket. A phase I study of futibatinib in 45 cholangiocarcinoma patients with FGFR alterations led to an ORR of 25% and DCR of 79% in patients with FGFR fusions and ORR of 18% and DCR of 76% in patients with other FGFR alterations [45]. Notably, futibatinib treatment led to responses in 4 of 13 patients previously treated with FGFR inhibitors, warranting further investigation for its potential role in overcoming treatment resistance to other FGFR inhibitors. Preclinical studies demonstrate that tumors from patients who have previously been treated with other FGFR inhibitors may acquire additional FGFR mutations, as seen in the circulating tumor DNA and/or subsequent tumor biopsies at the time of disease progression. Patient-derived cell lines and xenografts harboring these acquired mutations demonstrate sensitivity to futibatinib. Interestingly, strategic sequencing of FGFR2 inhibitors in response to emerging resistance clones led to prolonged growth suppression in vitro, raising the possibility that a similar strategy may be effective clinically [18]. As a class, FGFR inhibitors often lead to hyperphosphatemia relating to inhibition of FGF23FGFR1 signaling in the renal tubule. Other commonly reported adverse events include diarrhea, ocular toxicity (dry eye, blurry vision, retinal pigment epithelial detachment), nail dystrophy, and palmar plantar erythrodysesthesia. Of note, the most common grade 3 adverse event in FIGHT202 was hypophosphatemia, which may arise from continued use of low-phosphate diets and phosphate binders during the off-week of treatment.

4.4

BRAF V600E Mutations

The RAS family of oncogenes were among the earliest described. Drug targeting of RAS has proven exceptionally challenging due to (1) the picomolar affinity with which RAS binds GTP and (2) a relatively smooth protein structure devoid of pockets toward which a small molecule could be engineered [10]. The downstream effectors of this pathway have thus become attractive drug targets.

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BRAF is an immediate downstream effector of RAS in the mitogen-activated protein kinase (MAPK) pathway. BRAF mutations occur in many types of cancer, with the recurrent V600E mutation in the kinase domain the most common [11]. BRAF V600E mutation is found in approximately 5% of advanced biliary tract cancers [22]. Early clinical success targeting BRAF – specifically the V600E mutation – was seen in metastatic melanoma [9]. Resistance to BRAF inhibitors can occur through multiple mechanisms, a prominent one being independent activation of the downstream MEK kinases. Thus, dual inhibition of BRAF and MEK has emerged as a paradigm for more effective BRAF inhibition in multiple tumor types. The Rare Oncology Agnostic Research (ROAR) trial is a phase II trial of dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) in patients with BRAF V600E mutations in rare cancer types [42]. This study enrolled 43 patients with advanced biliary tract cancers (39 of which had intrahepatic cholangiocarcinoma). In this population, dabrafenib and trametinib led to an ORR of 51% and DCR of 91%. Of patients with a partial response, ongoing response rate at 6, 12, and 24 months was 67%, 36%, and 13%. Median PFS was 9 months and median OS 14 months. Thus, dabrafenib and trametinib represent a promising treatment option for advanced cholangiocarcinoma patients with BRAF V600E mutation.

5

Immunotherapy

The immune evasion of cholangiocarcinoma has been appreciated for years. An immunopathologic study shows that Fas ligand expression in early intrahepatic cholangiocarcinoma correlates with T cell apoptosis and hypothesizes this as mechanism of immune escape [39]. The role of the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis was characterized in a study showing upregulation of PD-L1 on cholangiocarcinoma and an inverse relationship between PD-L1 staining and number of CD8+ tumor-infiltrating lymphocytes [53]. A comprehensive characterization of different immuneinfiltrating cells in biliary cancers found that T lymphocytes are the most common infiltrating

cells: CD4+ T cells are found in the epithelium of 37% of biliary tract cancer, while CD8+ T cells are found in the epithelium of 48%. Infiltration with CD4+ or CD8+ T cells is associated with longer survival. Of note, biliary tumor subtype analysis showed this held for gallbladder cancer and extrahepatic cholangiocarcinoma but not intrahepatic cholangiocarcinoma [17]. These results provided preclinical rationale for clinical trials with immunotherapy in cholangiocarcinoma. Proof of concept that immunotherapy may be beneficial for select cholangiocarcinoma patients comes from clinical trials investigating PD-1 inhibitors in patients with mismatch repairdeficient (MMRd)/microsatellite-unstable (MSI-H) cholangiocarcinomas, representing 23 months) and were exclusively observed in patients with intrahepatic cholangiocarcinoma and gallbladder cancer. The median PFS was 2.9 months (95% CI, 2.2–4.6 months) and OS was 5.7 months (95% CI, 2.7–11.9 months). Compared to single-agent checkpoint inhibitor therapy, combination immunotherapy may be associated with higher incidence immune-related adverse events, as seen in 49% of patients in this study (15% of patients experienced grade 3 or 4 immune-related adverse events).

6

Conclusions and Future Directions

The nonsurgical management of cholangiocarcinoma is rapidly evolving with advances in systemic therapies and locoregional therapies. For patients with localized disease who undergo

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surgical resection, adjuvant therapy may further decrease the risk of disease recurrence and improve survival. Cytotoxic chemotherapy, with or without radiotherapy, are the current standard of care, though the optimal regimen and duration of cytotoxic chemotherapy and the precise contribution of radiotherapy remain to be clarified in ongoing and future studies. Targeted therapies and immunotherapies are novel therapeutic strategies currently under clinical study for the treatment of advanced or metastatic cholangiocarcinoma, and promising initial results provide strong rationale for their further investigation in the adjuvant setting. For patients with locally advanced and unresectable disease at the time of diagnosis, clinical trials are needed to define the optimal multimodality treatment approach. This may involve escalation of systemic therapy regimens (such as triplet chemotherapy regimens), sequencing systemic therapy (neoadjuvant therapy or perioperative/periadjuvant therapy), or combination of systemic therapy with locoregional therapy (such as sequencing chemotherapy with liver-directed therapy or radiotherapy). This may also involve rational combinations of novel therapeutic agents (such as combining liver-directed therapy or radiotherapy with immunotherapy) or utilizing targeted therapy options with high response rates (such as FGFR inhibitors) to maximize the chances of downstaging to allow for eventual surgical resection. For patients with advanced or metastatic cholangiocarcinoma, genomic profiling studies have led to further understanding of disease biology, paving the way for development of novel targeted therapies and immunotherapies. In the realm of targeted therapies, additional research is needed to further clarify resistance mechanisms and optimal sequencing of targeted agents (as in the case of FGFR inhibitors) or to develop rational combinations with other systemic therapy agents (as in the case of IDH inhibitors). With immunotherapy, additional studies are necessary to identify predictive biomarkers other than MMRd and MSI-H, to understand the immune microenvironment of cholangiocarcinoma, and to develop novel and/or combination immunotherapy strategies to enhance anti-tumor immunity and maximize clinical responses.

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References 1. Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, Cleary JM, Catenacci DV, Borad MJ, Bridgewater J, Harris WP, Murphy AG, Oh DY, Whisenant J, Lowery MA, Goyal L, Shroff RT, El-Khoueiry AB, Fan B, Wu B, Chamberlain CX, Jiang L, Gliser C, Pandya SS, Valle JW, Zhu AX. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020a;21(6):796–807. https:// doi.org/10.1016/s1470-2045(20)30157-1. 2. Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi R, Paulson AS, Borad MJ, Gallinson D, Murphy AG, Oh D-Y, Dotan E, Catenacci DV, Van Cutsem E, Ji T, Lihou CF, Zhen H, Féliz L, Vogel A. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020b; https://doi.org/10.1016/s1470-2045(20)30109-1. 3. Arai Y, Totoki Y, Hosoda F, Shirota T, Hama N, Nakamura H, Ojima H, Furuta K, Shimada K, Okusaka T, Kosuge T, Shibata T. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology. 2014;59 (4):1427–34. https://doi.org/10.1002/hep.26890. 4. Babina IS, Turner NC. Advances and challenges in targeting FGFR signalling in cancer. Nat Rev Cancer. 2017;17(5):318–32. https://doi.org/10.1038/nrc.2017.8. 5. Ben-Josef E, Guthrie KA, El-Khoueiry AB, Corless CL, Zalupski MM, Lowy AM, Thomas CR Jr, Alberts SR, Dawson LA, Micetich KC, Thomas MB, Siegel AB, Blanke CD. SWOG S0809: a phase II intergroup trial of adjuvant Capecitabine and gemcitabine followed by radiotherapy and concurrent Capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma. J Clin Oncol. 2015;33(24):2617–22. https://doi.org/10.1200/jco.2014.60.2219. 6. Boehm LM, Jayakrishnan TT, Miura JT, Zacharias AJ, Johnston FM, Turaga KK, Gamblin TC. Comparative effectiveness of hepatic artery based therapies for unresectable intrahepatic cholangiocarcinoma. J Surg Oncol. 2015;111(2):213–20. https://doi.org/10.1002/ jso.23781. 7. Buettner S, van Vugt JL, IJzermans JN, Groot Koerkamp B. Intrahepatic cholangiocarcinoma: current perspectives. Onco Targets Ther. 2017;10:1131– 42. PMID: 28260927; PMCID: PMC5328612. https:// doi.org/10.2147/OTT.S93629. 8. Cappelli A, Pettinato C, Golfieri R. Transarterial radioembolization using yttrium-90 microspheres in the treatment of hepatocellular carcinoma: a review on clinical utility and developments. J Hepatocell Carcinoma. 2014;1:163–82. https://doi.org/10.2147/jhc. S50472. 9. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T,

M. J. Breen et al. Schadendorf D, Ribas A, O’Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16. https://doi.org/10.1056/ NEJMoa1103782. 10. Dang CV, Reddy EP, Shokat KM, Soucek L. Drugging the ‘undruggable’ cancer targets. Nat Rev Cancer. 2017;17(8):502–8. https://doi.org/10.1038/nrc.2017.36. 11. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892): 949–54. https://doi.org/10.1038/nature00766. 12. Ebata T, Hirano S, Konishi M, Uesaka K, Tsuchiya Y, Ohtsuka M, Kaneoka Y, Yamamoto M, Ambo Y, Shimizu Y, Ozawa F, Fukutomi A, Ando M, Nimura Y, Nagino M. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg. 2018;105(3): 192–202. https://doi.org/10.1002/bjs.10776. 13. Edeline J, Benabdelghani M, Bertaut A, Watelet J, Hammel P, Joly J-P, Boudjema K, Fartoux L, Bouhier-Leporrier K, Jouve J-L, Faroux R, GuerinMeyer V, Kurtz J-E, Assénat E, Seitz J-F, Baumgaertner I, Tougeron D, De La Fouchardière C, Lombard-Bohas C, Boucher E, Stanbury T, Louvet C, Malka D, Phelip J-M. Gemcitabine and Oxaliplatin chemotherapy or surveillance in resected biliary tract cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): a randomized phase III study. J Clin Oncol. 2019a;37(8):658–67. https://doi.org/10.1200/jco.18. 00050. 14. Edeline J, Touchefeu Y, Guiu B, Farge O, Tougeron D, Baumgaertner I, Ayav A, Campillo-Gimenez B, Beuzit L, Pracht M, Lièvre A, Le Sourd S, Boudjema K, Rolland Y, Boucher E, Garin E. Radioembolization plus chemotherapy for first-line treatment of locally advanced intrahepatic cholangiocarcinoma: a phase 2 clinical trial. JAMA Oncol. 2019b;6(1):51–9. https://doi.org/10.1001/jamaoncol. 2019.3702. 15. Farshidfar F, Zheng S, Gingras MC, Newton Y, Shih J, Robertson AG, Hinoue T, Hoadley KA, Gibb EA, Roszik J, Covington KR, Wu CC, Shinbrot E, Stransky N, Hegde A, Yang JD, Reznik E, Sadeghi S, Pedamallu CS, Ojesina AI, Hess JM, Auman JT, Rhie SK, Bowlby R, Borad MJ, Zhu AX, Stuart JM, Sander C, Akbani R, Cherniack AD, Deshpande V,

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Mounajjed T, Foo WC, Torbenson MS, Kleiner DE, Laird PW, Wheeler DA, McRee AJ, Bathe OF, Andersen JB, Bardeesy N, Roberts LR, Kwong LN. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep. 2017;18(11):2780–94. https://doi. org/10.1016/j.celrep.2017.02.033. 16. Gangi A, Shah J, Hatfield N, Smith J, Sweeney J, Choi J, El-Haddad G, Biebel B, Parikh N, Arslan B, Hoffe SE, Frakes JM, Springett GM, Anaya DA, Malafa M, Chen DT, Chen Y, Kim RD, Shridhar R, Kis B. Intrahepatic cholangiocarcinoma treated with Transarterial Yttrium-90 glass microsphere Radioembolization: results of a single institution retrospective study. J Vasc Interv Radiol. 2018;29(8):1101–8. https://doi.org/10.1016/j.jvir.2018.04.001. 17. Goeppert B, Frauenschuh L, Zucknick M, Stenzinger A, Andrulis M, Klauschen F, Joehrens K, Warth A, Renner M, Mehrabi A, Hafezi M, Thelen A, Schirmacher P, Weichert W. Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer. Br J Cancer. 2013;109(10):2665–74. https://doi.org/ 10.1038/bjc.2013.610. 18. Goyal L, Shi L, Liu LY, Fece De La Cruz F, Lennerz JK, Raghavan S, Leschiner I, Elagina L, Siravegna G, Ng RWS, Vu P, Patra KC, Saha SK, Uppot RN, Arellano R, Reyes S, Sagara T, Otsuki S, Nadres B, Shahzade HA, Dey-Guha I, Fetter IJ, Baiev I, Van Seventer EE, Murphy JE, Ferrone CR, Tanabe KK, Deshpande V, Harding JJ, Yaeger R, Kelley RK, Bardelli A, Iafrate AJ, Hahn WC, Benes CH, Ting DT, Hirai H, Getz G, Juric D, Zhu AX, Corcoran RB, Bardeesy N. TAS-120 overcomes resistance to ATPcompetitive FGFR inhibitors in patients with FGFR2 fusion–positive intrahepatic cholangiocarcinoma. Cancer Discov. 2019;9(8):1064–79. https://doi.org/10. 1158/2159-8290.cd-19-0182. 19. Han K, Ko HK, Kim KW, Won HJ, Shin YM, Kim PN. Radiofrequency ablation in the treatment of unresectable intrahepatic cholangiocarcinoma: systematic review and meta-analysis. J Vasc Interv Radiol. 2015;26(7):943–8. https://doi.org/10.1016/j.jvir.2015. 02.024. 20. Hickey R, Mulcahy MF, Lewandowski RJ, Gates VL, Vouche M, Habib A, Kircher S, Newman S, Nimeiri H, Benson AB, Salem R. Chemoradiation of hepatic malignancies: prospective, phase 1 study of full-dose capecitabine with escalating doses of yttrium-90 radioembolization. Int J Radiat Oncol Biol Phys. 2014;88(5):1025–31. https://doi.org/10.1016/j.ijrobp. 2013.12.040. 21. Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. J Clin Oncol. 2012;30(16):1934–40. https://doi.org/10.1200/jco. 2011.40.5381. 22. Javle M, Bekaii-Saab T, Jain A, Wang Y, Kelley RK, Wang K, Kang H, Catenacci D, Ali S, Krishnan S, Ahn D, Bocobo A, Zuo M, Kaseb A, Miller V,

321 Stephens P, Meric-Bernstam F, Schroff R, Ross J. Biliary cancer: utility of next-generation sequencing for clinical management. Cancer. 2016;122(24):3838– 47. https://doi.org/10.1002/cncr.30254. 23. Javle M, Lowery M, Shroff RT, Weiss KH, Springfeld C, Borad MJ, Ramanathan RK, Goyal L, Sadeghi S, Macarulla T, El-Khoueiry A, Kelley RK, Borbath I, Choo SP, Oh D-Y, Philip PA, Chen L-T, Reungwetwattana T, Van Cutsem E, Yeh K-H, Ciombor K, Finn RS, Patel A, Sen S, Porter D, Isaacs R, Zhu AX, Abou-Alfa GK, Bekaii-Saab T. Phase II study of BGJ398 in patients with FGFRaltered advanced cholangiocarcinoma. J Clin Oncol. 2018;36(3):276–82. https://doi.org/10.1200/jco.2017. 75.5009. 24. Jusakul A, Cutcutache I, Yong CH, Lim JQ, Huang MN, Padmanabhan N, Nellore V, Kongpetch S, Ng AWT, Ng LM, Choo SP, Myint SS, Thanan R, Nagarajan S, Lim WK, Ng CCY, Boot A, Liu M, Ong CK, Rajasegaran V, Lie S, Lim AST, Lim TH, Tan J, Loh JL, McPherson JR, Khuntikeo N, Bhudhisawasdi V, Yongvanit P, Wongkham S, Totoki Y, Nakamura H, Arai Y, Yamasaki S, Chow PK-H, Chung AYF, Ooi LLPJ, Lim KH, Dima S, Duda DG, Popescu I, Broet P, Hsieh S-Y, Yu M-C, Scarpa A, Lai J, Luo D-X, Carvalho AL, Vettore AL, Rhee H, Park YN, Alexandrov LB, Gordân R, Rozen SG, Shibata T, Pairojkul C, Teh BT, Tan P. Wholegenome and Epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Discov. 2017;7(10):1116–35. https://doi.org/10.1158/ 2159-8290.cd-17-0368. 25. Kim RD, Chung V, Alese OB, El-Rayes BF, Li D, Al-Toubah TE, Schell MJ, Zhou JM, Mahipal A, Kim BH, Kim DW. A phase 2 multi-institutional study of Nivolumab for patients with advanced refractory biliary tract cancer. JAMA Oncol. 2020;6(6):1–8. https:// doi.org/10.1001/jamaoncol.2020.0930. 26. Klein O, Kee D, Nagrial A, Markman B, Underhill C, Michael M, Jackett L, Lum C, Behren A, Palmer J, Tebbutt N, Carlino M, Cebon J. Evaluation of combination Nivolumab and Ipilimumab immunotherapy in patients with advanced biliary tract cancers: subgroup analysis of a phase 2 nonrandomized clinical trial. JAMA Oncol. 2020; https://doi.org/10.1001/jamaon col.2020.2814. 27. Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, Falk S, Gillmore R, Wadsley J, Patel K, Anthoney A, Maraveyas A, Waters JS, Hobbs C, Barber S, Ryder D, Ramage J, Davies LM, Bridgewater JA, Valle JW, Group obotABCW. ABC-06|a randomised phase III, multi-centre, open-label study of active symptom control (ASC) alone or ASC with oxaliplatin/5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced/metastatic biliary tract cancers (ABC) previously-treated with cisplatin/gemcitabine (CisGem) chemotherapy. J Clin Oncol. 2019;37(15_suppl):4003. https://doi.org/10. 1200/JCO.2019.37.15_suppl.4003.

322 28. Lee J, Park SH, Chang HM, Kim JS, Choi HJ, Lee MA, Jang JS, Jeung HC, Kang JH, Lee HW, Shin DB, Kang HJ, Sun JM, Park JO, Park YS, Kang WK, Lim HY. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2012;13(2):181–8. https://doi.org/10.1016/ s1470-2045(11)70301-1. 29. Lee H, Wang K, Johnson A, Jones DM, Ali SM, Elvin JA, Yelensky R, Lipson D, Miller VA, Stephens PJ, Javle M, Ross JS. Comprehensive genomic profiling of extrahepatic cholangiocarcinoma reveals a long tail of therapeutic targets. J Clin Pathol. 2016;69(5):403–8. https://doi.org/10.1136/jclinpath-2015-203394. 30. Leone F, Marino D, Cereda S, Filippi R, Belli C, Spadi R, Nasti G, Montano M, Amatu A, Aprile G, Cagnazzo C, Fasola G, Siena S, Ciuffreda L, Reni M, Aglietta M. Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild-type KRAS advanced biliary tract cancer: a randomized phase 2 trial (Vecti-BIL study). Cancer. 2016;122(4):574–81. https://doi.org/10.1002/cncr. 29778. 31. Lowery MA, Burris HA 3rd, Janku F, Shroff RT, Cleary JM, Azad NS, Goyal L, Maher EA, Gore L, Hollebecque A, Beeram M, Trent JC, Jiang L, Fan B, Aguado-Fraile E, Choe S, Wu B, Gliser C, Agresta SV, Pandya SS, Zhu AX, Abou-Alfa GK. Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study. Lancet Gastroenterol Hepatol. 2019;4(9):711–20. https://doi. org/10.1016/s2468-1253(19)30189-x. 32. Malka D, Cervera P, Foulon S, Trarbach T, de la Fouchardiere C, Boucher E, Fartoux L, Faivre S, Blanc JF, Viret F, Assenat E, Seufferlein T, Herrmann T, Grenier J, Hammel P, Dollinger M, Andre T, Hahn P, Heinemann V, Rousseau V, Ducreux M, Pignon JP, Wendum D, Rosmorduc O, Greten TF. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncol. 2014;15(8):819–28. https://doi.org/10.1016/s1470-2045(14)70212-8. 33. Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, Geva R, Gottfried M, Penel N, Hansen AR, Piha-Paul SA, Doi T, Gao B, Chung HC, Lopez-Martin J, Bang YJ, Frommer RS, Shah M, Ghori R, Joe AK, Pruitt SK, Diaz LA Jr. Efficacy of Pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38(1):1– 10. https://doi.org/10.1200/jco.19.02105. 34. Mazzaferro V, El-Rayes BF, Droz Dit Busset M, Cotsoglou C, Harris WP, Damjanov N, Masi G, Rimassa L, Personeni N, Braiteh F, Zagonel V, Papadopoulos KP, Hall T, Wang Y, Schwartz B, Kazakin J, Bhoori S, De Braud F, Shaib WL. Derazantinib (ARQ 087) in advanced or

M. J. Breen et al. inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. Br J Cancer. 2019;120(2):165– 71. https://doi.org/10.1038/s41416-018-0334-0. 35. Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, Hama N, Hosoda F, Urushidate T, Ohashi S, Hiraoka N, Ojima H, Shimada K, Okusaka T, Kosuge T, Miyagawa S, Shibata T. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47(9):1003–10. https://doi.org/10.1038/ng.3375. 36. Neuzillet C, Casadei-Gardini A, Brieau B, Vivaldi C, Brandi G, Tougeron D, Filippi R, Vienot A, Silvestris N, Pointet AL, Lonardi S, Rousseau B, Scartozzi M, Dahan L, Aprile G, Le Sourd S, Evesque L, Meurisse A, Lièvre A, Vernerey D. Fluropyrimidine single agent or doublet chemotherapy as second line treatment in advanced biliary tract cancer. Int J Cancer. 2020; https://doi.org/10.1002/ijc. 33146. 37. Primrose JN, Fox RP, Palmer DH, Malik HZ, Prasad R, Mirza D, Anthony A, Corrie P, Falk S, Finch-Jones M, Wasan H, Ross P, Wall L, Wadsley J, Evans JTR, Stocken D, Praseedom R, Ma YT, Davidson B, Neoptolemos JP, Iveson T, Raftery J, Zhu S, Cunningham D, Garden OJ, Stubbs C, Valle JW, Bridgewater J, Primrose J, Fox R, Morement H, Chan O, Rees C, Ma Y, Hickish T, Falk S, FinchJones M, Pope I, Corrie P, Crosby T, Sothi S, Sharkland K, Adamson D, Wall L, Evans J, Dent J, Hombaiah U, Iwuji C, Anthoney A, Bridgewater J, Cunningham D, Gillmore R, Ross P, Slater S, Wasan H, Waters J, Valle J, Palmer D, Malik H, Neoptolemos J, Faluyi O, Sumpter K, Dernedde U, Maduhusudan S, Cogill G, Archer C, Iveson T, Wadsley J, Darby S, Peterson M, Mukhtar A, Thorpe J, Bateman A, Tsang D, Cummins S, Nolan L, Beaumont E, Prasad R, Mirza D, Stocken D, Praseedom R, Davidson B, Raftery J, Zhu S, Garden J, Stubbs C, Coxon F. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019;20(5):663– 73. https://doi.org/10.1016/s1470-2045(18)30915-x. 38. Ray CE Jr, Edwards A, Smith MT, Leong S, Kondo K, Gipson M, Rochon PJ, Gupta R, Messersmith W, Purcell T, Durham J. Metaanalysis of survival, complications, and imaging response following chemotherapy-based transarterial therapy in patients with unresectable intrahepatic cholangiocarcinoma. J Vasc Interv Radiol. 2013;24(8):1218–26. https://doi. org/10.1016/j.jvir.2013.03.019. 39. Shimonishi T, Isse K, Shibata F, Aburatani I, Tsuneyama K, Sabit H, Harada K, Miyazaki K, Nakanuma Y. Up-regulation of fas ligand at early stages and down-regulation of Fas at progressed stages of intrahepatic cholangiocarcinoma reflect evasion from immune surveillance. Hepatology. 2000;32(4 Pt 1):761–9. https://doi.org/10.1053/jhep.2000.18192. 40. Shroff RT, Javle MM, Xiao L, Kaseb AO, Varadhachary GR, Wolff RA, Raghav KPS,

16

Nonsurgical Management of Cholangiocarcinoma

Iwasaki M, Masci P, Ramanathan RK, Ahn DH, Bekaii-Saab TS, Borad MJ. Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial. JAMA Oncol. 2019a;5(6):824–30. https://doi.org/10.1001/ jamaoncol.2019.0270. 41. Shroff RT, Kennedy EB, Bachini M, Benkaii-Saab T, Craine C, Edeline J, El-Khoueiry A, Feng M, Katz M, Primrose J, Soares H, Valle J, Maithel S. Adjuvant therapy for resected biliary tract cancers: ASCO clinical practice guideline. J Clin Oncol. 2019b;37(12):1015– 27. https://doi.org/10.1200/JCO.18.02178. 42. Subbiah V, Lassen U, Élez E, Italiano A, Curigliano G, Javle M, de Braud F, Prager GW, Greil R, Stein A, Fasolo A, Schellens JHM, Wen PY, Viele K, Boran AD, Gasal E, Burgess P, Ilankumaran P, Wainberg ZA. Dabrafenib plus trametinib in patients with BRAF(V600E)-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol. 2020; https://doi.org/10.1016/ s1470-2045(20)30321-1. 43. Sweeney J, Parikh N, El-Haddad G, Kis B. Ablation of intrahepatic cholangiocarcinoma. Semin Interv Radiol. 2019;36(4):298–302. https://doi.org/10.1055/s-00391696649. 44. Tao R, Krishnan S, Bhosale PR, Javle MM, Aloia TA, Shroff RT, Kaseb AO, Bishop AJ, Swanick CW, Koay EJ, Thames HD, Hong TS, Das P, Crane CH. Ablative radiotherapy doses Lead to a substantial prolongation of survival in patients with inoperable intrahepatic cholangiocarcinoma: a retrospective dose response analysis. J Clin Oncol. 2016;34(3):219–26. https:// doi.org/10.1200/jco.2015.61.3778. 45. Tran B, Meric-Bernstam F, Arkenau HT, Bahleda R, Kelley RK, Hierro C, Ahn D, Zhu A, Javle M, Winkler R, He H, Huang J, Goyal L. Efficacy of TAS-120, an irreversible fibroblast growth factor receptor inhibitor (FGFRi), in patients with cholangiocarcinoma and FGFR pathway alterations previously treated with chemotherapy and other FGFRi’s. Ann Oncol. 2018;29:ix49–50. https://doi.org/10.1093/ annonc/mdy432.007. 46. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273–81. https://doi.org/10.1056/ NEJMoa0908721.

323 47. Valle JW, Wasan H, Lopes A, Backen AC, Palmer DH, Morris K, Duggan M, Cunningham D, Anthoney DA, Corrie P, Madhusudan S, Maraveyas A, Ross PJ, Waters JS, Steward WP, Rees C, Beare S, Dive C, Bridgewater JA. Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial. Lancet Oncol. 2015;16(8):967–78. https:// doi.org/10.1016/s1470-2045(15)00139-4. 48. Waitkus MS, Diplas BH, Yan H. Biological role and therapeutic potential of IDH mutations in cancer. Cancer Cell. 2018;34(2):186–95. https://doi.org/10.1016/j. ccell.2018.04.011. 49. Wang DS, Louie JD, Sze DY. Evidence-based integration of Yttrium-90 Radioembolization in the contemporary Management of Hepatic Metastases from colorectal cancer. Tech Vasc Interv Radiol. 2019;22(2):74–80. https://doi.org/10.1053/j.tvir.2019.02.007. 50. White J, Carolan-Rees G, Dale M, Patrick HE, See TC, Bell JK, Manas DM, Crellin A, Slevin NJ, Sharma RA. Yttrium-90 Transarterial Radioembolization for chemotherapy-refractory intrahepatic cholangiocarcinoma: a prospective, observational study. J Vasc Interv Radiol. 2019;30(8):1185–92. https://doi.org/10. 1016/j.jvir.2019.03.018. 51. Wu YM, Su F, Kalyana-Sundaram S, Khazanov N, Ateeq B, Cao X, Lonigro RJ, Vats P, Wang R, Lin SF, Cheng AJ, Kunju LP, Siddiqui J, Tomlins SA, Wyngaard P, Sadis S, Roychowdhury S, Hussain MH, Feng FY, Zalupski MM, Talpaz M, Pienta KJ, Rhodes DR, Robinson DR, Chinnaiyan AM. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 2013;3(6):636–47. https://doi.org/10.1158/ 2159-8290.Cd-13-0050. 52. Yang L, Shan J, Shan L, Saxena A, Bester L, Morris DL. Trans-arterial embolisation therapies for unresectable intrahepatic cholangiocarcinoma: a systematic review. J Gastrointest Oncol. 2015;6(5):570–88. https://doi.org/ 10.3978/j.issn.2078-6891.2015.055. 53. Ye Y, Zhou L, Xie X, Jiang G, Xie H, Zheng S. Interaction of B7-H1 on intrahepatic cholangiocarcinoma cells with PD-1 on tumor-infiltrating T cells as a mechanism of immune evasion. J Surg Oncol. 2009;100(6):500–4. https://doi.org/10.1002/jso.21376. 54. Zhang SJ, Hu P, Wang N, Shen Q, Sun AX, Kuang M, Qian GJ. Thermal ablation versus repeated hepatic resection for recurrent intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2013;20(11):3596–602. https://doi.org/10.1245/s10434-013-3035-1.

Surgical Treatment of Intrahepatic Cholangiocarcinoma

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Ki-Hun Kim and Jeong-Ik Park

Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 2 Preoperative Evaluation: Resectability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 3 Staging Laparoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 4 Lymphadenectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 5 Resection Margin Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328 6 Recurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 7 Minimally Invasive Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 8 Liver Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330

Abstract

The second most common primary liver cancer is intrahepatic cholangiocarcinoma (iCCA). The only potentially curative treatment for iCCA is surgical resection, although the

K.-H. Kim (*) Division of Hepatobiliary surgery and Liver transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea e-mail: [email protected] J.-I. Park Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea e-mail: [email protected]

majority of patients will present with unresectable, locally advanced, or metastatic disease at diagnosis. The focus of surgical management is margin-negative resection with preservation of an adequate liver remnant volume and function. Extensive liver resection including adjacent involved structures such as the extrahepatic bile duct, major vessels, and diaphragm may be required to achieve negative resection margins. For patients with high-risk features, the routine use of diagnostic laparoscopy with the selective use of laparoscopic ultrasonography is recommended to identify occult metastatic disease. Among the prognostic factors such as lymph node (LN) involvement, tumor size, multicentricity, margin status, tumor differentiation, and vascular invasion, LN metastasis is the most important prognostic

© Springer Nature Switzerland AG 2022 C. Doria, J. N. Rogart (eds.), Hepato-Pancreato-Biliary Malignancies, https://doi.org/10.1007/978-3-030-41683-6_17

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factor for patients undergoing curative-intent resection. Regional lymphadenectomy is recommended at the time of hepatectomy due to the high incidence of LN metastasis and its prognostic relevance. Even in patients who undergo R0 resection, the recurrence rates are high and the long-term survival remains poor. Despite the poor outcomes of liver transplantation for iCCA, liver transplantation may be a therapeutic option for selected patients with early-stage iCCA, especially for patients with an adequate response to neoadjuvant therapy. Keywords

Cholangiocarcinoma · Bile duct · Intrahepatic · Surgery · Resection

1

Introduction

The second most common primary liver cancer is intrahepatic cholangiocarcinoma (iCCA), accounting for 10–15% of primary liver cancer. iCCA arises from the malignant proliferation of epithelial cells located proximal to the second-degree bile ducts, which distinguish it anatomically from the two other types of cholangiocarcinoma (CCA), perihilar CCA (pCCA), which involves the common hepatic duct and its bifurcation, and distal CCA, involving the common bile duct down to its entry into the duodenum. While still much less common than extrahepatic CCA, the incidence of iCCA has been increasing worldwide over the last three decades [1–4]. There are many available locoregional treatment modalities for iCCA patients. Unfortunately, most modalities have limited therapeutic roles due to inherent limitations and the lack of durable tumor response. Therefore, surgical resection remains the mainstay treatment for patients with resectable disease [5]. Surgery offers the only opportunity for longterm survival. Unfortunately, because of the lack of effective screening strategies, as well as delayed disease presentation, approximately

45–55% of patients have unresectable disease at presentation and another 15% have unresectable disease due to tumor multifocality, locally advanced tumors, or metastatic disease, leaving only about 35% of the patients finally eligible for surgical resection [2, 6–8]. Compared to other liver malignancies, iCCA is related to lower resectability and worse survival rates. iCCA lesions are frequently multifocal due to the tendency for high invasiveness, lymph node metastasis, and vascular invasion, which are the main reasons for the poor long-term survival of patients after resection. Therefore, aggressive surgical strategies to achieve margin-negative (R0) resections are necessary for the long-term survival of patients [9]. Even in patients who successfully undergo R0 resection, the recurrence rates are high and longterm survival remains poor. The median survival is only 20–40 months with 5-year survival rates between 14% and 49% [4, 7, 10].

2

Preoperative Evaluation: Resectability

The resectability of iCCA is defined as the ability to achieve R0 resection with preservation of an adequate future liver remnant (FLR), which means two or more contiguous liver segments with adequate arterial and portal inflow, biliary drainage, and venous outflow [5]. The presence of distant metastasis, extensive locoregional disease, underlying medical comorbidities, and estimated function of the post-hepatectomy liver remnant are major determinants of resectability. In general, iCCA is considered unresectable in the presence of bilateral multifocal or multicentric tumors, extrahepatic disease, or the involvement of lymph nodes beyond the regional basin (i.e., celiac and the para-aortic lymph nodes) [2]. However, tumor size, multicentric tumors, and vascular invasion should not be considered absolute contraindications if negative margins can be achieved [11]. The preoperative assessment of both liver quality and FLR volume remaining after resection is

17

Surgical Treatment of Intrahepatic Cholangiocarcinoma

essential for minimizing the risk of posthepatectomy liver failure. For normal livers, the general consensus is that 25–30% remnant is the least essential volume. For patients with underlying hepatic steatosis, the FLR should be at least 30%, and for those with liver cirrhosis, at least 40% is recommended due to the risk of posthepatectomy liver failure [11, 12]. For patients with marginal or inadequate predicted FLR volume and function, portal vein embolization (PVE) and most recently, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) are usually employed to cause hypertrophy of the contralateral lobe and achieve greater FLR volume. The basic principle of PVE involves occluding a branch of the portal venous flow, which subsequently leads to ipsilateral hepatic atrophy and compensatory contralateral hypertrophy [13]. A recent survey conducted at Japanese highvolume centers proposed that PVE should be performed for FLR volume enhancement if the FLR volume is 3 to 6 months (Fig. 4). A meta-analysis of 7 randomized trials comparing metal stents with plastic stents analyzing 724 patients found that metal stents were associated with a significantly lower relative risk of stent occlusion at 4 months (relative risk 0.44; 95% confidence interval (CI), 0.3–0.63; P < 0.01) and recurrent biliary obstruction (relative risk 0.52; 95% CI, 0.39–0.69; P < 0.01). No significant difference in 30-day mortality, complications, or technical therapeutic success was noted [8]. The most important factor to consider while draining CCA is the location of the tumor. Patients with perihilar CCA stenting can be complex and challenging due to severe stenosis affecting the ducts that merge at acute angles. Sangchan et al. [9] randomized patients with perihilar CCA to placement of a single 10-mm X 100-mm SEMS

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Fig. 3 (a) Endoscopic view of the distal end of two plastic stents coming out of the ampulla. (b) Cholangiogram showing appropriate placement of the two biliary plastic stents

and then placement of a 7-Fr or 10-Fr plastic stent. Intention-to-treat analysis revealed that SEMS were superior in terms of rates of successful drainage (70.4% vs. 46.3%, P ¼ 0.011) and median survival (126 vs. 49 days, P ¼ 0.002). Additionally, average patency rates of metal stents are around 10–12 months compared with 3–4 months for plastic stents.

S. Singh et al.

However, limitations of uncovered metal stents use include cost and tumor ingrowth that can lead to obstruction and subsequent cholangitis. Also, because metal stents cannot be adjusted or removed, histological confirmation of malignancy should be obtained before placement. Additionally, despite multiple advantages of metal stents, many endoscopists prefer plastic stents in patients who are receiving repeat endobiliary ablative therapy. For distal malignant biliary obstruction, there was no significant difference in stent patency duration, patient survival, and complication rates for covered SEMS although covered stents were associated with a higher migration rate, whereas uncovered SEMS had higher rate of tumor ingrowth in a randomized, multicenter, nonblinded study [10]. In a meta-analysis involving 1078 patients with distal malignant biliary obstruction, it was shown that covered SEMS did not appear to have higher patency but were associated with higher migration rates [11]. This meta-analysis also showed no significant difference in complication rates including cholecystitis. Another controversial topic regarding biliary drainage is unilateral vs bilateral drainage. Previously it was believed that drainage of around 30% of liver was adequate for palliation of jaundice. With the emergence of highly sensitive imaging such as computerized tomography with pancreatic protocol and magnetic resonance cholangiopancreatography which can be used to quantify viable liver and variations in biliary drainage, it is now believed that at least 50% of the liver should be decompressed. This new approach may require bilateral drainage over unilateral drainage. In patients with Bismuth I tumors, unilateral stenting is usually sufficient; however, endoscopic drainage of hilar tumors often now requires bilateral stenting. Cassani et al. [12] compared the overall survival of patients with CCA based on clinical achievement of biliary decompression. This study included 199 patients with obstructing CCA who underwent a total of 504 procedures. Patients who underwent successful biliary decompression had substantially prolonged overall survival compared with those patients in whom decompression was not achievable (15.2 vs. 4.8 months). Resolution

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Fig. 4 Metal stents for biliary drainage. (a) Cholangiogram showed a common bile duct stricture with proximal biliary dilatation. (b) Fluoroscopic view after placement of

bilateral uncovered self-expanding metal stents (SEMS). (c) Endoscopic view of transpapillary placement of distal ends of the SEMS

of jaundice was also observed more frequently in patients who underwent successful bilateral biliary stent placement than in those who underwent unilateral intervention. Though ERCP is the preferred method for biliary decompression, tumor extension, previous surgery, and severely altered anatomy can lead to unsuccessful biliary cannulation in a minority of cases. Our approach is to try to achieve bilateral drainage, and we usually start with plastic stents while we await final cytology and pathology results. Subsequently our goal is to change to uncovered metal stents during follow-up ERCP in 3 months or so at which time we also consider the option of endoscopic local therapy (discussed below) if the patient is a candidate.

utilized. However, these procedures have their own disadvantages including decreased quality of life due to presence of external drains and increased morbidity and mortality compared to endoscopic procedures. The need to traverse the liver for PTBD carries its own risk which adds to its morbidity. Other adverse outcomes include catheter dislodgement, recurrent infection, acute cholangitis, pneumothorax, and cosmetic problems due to external drainage [13, 14]. First described by Giovanni and colleagues in 2001, EUS-guided guided biliary drainage (EUS-BD) is an upcoming endoscopic modality which has shown promising results to achieve drainage in patients where ERCP has not been successful. Though there have been no head-tohead studies comparing PTBD vs EUS-BD, it is believed that EUS-BD may be superior given the better quality of life achieved due to internal placement of the stent. Kahaleh [15] et al. performed interventional EUS-guided cholangiography and biliary decompression successfully in 21 of 23 patients with failed ERCP, an overall success rate of 91%. Before this technique replaces percutaneous transhepatic cholangiography as the modality of drainage in patients with failed ERCP, further comparative studies are needed. EUS-BD has multiple approaches which are either extrahepatic or intrahepatic [13, 14, 16]. In the extrahepatic approach, the CBD can be accessed through the duodenum or gastric antrum. Biliary drainage is possible by choledochoduodenostomy

3

Endoscopic Ultrasound (EUS)Guided Biliary Drainage

ERCP is the most common technique used for drainage in patients with biliary obstruction secondary to CCA. The reason for this is the high success rate of drainage which is approximately close to 90%. The causes for failure of ERCP include periampullary diverticula, post-surgical anatomy, tumor involvement of the papilla, gastric/duodenal obstruction, and biliary sphincter stenosis [13]. Traditionally in patients who cannot undergo ERCP for drainage, non-endoscopic procedures such as percutaneous transhepatic biliary drainage (PTBD) or surgery have been

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or transpapillary stent placement which can be performed via a technique called rendezvous. In the intrahepatic approach, the left lobe of the liver can be accessed by the gastric wall and less commonly from the esophagus and jejunum. Biliary drainage is possible via the extrahepatic approach via hepaticogastrostomy or transpapillary stent placement via rendezvous technique or anterograde technique. EUS-guided choledocoduodenostomy is performed with the identification of the extrahepatic bile duct from the duodenal bulb. After successful identification of the bile duct, a 19 or 22 G needle is advanced, and a puncture is made which leads to aspiration of bile after which a cholangiogram is obtained after contrast injection. After the guidewire is inserted at the puncture site, a new fistula can be created by precut or catheter balloon dilation. Fluoroscopy can be utilized to confirm absence of any intra-abdominal leakage of contrast. Subsequently a fully covered SEMS can be placed for drainage. Although not FDA approved for biliary drainage, cautery-enhanced lumen-apposing metal stents (LAMS) have also been used for direct biliary drainage and obviates the need for tract dilation. However, smaller caliber sizes are not available in the USA. EUS rendezvous is performed by first positioning the echoendoscope in the stomach or duodenum to visualize the bile ducts. After successful identification of the bile duct, a 19 or 22 G needle is advanced and, a puncture is made which leads to aspiration of bile after which a cholangiogram is obtained after contrast injection to display the intrahepatic and extrahepatic bile ducts. After confirmation of puncture, a guidewire is inserted and advanced across the papilla into the duodenum at which point the EUS scope is removed leaving the guidewire in place. Subsequently a duodenoscope is passed over the previously EUS placed guidewire up to the papilla. A snare can be used to pull back the guidewire out the working channel of the duodenoscope for over the wire cannulation which leads to eventual access to the common bile duct. Now a standard ERCP can be performed with transpapillary stent placement for drainage.

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EUS-guided hepaticogastrostomy approach involves accessing a peripheral branch of the left intrahepatic system using EUS via a transgastric approach. Similar to choledocoduodenostomy and rendezvous, after removal of the needle used to make the puncture, bile is aspirated with subsequent contrast injection to visualize the ducts. Subsequently the tract between the stomach and left intrahepatic system can be dilated using an ERCP cannula, cystotome, bougie, or dilating balloon with eventual self-expandable metal stent placement. Though EUS-BD techniques have a published success rate of over 70%, there is no consensus about the best EUS-BD technique, and it is currently not standard of care. There have been multiple studies comparing hepaticogastrostomy and choledocoduodenostomy approaches with no difference in effectiveness or safety between the two procedures [17, 18]. In regard to EUS-BD vs PTBD, Sharaiha [19] and colleagues conducted a systematic review and meta-analysis to compare the efficacy and safety of EUS-BD vs PTBD analyzing 9 studies with 483 patients. Even though there was no difference in technical success between the two procedures, EUS-BD was associated with better clinical success, lower rate of reintervention, and fewer postprocedure adverse events. It is important to note that these procedures were performed at expert centers and reported complications included lifethreatening peritonitis, bile leaks, and perforation. Further studies are needed to determine the role for EUS-guided biliary drainage and the optimal techniques and tools needed to minimize adverse events while optimizing outcomes.

4

ERCP-Directed Photodynamic Therapy (PDT)

Photodynamic therapy (PDT) involves systemic delivery of a photosensitizing agent which concentrates inside target tumor cells and is then activated by exposure to light at a specific wavelength (Fig. 5). The subsequent generation of oxygen free radicals leads to apoptosis of tumor cells via various mechanisms. It is also believed to

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Endoscopic Palliative Management of Cholangiocarcinoma

Fig. 5 PDT laser through cholangioscope in a malignant stricture

have antiangiogenic effects which lead to hypoxia and ischemic death of tumor cells [20]. PDT was first approved by the FDA in 1995 for the treatment of endobronchial non-small cell lung cancer, Barrett’s esophagus with high-grade dysplasia, and esophageal cancer, and although it is off-label use, it is now widely used for palliation in patients with unresectable CCA. Many photosensitizing agents have been used for PDT; however, the most commonly used photosensitizer in the USA is porfimer sodium (Photofrin, Pinnacle Biologics, IL, USA) [21]. Other available photosensitizers include hematoporphyrin oligomers (Photosan which was developed by SeeLab, in Wesselburenerkoog, Germany), meta tetra hydroxyphenyl chlorin (Foscan, Biolitec Pharma, Dublin, Ireland), meso-tetra hydroxyphenyl chlorin (Temoporfin, Biolitec Pharma, Dublin, Ireland). Porfimer sodium is administered intravenously at a dose of 2 mg/kg of body weight, and it is avidly absorbed by the malignant biliary epithelial cells. Approximately 48–72 hours after administration of the photosensitizer, ERCP is performed and photoactivation is achieved via a laser light which is delivered by an endoscopically placed fiber which can be delivered under fluoroscopic guidance or directly placed at the tumor site

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through a cholangioscope (Fig. 5). The benefit of this therapy is that the laser fiber does not need direct contact within a malignant stricture since the laser light travels through bile and activates the drug within the biliary tree. This may be especially useful in tight or multifocal strictures. The diode laser system delivers light with a wavelength of 630 nm with a light dose of 180–200 J/cm2 for treatment of 750 seconds which completes one treatment, followed by stent placement [21]. Multiple sessions of PDT can be performed with stent changes every 3 months with limited data on improved outcomes. PDT through SEMS has been reported, but these cause significant light absorption with transmittance ranging from 40% to 50%, which requires repeated adjustment of PDT dosing. In the first randomized controlled trial involving 39 patients with unresectable CCA, Ortner et al. [20] showed that patients who received unilateral or bilateral PDT with stenting had significantly prolonged survival (median 493 vs. 98 d, P < 0.0001) and improved biliary drainage and quality of life compared with those who received only stenting without PDT. Also of note, 70% of patients received more than one treatment with a mean number of sessions of approximately 2.4. In a meta-analysis of 6 studies including 170 patients by Legget and associates [22], PDT followed by biliary stenting was associated with increased length of survival (265 days) and reduced risk of death compared to stenting alone. Another study involving 7 centers in Austria used poly hematoporphyrin as the photosensitizer which was activated during ERCP or percutaneous transhepatic biliary drainage (PTBD) in 88 patients with 79 of them with Bismuth IV CCA. On multivariate analysis, the number of PDT treatment sessions was the only independent predictor of survival [23]. A study by Gonzalez-Carmona et al. [24] in 2019 studied the role adjunct of PDT and chemotherapy on survival. Out of 353 patients with CCA in this study, 96 had unresectable extrahepatic CCA and were stratified according to type of treatment which included combination of PDT and chemotherapy (36 patients), PDT only

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(34 patients), and chemotherapy only (26 patients). Patients in the combination arm had a median survival of 20 months, 15 months in PDT alone, and 10 months in chemotherapy alone group. In multivariate analysis, combination therapy and photodynamic therapy alone (HR: 0.41, 95% CI: 0.22–0.77, P ¼ 0.006), metal stenting, and radiofrequency ablation were independent predictors of longer survival. Besides this study, there have been multiple other studies that showed an improved overall survival in chemotherapy plus PDT vs PDT alone [25–27]. Another meta-analysis by Lu and colleagues [28] showed similar results where patients with PDT plus stenting showed a statistically significant improvement in survival compared to biliary stenting alone. Of the eight trials included in their study, half also assessed the effect of PDT on bilirubin levels with two showing a statistically significant decrease in serum bilirubin levels, whereas the other two trials showed only a trend toward a significant decrease. Besides survival and decrease in serum bilirubin levels, there is also evidence that PDT may improve patency of metal stents. Lee and colleagues [29] did a retrospective analysis where 18 patients were treated with PDT followed by use of uncovered metal stents vs 15 patients with uncovered metal stents alone. The PDT group was found to have statistically significant longer stent patency compared with the stent only group (median 244 vs. 177 days). No studies have shown successful use of PDT as a neoadjuvant therapy. Wagner and colleagues [30] studied the neoadjuvant use of PDT followed by surgical resection within 30–72 days after PDT in seven patients. When compared with a similar cohort of 35 patients who underwent surgical resection without prior PDT, no difference in overall survival was found. The most common side effect of PDT is skin photosensitivity including pruritus, diffuse pain, skin erythema, and even blistering. Due to the risk of severe cutaneous side effects and skin photosensitization, patients who receive PDT are advised to avoid direct or indirect sunlight for 4 to 6 weeks which is something that should be factored into decision-making before starting

S. Singh et al.

therapy due to the poor quality of life. There has been some promising data with the use of secondgeneration photosensitizers, metatetra and temoporfin, to minimize light toxicity [31]. Cost of care is another major consideration when PDT is used in practice especially when compared to RFA. The current fiber-optic laser diffuser costs approximately 85 USD, and in 2017, the average cost of a single vial of porfimer sodium was approximately $24,500 USD with each patient requiring an average of two vials for each session [21]. However, despite the high cost, Medicare and most private insurance companies have continued to cover the cost. Despite numerous studies showing promising data about stent patency and even survival, the financial considerations and photosensitivity related to PDT have resulted in limited use of this technique. There are still many questions that need to be addressed before PDT is ready for routine use in palliation of cholangiocarcinoma, but when feasible, PDT should be discussed with unresectable CCA patients.

5

ERCP-Guided Radiofrequency Ablation (RFA)

Radiofrequency ablation (RFA) of biliary neoplasms involves passage of RFA catheters over a wire directly into the malignant stricture to apply high-frequency alternating current to the tumor with leads to generation of thermal energy and causes local necrosis and destruction of neoplastic tissue (Fig. 6). It has also been suggested that RFA might induce indirect antitumoral effects such as T cell activation or stimulation of localized inflammatory response in addition to direct thermal energy effects [21]. RFA has been used to treat various cancers including primary and secondary liver cancers for over 20 years. Initially percutaneous RFA was being utilized for treatment of hilar CCA; however, given the technical difficulty to reach hilar tumors percutaneously, an 8 Fr bipolar RFA catheter that could be deployed over a guidewire during ERCP was approved by the FDA in 2009. RFA is performed with a therapeutic duodenoscope and

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Endoscopic Palliative Management of Cholangiocarcinoma

Fig. 6 RFA probe in metal stent obstruction

requires a prior biliary sphincterotomy. The RFA catheter is passed over a guidewire within the biliary system via fluoroscopic guidance and requires direct tissue contact to result in tissue destruction (Fig. 6). There are currently two catheters available for biliary RFA [1, 21]. The Habib EndoHPB (Boston Scientific, Marlborough, Massachusetts, USA) is an 8Fr, 1.8-m-long catheter with two bipolar electrodes spaced 8 mm apart with a heating zone or ablative field that is 25 mm in length. The catheter can be powered by commonly available electrosurgical units that can deliver 7 or 10 watts of energy for 120 seconds. The ELRA endobiliary RFA catheter (TaeWoong Medical, South Korea) is 7 Fr, 1.75 m long with multiple bipolar electrodes that span a length of either 18 mm or 33 mm. Unlike the Habib EndoHPB catheter, this electrode must be connected to a proprietary electrosurgical unit made by the same manufacturer. Similar to ERCP-guided photodynamic therapy, biliary stenting is indicated after RFA to maintain biliary patency. Plastic stents should be used if future RFA sessions are anticipated or metal stents if only a single RFA session is planned. Steel and associates [32] were the first to report data on ERCP-directed RFA using the Habib EndoHPB followed by SEMS placement in 22 patients (16 pancreatic ca and 6 CCA) with good 30-day safety and 90-day patency rates. RFA was delivered in 21 of these patients and all but 1 had successful biliary decompression that persisted to 30 days; 16 patients maintained biliary patency at 90 days.

341

Since then, several studies have had positive results when evaluating the safety and efficacy of RFA on biliary stent patency and overall patient survival. One of the most instrumental studies supporting RFA use was a randomized control trial by Yang and colleagues [33] with 65 patients with unresectable extrahepatic cholangiocarcinoma who underwent RFA combined with biliary stenting (n ¼ 32) vs biliary stenting alone (n ¼ 33). Over the next 21 months, the mean survival time was significantly longer in the RFA + stent group vs biliary stenting alone (13.2 months vs. 8.3 months). In addition, the stent patency of RFA plus stent group was significantly longer vs stent only group (6.8 vs. 3.4 months). Sofi and colleagues [34] analyzed 9 studies including 505 patients finding that the difference in stent patency when using RFA was approximately 50 days compared to biliary stent placement without RFA. Further analysis also showed that RFA may be associated with improved survival. Another meta-analysis by Zheng [35] and colleagues included 263 patients who underwent endoscopically delivered RFA for malignant biliary obstruction secondary to CCA (65.8%), pancreatic cancer, metastatic cancer, or others. According to this study, RFA led to a significant improvement in bile duct diameter at the site of the stricture, with an average increase from 1.189 mm before the procedure to 4.635 mm after the procedure, indicating an average increase of 3.446 mm owing to RFA. When assessing stent patency, they found the median duration of post-RFA stent patency was 7.6 months (95% CI, 6.9–8.4 months). This study also demonstrated that the 30-day, 90-day, and 2-year mortality were 2% (95% CI, 0.5– 5.9%), 21% (95% CI, 5–37%), and 48% (95% CI, 37–59%), respectively. Though RFA has shown promising results in biliary stent patency and patient survival, it is important to note initial reports that included life-threatening complications. In a retrospective series from Austria, 58 patients underwent 84 RFA procedures for malignant biliary obstruction secondary to biliary or pancreatic cancers [36]. RFA-related complications included five cases of cholangitis, three cases

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of hemobilia, two cases of cholangiosepsis, and one case each of gallbladder empyema and hepatic coma. In a smaller study by Tal and colleagues [37] where RFA was used for malignant hilar strictures in 12 patients, 3 patients developed hemobilia 4–6 weeks post-RFA (2 died of hemorrhagic shock), whereas 4 patients developed recurrent cholangitis. Given the close proximity of the common hepatic duct to the hepatic artery branches, there is a possibility of pseudoaneurysm as a complication which can lead to hemobilia. To prevent this complication, it is advisable to use a lower setting of 7 W when treating perihilar and intrahepatic strictures, whereas a setting of 10 W may be used to treat extrahepatic biliary strictures. In addition to hemobilia, perforation is a worrisome complication which is why when ERCP-directed RFA is applied to the distal CBD, it is recommended to cease ablation if the duodenal wall takes on a whitish ablated look due to thermal injury. In addition, cholecystitis has also been reported with an incidence of approximately around 10%. Despite the emerging data showing positive effects in terms of stent patency and now survival as well, there are multiple concerns and uncertainties before RFA becomes standard of care for unresectable cholangiocarcinoma. The exact mechanism of action of RFA is still unclear, and how to incorporate it into current treatment algorithms and current chemotherapy protocols still needs to be established. Another topic that requires further work is to figure out how many sessions, timing, and the type of stents which will provide the most benefit. The approach to extrahepatic distal/mid bile duct cholangiocarcinomas will be different than hilar tumors especially those involving both sides of the biliary tree. Quantification of response and adjustment of energy dose based on the response also needs to be established. The role of intraductal ultrasound and cholangioscopy in assessing posttreatment changes is still evolving. Nevertheless, radiofrequency ablation has shown encouraging results and is easy to use with less equipment requirements compared to PDT and localized brachytherapy.

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6

PDT Versus RFA

ERCP-directed PDT and RFA are promising palliative therapies for unresectable CCA; however, not much has been reported comparing the two modalities. PDT is typically used for multifocal CCAs (Bismuth III, IV), whereas RFA is more effective for more distal lesions (Bismuth I, II) or pancreatic cancer. As mentioned earlier in the chapter, both have shown to improve duct patency; however, both have their own advantages. The benefit of RFA is that it can also open occluded metal stents (Fig. 6) via necrosis using direct contact. PDT on the other hand does not require direct contact and utilizes an immunological effect to downsize the tumor. Comparing logistics, RFA is less expensive and easier to use, whereas PDT requires coordination of multiple resources and more expensive given the increased cost of the laser and Photofrin. In addition, RFA is FDA approved, whereas PDT is used an off-label therapy in cholangiocarcinoma. Strand and colleagues [38] were the only group to retrospectively compare overall survival in 48 patients who underwent RFA (n ¼ 16) versus PDT (n ¼ 32). The location of the tumor was predominantly perihilar in both groups though the patients in the PDT group had more advanced disease with perihilar CCAs. Though the RFA group had a lower mean number of plastic stents placed per month (0.45 vs. 1.10, P ¼ 0.001), both groups had similar survival (9 months for RFA vs. 8 months for PDT). In addition, patient who received ERCP-directed RFA had more episodes of stent occlusion and cholangitis per month compared with those who received PDT.

7

ERCP-Guided Brachytherapy or Intraluminal Brachytherapy (ILBT)

ERCP-guided radiation therapy has also shown some promise combining the expertise of therapeutic endoscopy and radiation oncology. ERCPdirected brachytherapy was first reported in 2006 as a part of neoadjuvant treatment protocol before liver transplantation [39]. Initially the use of

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Endoscopic Palliative Management of Cholangiocarcinoma

brachytherapy was low-dose rate (LDR) which is under 90% are benign and present in young to middle-aged subjects. • Incidence in women is double than that of men. • Usually asymptomatic and discovered incidentally. – Traumatic neuroma • Typically manifest more than 2 years from the initial insult. • Median time to diagnosis is 5 years. • Most patients typically undergo surgical intervention as malignancy cannot be definitively excluded. – Intraductal papillary neoplasia of the bile duct • Previously termed cystadenoma/cystadenocarcinomas with bile duct communication • Disease spectrum ranging from benign to malignant • Long-term survival achieved with complete resection – Paraganglioma • Found almost exclusively in the periampullary region. • Preoperative pathologic diagnosis difficult based on endoscopic biopsy alone given the submucosal nature.

E. V. Campbell III and P. Jamidar

• No death secondary to this tumor has been reported. • Best managed by resection. • Malignant – Cystadenocarcinoma • Much more common in females. • Prognosis is excellent after complete surgical resection. – Embryonal rhabdomyosarcoma • Biliary tree rhabdomyosarcoma with central tumor necrosis can mimic the appearance of a choledochal cyst. • Surgical management determined by tumor location and extent. • Resection of tumor following neoadjuvant chemotherapy has been associated with good outcomes. – Diffuse large B cell lymphoma • Median age of diagnosis is 64 with a slight predominance in Caucasian males. • Given the aggressive nature of DLBCL, chemotherapy is typically given, even in the case of an R0 resection. – Melanoma • Common age of diagnosis is 40–50 years of age. • Treatment based on presence or absence of metastases. – Carcinoid • Female to male ratio 1.5:1. • Most common anatomic location was CBD, followed by perihilar region and CHD. • Type of surgical resection based on location. – Paraganglioma • Found almost exclusively in the periampullary region. • Preoperative pathologic diagnosis difficult based on endoscopic biopsy alone given the submucosal nature. – Squamous cell carcinoma • Male-to-female ratio 16:9 • Mortality rate of up to 64%

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Rare Tumors of the Bile Ducts

References 1. Lee S, Kim KW, Jeong WK, Yu E, Jang KT. Magnetic resonance imaging findings of biliary Adenofibroma. Korean J Gastroenterol. 2019;74(6):356–61. 2. Kaminsky P, Preiss J, Sasatomi E, Gerber DA. Biliary adenofibroma: a rare hepatic lesion with malignant features. Hepatology. 2017;65(1):380–3. 3. Chen L, Xu MY, Chen F. Bile duct adenoma: a case report and literature review. World J Surg Oncol. 2014;12:125. 4. Hasebe T, Sakamoto M, Mukai K, Kawano N, Konishi M, Ryu M, et al. Cholangiocarcinoma arising in bile duct adenoma with focal area of bile duct hamartoma. Virchows Arch. 1995;426(2):209–13. 5. Xu LM, Hu DM, Tang W, Wei SH, Chen W, Chen GQ. Adenomyoma of the distal common bile duct demonstrated by endoscopic ultrasound: a case report and review of the literature. World J Clin Cases. 2019;7 (21):3615–21. 6. Kumari N, Vij M. Adenomyoma of ampulla: a rare cause of obstructive jaundice. J Surg Case Rep. 2011;2011(8):6. 7. Zaharie R, Mois E, Al Hajjar N, Zdrehus C, Rusu I, Zaharie F. A rare case of ciliated foregut cyst of the common hepatic duct. J Gastrointestin Liver Dis. 2019;28(3):264. 8. Bishop KC, Perrino CM, Ruzinova MB, Brunt EM. Ciliated hepatic foregut cyst: a report of 6 cases and a review of the English literature. Diagn Pathol. 2015;10:81. 9. Ahmad Z, Uddin N, Memon W, Abdul-Ghafar J, Ahmed A. Intrahepatic biliary cystadenoma mimicking hydatid cyst of liver: a clinicopathologic study of six cases. J Med Case Rep. 2017;11(1):317. 10. Quinn PL, Abdelfatah E, Galan MA, Ahlawat SK, Chokshi RJ. Malignant granular cell tumor of the bile duct. ACG Case Rep J. 2019;6(8):e00193. 11. te Boekhorst DS, Gerhards MF, van Gulik TM, Gouma DJ. Granular cell tumor at the hepatic duct confluence mimicking Klatskin tumor. A report of two cases and a review of the literature. Dig Surg. 2000;17(3):299–303. 12. Chung EB. Multiple bile-duct hamartomas. Cancer. 1970;26(2):287–96. 13. Elsoueidi R, Mularz SJ, Richa EM. Bile duct hamartoma mimicking metastatic cholangiocarcinoma. J Gastrointest Cancer. 2017;48(1):87–8. 14. Yang XY, Zhang HB, Wu B, Li AJ, Fu XH. Surgery is the preferred treatment for bile duct hamartomas. Mol Clin Oncol. 2017;7(4):649–53. 15. Panda N, Brackett D, Eymard C, Kawai T, Markmann J, Kotton CN, et al. Liver transplantation for recurrent cholangitis from Von Meyenburg complexes. Transplant Direct. 2019;5(3):e428.

361 16. Fenoglio L, Severini S, Cena P, Migliore E, Bracco C, Pomero F, et al. Common bile duct schwannoma: a case report and review of literature. World J Gastroenterol. 2007;13(8):1275–8. 17. Lalchandani P, Korn A, Lu JG, French SW, Hou L, Chen KT. Traumatic bile duct neuroma presenting with acute cholangitis: a case report and review of literature. Ann Hepatobiliary Pancreat Surg. 2019;23(3):282–5. 18. Wu CH, Chiu NC, Yeh YC, Kuo Y, Yu SS, Weng CY, et al. Uncommon liver tumors: case report and literature review. Medicine (Baltimore). 2016;95(39):e4952. 19. Raney RB, Maurer HM, Anderson JR, Andrassy RJ, Donaldson SS, Qualman SJ, et al. The intergroup rhabdomyosarcoma study group (IRSG): major lessons from the IRS-I through IRS-IV studies as background for the current IRS-V treatment protocols. Sarcoma. 2001;5(1):9–15. 20. Kinariwala DJ, Wang AY, Melmer PD, McCullough WP. Embryonal rhabdomyosarcoma of the biliary tree: a rare cause of obstructive jaundice in children which can mimic choledochal cysts. Ind J Radiol Imaging. 2017;27(3):306–9. 21. Wong DL, Deschner BW, King LC, Glazer ES. Primary diffuse large B cell lymphoma of the common bile duct. J Gastrointest Surg. 2020; 22. Zakaria A, Al-Obeidi S, Daradkeh S. Primary non-Hodgkin’s lymphoma of the common bile duct: a case report and literature review. Asian J Surg. 2017;40(1): 81–7. 23. Ito Y, Miyauchi M, Nakamura T, Takahara N, Nakai Y, Taoka K, et al. Significance of biopsy with ERCP for diagnosis of bile duct invasion of DLBCL. Int J Hematol. 2019;110(3):381–4. 24. Dote H, Ohta K, Nishimura R, Teramoto N, Asagi A, Nadano S, et al. Primary extranodal non-Hodgkin’s lymphoma of the common bile duct manifesting as obstructive jaundice: report of a case. Surg Today. 2009;39(5):448–51. 25. Addepally NS, Klair JS, Lai K, Aduli F, Girotra M. Primary bile duct melanoma causing obstructive jaundice. ACG Case Rep J. 2016;3(4):e128. 26. Yasuda T, Imai G, Takemoto M, Yamasaki M, Ishikawa H, Kitano M, et al. Carcinoid tumor of the extrahepatic bile duct: report of a case. Clin J Gastroenterol. 2013;6(2):177–87. 27. Colle E, Zouhry I, Colignon N, Mourra N. Paraampullary gangliocytic paraganglioma. Clin Res Hepatol Gastroenterol. 2018;42(4):291–3. 28. Kwon J, Lee SE, Kang MJ, Jang JY, Kim SW. A case of gangliocytic paraganglioma in the ampulla of Vater. World J Surg Oncol. 2010;8:42. 29. Kang M, Kim NR, Chung DH, Cho HY, Park YH. Squamous cell carcinoma of the extrahepatic common hepatic duct. J Pathol Transl Med. 2019;53(2): 112–8.

Part III Gallbladder Cancer

Diagnosis and Evaluation of Gallbladder Cancer

20

Unal Aydin

Contents 1 Epidemiology and Etiological Factors of Gallbladder Cancer . . . . . . . . . . . . . . . . . 365 2 Diagnosis and Staging of Gallbladder Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367 3 Surgical Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368 4 Extensive Lymphadenectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368 5 Oncologic Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369 6 Timing of Margin-Clearing Surgery for Incidental Gallbladder Cancer . . . . . 370 7 Port Site Resection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370

Abstract

Keywords

Gallbladder cancer is a malignancy of the biliary tract which is not frequent in welldeveloped countries but common in developing countries. Late diagnosis and poor prognosis are the main problems for the treatment of gallbladder carcinoma (GBC). The absence of a serosal shield of the gallbladder neighboring to the liver can enable hepatic invasion, and metastatic progression is one of the major causes of its low survival [1].

Gallbladder · Cancer · Surgery · Oncology

U. Aydin (*) Professor of Surgery; Private Clinician, Hepatopancreatobiliary Surgery, Izmir, Turkey e-mail: [email protected]

1

Epidemiology and Etiological Factors of Gallbladder Cancer

Although the worldwide occurrence of gallbladder cancer is less than 2/100000 individuals, this has been recorded with extensive variance changing from geographic regions [2]. Although gallbladder cancer is more common in females, still in some countries like Korea, Iceland, and Costa Rica, higher mortality rate has been reported for males compared to female individuals [3]. GBC occurs mainly after the age of 60 in both sexes [4]. The development of gallbladder cancer has been linked to various genetic and environmental associating actors. Chronic infection of the

© Springer Nature Switzerland AG 2022 C. Doria, J. N. Rogart (eds.), Hepato-Pancreato-Biliary Malignancies, https://doi.org/10.1007/978-3-030-41683-6_22

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gallbladder and environmental exposure to specific chemicals, heavy metals, and even many dietary factors have been found to be associated with GBC formation. The dramatic association of GBC with female gender and certain geographical regions (mostly developing countries) has been proposed to be influenced by various female hormones, cholesterol metabolism, and salmonella infections in current literature [3, 5]. Considering the fact that GBC increases with age, like many other cancer diseases, one of the reasons for this phenomenon may be due to increasing proportion of aged population. Gallbladder cancer occurs two to six times more often in women than men in most countries; therefore, sex is a recognized risk factor for gallbladder cancer. This may suggest a role of female sex hormones. Estrogen increases biliary cholesterol saturation and decreases bile salt secretion; meanwhile, progesterone worsens gallbladder emptying to promote the development of gallstones, which is the most important risk factor for gallbladder cancer. Obese individuals have an increased risk of developing gallbladder cancer. Overweight and obesity were associated with 14 and 56% higher risk of gallbladder cancer. The association between obesity and risk of gallbladder cancer is stronger in women than in men, and overweight is only associated with gallbladder cancer in women. Obesityrelated mediators such as insulin-like growth factor (IGF)-1, adipokines, inflammatory factors, and pro-inflammatory cytokines may trigger cancerrelated steps. Leptin and adiponectin secreted by adipose tissue are also important factors in carcinogenesis. Gallbladder cancer has also been associated with multiple familial polyposis/Gardner syndrome and Peutz-Jeghers syndrome. Multiple genetic mutations are likely involved in the pathogenesis of gallbladder cancer. The early molecular changes may include p53 mutation, cyclooxygenase-2 overexpression, mitochondrial DNA mutations, and abnormal hypermethylation of various tumor suppressor gene promoters. Among patients with gallbladder cancer, 70–90% have a history of gallstones. Furthermore, the incidence of gallbladder cancers is

U. Aydin

well correlated with the prevalence of gallstone disease. However, compared to the high prevalence of gallstones, gallbladder cancer occurs in less than 1% of patients with gallstones; therefore, gallstones alone cannot be considered a single cause of gallbladder cancer. Although most gallbladder polyps are benign, malignant polyps are present in some cases. Polyp size is the most important risk factor for malignancy, with gallbladder polyps larger than 10 mm significant predictors of malignancy, while most polyps less than 10 mm are benign and remain static for long periods. Other factors predicting malignancy include solitary sessile polyps, presence of gallstones, patient age over 50 years, and, most importantly, rapid polyp growth. The development of gallbladder cancer has been linked to various genetic and environmental associating actors. Chronic infection of the gallbladder and environmental exposure to specific chemicals, heavy metals, and even many dietary factors have been found to be associated with GBC formation. The dramatic association of GBC with female gender and certain geographical regions (mostly developing countries) has been proposed to be influenced by various female hormones, cholesterol metabolism, and salmonella infections in current literature. Other well-known GBC-associated risk factors such as porcelain gallbladder, Mirizzi’s syndrome, and bile reflux also play a major role as predisposing factors of this disease [6]. Family history of gallstones, tobacco consumption, chemical exposure and high concentrations of secondary bile acids, and excessive intake of fried foods (reused oil) increase the risk for GBC [7]. Convincing evidence also exists for the presence of gallstones as strongly associated factor for gallbladder cancer etiology [8]. Most of the etiological factors are summarized in Table 1. The Swedish Family-Cancer Database and Utah Cancer Registry have reported the first data on familial clustering of GBC [9], in which it was estimated that 26% of gallbladder cancers are familial. The significant risk in third-degree relatives and the disease manifestation in several high-risk pedigrees as reported in previous studies

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Diagnosis and Evaluation of Gallbladder Cancer

Table 1 Risk Factors Major risk Old age Female sex Cholelithiasis Family history Chronic cholecystitis Porcelain gallbladder Salmonella infections H. pylori presence Pancreatobiliary duct v. High BMI

Dependent factors Tobacco consumption Mustard oil Argan oil Early age pregnancy Benzene exposure Red chili pepper Other dietary

give a strong indication for genetic susceptibility to GBC. The high-risk heritable factors are likely to contribute to a large extent to this cancer further modulated by environmental factors. The nationwide Swedish Family-Cancer Database from the Swedish Cancer Registry (10.2 million individuals from the years 1961 to 1998) has reported maternal transmission favoring over paternal in familial gallbladder cancers [10]. Furthermore, the clustering of gallbladder cancer within families plays a critical role of genetics in its development. Gallbladder carcinoma develops through a series of events before growing into invasive malignancy. Any exposure to carcinogens may cause the normal gallbladder epithelium to develop metaplasia which subsequently forms dysplasia to carcinoma in situ (CIS) and finally proceeds to invasive carcinoma in about 15 years [11]. The multistage pathogenesis of gallbladder carcinoma begins with gallstones giving rise to a condition called chronic cholecystitis, which increases to risk to gallbladder cancer formation. More than 90% of patients with gallbladder carcinoma show dysplasia and CIS [12]. There is an unusual asymmetric thickening of the gallbladder wall with infiltration to surrounding structures in gallbladder cancer. Maximum cases reported in carcinomas of gallbladder are adenocarcinomas (80–95%). Adenocarcinomas can further be of papillary, tubular, mucinous, or signet cell type. Some other types which are present in very low frequency include squamous cell carcinoma (16%),

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undifferentiated or anaplastic carcinoma (2–7%), and adenosquamous carcinoma (1–4%). Most of GBCs (60%) are found in the fundus, near about 30% in the body, and 10% in the neck region.

2

Diagnosis and Staging of Gallbladder Cancer

The symptoms and signs of gallbladder cancer are vague, and most gallbladder cancers are diagnosed during or after cholecystectomy performed for other indications [13–15]. Weight loss and jaundice, when present, generally indicate advanced disease with a low likelihood of longterm survival. Gallbladder polyps are a common finding on abdominal ultrasound, with the overwhelming majority being benign and, in general, safe to be followed with serial ultrasound exams. Larger polyps (>1 cm) are more likely to be neoplastic; however, the overall invasive cancer rate is 90%) and lowest for peritoneal metastases. Gallbladder cancers frequently metastasize to regional lymph nodes, with up to 33% of patients with T2 tumors and up to 60% of patients with T3 tumors harboring nodal metastases [15]. It has long been recognized that periaortic and aortocaval nodes portend a similar prognosis as distant metastatic disease. Further, “skip” metastases (e.g., retropancreatic nodal metastases without hepatoduodenal ligament node metastases) are found in 3–5% of patients.

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Surgical Treatment

The gallbladder lacks a peritoneal covering on its hepatic-facing side. Instead, the boundary between the gallbladder and liver is the cystic plate, which is a continuation of Glisson’s capsule. For this reason, gallbladder cancers that invade the muscularis (i.e., T1b–T2) have a propensity to invade the liver. Up to 33% of patients with T2 tumors have micrometastases in the adjacent liver parenchyma. It is for this reason that simple cholecystectomy, performed for benign disease, is inadequate for all but the earliest-stage (i.e., T1a) gallbladder cancers. Simple cholecystectomy involves dissection between the gallbladder muscularis and the cystic plate. This approach is not optimal for patients with T2–T4 tumors as it risks leaving residual disease. Moreover, simple cholecystectomy typically does not include removal of cystic duct lymph nodes, and as a result, nodal staging is inadequate with this procedure. Radical (extended or margin-clearing) cholecystectomy removes the gallbladder with a margin of normal liver tissue and includes regional lymphadenectomy. This procedure is used to improve staging and decrease the risk of recurrence. In addition to liver resection, adequate lymphadenectomy of the porta hepatis should be performed with the goal of assessing six or more regional nodes. The degree of hepatic resection should be tailored based on the anatomic location of the primary gallbladder tumor. Experts agree that at a minimum the liver surrounding the gallbladder fossa in segments 4b/5 should be resected for optimal margin clearance [17]. Given the proximity of the gallbladder infundibulum to the porta hepatis and liver inflow structures (particularly the right hepatic artery, right portal vein, and right and common bile duct), tumors near the right portal structures may require more extensive hepatectomy, at times a formal right hemi-hepatectomy or right trisegmentectomy, for margin clearance. More advanced (T3–T4) tumors may involve the stomach, right colon, and/or duodenum as well as the liver. In these cases, en bloc resection of the involved organs with gastrectomy, colectomy, duodenal resection, or pancreatoduodenectomy may be required to achieve clear margins.

Five-year survival for patients with lymph node metastases is 10–25% in most Western series. These rates are lower than those reported in Japanese and Korean series, and the reasons underlying this survival difference are currently unknown [17, 18]. Given the prognostic significance of lymph node metastases, lymphadenectomy is valuable for staging. Several groups have shown that nodal metastases are more commonly encountered when at least three lymph nodes are retrieved, while more recent data suggest four nodes may be adequate for staging. Furthermore, patients staged as N0 based on the retrieval of at least six lymph nodes showed improved 5-year disease-specific survival vs. those staged as N0 based on fewer nodes (72% vs. 45%, P < 0.01). These data highlight the importance of retrieving between four and seven nodes, and ideally at least six nodes, for adequate staging [18, 19].

4

Extensive Lymphadenectomy

Peritumoral lymph nodes are classified in Fig. 1. The number of nodes resected is important in accurate evaluation of nodal metastasis. Some studies have indicated that six or more nodes should be resected. Kishi and colleagues presented in their series that medians of 5 and 12–18 nodes were resected in 145 node-negative and 114 node-positive patients, respectively. Six or more nodes were sampled in 68 and 99 patients, respectively, and therefore, accurate staging, particularly of node-positive patients, was found to be feasible in their series. Even though the numbers rather than the sites of nodal metastasis impact on prognosis, sites are important in defining the regional lymph nodes and standardizing the extent to which they should be dissected or sampled routinely. They demonstrated no difference in survival between patients with Na M0 and Nb M0 disease, whereas there was a difference in patients with Nb M0 and Nc M0 disease. The superior mesenteric artery routine dissection remains unclear because of the small number of patients in the Nc group in their series. However, the present results showed that nodal metastases beyond regions A and B

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Diagnosis and Evaluation of Gallbladder Cancer

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Fig. 1 1 Regional lymph nodes defined by the AJCC (region A), Japanese Society of Hepato-Biliary-Pancreatic Surgery (regions A and B), and UICC (regions A, B, and C) modified from the diagram as demonstrated by Kishi and colleagues

were associated with a prognosis comparable to that of patients with distant metastases. Therefore, routine dissection of region C nodes is not recommended [20].

5

Oncologic Approach

Biliary tract cancers, including gallbladder cancer, have a poor prognosis, with an estimated 5-year overall survival of less than 20%. For patients with advanced-stage or unrespectable biliary tract cancers, the first-line systemic chemotherapy is a combination of gemcitabine and cisplatin. Recently, a phase II trial of gemcitabine, cisplatin, and nab-paclitaxel on days 1 and 8 of 21-day cycles for biliary tract cancer patients, including gallbladder cancer, was reported [21].

Until recently, there was no established secondline therapy for biliary tract cancers as the standard of care. In a systemic review on second-line therapy biliary tract cancer treatment, based on 20 studies, the weighted overall response rate was estimated at 5.1%, and the median progressionfree survival was 4 months [10]. In another study, median overall survival for patients with biliary tract cancers from the start of second-line therapy was 11 months (95% CI: 8.8–13.1) and in particular 9.4 months (95% CI: 7.2–12.3) for the 24.8% patients with gallbladder cancer [22]. Trastuzumab and pertuzumab combination therapy was investigated in 11 patients with HER2-positive biliary cancer (HER2-amplified/ overexpressed, n ¼ 8; HER2- mutated, n ¼ 3). At a median follow-up of 4.2 months (range, 2.0–12.0 months), four patients had partial

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responses, and three had stable disease for >4 months, further suggesting the value of Her2/neu targeting in gallbladder cancer [23]. Immunotherapy with checkpoint inhibitors is now being explored in biliary tract cancers, and preliminary data suggests modest efficacy with single-agent checkpoint inhibitors. The largest study in this regard thus far has been the KEYNOTE-158 study with pembrolizumab [24].

6

Timing of Margin-Clearing Surgery for Incidental Gallbladder Cancer

In general, re-resection for patients who have already undergone simple cholecystectomy occurs at the discretion of the treating surgeon with consideration of several factors, including recovery from the initial cholecystectomy, completion of preoperative staging, and addressing complications/optimizing comorbidities for a major operation. Most patients undergo reoperation within 2–3 months of their initial cholecystectomy.

7

Port Site Resection

Up to 20% of patients with gallbladder cancer who previously underwent laparoscopic cholecystectomy will develop peritoneal metastases at laparoscopic port sites. Many surgeons routinely excise port sites at reoperation in patients with IGBC. It is unclear whether this practice is associated with improved cancer-specific survival. In fact, at least two groups have been unable to demonstrate a survival difference associated with routine port site resection for patients undergoing reoperation for gallbladder cancer. Moreover, both French and US multi-institutional studies have shown recurrence rates between 30 and 40% regardless of port site resection.

References 1. Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clin Epidemiol. 2014;6:99–109.

2. Shaffer EA. Gallbladder cancer: the basics. Gastroenterol Hepatol (N Y). 2008;4:737–41. 3. Hariharan D, Saied A, Kocher HM. Analysis of mortality rates for gallbladder cancer across the world. HPB (Oxford). 2008;10:327–31. 4. Wi YJ, Woo HT, Won YJ, Jang JY, Shin AS. Trends in gallbladder cancer incidence and survival in Korea. Cancer Res Treat. 2018;50(4):1444–51. 5. Pilgrim CH, Groeschl RT, Christians KK, Gamblin TC. Modern perspectives on factors predisposing to the development of gallbladder cancer. HPB (Oxford). 2013;15:839–44. 6. Jain K, Sreenivas V, Velpandian T, Kapil U, Garg PK. Risk factors for gallbladder cancer: a case-control study. Int J Cancer. 2013;132:1660–6. 7. Hsing AW, Bai Y, Andreotti G, Rashid A, Deng J, Chen J, Goldstein AM, Han TQ, Shen MC, Fraumeni JF, Gao YT. Family history of gallstones and the risk of biliary tract cancer and gallstones: a population-based study in Shanghai, China. Int J Cancer. 2007;121:832–8. 8. Jackson HH, Glasgow RE, Mulvihill SJ, CannonAlbright LA. Familial risk in gallbladder cancer. J Am Coll Surg. 2007;205:S38–S138. 9. Hemminki K, Li X. Familial liver and gall bladder cancer: a nationwide epidemiological study from Sweden. Gut. 2003;52:592–6. 10. Albores-Saavedra J, Alcántra-Vazquez A, Cruz-Ortiz H, HerreraGoepfert R. The precursor lesions of invasive gallbladder carcinoma. Hyperplasia, atypical hyperplasia and carcinoma in situ. Cancer. 1980;45:919–27. 11. Roa I, Araya JC, Villaseca M, De Aretxabala X, Riedemann P, Endoh K, Roa J. Preneoplastic lesions and gallbladder cancer: an estimate of the period required for progression. Gastroenterology. 1996;111:232–6. 12. D'Hondt M, Lapointe R, Benamira Z, et al. Carcinoma of the gallbladder: patterns of presentation, prognostic factors and survival rate. An 11-year single centre experience. Eur J Surg Oncol. 2013;39:548–53. 13. Duffy A, Capanu M, Abou-Alfa GK, et al. Gallbladder cancer (GBC): 10-year experience at Memorial Sloan Kettering Cancer Centre (MSKCC). J Surg Oncol. 2008;98:485–9. 14. Fuks D, Regimbeau JM, Le Treut YP, et al. Incidental gallbladder cancer by the AFC-GBC-2009 study group. World J Surg. 2011;35:1887–97. 15. Park JY, Hong SP, Kim YJ, et al. Long-term follow up of gallbladder polyps. J Gastroenterol Hepatol. 2009;24: 219–22. 16. Fong Y, Jarnagin W, Blumgart LH. Gallbladder cancer: comparison of patients presenting initially for definitive operation with those presenting after prior noncurative intervention. Ann Surg. 2000;232:557–69. 17. Aloia TA, Jarufe N, Javle M, et al. Gallbladder cancer: expert consensus statement. HPB (Oxford). 2015;17: 681–90. 18. Chijiiwa K, Noshiro H, Nakano K, et al. Role of surgery for gallbladder carcinoma with special reference to lymph node metastasis and stage using Western

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and Japanese classification systems. World J Surg. 2000;24:1271–6; Discussion 1277 19. Kishi Y, Shimada K, Hata S, et al. Definition of T3/4 and regional lymph nodes in gallbladder cancer: which is more valid, the UICC or the Japanese Staging System? Ann Surg Oncol. 2012;19:3567–73. 20. Kishi Y, Nara S, Esaki M, Hiraoka N, Shimada K. Extent of lymph node dissection in patients with gallbladder cancer. Br J Surg. 2018;105(12):1658–1664. 21. Shroff RT, Javle MM, Xiao L, et al. Gemcitabine, Cisplatin, and nab-Paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial. JAMA Oncol. 2019;5:824–30.

371 22. Goff LW, Lowery MA, Jordan E, et al. Second-line chemotherapy (CTx) outcomes in advanced biliary cancers (ABC): a retrospective multicenter analysis. J Clin Oncol. 2016;34:437. 23. Javle MM, Hainsworth JD, Swanton C, et al. Pertuzumab + trastuzumab for HER2-positive metastatic biliary cancer: preliminary data from MyPathway. J Clin Oncol. 2017;35:402. 24. Ueno M, Chung HC, Nagrial A, et al. Pembrolizumab for advanced biliary adenocarcinoma: results from the multicohort, phase 2 KEYNOTE-158 study. Ann Oncol. 2018;29:viii205–70.

Pathogenesis, Epidemiology, and Prognosis of Gallbladder Cancer

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Lauren Margetich

Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373 2 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373 3 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374 4 Genetic Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375 5 Exposures Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376 6 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378

Abstract

Gallbladder carcinoma is the fifth most common gastrointestinal cancer. It has a female predominance, and its incidence is highest in South America. Its pathogenesis is thought to be mostly related to cascade events related to chronic inflammation. Unfortunately, the overall prognosis of gallbladder cancer is poor. Keywords

Gallbladder cancer

1

Introduction

Biliary tract cancers include intrahepatic bile duct cancers, extrahepatic bile tract cancers and gallbladder cancers.

2

Epidemiology

Gallbladder carcinoma is the most common biliary tract cancer and the fifth most common cancer of the digestive tract [1]. According to the American Cancer Society’s publication, there is an estimated 11,980 adults in the United States that will be diagnosed with gallbladder and other biliary tract cancers in 2021 with four out of ten being specifically gallbladder cancers [2]. Gallbladder carcinoma is found in 0.2–3% of all

L. Margetich (*) Mount Sinai, NY, USA © Springer Nature Switzerland AG 2022 C. Doria, J. N. Rogart (eds.), Hepato-Pancreato-Biliary Malignancies, https://doi.org/10.1007/978-3-030-41683-6_21

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cholecystectomy patients and found in 3.4% of autopsies on patients older than 60 years old with cholelithiasis [1]. Gallbladder cancer occurs more often in females than males with two peaks when most commonly diagnosed: between 50 and 60 years old and between 70 and 80 years old [1] or an average age between 65 and 72 years old [3]. It has a three to six times higher incidence rate in females over males [3]. The highest incidence rate is found in Chile, South America, with a rate of 12.3 per 100,000 for males and 27.3 per 100,000 for females [1]. The United States averages an incidence rate closer to 0.9 per 100,000 for females and 0.5 per 100,000 for males. Unsurprisingly, countries with higher incidence rates have higher mortality rates from gallbladder cancer, and countries with higher cholecystectomy rates show lower incidence of gallbladder cancer. The relationship between the latter is that countries with higher rates of cholecystectomy remove the gallbladder when the patient has risk factors, thus stopping the carcinoma before it develops [1]. Prevalence of gallbladder cancer also differs between races. Blacks, Hispanics, Alaskan natives, American Indians, and Asian Pacific Islanders have higher rates than their non-Hispanic white counterparts. American Indians have an annual rate of 8.9 per 100,000 [4]. See Table 1 under pathogenesis for more risk factors contributing to gallbladder cancer.

3

Pathogenesis

A patient’s risk factors for developing gallbladder cancer are listed in Table 1. Gallbladder cancer types include adenocarcinomas, squamous cell carcinoma, undifferentiated or anaplastic carcinoma, and adenosquamous carcinoma [4]. Adenocarcinomas are the most common type of gallbladder cancer in 80–95% of cases, which arises from the gallbladder mucosa and progresses from dysplasia to carcinoma due to chronic inflammation [4]. Chronic inflammation typically takes 15 years before it becomes invasive carcinoma. Chronic inflammation leads to DNA damage, tissue proliferation, cytokine and growth factor release, and calcium deposits to the gallbladder wall [5]. Repeated DNA damage causes the cells to attempt to restore themselves and to release cytokines and growth factors [1]. Chronic calcium depositions to the wall cause the gallbladder to increase its fragility, which is called a porcelain gallbladder and is thought to be a proxy for an inflammation condition [5]. Porcelain gallbladders are rare, only seen in less than 1% of gallbladder pathology, but they do have a high association with gallbladder cancer in 25% of patients [5]. Chronic cholecystitis causes asymmetric thickening of the gallbladder wall [4]. Adenocarcinomas are subdivided into papillary, tubular, mucinous, and signet cell types [4]. Papillary adenocarcinomas are associated with a Kirsten rat sarcoma virus (KRAS) mutation

Table 1 Risk factors for developing gallbladder cancer further stratified based on demographic factors, gallbladder abnormalities, exposures, and infections

Demographic factors • Older age • Female sex • Obesity • Geographical (South American, Indian, Asian Pacific Islanders) • Ethnicity (Caucasian, American Indian, Hispanic, Black) • Genetic predisposition • Crohn’s disease • Pernicious anemia

Gallbladder pathologies/ abnormalities • Cholelithiasis • Porcelain gallbladder • Congenital biliary cysts • Pancreaticobiliary junction anomalies • Cystic duct dilation • Polyps • Primary sclerosing cholangitis • Pancreatobiliary reflux

Exposures • Heavy metals • Medications: methyldopa, OCP, isoniazid, estrogen • Smoking • Arsenic

Infections • Salmonella • Helicobacter • Liver fluke

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Pathogenesis, Epidemiology, and Prognosis of Gallbladder Cancer

with pancreatobiliary reflux instead of gallstones [1]. Papillary adenocarcinoma is usually seen in younger patients compared to the other subtypes of gallbladder cancer and typically has anatomical abnormalities, for example, cystic duct dilation or abnormal pancreatico-choledochoductal junction [1]. Polyps do not usually become carcinogenic, however, when the polypoid lesions are greater than 10 mm, are sessile polyps, or show rapid growth, they have been associated with gallbladder cancer and thus are recommended to be removed for cancer risk reduction. Biliary tract cancers have also been linked to specific bacterial infections. Salmonella typhi has been found in 40% of patients with gallbladder cancer, and areas with higher typhoid infections have higher incidence of gallbladder cancer. These bacterial infections lead to the degradation of bile, chronic inflammation and irritation to the gallbladder wall, which is speculated to alter the tumor suppressor genes [1]. Cholelithiasis, also known as gallstones, is a known risk factor for developing gallbladder cancer with up to 90% of patients with gallbladder cancer also having a history of gallstones [3]. Having a medical history of gallstones increases the risk of developing gallbladder cancer by 8.3 higher compared to the general population [5]. However, only 0.5%–3% of patients with gallstone history will develop gallbladder cancer [3]. The risk of gallbladder cancer increases as the stone size increases with stone measuring larger than 3 cm being 9.2–10.1 greater risk than stone measuring less than 1 cm [5]. This is thought to be due to the inflammation and irritation that the stone causes to the local epithelial [5]. Risk factors for developing gallstones include obesity, metabolic syndromes, and diabetes [1]. There are gallstones present in almost 100% of all squamous cell and adenosquamous cell carcinomas [1]. Squamous cell carcinomas take longer time to develop, and so, most patients with squamous cell carcinomas are of older age [1]. Gallbladder cancer is spread through local invasion of nearby structures, lymphatic dissemination, peritoneal spread, or hematogenous spread [5]. Local spread is most commonly via the liver as

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there is no serosa layer between the gallbladder and the liver but can also spread to the bile duct, duodenum, colon, parietal wall, and abdominal viscera [5]. Obese patients or patients with a BMI greater than 30 kg/m2 have an increased risk of developing gallbladder cancer. BMI has a direct correlation with increased risk of gallbladder cancer with a relative risk increase of 1.59 for women and 1.09 for men for every five-point increase in BMI. Even in the absence of gallstones, patients with diabetes mellitus are at an increased risk for gallbladder cancer. Primary sclerosing cholangitis causes chronic inflammation and increases the risk of developing gallbladder cancer [1]. Any gallbladder mass regardless of size is adenocarcinomas more than 50% of the time in patients with primary sclerosing cholangitis [1].

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Genetic Pathogenesis

Chronic inflammation is hypothesized to increase genetic mutations and cause malignant transformation. Changes in oncogenes, tumor suppressor genes, DNA repair genes, and epigenetic changes are thought to be involved in the genetic alterations that can lead to gallbladder cancer [4]. Specific mutations have been detected in gallbladder cancer [4]. KRAS oncogene can increase abnormal growth signals [4]. Point mutations in KRAS are thought to lead to atypical epithelium and thus carcinoma. TP53 is a tumor suppressor gene and functions in multiple mechanisms against cancer development including maintaining genome integrity and stability and apoptosis [4]. When a cell loses TP53 function, the cell increases its capability to become cancerous [4]. Studies have shown that 27–70% of gallbladder cancer specimens have mutations in TP53, usually from a missense mutation resulting in a nonfunctional protein [4]. Receptor tyrosine-protein kinase erb-B2 (C-erb-B2) oncogene is an epidermal growth

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receptor associated with tyrosine kinase activity [4]. Via immunohistochemistry, c-erb-B2 expression has been positive in 10–46% of gallbladder cancers [4].

Gallbladder cancer stage I

5

II

Exposures Pathogenesis

Carcinogens can convert normal epithelial cells into metaplasia which later leads to dysplasia and carcinoma in situ and then invasive carcinoma [4]. The progression of these stages typically occurs over 15 years [4]. Patients with gallbladder cancer show dysplasia and carcinoma in situ in over 90% of cases [4].

6

Prognosis

IIIB

The overall prognosis of gallbladder cancer is poor as it is the most aggressive biliary tract cancer with a high recurrence rate [3, 6]. Gallbladder cancer is mostly diagnosed at a late stage as it is generally silent and asymptomatic when it begins growing, and only one of every five patients with gallbladder cancer will be diagnosed when the cancer is localized only to the gallbladder [3]. Once diagnosed with gallbladder cancer, the average survival rate is only 6 months with a low 5-year survival rate of 2–19% (8; [2]). The site of the gallbladder cancer and the spread of the cancer will affect the survival rate. According to American Cancer Society’s publication of gallbladder fact in 2021, if the cancer has spread beyond the gallbladder to nearby organs, structures, or lymph nodes, then the 5-year survival rate is 28%, and if the cancer has spread to distant sites in the body, then the 5-year survival rate decreases to 2% [2]. See the table below for survival rates based on cancer stage according to data from the National Cancer Database of American College of Surgeons [3, 7] (Fig. 1). Gallbladder cancer stage 0 (carcinoma in situ)

Description of cancer stage Abnormal cells in the mucosa

IIIA

Five-year survival rate percentage 80 (continued)

IVA

IVB

Description of cancer stage Cancer cells found in the mucosal layer and may also be in the muscle layer Cancer is in muscle layer of the gallbladder wall and to the connective tissue layers of the gallbladder. It has not spread to the liver Cancer is in the connective tissue and also one of the following: the serosa, the liver, or one nearby organ/ structure Cancer is found in the mucosa, may be found in other layers of the gallbladder and/or spread to a nearby organ or structure, and may spread to one of three nearby lymph nodes Cancer has spread to the portal vein or hepatic artery or to two or more organs/ structures other than the liver Cancer has spread to at least four nearby lymph nodes or it has spread to other parts of the body, i.e., the peritoneum or liver

Five-year survival rate percentage 50

28

8

7

4

2

Most patients in developing countries will have a diagnosis as an incidental finding by the pathologist after a routine cholecystectomy [1]. Once gallbladder cancer has become symptomatic, the cancer is likely nonresectable and incurable [1]. Most patients with symptoms complain of vague abdominal symptoms including anorexia and weight loss. It should be considered on the differential diagnosis for any patient complaining of unexplained weight loss, obstructive jaundice, or worsening intense abdominal

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Pathogenesis, Epidemiology, and Prognosis of Gallbladder Cancer

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Fig. 1 A cross-sectional cut through the gallbladder with the layers of the gallbladder. From interior to exterior: epithelium or mucosal layer, lamina proprio or submucosal layer, mucosal layer, perimuscular fibrous tissue or connective tissue layer, and then serosal layer

pain [6]. Imaging with ultrasound can be helpful in detecting a mass in the gallbladder, and CT can help determine if there is spread to the lymph nodes, liver, or distant metastasis. MRI is of little benefit over imagining with ultrasound or CT for diagnosis unless it is an Magnetic resonance cholangiopancreatography (MRCP) which has a 100% sensitivity and 87% specificity. There are no reliable tumor markers available for gallbladder cancer [4]. Carcinoembryonic antigen (CEA) and Cancer antigen 19-9 (CA-19-9) are the two most often used as in advanced disease they are most often elevated; however, they lack specificity [4]. Tumor markers used for nearby structures for gastric, liver, or pancreatic cancers have been shown to be beneficial to diagnosis of gallbladder cancer [4]. The overall prognosis of gallbladder cancer is poor with a high recurrence rate [6]. Squamous cell carcinoma is usually spread more aggressively locally and is less sensitive to chemotherapy and thus has a poorer prognosis compared to adenocarcinomas [1]. Patients are also grouped depending on treatment options according to stages. Localized gallbladder cancer includes stage one where the cancer is found in the gallbladder wall and can be completely resected with cholecystectomy [7].

Nonresectable, recurrent, and metastatic gallbladder cancers include stages two through four [7]. Chemotherapy classes to treat gallbladder cancer include gemcitabine, fluoropyrimidines, and platinum compounds and typically in combination as monotherapy has not been shown to be as effective. The current first-line treatment for fit patients includes gemcitabine (1000 mg/m) plus cisplatin (25 mg/m) [6]. Patients who are less fit could be offered a less potent and more tolerable option of single-agent capecitabine which in one study showed to prolong life compared to their counterparts only receiving supportive care from 4.5 months to 9.9 months [6]. Radiation therapy has not been shown to increase 5-year survival rates, but a study has shown that there is statistically significant improvement in survival rates at 1 year. Patients with gallbladder cancer are monitored with ultrasound, hepatic function tests, and tumor markers [6]. Ultrasounds should be followed every 6 months for at least the first 2 years and then once a year for up to 5 years according to the National Comprehensive Cancer Network (NCCN) recommendations [6]. Labs should be monitored every 4 months for the first 2 years and then every 6 months for the next 3 years [6]. Unfortunately, patients with local spread to surrounding structures or metastatic gallbladder

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cancer are recommended for palliative goaled treatment [6]. Palliative treatment for locally spread cancer can include radiation; however, this rarely controls gallbladder cancer [6].

References 1. Goetze TO. Gallbladder carcinoma: prognostic factors and therapeutic options. World J Gastroenterol. 2015;21(43):12211–7. https://doi.org/10.3748/wjg.v21. i43.12211. 2. Gallbladder Cancer – Statistics. Cancer.Net, 24 February 2021. www.cancer.net/cancer-types/gallbladder-cancer/ statistics. 3. Schmidt MA, Marcano-Bonilla L, Roberts LR. Gallbladder cancer: epidemiology and genetic risk

L. Margetich associations. Chin Clin Oncol. 2019;8(4):31. https://doi. org/10.21037/cco.2019.08.13. 4. Sharma A, Sharma KL, Gupta A, Yadav A, Kumar A. Gallbladder cancer epidemiology, pathogenesis and molecular genetics: recent update. World J Gastroenterol. 2017;23(22):3978–98. https://doi.org/ 10.3748/wjg.v23.i22.3978. 5. Kanthan R, Senger JL, Ahmed S, Kanthan SC. Gallbladder cancer in the 21st century. J Oncol. 2015;2015:967472. https://doi.org/10.1155/2015/ 967472. 6. Recio-Boiles A, Kashyap S, Babiker HM. Gallbladder cancer. [Updated 2020 Nov 19]. In: StatPearls [Internet]. Treasure Island: StatPearls Publishing; 2021 January. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK442002/ 7. Gallbladder Cancer Treatment (PDQ ®)–Patient Version. National Cancer Institute; 2020. www.cancer.gov/types/ gallbladder/patient/gallbladder-treatment-pdq.

Pathology of Gallbladder Carcinoma

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Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380

2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380 2.1 Gross Appearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380 2.2 Microscopic Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381 3

Diagnostic Criteria and Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383

4

Molecular Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384

5 Pathological Classification and Staging (pTNM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384 5.1 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385 6

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385

7

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385

Abstract

Carcinoma of the gallbladder is a rare but fatal malignancy that is commonly found incidentally during routine cholecystectomy. These tumors can be clinically silent and may have subtle macroscopic features that can be missed on gross examination, thus highlighting the importance of thorough and adequate sampling.

N. Setia University of Chicago, Chicago, IL, USA e-mail: [email protected] K. E. Boylan (*) University of Utah, Salt Lake City, UT, USA e-mail: [email protected]

The most common form of carcinoma is biliarytype or pancreatobiliary-type adenocarcinoma, although many subtypes can be found within this larger category of adenocarcinoma. Several benign mimics of adenocarcinoma exist, including Rokitansky-Aschoff sinuses, ducts of Luschka, and adenomyomatous changes, which pose diagnostic dilemmas for pathologists. Few carcinoma subtypes tend to present at a later stage and have been associated with worse clinical outcomes, including mucinous adenocarcinoma, poorly cohesive carcinoma, and pure squamous cell carcinoma. In general, the prognosis is inversely related to the depth of tumor invasion, with tumors confined to the muscular wall having a better clinical outcome and likelihood of curable disease, while those

© Springer Nature Switzerland AG 2022 C. Doria, J. N. Rogart (eds.), Hepato-Pancreato-Biliary Malignancies, https://doi.org/10.1007/978-3-030-41683-6_23

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with deep invasion have poor 5-year overall survival rates. Keywords

Gallbladder Carcinoma · Malignant Tumors of the Gallbladder

1

Introduction

Carcinoma of the gallbladder is a rare but fatal malignancy that is commonly found incidentally during routine cholecystectomy. The prevalence and incidence of these tumors varies widely across geographic regions. The exact pathogenesis is not fully understood at this time, but evaluation of high-incidence populations have identified several possible correlations (refer to ▶ Chap. 21, “Pathogenesis, Epidemiology, and Prognosis of Gallbladder Cancer” for further details). This chapter focuses on the pathologic features of these tumors, including gross appearance, histologic subtypes and corresponding prognosis, molecular pathology, as well as grading and staging criteria.

2

Clinical Features

Gallbladder carcinoma is commonly found incidentally, with greater than 50% of cases identified in clinically inapparent scenarios [1]. There are no specific clinical symptoms, and they are shared with symptoms associated with chronic cholecystitis and cholelithiasis, including postprandial and right upper quadrant abdominal pain (refer to ▶ Chap. 20, “Diagnosis and Evaluation of Gallbladder Cancer”). As discussed in the Pathogenesis, Epidemiology, and Prognosis chapter, the incidence varies widely based on geographic region and ethnicity of the patient. Some of the highest incidence areas include the indigenous Mapuche people of Chile, India, eastern Asia, and few central and eastern European countries [1]. Gallstones, certain infections, specific genetic polymorphisms (DCC, CYP1A1, CYP17A1 (P450C17), ERCC2, OGG1, and ABCG8),

inflammatory disorders (primary sclerosing cholangitis), and certain genetic syndromes (Peutz-Jeghers syndrome, Gardner syndrome) have been associated with a higher risk of gallbladder carcinoma but have not been established as direct causative agents. In addition, carcinoma of the gallbladder can be seen with a precursor lesion, biliary intraepithelial neoplasia (BilIN), and may arise in association with intracholecystic papillary-tubular neoplasms (ICPNs).

2.1

Gross Appearance

One of the most unusual and concerning aspects of gallbladder carcinoma is that it can be commonly overlooked during gross examination, with up to 30–70% of cases being missed on the first evaluation [1]. Given this wide variability in detection rates, newer guidelines recommend submitting at least three full-thickness randomly selected sections of the gallbladder mucosa and wall, along with the cystic duct margin. If dysplasia, particularly high-grade BilIN, or superficially invasive carcinoma are identified in the preliminary sampling, then extensive sampling, including possible entire submission of the gallbladder, is recommended [2, 3]. Furthermore, certain clinical scenarios with higher risks of carcinoma, such as primary sclerosing cholangitis, anomalous union of the pancreatobiliary ducts, choledochal cysts, and hyalinizing cholecystitis (“porcelain gallbladder”) require extensive upfront sampling. Polypoid masses should also be adequately sampled, especially in those that are larger than 2 cm, due to the increased risk of harboring carcinoma. Most gallbladder carcinomas arise in the fundus (70%). As noted above, the tumors can be deceptively bland with a diffuse growth pattern, especially in superficially invasive tumors. Larger tumors may have a flat, white-gray, granular appearance. They may also arise from intracholecystic papillary neoplasms, which will have a papillary, exophytic growth pattern. Depending on the subtype of carcinoma, the tumors may also display gelatinous features in mucinous carcinoma or flesh-like texture in tumors with a sarcomatoid component.

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2.2

Pathology of Gallbladder Carcinoma

381

Microscopic Description

Biliary intraepithelial neoplasia (BilIN) is the most common precursor lesion for carcinoma of the gallbladder and is associated with invasive carcinoma in 40–60% of cases [4]. In addition, more than 80% of gallbladder carcinomas reveal foci of BilIN [5]. As described in the Pathology of Cholangiocarcinoma chapter, the severity of dysplasia is divided into low grade (BilIN-1 and BilIN-2) and high grade (BilIN-3), which mirrors the grading schemes of dysplasia seen in the pancreatic ducts (pancreatic intraepithelial neoplasia; PanIN). Low-grade dysplasia reveals hyperchromatic nuclei with pseudostratification, while high-grade dysplasia reveals increased nuclear to cytoplasmic ratios and marked loss of nuclear polarity. Intracholecystic papillary-tubular neoplasms (ICPNs) are another precursor lesions associated with gallbladder carcinoma and are defined as noninvasive, exophytic neoplasms arising in the gallbladder mucosa. The architecture of these lesions is predominantly papillary to tubulopapillary to villous. An increased risk of malignancy has been associated with lesions greater than 1 cm in size, as well as lesions with significant papilla formation [4]. These lesions can be composed of a variety of cell types, including gastric (foveolar), biliary, intestinal, and oncocytic, with significant overlap in morphologic types present in one single lesion [1]. Of note, biliary and foveolar phenotypes have been found to harbor higher frequency of invasive carcinoma 60–70% [4, 6]; thus, ICPNs with these predominant cell types should be documented in the pathologic report and extensively sampled to evaluate for possible invasive carcinoma. The most common subtype of gallbladder carcinoma is adenocarcinoma, encompassing several different morphologic patterns described below (Fig. 1). Additional subtypes include squamous cell carcinoma, undifferentiated carcinoma, primary hepatoid carcinoma, and sarcomatoid carcinoma. A histologic grade is assigned based on the amount of glandular formation within the tumor for traditional adenocarcinomas. Grade 1 is defined as well-differentiated with greater than 95% glandular formation, while grade 2 is defined

Fig. 1 Invasive adenocarcinoma of the gallbladder extending through the muscular layer (4x)

as moderately differentiated with 50% to 95% glandular formation, and grade 3 is defined as poorly differentiated with 49% or less glandular formation (Fig. 2). Some studies have identified the presence of poorly differentiated tumors to be independent prognostic factors of recurrence after curative resection for stage II cancers [7]. Biliary-type, or pancreatobiliary-type, adenocarcinoma is the most common subtype within the broad category of adenocarcinoma. This tumor morphology is typically composed of small, bland, tubular glands lined by cuboidal to columnar cells, frequently arranged in a random and haphazard distribution. The nuclear size variation can be deceptively bland, but rare foci of four to one nuclear variation should be able to be

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Fig. 2 Well-differentiated adenocarcinoma (a) and poorly differentiated adenocarcinoma (b) of the gallbladder (20x)

identified within the tumor. The cytoplasmic features can range from mucin-containing to foamy to attenuated and scant. These tumors are also often associated with a dense, collagenous desmoplastic stromal reaction. Perineural and lymphovascular invasion are common findings and can be useful features for solidifying the diagnosis of carcinoma when considering other benign mimics described below (Fig. 3). Although most are well to moderately differentiated in terms of histologic grade, this subtype can also display poor differentiation with sheets and single malignant cells, as well as a “large duct” pattern, akin to that seen in primary pancreatic adenocarcinomas. Micropapillary variants may also be identified, which display small nests and tufts of tumor clusters, each with an “inside-out” growth pattern. Finally, it is not uncommon for these tumors to be accompanied by a second component of a subtype described below. Intestinal-type adenocarcinoma resembles that seen in the lower tubular gastrointestinal tract, with columnar cells, with pencillate, pseudostratified nuclei. This subtype is extremely rare as a primary gallbladder site, and careful evaluation for metastatic disease should be excluded with review of prior clinical history and correlation with colonoscopy reports.

N. Setia and K. E. Boylan

Fig. 3 Perineural invasion (a; 20x) and lymphovascular invasion (b; 40x) are common findings in adenocarcinoma of the gallbladder

Mucinous adenocarcinoma can also be found in the gallbladder and requires the presence of greater than 50% extracellular mucin in the tumor for diagnosis. They may display signet ring cell features, as commonly seen in mucinous adenocarcinomas in other primary sites. These cancers tend to grow to large sizes, behave more aggressively, and are microsatellite stable. Clear cell carcinoma is composed of sheets of clear cells arranged in an alveolar pattern. They are commonly seen with a component of traditional biliary-type adenocarcinoma. If a component of adenocarcinoma is not identified after thorough sampling, then metastatic clear cell renal cell carcinoma should be excluded via review of clinical history, imaging findings, and possible immunohistochemical evaluation before making the diagnosis of pure clear cell carcinoma of the gallbladder. Poorly cohesive carcinoma is defined as sheets of single malignant cells that may display signet ring cell features, in which intracytoplasmic mucin pushes the nucleus to the periphery of the cell, resembling a “signet ring” that is commonly worn as jewelry. These cells tend to infiltrate the muscular wall, causing a firm appearance

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Pathology of Gallbladder Carcinoma

resembling linitis plastica. This subtype also has a more aggressive course. Adenosquamous carcinoma is composed of both traditional glandular adenocarcinoma and classic squamous cell carcinoma, with the latter comprising at least greater than 25% of the tumor morphology. These tumors are rare and make up approximately 4% of the carcinomas of the gallbladder [8]. Squamous cell carcinoma is exceedingly rare in pure form, accounting for less than 1% of all gallbladder carcinomas. Surrounding in situ components are typically identified and these tumors commonly display keratinization. They present at an advanced stage and have a worse prognosis, with a propensity for invasion into the liver [8, 9]. Undifferentiated carcinoma is composed of solid sheets of malignant cells without identifiable glandular architecture. They may resemble medullary carcinoma and lymphoepithelial-like carcinoma of the upper aerodigestive tract. The presence of undifferentiated carcinoma is an independent prognostic factor for poor survival [10]. Primary hepatoid carcinoma is a rare tumor and must be separated from a primary hepatocellular carcinoma invading the liver, and otherwise will display Hep-Par-1 positivity by immunohistochemistry. Sarcomatoid carcinoma can display variable morphology, from bland spindled cells to pleomorphic anaplastic giant cells and occasionally heterologous differentiation, such as skeletal muscle, bone, and cartilage. In addition to determining the histologic subtype of carcinoma, the pertinent pathologic findings should be reported, including the presence or absence of gallstones. This is of importance because an absence of gallstones may signify the presence of a structural abnormality, such as anomalous choledocho-pancreatic junction, or underlying systemic condition, such as inflammatory bowel disease or primary sclerosing cholangitis (PSC), which both carry an increased risk of harboring dysplasia and adenocarcinoma [11]. Diffuse calcification, also known as porcelain gallbladder, has been associated with a higher risk of carcinoma; however, this relationship has been recently questioned, and newer research studies have suggested that the presence of focal

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mucosal calcification may have a higher propensity for harboring gallbladder carcinoma [12].

3

Diagnostic Criteria and Differential Diagnosis

The top differential diagnosis of welldifferentiated adenocarcinoma of the gallbladder includes Rokitansky-Aschoff sinuses, ducts of Luschka, hyalinizing cholecystitis, and adenomyomatous changes [13, 14]. These benign mimics can pose diagnostic challenges for pathologists, given that they commonly display small, bland glands penetrating the muscular wall with a pseudoinfiltrative appearance or are present in seemingly abnormal locations. However, upon closer inspection, no significant cytologic atypia is appreciated, and there is a maintenance of the normal lobular architecture. Further diagnostic challenges include Rokitansky-Aschoff sinus involvement by high-grade BilIN. Helpful features in distinguishing carcinoma from these mimics include connection of the glands and larger ducts to the luminal surface, a mixture of normal biliary epithelium, and lack of a desmoplastic stromal reaction. The presence of extensive perineural invasion is a helpful indicator of adenocarcinoma; however, changes that mimic perineural invasion can also be seen in adenomyomatous changes [15, 16]. Immunohistochemistry is not typically needed for the diagnosis of primary gallbladder carcinoma, especially in the setting of a solitary predominant mucosal mass, ICPNs, or background of BilIN; however, pancreatobiliary-type adenocarcinoma is positive for CK-7, CK-19, CEA, MUC-1, and variably positive for CK-20 [5]. Immunohistochemical stains may be helpful in excluding metastatic disease, such as a clear cell renal cell carcinoma in the setting of a pure clear cell carcinoma morphology. Fine needle aspiration (FNA) is rarely performed for cytologic examination, especially that these tumors are often incidentally found upon routine cholecystectomy; however, FNA is more commonly used in areas with a higher incidence.

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Molecular Pathology

Common molecular changes in gallbladder carcinoma include activating point mutations in KRAS (10–67%), TP53 inactivation, and allelic losses of several chromosomal loci, including 3p, 8p, 9q, 18q, and 22q [5, 17]. HER-2/neu (ERBB2) overexpression has a variable frequency of 33–64%, and several newer studies are evaluating the possible benefit of ERBB2-targeted therapy, as seen with other gastrointestinal cancers; however, further clinical trial data is needed. Microsatellite instability may also have therapeutic implications.

5

Pathological Classification and Staging (pTNM)

Staging of gallbladder carcinoma follows the American Joint Committee on Cancer (AJCC) 8th edition [18]. The primary pathologic stage (pT classification) is defined by the depth of tumor invasion (Table 1). pT0 is defined as the lack of evidence of a primary tumor in the specimen. pTis is defined as the presence of carcinoma in situ, where the neoplastic cells are

indistinguishable from invasive carcinoma, but remains confined within the glandular basement membrane, which may also be referred to as highgrade dysplasia. Tumor invading into the lamina propria is defined as pT1a, while invasion into the muscular layer is defined as pT1b. While these definitions are seemingly straightforward, making the distinction during histologic examination can be quite challenging with some studies showing limited reproducibility amongst pathologists [19]. Tumor that invades into the perimuscular connective tissue on the peritoneal side, without involvement of the serosa (visceral peritoneum) is defined as pT2a, while tumor invading the perimuscular connective tissue on the hepatic side, without extensions into the liver is defined as pT2b, which is associated with a worse outcome. Tumor that perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts, is defined as pT3. Finally, tumor that invades the main portal vein or hepatic artery, or tumor that invades two or more extrahepatic organs or structures is defined as pT4.

Table 1 Definition of TMN categories for carcinoma of the gallbladder [1, 18] T category T0 Tis T1a T1b T2a T2b T3

T4 N category N not assigned N0 N1 N2 M category Not applicable M1

Criteria No evidence of primary tumor Carcinoma in situ Tumor invades the lamina propria Tumor invades the muscular layer Tumor invades perimuscular connective tissue on the peritoneal side, without involvement of the serosa (visceral peritoneum) Tumor invades the perimuscular connective tissue on the hepatic side, with no extension into the liver Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts Tumor invades main portal vein or hepatic artery or invades two or more extrahepatic organs or structures Criteria No regional lymph nodes submitted or found No regional lymph node metastasis Metastasis to 1–3 regional lymph nodes Metastasis to 4 or more regional lymph nodes Criteria Cannot be determined from submitted specimen(s) Distant metastasis present

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Pathology of Gallbladder Carcinoma

The pN classification is based on the presence of lymph node involvement. Regional lymph nodes include those along the common bile duct, hepatic artery, portal vein, and cystic duct. “pN not assigned” is defined as no regional lymph nodes submitted or found. pN0 is defined as no evidence of regional lymph node metastasis. pN1 is defined as metastasis to one to three regional lymph nodes, while involvement of four of more regional lymph nodes is defined as pN2. Few studies have reported that micrometastasis or isolated tumor cells present in lymph nodes have been associated with poor outcomes [20], but larger studies have not been able to validate these results. Therefore, multiple deeper levels and immunohistochemical stains for cytokeratins are not recommended at this time to detect micrometastasis that are not apparent on routine hematoxylin and eosin sections. The pM classification is defined as the presence or absence of distant metastasis. Metastatic disease to the celiac and superior mesenteric and peripancreatic lymph nodes is considered pM1 disease.

5.1

Prognosis

In general, prognosis is largely dependent on the depth of invasion. Tumors that are confined to the muscular wall tend to have the best outcomes and can be surgically managed and even cured in many instances. Deeply invasive tumors have a 5-year overall survival rate ranging from 40% to 75%. Location of the carcinoma on the serosal or hepatic surface has also been found to have differences in prognosis, with hepatic locations portending a worse outcome. Metastatic disease to regional lymph nodes has also been shown to have poor prognostic implications, with patients who have a single lymph node metastasis having a higher 5-year survival rate (33%) compared to those with two or more lymph node metastases (0%); [21]. As previously noted, involvement of Rokitansky-Aschoff sinuses by adenocarcinoma is adverse prognostic factor [22]. The extent of mucosal carcinoma and cystic duct margin status have also been identified as possible prognostic indicators. Perineural invasion has been identified as adverse prognostic factor in some studies,

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but this has not been validated across all studies [23]. Along the same lines, lymphovascular invasion has been reported to be an adverse prognostic factor [24]. Complete surgical resection with clear margins has shown to have better survival advantages [25], as discussed further in the following chapters on surgical management and prognosis.

6

Conclusion

Gallbladder carcinoma is a rare but fatal malignancy that can be difficult to detect in the early stages of disease progression, even with the most advanced tools of medicine. This malignant tumor ranges from being identified during a routine cholecystectomy to being found in association with a precursor lesion, chronic inflammatory disorders, and certain genetic syndromes. Pathologic diagnosis can be challenging to make due to the subtle gross and microscopic characteristics of this tumor, as well as the many benign histologic mimics that pose diagnostic dilemmas. Prognosis is largely based on the depth of tumor invasion, with tumors that are confined to the mucosa having an excellent prognosis when treated with the appropriate surgical management, while those tumors that are deeply invasive, poorly differentiated, and/or associated with extensive metastatic disease have poor prognostic implications.

7

Cross-References

▶ Diagnosis and Evaluation of Gallbladder Cancer ▶ Pathogenesis, Epidemiology, and Prognosis of Gallbladder Cancer ▶ The Pathophysiology and Pathology of Intrahepatic and Extrahepatic Cholangiocarcinomas

References 1. WHO Classification of Tumours Editorial Board. Digestive system tumours. Lyon: International Agency for Research on Cancer; 2019. p. 283–8. 2. Aloia TA, Jarufe N, Javle M, et al. Gallbladder cancer: expert consensus statement. HPB (Oxford). 2015;17 (8):681–90.

386 3. Adsay V, Saka B, Basturk O, Roa JC. Criteria for pathologic sampling of gallbladder specimens. Am J Clin Pathol. 2013;140(2):278–80. 4. Odze RD, Goldblum JR. Odze and Goldblum’s surgical pathology of the GI tract, liver, biliary tract, and pancreas. 3rd ed. Philadelphia: Elsevier; 2015. 5. Bal MM, Ramadwar M, Deodhar K, et al. Pathology of gallbladder carcinoma: current understanding and new perspectives. Pathol Oncol Res. 2015;21(3):509–25. 6. Albores-Saavedra J, Chable-Montero F, GonzalezRomo MA, et al. Adenomas of the gallbladder. Morphologic features, expression of gastric and intestinal mucins, and incidence of high-grade dysplasia/carcinoma in situ and invasive carcinoma. Hum Pathol. 2012;43(9):1506–13. 7. Park JS, Yoon DS, Kim KS, et al. Actual recurrence patterns and risk factors influencing recurrence after curative resection with stage II gallbladder carcinoma. J Gastrointest Surg. 2007;11(5):631–7. 8. Roa JC, Tapia O, Cakir A, et al. Squamous cell and adenosquamous carcinomas of the gallbladder: clinicopathological analysis of 34 cases identified in 606 carcinomas. Mod Pathol. 2011;24(8):1069–78. 9. Samuel S, Mukherjee S, Ammannagari N, et al. Clinicopathological characteristics and outcomes of rare histologic subtypes of gallbladder cancer over two decades: a population-based study. PLoS One. 2018;13(6):e0198809. 10. Park HJ, Jang KT, Choi DW, et al. Clinicopathologic analysis of undifferentiated carcinoma of the gallbladder. J Hepatobiliary Pancreat Sci. 2014;21(1):58–63. 11. Lewis JT, Talwalkar JA, Rosen CB, Smyrk TC, Abraham SC. Prevalence and risk factors for gallbladder neoplasia in patients with primary sclerosing cholangitis: evidence for a metaplasia-dysplasia-carcinoma sequence. Am J Surg Pathol. 2007;31(6):907–13. 12. Stephen AE, Berger DL. Carcinoma in the porcelain gallbladder: a relationship revisited. Surgery. 2001;129 (6):699–703. 13. Singhi A, Adsay NV, Swierczynski SL, et al. Hyperplastic Luschka ducts: a mimic of adenocarcinoma in the gallbladder fossa. Am J Surg Pathol. 2011;35(6): 883–90. 14. Giang TH, Ngoc TT, Hassell LA. Carcinoma involving the gallbladder: a retrospective review of 23 cases –

N. Setia and K. E. Boylan pitfalls in diagnosis of gallbladder carcinoma. Diagn Pathol. 2012;7:10. 15. Albores-Saavedra J, Henson DE. Adenomyomatous hyperplasia of the gallbladder with perineural invasion. Arch Pathol Lab Med. 1995;119:1173–6. 16. Albores-Saavedra J, Keenportz B, Bejarano PA, et al. Adenomyomatous hyperplasia of the gallbladder with perineural invasion: revisited. Am J Surg Pathol. 2007;31:1598–604. 17. Sharma A, Sharma KL, Gupta A, et al. Gallbladder cancer epidemiology, pathogenesis and molecular genetics: recent update. World J Gastroenterol. 2017;23(22):3978–98. 18. Amin MB, Edge SB, Greene FL, et al., editors. AJCC cancer staging manual. 8th ed. New York: Springer; 2017. 19. Adsay NV, Bagci P, Tajiri T, et al. Pathologic staging of pancreatic, ampullary, biliary, and gallbladder cancers: pitfalls and practical limitations of the current AJCC/UICC TNM staging system and opportunities for improvement. Semin Diagn Pathol. 2012;29(3): 127–41. 20. Sasaki E, Nagino M, Ebata T, et al. Immunohistochemically demonstrated lymph node micrometastasis and prognosis in patients with gallbladder carcinoma. Ann Surg. 2006;244(1):99–105. 21. Endo I, Shimada H, Tanabe M, et al. Prognostic significance of the number of positive lymph nodes in gallbladder cancer. J Gastrointest Surg. 2006;10(7):999– 1007. 22. Roa JC, Tapia O, Manterola C, et al. Early gallbladder carcinoma has a favorable outcome but RokitanskyAschoff sinus involvement is an adverse prognostic factor. Virchows Arch. 2013;463(5):651–61. 23. Yamaguchi R, Nagino M, Oda K, et al. Perineural invasion has a negative impact on survival of patients with gallbladder carcinoma. Br J Surg. 2002;89(9): 1130–6. 24. Aramaki M, Matsumoto T, Shibata K, et al. Factors influencing recurrence after surgical treatment for T2 gallbladder carcinoma. Hepato-Gastroenterology. 2004;51(60):1609–11. 25. Balachandran P, Agarwal S, Krishnani N, et al. Predictors of long-term survival in patients with gallbladder cancer. J Gastrointest Surg. 2006;10(6):848–54.

Nonsurgical Management of Gallbladder Cancer

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Neel Gandhi and Timothy Chen

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388

2

Adjuvant Therapy for GBC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388

3 3.1 3.2 3.3

Locally Advanced/Unresectable GBC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Systemic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brachytherapy and External Beam Radiation therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stereotactic Body Radiation Therapy (SBRT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

390 390 390 391

4 Systemic Management of Metastatic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391 4.1 Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391 4.2 Precision Medicine and Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391 5

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

Abstract

Gallbladder cancer is an uncommon malignancy and historically thought to have a poor prognosis. Nevertheless, interdisciplinary approaches to care and the advent of precision medicine have improved overall survival outcomes. Most agree that for patients with at least Stage IB disease, adjuvant chemotherapy and chemoradiation therapy improve overall survival. There are no standard guidelines for adjuvant radiation, but many agree to perform adjuvant radiation for R1

disease. Modern chemotherapy protocols have improved response rates for locally advanced disease; yet no clear guidelines for neoadjuvant therapy have been established. External beam, stereotactic radiation, and brachytherapy can provide local palliation and improve hyperbilirubinemia. Gemcitabine- and 5-FU-based chemotherapy combinations have long demonstrated activity in this disease; however, targeted therapy approaches including immunotherapy will serve as new treatment modalities in the future. Keywords

N. Gandhi (*) · T. Chen Capital Health Cancer Center, Pennington, NJ, USA e-mail: [email protected]; [email protected]

Gallbladder cancer · Chemoradiation · Precision medicine · Immunotherapy

© Springer Nature Switzerland AG 2022 C. Doria, J. N. Rogart (eds.), Hepato-Pancreato-Biliary Malignancies, https://doi.org/10.1007/978-3-030-41683-6_24

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N. Gandhi and T. Chen

Introduction

Gallbladder cancer (GBC) can present insidiously, and most cases are incidentally diagnosed at the time of cholecystectomy. GBC also has the potential to present as metastatic disease. In addition to the liver, stomach, pancreas, and small bowel, GBC can penetrate the peritoneum resulting in life-threatening peritoneal metastasis. Analysis of the SEER database from 2010 to 2016 for GBC [1] reveal an overall 5-year survival rate of 19%, delineating 65% for localized disease, 28% for regional disease, and 2% for distant disease. As the incidence of GBC is substantially lower than other gastrointestinal malignancies, there are few prospective randomized clinical trials to help guide therapy decisions. Typically, retrospective and prospective trials incorporate GBC patients with intrahepatic and extrahepatic cholangiocarcinoma under the umbrella of biliary tract cancers. Management is largely similar although there are subtle differences as discussed in this chapter. When GBC is identified at the time of cholecystectomy, re-resection with lymphadenectomy is indicated. This of course would ensure adequate surgical staging. There have been recent changes to the AJCC staging which emphasize the anatomical origin of the tumor. The most notable is the subdivision of T2. Invasion of the perimuscular tissue on the peritoneal side of the gallbladder is staged as T2a, whereas invasion of the perimuscular tissue on the hepatic side is T2b. This anatomical distinction is critical to predict for both locoregional and systemic relapse. The following risk factors are important when assessing risk of relapse: the age of the patient, TNM stage and lymphatic invasion, tumor differentiation, margin positivity, perineural invasion, and postoperative CA19-9 levels. In addition, lymphatic invasion and margin positivity, perineural invasion (PNI), and postoperative CA19-9 levels are particularly critical determinants of determining risk of relapse. The biliary tree has an extensive neural system, which mainly consists of autonomic nerves. However, the mechanism of tumor cell progression through the biliary neural network has not been identified.

High rates of PNI (approximately 75–85%) have been reported in biliary tract cancers. Identification of PNI has prompted further resection of the extrahepatic bile duct [2]. Given the general aggressiveness of GBC, PNI is likely a significant predictor of systemic relapse. In addition, it is well known that postoperative elevated CA19-9 levels are highly predictive of OS in pancreatic cancer. This has similarly been demonstrated after resection of biliary tract malignancies [3]. Kim et al. reported that postoperative CA19-9 level is associated with locoregional control, disease-free survival, and OS in the univariate analysis for extrahepatic biliary tract cancer [4]. After curative surgery, a persistently elevated postoperative CA19-9 level could imply microscopic residual disease and hence predict for systemic relapse. Of note all the clinical trials presented here involve adenocarcinoma of the gallbladder. As there is limited data to guide treatment of squamous or adeno-squamous gallbladder cancer, management of these subtypes can be treated similarly to adenocarcinoma. Small cell carcinoma of the gallbladder (1–5% of all GBCs) is managed similarly to small cell lung cancer which includes systemic chemo-immunotherapy.

2

Adjuvant Therapy for GBC

A meta-analysis by Horan et al. [5] demonstrated that adjuvant therapy improves survival for biliary tract cancers. There was statistical benefit in survival seen in adjuvant chemotherapy and chemoradiation therapy but not in adjuvant radiation therapy. The lingering question is whether chemotherapy alone or chemoradiation therapy is an optimal treatment. Particularly for marginpositive disease, postoperative adjuvant radiotherapy could reduce locoregional failure and may have survival benefits. However, these results vary across the literature. There have been no randomized controlled trials to provide clear indications of adjuvant radiotherapy. Analyzing the pattern of failure in GBC patients who underwent curatively resection could help us identify these indications. Gwak et al. [6] noted that adjuvant radiotherapy decreased locoregional failure for

23

Nonsurgical Management of Gallbladder Cancer

extrahepatic bile duct cancer. The authors compared outcomes of surgery alone (group I) and surgery followed by adjuvant radiotherapy (group II) in patients with extrahepatic bile duct cancers. Local failure rate was decreased in group II (62% vs. 36%; p ¼ 0.02), while no difference was found in the 5-year OS rates (12% vs. 21%; p > 0.5). This principle could clearly apply to GBC in addressing the role of radiation therapy. One particularly interesting analysis is by Wang [7], where a nomogram was developed for predicting benefit for adjuvant chemotherapy and chemoradiation therapy for resected gallbladder cancer. Patients were analyzed retrospectively from 1995 and 2005 utilizing the SEER Medicare database. This nomogram is still available online, and with the exception of N2 disease, adjuvant chemoradiotherapy was deemed superior to chemotherapy in every instance. This analysis could be flawed by lack of high-quality randomized prospective data and inherent patient selection bias and is not widely used. Given benefit of locoregional control with adjuvant radiation therapy, SWOG S0809 [8] was designed to determine 2-year survival with adjuvant chemoradiation therapy with extrahepatic bile duct cancer and GBC. Seventy-nine patients, 32% of which had GBC, were treated with four cycles of adjuvant gemcitabine (1000 mg/m2 day 1 and day 8) plus capecitabine (1500 mg/m2 day 1–14) every 21 days followed by concurrent radiation therapy with capecitabine (1300 mg/m2 daily). The 2-year overall survival was estimated to be 65%. There were expected toxicities such as cytopenias and diarrhea. This is likely proof of concept for the benefit of adjuvant chemoradiation therapy and could serve as a template for those patients that would benefit from adjuvant radiation. Generally, the field of adjuvant radiotherapy includes the tumor and tumor bed and critical areas of potential lymphatic drainage. For GBC, the emphasis is on the pericholedocal and duodenopancreatic lymph nodes. In patients who have undergone a radical resection, the radiation portal would include preoperative gross tumor volume as defined by preoperative imaging studies, a margin of 2.5–3.0 cm beyond ductal involvement as seen in the cholangiogram or CT scan, and

389

regional lymph nodes (porta hepatitis, pancreaticoduodenal, and celiac axis.) Typical external beam radiation therapy dose ranges from 40 to 45 Gy delivered in 20–25 fractions 5 days a week. IMRT treatment planning is usually required to maximize the radiation dose to the planning target volume and minimize the radiation distribution to the surrounding organs at risk, such as bowel, normal liver, kidney, and spinal cord. Treating with systemic therapy alone is also a very reasonable option if there is no significant concern about locoregional failure. There have been several trials demonstrating a survival benefit. The phase III BILCAP trial [9] suggests that there is evidence of a survival benefit of adjuvant capecitabine therapy for resected GBC. In this study, 447 patients with either completely resected cholangiocarcinoma or muscle-invasive (T1b or higher) GBC were randomized to placebo or eight cycles of capecitabine monotherapy (1250 mg/m2 twice a day, days 1–14 every 21 days). Median survival was 51 months in the treatment group vs. 36 months in the placebo arm. However, this trial was not statistically significant, and only 18% of the total patients in this study had GBC. Many clinicians have extrapolated from the metastatic setting and utilized gemcitabine or gemcitabine combinations (i.e., gemcitabine plus cisplatin) as adjuvant therapy for resected GBC. A small retrospective analysis of resected GBC demonstrated improved survival utilizing gemcitabine after R1 or R2 resections [10]. However, there is no reliable randomized data supporting the use of gemcitabine or gemcitabine combinations for adjuvant therapy for GBC. In summary, clearly there is evidence for both adjuvant chemotherapy and chemoradiation after resected GBC. It is unclear whether chemoradiation is superior to chemotherapy, and the systemic backbone of treatment has not been established. The trials noted above in Table 1 clearly support adjuvant chemotherapy or chemoradiation therapy; however, all these analyses had limitations. The results of the ACTICCA-1 which is still accruing in Europe are eagerly awaited. This is a phase III randomized study comparing adjuvant cisplatin/ gemcitabine chemotherapy with the standard of care: observation (Stage I) or observation plus

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Table 1 Summary of selected prospective adjuvant trials for GBC (Gem ¼ gemcitabine, Cap ¼ capecitabine, MMC ¼ mitomycin, 5-FU ¼ 5-fluorouracil) Adjuvant trials BILCAP (Phase III) SWOG S0809 (Phase II)

# of patients 223 79

Regimen Eight cycles of cap vs. placebo Gem/cap x four cycles followed by Cap+RT

capecitabine (Stage II) after curative resection of biliary tract cancer. Patients with R1 resections will be allowed to go on chemotherapy with radiation. ASCO in 2019 updated their clinical practice guidelines to suggest capecitabine monotherapy for 6 months and to offer radiation for positive margins, emphasizing the BILCAP trial as the highest quality of evidence. NCCN guidelines were somewhat more flexible suggesting either chemotherapy or chemoradiation as adjuvant therapy for both nodenegative and node-positive disease. A decision for adjuvant therapy should be made in a multidisciplinary fashion with input from medical, surgical, and radiation oncology.

3 3.1

Locally Advanced/Unresectable GBC

Overall survival 51 months vs. 36 months placebo 35 months

Limitations Low number of GBC patients Nonrandomized

for locally advanced and metastatic biliary tract cancer [12]. Sixty patients were enrolled in this study, and 13 patients were noted to have GBC. This study demonstrated a 45% response rate and an overall survival of 19 months. Interestingly, 12 patients on this study were converted to resection, and there were two pathologic complete responses. However, there was significant treatment-associated toxicity, with a third of patients having Grade 3 or higher events with neutropenia being the most common. A select group of patients who desire aggressive therapy could be candidates for an aggressive induction systemic regimen with or without radiation. This clearly needs to be studied prospectively in a randomized-controlled trial.

3.2

Brachytherapy and External Beam Radiation therapy

Systemic Therapy

Patients deemed to have unresectable disease (by basis of extensive locoregional invasion) would be eligible for chemotherapy with or without radiation. There are no established guidelines for locally advanced/unresectable GBC as there are in other pancreaticobiliary tumors. Chemoradiation protocols as outlined previously could be used for locally advanced disease, and systemic management for unresectable GBC should follow guidelines for metastatic disease as outlined later in this chapter. Intensifying the systemic backbone could potentially improve locoregional responses as seen with modified FOLFIRINOX in pancreatic cancer. Indeed, neoadjuvant chemotherapy and chemoradiation therapy have been studied in a retrospective fashion for GBC, with some patients being able to convert to resection [11]. This was also demonstrated in a recent phase II study testing a modern combination of cisplatin/gemcitabine/nab-paclitaxel

Patients with locally advanced disease with significant hyperbilirubinemia remain a significant therapeutic challenge. An emphasis should be made on symptom palliation which would include placement of biliary stents or external drainage. Brachytherapy with external beam radiation therapy would remain an option for palliation. These procedures should be performed in a sterile environment and ensure the continuous drainage of bile. Patients with bilirubin greater than 2.5 mg after biliary drainage and patients with ascites are not candidates for brachytherapy. Combined intraluminal brachytherapy with external beam radiation therapy has been described in multiple studies in patients with unresectable hilar cholangiocarcinoma and GBC. Their efficacy and result vary. Most of these brachytherapies were performed by both the radiation oncologist and interventional radiologist. Under the guidance of PTC (percutaneous transhepatic cholangiogram), a

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Nonsurgical Management of Gallbladder Cancer

391

percutaneous drainage catheter would pass through the tumor area. The 5 French brachytherapy catheter is then inserted within the drainage catheter. Three-dimensional computer-guided HDR brachytherapy planning is applied and prescribed to the treatment length. Due to the rapid radiation dose drop-off, intraluminal brachytherapy alone is usually insufficient in covering the tumor cells located more than 1.5 cm away from the catheter. Thus, most radiation oncologists advocate the combination of EBRT+ brachytherapy.

medical comorbidities and liver function is important in selecting a treatment plan. If appropriate and available, patients should be encouraged to enroll on a clinical trial. Of note metastatic GBC patients may have also chronic hyperbilirubinemia because of either biliary obstruction or metastatic parenchymal liver metastasis. If there is evidence of biliary obstruction, adequate drainage including palliative stenting is essential in these patients if possible, as systemic treatment can be challenging in this instance.

3.3

4.1

Stereotactic Body Radiation Therapy (SBRT)

Combining both technological advancement and a higher radiobiological effective dose (RBE), SBRT has generated superior tumor control in many other cancer sites. SBRT has been combined with chemotherapy to treating unresectable/locally advanced extrahepatic cholangiocarcinoma and gallbladder cancer. Polistina et al. [13] presented data on ten patients using SBRT with 30 Gy in three fractions combined with weekly gemcitabine to unresectable for locally advanced hilar cholangiocarcinoma. The metal stent was used for tracking. The radiological response was observed in 80% of the patients. The median time to progression was 30 months. Acute toxicity included vomiting, gastritis, leukopenia, or duodenal bleeding. Momm et al. [14] applied fractionated SBRT with 32–56 Gy in 3–4 Gy per fraction combined with gemcitabine- or 5-FU-based chemotherapy. The medium time to tumor progression was 32.5 months. SBRT can therefore be offered for palliative measures for treatment of locally advanced disease.

4

Systemic Management of Metastatic Disease

Metastatic GBC has historically carried a poor prognosis with treatment goals focused on alleviating symptoms and extending overall survival. However recent advances in treatment including precision medicine and immunotherapy have improved on long-term survival. An assessment of each patient’s performance status including

Chemotherapy

With respect to chemotherapy, the standard of care for metastatic disease is cisplatin/gemcitabine based on the ABC-02 trial [15]. Patients were randomized to cisplatin (25 mg/m2 day 1 and day 8) plus gemcitabine (1000 mg/m2 day 1 and 8) compared to gemcitabine alone. The results demonstrated a nearly 12 months’ overall survival in comparison with gemcitabine alone (8.1 months). Other gemcitabine combinations (with capecitabine) have also been studied and are reasonable alternatives, yet no regimen has been demonstrated to be superior in randomized studies. For patients with hyperbilirubinemia, a capecitabine/oxaliplatin combination (CAPOX) is an excellent choice as both chemotherapeutic agents are not cleared by the liver. CAPOX has been shown in a phase III study to be non-inferior to gemcitabine/oxaliplatin as shown in Table 2 [16]. Unfortunately, responses are shortlived, and patients will ultimately require secondline treatment. Chemotherapy options include regimens not utilized in the frontline setting. FOLFOX of note is a very effective second-line regimen [17]. Progression-free survival, however, is significantly lower with second-line therapies. In this instance utilizing targeted therapy and immunotherapy can be beneficial.

4.2

Precision Medicine and Immunotherapy

Given modest improvement with chemotherapy alone, there have been tremendous efforts to utilize precision medicine to treat GBC. It is

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Table 2 Summary of selected prospective metastatic trials for GBC (Gem ¼ gemcitabine, CAP ¼ capecitabine, Ox ¼ oxaliplatin, Cis ¼ cisplatin) Metastatic trials ABC-2 (Phase III) ABC-6 (Phase III) Non-inferiority study (Phase III)

# of patients 410

Regimen Gem/cis vs. gem alone

Overall survival 11.7 months vs. 8.1 months

Key point Standard of Care

162

ASC + mFOLFOX vs. ASC alone CAPOX vs. GemOx

6.2 months vs. 5.3 months

2x survival at 12 months CAPOX non-inferior to GemOX

140

important to discuss recently identified research with respect to molecular markers of carcinogenesis and triggers of immune system activation. An elegant review by Valle presented the role of precision medicine in the management of biliary tract cancers [18]. Interestingly nearly 36% of GBC specimens carried a mutation in the ERBB family of proteins. There have been several case reports published showing dramatic response to HER2 therapy in gallbladder cancer, particularly using the trastuzumab/pertuzumab combination [19, 20]. The ERRB2/3 pathway appears to be unique to GBC and not as overexpressed in other biliary tract cancers. This pathway has been shown to activate PI3 kinase and stimulate expression of PDL1 in GBC [21]. This communication is interesting given known expression of PDL1 in biliary tract malignancies. Other common mutations identified in GBC include KRAS, CDK2A, and the PIK3CA gene. IDH mutations and FGFR alteration have been the subject of recent news, and specifically pemigatinib was approved by the FDA for treatment of cholangiocarcinoma with FGFR alterations [22]. There has been similar excitement with TRK fusion-positive cancers, and a recent publication demonstrated that larotrectinib displayed remarkable activity across a wide range of cancers including biliary tract [23]. However, IDH, FGFR mutants, and even TRK fusions are rare in GBC. Precision approaches to therapy have also been studied in the MOSCATO-1 trial [24] which investigated genomic screening and clinical outcome in advanced cancer. An in-depth analysis of this study demonstrated that advanced biliary tract cancers have a high propensity to match to molecular target agents. For this reason, utilizing

10.6 months vs. 10.4 months

precision medicine should become part of the standard approach to determining treatment options for advanced GBC. However, there remain logistical challenges, namely, access to clinical trials testing targeted agents in GBC and ability of insurance to approve non-formulary medications for off-label use. Given the hypothesis of chronic inflammation as a signature for carcinogenesis, there has been interest in studying the immunologic tumor environment as a potential for immunotherapy. Identifying biomarkers to predict for immune response is essential to determining candidacy for therapy. It is known that immune cells such as cytotoxic T cell lymphocytes are present in biliary tract specimens. Further research has demonstrated that biliary tract cancers including GBC express PDL1, suggesting this to be an intrinsic mechanism for tumor growth. The degree of PDL1 expression has been validated as a biomarker to predict tumor response in other cancers. A recent analysis supports utilizing this approach in biliary tract cancer [25]. In this study, nivolumab was tested in 46 patients with advanced biliary tract cancer responding to treatment. Ten of these patients were assessed to have a partial response, and nine of these ten patients demonstrated PDL1 overexpression. In addition, a recent clinical trial demonstrated that dual checkpoint inhibitor immunotherapy had significant activity in patients with GBC unselected for PDL1 expression [26]. Thirty-nine patients received nivolumab at 3 mg/kg IV q3 weeks and ipilimumab 1 mg/kg in q3 weeks for four doses followed by nivolumab 3 mg/kg IV q2 weeks as maintenance. The response rate was 23% with a 44% disease control rate. All patients that responded were intrahepatic cholangiocarcinoma or GBC. This again is proof of

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Nonsurgical Management of Gallbladder Cancer

concept that immunotherapy approaches to treatment will improve long-term patient outcomes in the future. Hence further clinical trials need to be performed to test immunotherapy in advanced GBC, focusing specifically on biomarker-driven treatment selections. Trials in particular could exploit the ERBB2 pathway and consider combining HER2 and PDL1 therapy in the future. In addition to PDL1 expression, mismatch repair deficiency and high tumor mutational burden have been both identified in GBC. Patients with deficiency in the DNA repair mechanisms are thought to have mutagenic tumors. These patients have been demonstrated to response to single agent checkpoint inhibition. It has reported that 5% of GBC displays mismatch repair deficiency [27]. Similarly, patients with high TMB (which is a more global study of mutational burden) have been shown to respond as well. Pembrolizumab was approved in 2017 for treatment of all tumors displaying mismatch repair deficiency. At the time of writing, there is no similar approval for tumors with high TMB.

5

Summary

Nonsurgical management of GBC has historically been challenging given lack of randomized data to guide therapy decisions. Nevertheless, recent prospective analyses along with national guidelines have been helpful. Clearly a multidisciplinary approach to treating gallbladder cancer is critical for patient care. Recent molecular and genetic studies have identified several actionable mutations that will be critical for new targeted therapy. This along with immunotherapy treatments should serve as a new paradigm for future clinical trial design and development.

References 1. American Cancer Society. Survival rates for gallbladder cancer. 2021. https://www.cancer.org/cancer/gallbladdercancer/detection-diagnosis-staging/survival-rates.html. 2. Maruyama S, et al. Indications for extrahepatic bile duct resection due to perineural invasion in patients with gallbladder cancer. World J Surg Oncol. 2019;17 (1):200.

393 3. Hatzeras I, et al. Elevated CA 19-9 levels portends poor prognosis in patients undergoing resection of biliary malignancies. HPB (Oxford). 2010;12(2):134–8. 4. Kim TH, Han SS, Park SJ, et al. Role of adjuvant chemoradiotherapy for resected extrahepatic biliary tract cancer. Int J Radiat Oncol Biol Phys. 2011;81: e853–9. 5. Horgan AM, et al. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and metaanalysis. J Clin Oncol. 2012;30(16):1934. 6. Gwak HK, Kim WC, Kim HJ, Park JH. Extrahepatic bile duct cancers: surgery alone versus surgery plus postoperative radiation therapy. Int J Radiat Oncol Biol Phys. 2010;78:194–8. 7. Wang SJ, et al. Nomogram for predicting the benefit of adjuvant chemoradiotherapy for resected gallbladder cancer. J Clin Oncol. 2011;20(35):4627. 8. Ben-Josef E, et al. SWOG S0809: a phase II intergroup trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma. J Clin Oncol. 2015;33(24):2617. 9. Primrose J, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomized, controlled, multicentre, phase 3 study. Lancet Oncol. 2019;20(5):663–73. 10. Nakamura M, et al. Gemcitabine-based adjuvant chemotherapy for patients with advanced gallbladder cancer. Anticancer Res. 2014;34(6):3125–9. 11. Hakeen A, et al. The role of neoadjuvant chemotherapy or chemoradiotherapy for advanced gallbladder cancer – a systematic review. Eur J Surg Oncol. 2019;45: 83–91. 12. Shroff R, et al. Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers. A phase 2 clinical trial. JAMA Oncol. 2019;5(6):824–30. 13. Polistina FA, et al. Chemoradiation treatment with gemcitabine plus stereotactic body radiotherapy for unresectable, nonmetastatic, locally advanced hilar cholangiocarcinoma. Radiother Oncol. 2011;99: 120–3. 14. Momm F, et al. Stereotactic fractionated radiotherapy for Klatskin’s tumors. Radiother Oncol. 2010;95:99–102. 15. Valle J, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273. 16. Kim ST, et al. Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: a multicenter, openlabel, randomized, phase III, noninferiority trial. Ann Oncol. 2019;30(5):788. 17. Lamarca A, et al. ABC-06. A randomized phase III, multicentre, open-label study of active symptom control (ASC) alone or ASC with oxaliplatin/5-FU chemotherapy (ASC+mFOLFOX) for patients with locally advanced/metastatic biliary tract cancers (ABC) previous-treated with cisplatin/gemcitabine chemotherapy. J Clin Oncol. 2019;37(Suppl 15):4003.

394 18. Valle JW, et al. New horizons for precision medicine in biliary tract cancers. Cancer Discov. 2017;7(9):943–62. 19. Javle M, et al. HER2/neu-directed therapy for biliary tract cancer. J Hematol Oncol. 2015;8:58. 20. Patel A, et al. Genomic landscape and targeted treatment of gallbladder cancer: results of a first ongoing prospective study. South Asian J Cancer. 2020;9(2): 74–9. 21. Li M, et al. Genomic ERBB2/ERBB3 mutations promote PD-L1 mediated immune escape in gallbladder cancer: a whole-exome sequencing analysis. Gut. 2019;68(6):1024–33. 22. Abou-Alfa GK, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21(5):671–84.

N. Gandhi and T. Chen 23. Drilon A, et al. Efficacy of Larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378:731–9. 24. Verlingue L, et al. Precision medicine for patients with advanced biliary tract cancers: an effective strategy within the prospective MOSCATO-1 trial. Eur J Cancer. 2017;87:122. 25. Kim RD, et al. A phase 2 multi-institutional study of nivolumab for patient with advanced refractory biliary tract cancer. JAMA Oncol. 2020;6(6):888. 26. Klein O, et al. Evaluation of combination nivolumab and ipilimumab immunotherapy in patients with advanced biliary tract cancers: subgroup analysis of a phase 2 nonrandomized clinical trial. JAMA Oncol. 2020;6(9):1405. 27. Silva VWK, et al. Biliary carcinomas: pathology and the role of DNA mismatch repair deficiency. Chin Clin Oncol. 2016;5(5):62.

Part IV Pancreatic Malignancies

Approach to the Patient with a Pancreatic Mass

24

Daniel Lew, Shreyas Srinivas, and Karl Kwok

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398

2 2.1 2.2 2.3 2.4 2.5

Differential Diagnosis for Pancreatic Masses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cystic Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Solid Exocrine/Space Occupying Masses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Autoimmune Pancreatitis (AIP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pancreatic Ductal Adenocarcinoma (PDAC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Solid Endocrine Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3

General Considerations for Diagnosis of a Pancreatic Mass . . . . . . . . . . . . . . . . . 407

4

Algorithm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410

5

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410

398 398 398 398 402 406

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411

Abstract

“Pancreatic mass” is a term that instantly terrifies patients. However, the list of possible etiologies is broad, and includes even benign

D. Lew Kaiser Permanente, Baldwin Park Medical Center, Baldwin Park, CA, USA e-mail: [email protected] S. Srinivas Department of Internal Medicine, Kaiser Permanente, Fontana Medical Center, Fontana, CA, USA e-mail: [email protected]

lesions (for instance, pancreatic cysts incorrectly referred to as a mass). Using a systematic, algorithmic approach for evaluating focal pancreatic lesions, a physician can not only select the proper diagnostic tests but also involve the appropriate multispecialty services in a timely manner. Keywords

Pancreatic Ductal Adenocarcinoma · Autoimmune pancreatitis · Chronic pancreatitis · Solid pseudopapillary epithelial neoplasm · Acinar cell carcinoma · Neuroendocrine tumor

K. Kwok (*) Division of Gastroenterology, Kaiser Permanente, Los Angeles Medical Center, Los Angeles, CA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2022 C. Doria, J. N. Rogart (eds.), Hepato-Pancreato-Biliary Malignancies, https://doi.org/10.1007/978-3-030-41683-6_26

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Introduction

Because of the generally grim prognosis for pancreatic ductal adenocarcinoma (PDAC), simply the mention of a “pancreatic mass” is instantly terrifying to the patient. On the one hand, surgery is the only hope for long-term cure in situations of resectable PDAC. On the other hand, because the list of possible etiologies includes treatable and even benign conditions (or even pancreatic cysts mislabeled as a pancreatic mass), proper context and diagnosis is the cornerstone to correct management and prognosis. Although many physicians have a working knowledge of the top two or three possibilities for pancreatic masses, the differential diagnosis is quite expansive – ranging from benign lesions such as autoimmune pancreatitis or chronic pancreatitis to malignant lesions such as solid transformation of cystic neoplasm, acinar cell carcinoma, or lymphoma, and to rare lesions such as pancreatoblastoma [1]. In the absence of symptoms attributable to pancreatic disease (e.g., obstructive jaundice or pancreatitis), most often the pancreatic mass is incidentally discovered in the course of workup of another clinical issue. For instance, in a fiveyear review of over 100 patients at a large academic surgical practice, the asymptomatic pancreatic lesion was most often seen during investigation of genitourinary/renal complaints (16%), evaluation of abnormal liver function tests (13%), or even during workup of chest pain (6%) [2]. Therefore, the goal of this chapter is not only to review the differential diagnoses of pancreatic mass lesions, but also offer a compendium of the available literature, as well as a diagnostic strategy to approach pancreatic mass lesions.

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Differential Diagnosis for Pancreatic Masses

It is important to develop a systematic framework when assessing a pancreatic lesion. Because it is not uncommon for pancreatic cysts to be labeled under the umbrella term of “pancreatic mass” in

radiology reports, we will begin our differential diagnosis by discussing briefly pancreatic cystic lesions. Next, attention is turned toward solid exocrine or space occupying pancreatic lesions (both benign and malignant), followed by a discussion of solid endocrine lesions (neuroendocrine tumors).

2.1

Cystic Lesions

With the increasing use of cross-sectional imaging, the prevalence of incidental pancreatic cysts has increased with an incidence ranging from 2–15% in asymptomatic individuals [3].

2.2

Solid Exocrine/Space Occupying Masses

Because of the expansive differential diagnoses for solid pancreatic masses, it is necessary to approach this systematically – from common and uncommon to benign and malignant, as well as metastatic lesions to the pancreas.

2.2.1 Benign The two main benign solid exocrine masses are autoimmune pancreatitis and chronic pancreatitis. Both disease processes can have inflammatory masses that may mimic PDAC, and the underlying parenchymal/ductal changes may make it difficult to differentiate an inflammatory mass from an underlying malignancy.

2.3

Autoimmune Pancreatitis (AIP)

Autoimmune pancreatitis (AIP) was first described by Japanese researchers in 1995 as an autoimmune process generally responsive to steroids. Six years later, a different group of Japanese researchers identified the presence of elevated IgG4 levels in Japanese patients with AIP. This understanding was further refined 2 years later, when scientists identified extra-pancreatic involvement of IgG4laden plasma cells, confirming AIP can be involved in a systemic disease known as IgG4-related

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Approach to the Patient with a Pancreatic Mass

disease [4]. Fourteen years after initial reports of a steroid-responsive pancreatitis, two types of AIP were recognized: type I AIP, which refers to lymphoplasmacytic sclerosing pancreatitis, and type II AIP, which refers to idiopathic duct-centric pancreatitis [5]. AIP has a low prevalence of roughly 60 years old, presence of obstructive jaundice, weight loss in the last 6 months, elevated ALT, AST, and CA 19-9 [28]. However, these models have never been tested in a prospective study and these risk factors can also be seen in patients with CP. In summary, it is crucial to differentiate malignant from benign lesions to prevent misdiagnosis and delay in management. While there is

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significant overlap in terms of clinical presentation and imaging findings, there are still clues in the diagnostic workup that can help in the diagnosis.

2.3.2 Malignant Malignant exocrine pancreatic masses of course will include PDAC, which has the worst prognosis and any evaluation of a pancreatic mass should exclude PDAC. Beyond PDAC, we will go over other solid malignant exocrine masses including solid pseudopapillary tumor, acinar cell carcinoma, lymphoma, pancreatoblastoma, and metastases to the pancreas.

2.4

Pancreatic Ductal Adenocarcinoma (PDAC)

Pancreatic ductal adenocarcinoma (PDAC) accounts for over 90% of all malignant exocrine tumors in the pancreas. It is currently the fourth leading cause of cancer-related deaths in the USA and is projected to become the second leading cause by 2030 [29]. The five-year relative survival rate is 9%, but does improve to 20–30% if the patient is able to undergo surgical resection for early disease [30]. Unfortunately, only 25% of patients are found at a stage where surgical resection is possible. Thus, given the significant mortality associated with PDAC and its aggressive nature, it is imperative to always consider PDAC in a patient with a pancreatic mass to avoid misdiagnosis or any delay in diagnosis. There is a slight male predominance in PDAC cases, with an incidence of 15.08 males per 100,000 and 11.59 females per 100,000. African Americans have a higher risk compared to the White population with an incidence of 16.3 per 100,000 compared to 13.0 per 100,000 [31]. Most patients are diagnosed with sporadic PDAC over 50 years old with the highest peak between 60 and 80 years old. Other factors in a patient’s history that should raise suspicion for PDAC in a newly diagnosed pancreatic mass include alcohol abuse; smoking; obesity; new-onset diabetes above the age of 50; chronic pancreatitis; an index episode of acute pancreatitis over 40 years old; family

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Approach to the Patient with a Pancreatic Mass

history of PDAC in at least two first-degree relatives; or patients who have inherited cancer syndromes such as hereditary pancreatitis, PeutzJeghers syndrome, familial atypical malignant mole and melanoma syndrome, BRCA1/BRCA2 mutations, and hereditary nonpolyposis colorectal cancer syndrome [32]. Patients often present with generalized fatigue, weight loss, and abdominal pain, which can be seen in 80% of patients. Jaundice can also occur in 50–60% of patients due to PDAC located in the head of the pancreas causing ductal obstruction. Another common clinical finding is steatorrhea from fat malabsorption due to pancreatic duct obstruction (and therefore insufficient pancreatic lipase release) [33]. If there is high clinical suspicion that the pancreatic mass is malignant, CA 19-9 can aid in the diagnosis. However, a caveat is that CA 19-9 can be falsely elevated in patients with cholangitis with false positive rates ranging from 10–60% [14]. It is similarly well known that up 10% of the Caucasian population may not express the Lewis blood group antigen and hence have unmeasurable CA 19-9 levels, even in the presence of PDAC. Biopsies should be obtained if CT or MRI are inconclusive and can be obtained endoscopically with EUS (or less commonly, percutaneously via interventional radiology, given the potential for tumor seeding with the percutaneous route, and the increased diagnostic accuracy and ability to further evaluate the lesion with EUS, endoscopic biopsies are strongly preferred if available) [34]. Histologically, there is an intense desmoplastic reaction within the tumor composed of fibroblasts, inflammatory cells, endothelial cells, and a complex extracellular matrix. Other findings commonly seen include perineural and vascular invasion, disorganized array of glands, and large variations in size of the nuclei [35].

2.4.1

Solid Pseudopapillary Epithelial Neoplasm (SPEN) Solid pseudopapillary epithelial neoplasm (SPEN) is a rare tumor first described by Frantz in 1959. There have been many historical names due to both solid and papillary components

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including solid and papillary tumor, solid-cystic tumor, papillary cystic tumor, and papillary epithelial neoplasm. In 1996, the WHO classification has classified these tumors as “solid pseudopapillary tumors.” SPEN are rare tumors, accounting for 0.13–2.7% of pancreatic tumors. Tumors are commonly located in the tail or the head. There is a strong predilection for women, affecting 10 females:1 male. The average age of diagnosis is 22 years old, which is in stark contrast to PDAC and the other solid pancreatic tumors with an average age of diagnosis in the sixth decade of life [36]. The overall behavior of SPEN is less aggressive than other pancreatic tumors, with an associated better prognosis as most cases are benign, indolent, or low-grade malignant tumors. However, metastatic disease can occur with one series noting 15% of cases having metastasis at initial diagnosis. Metastatic disease most commonly affects the liver or the omentum [36]. Prognosis is very good after surgical resection of isolated pancreatic SPEN with a five-year survival rate of 95–97% [37]. Even with liver metastasis, surgery can still be offered, with either resection or ablation of the liver metastasis [36]. If the initial assessment has deemed the tumor to be unresectable, case reports have shown that neoadjuvant chemoradiation to be effective for tumor debulking and downstaging so that surgery can ultimately be performed [36]. The clinical presentation includes nonspecific symptoms such as abdominal pain, palpable abdominal mass, and abdominal discomfort. Moreover, 15–30% of patients are asymptomatic with SPEN diagnosed as an incidental finding [36, 38]. The diagnosis is primarily imaging driven; laboratory studies are generally not helpful for diagnosis of SPENs. Typical imaging findings include a heterogenous, well-encapsulated mass with solid and cystic components (Fig. 5) [39]. Additionally, SPENs have varying degrees of internal hemorrhage cystic degeneration, and peripheral calcifications. Findings suggestive of malignant disease include pancreatic duct dilation, vessel invasion, and metastases. Some studies have suggested MRI to be superior to CT for diagnosis

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Fig. 5 SPEN in the tail of the pancreas showing the classic well-encapsulated mass

due to increased ability of MRI to depict the tumor capsule and intratumoral hemorrhage. Biopsies may be helpful for SPENs which do not look prototypical (e.g., situations in which the lesion is more homogeneous than expected, or poorly encapsulated than expected). Histologically, myxoid stroma with branching papillae is consistent for SPENs. There are other variants, including clear cell, pleomorphic, and oncocytic. Histologic features that correlate with malignant disease include extensive necrosis, nuclear atypia, high mitotic rate, and sarcomatid areas. Similar to other pancreatic tumors such as PDAC, angioinvasion and deep invasion of surrounding pancreatic parenchyma are also associated with malignancy [36, 38]. In summary, SPENs are diagnosed in young women with abdominal pain, a palpable mass, or incidentally. Typical imaging findings include a heterogenous, well-encapsulated mass, and overall prognosis is good.

2.4.2 Acinar Cell Carcinoma (ACC) Acinar cell carcinoma (ACC) is rare and accounts for 1–2% of all pancreatic malignant tumors [40]. Patients tend to be slightly younger on initial diagnosis when compared to PDAC, with a mean age of 58 years (range 28–85 years) [41]. There is a male predominance (3.6 males: 1 female), and similar to PDAC, African Americans have a higher risk for ACC compared to Caucasians.

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Although not as dismal of a prognosis as PDAC, ACC is still generally associated with a poor prognosis with 40% of patients having nodal metastasis and 13% of patients having distant metastasis on initial diagnosis. The five-year survival rate for resectable tumors range from 42–77%, while the five-year survival rate for unresectable tumors is 22% [40]. Patients often present with nonspecific symptoms of weight loss (52%), abdominal pain (32%), nausea and vomiting (20%), weakness, anorexia, or diarrhea (8%) [40]. A unique presentation in patients with ACC is pancreatic panniculitis and lipase hypersecretion syndrome. Given that this tumor arises from acinar cells, release of excessive amounts of pancreatic enzymes including lipase, amylase, trypsin, and chymotrypsin can occur. Thus, it is important to check serum lipase and amylase in these patients, although serum levels may not be elevated [41]. In 10% of patients with ACC, extremely high levels of lipase can be seen with a mean serum lipase of 11,560 U/l. A lipase cutoff of 4,414 U/l was found to have the best sensitivity of 73% and specificity of 82.1% to differentiate between malignancy and pancreatitis (AUC ¼ 0.785, 95% CI 0.68 to 0.89) [42]. As a result of the high levels of lipase, lipase hypersecretion syndrome can occur, which can manifest as pancreatic panniculitis and arthritis. Up to 45% of patients can present with pancreatic panniculitis before the underlying disease is recognized. Thus, this finding can serve as an important diagnostic aid for identifying the underlying disease. The panniculitis is characterized as subcutaneous nodules which commonly start on the extremities and spread throughout the body. The mechanism of panniculitis development is not well understood but is thought to be due to lipase and amylase causing lipolysis and fat necrosis in the skin. Lipase hypersecretion syndrome, while most commonly seen in patients with ACC, is not specific to ACC and has been seen in patients with PDAC or other pancreatic diseases that have high lipase levels [42]. Serum tumor markers such as CA 19-9 are not uniformly elevated in these patients. Other tumor markers may also be elevated including alpha fetoprotein (AFP) and CEA [43].

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Imaging findings include a well-demarcated and exophytic lesion, in contrast to PDAC which is often ill-defined, with a thin, enhanced capsule. Central calcification and hypodensity are also commonly seen, which are not usually seen with PDAC. Furthermore, ductal obstruction is not as commonly seen as in PDAC, even with ACC located in the head, due to the tumor cell origin (acinar cell versus pancreatic ductal cells). Lesions often enhance homogenously but less than the surrounding parenchyma [44]. Biopsies are often necessary to support the diagnosis. Histologically, solid and acinar patterns are commonly seen with abundant zymogen granules seen in the cytoplasm which appear eosinophilic and granular. Furthermore, these zymogen granules can be stained with periodic acid-Schiff (PAS) for confirmation [45]. Primary Pancreatic Lymphoma (PPL) Primary pancreatic lymphoma (PPL) is extremely rare and accounts for less than 0.5% of malignant pancreatic tumors and less than 1% of extranodal non-Hodgkin’s lymphoma (NHL). There is again a male predominance (7 males:1 female), and patients are usually diagnosed in their 60s (range 40–84 years) [46]. Prognosis is superior compared with PDAC with 84% of patients diagnosed with stage I and II disease, and as result, the fiveyear survival rate is 56% [47]. Because this is a hematologic malignancy, treatment primarily consists of chemotherapy with or without radiotherapy, which highlights the importance of undertaking pretreatment biopsy so that proper treatment may be offered. Clinically, patients most commonly present with abdominal pain (83%), weight loss (50%), and jaundice (37%). The classic B-type symptoms of nodal NHL (fevers, chills, and night sweats) can also be seen in 38% of patients [47]. Lesions are more commonly found in the head of the pancreas, and can have varying sizes of 2–15 cm [48]. On imaging, there have been two patterns of CT findings described in the literature: [1] a welldefined mass or [2] a large infiltrating lesion with poorly defined contours. On MRI, lesions appear as a homogenous mass on T1-weighted images

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with subtle postcontrast enhancement and are heterogenous on T2-weighted images [49]. Given their predilection for the head of the pancreas, nonspecific clinical symptoms, and solitary mass on imaging, PPL is commonly mistaken for PDAC. However, there are clues on imaging that may favor PPL over PDAC including enlargement of lymph nodes below the renal vein, and infiltration of the retroperitoneum or surrounding organs. Furthermore, despite the mass located in the head of the pancreas, significant pancreatic duct dilation is not commonly seen with PPL as compared to PDAC [49]. It is also very important to distinguish PPL from secondary involvement of the pancreas by lymphoma given the potential different management options and prognosis. The absence of superficial or mediastinal lymphadenopathy and a main pancreatic mass with lymph node involvement only in the peripancreatic region are signs suggestive of PPL [50]. Unless contraindicated, biopsies should be obtained along with flow cytometry given the primary treatment is chemotherapy. Histologically, most PPLs are intermediate or high-grade NHL with diffuse large cell lymphoma seen in 60%. Most cases are B cell lymphomas, and as such, CD20 expression is seen on flow cytometry [51].

2.4.3 Pancreatoblastoma Pancreatoblastomas are rare malignant pancreatic tumors that are thought to originate from stem cells. The name “pancreatoblastoma” was derived from histological resemblance to fetal pancreatic tissue [52]. Pancreatoblastomas are almost exclusively found in children. For instance, 25% of all childhood pancreatic tumors are pancreatoblastomas, while only 0.5% of malignant pancreatic tumors in adults are pancreatoblastomas. This tumor is aggressive with more than half of patients having locally advanced or metastatic disease on initial diagnosis. Interestingly, pancreatoblastoma prognosis is much better for children compared to adults, with five-year survival of 79% compared to a median survival of 15 months, respectively [52]. Patients present with abdominal pain (45%), weight loss (29%), and jaundice (19%). There is a predilection for being located in the head or the

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tail. For children (but not with adults) with pancreatoblastoma, AFP may be elevated. Imaging findings suggestive of pancreatoblastoma include a multilobulated, multiseptated, well-defined lesion. On MRI, there is heterogenous enhancement with low to intermediate signal intensity on T1-weighted images and high signal intensity on T2-weighted images [53]. Histologically, pancreatoblastomas are composed of small, polygonal, or spindle-shaped cells mixed with acinar, duct, or islet cells and “squamoid” bodies or nests, which give it a squamous appearance [54]. The typical treatment is surgical unless contraindicated.

2.4.4 Metastases Roughly 2% of malignant pancreatic tumors are metastatic deposits from malignancies elsewhere in the body. Many studies and autopsy series have suggested renal cell carcinoma (RCC) is the most common malignancy to metastasize to the pancreas, ranging from 45–62% of all metastatic tumors [55]. Other cancers which can metastasize to the pancreas include lung (small cell lung cancer), colon, breast, and melanoma [56]. Surgical resection is the preferred treatment for isolated pancreatic metastasis, with a systematic review reporting a five-year survival rate of 50% after resection. However, the majority of patients had primary RCC, which has a better prognosis compared to other primary malignancies with five-year survival of 70% [56]. Of note, pancreatic metastasis from RCC occurs on average 7–10 years after nephrectomy, and has even been known to occur more than 20 years after nephrectomy [57]. Metastatic processes in the pancreas often present a diagnostic dilemma, mostly in differentiating between primary and secondary neoplasms. Both clinical and radiographic presentations can be similar. Lesions may be found during routine surveillance of the primary tumor or by the onset of nonspecific symptoms. Pancreatic metastases can invade the pancreatic duct epithelium, thus mimicking primary PDAC. Symptom presentation for secondary pancreatic tumors is often nonspecific and can include abdominal pain, back pain, weight loss, nausea, melena, and jaundice. They may manifest in two main settings, either in

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the setting of widespread disease or as an isolated mass of the pancreas [58]. On imaging, CT scan is preferred given the ability to identify extra-pancreatic metastases, which can help differentiate between a primary and secondary pancreatic tumor. Metastatic lesions from RCC appear hypervascular on CT scans with well-defined margins and central low attenuation, which are similar imaging findings to NETs. A retrospective study found that NETs were larger (37 mm vs. 26 mm), more often solitary, contained calcifications, and more heterogenous when compared to pancreatic tumors from primary RCC [59]. Therefore, as in several other clinical situations detailed in this chapter, EUS-guided biopsy remains the cornerstone of accurate diagnosis.

2.5

Solid Endocrine Lesions

2.5.1 Neuroendocrine Tumor (NET) Neuroendocrine tumors (NETs) are neoplasms that originate in the endocrine tissues of the pancreas, and they account for approximately 2–3% of all pancreatic tumors [60]. Incidence rates have been rising, likely due to increased detection of incidental NETs with the increased use of crosssectional imaging. NETs can be subdivided into functional and nonfunctional tumors based on hormone secretion and the resulting clinical syndrome. Insulinoma, gastrinoma, glucagonoma, somatostatinoma, and vasoactive intestinal polypeptide (VIPoma) are examples of functioning NETs where the primary hormone secreted is insulin, gastrin, glucagon, somatostatin, and VIP, respectively. Around 50–75% of patients have nonfunctioning tumors [61]. In general, prognosis is defined by the grade and stage of the tumor rather than the functionality, although functional tumors often lead to diagnosis at an earlier stage given the presence of symptoms. Tumor grading relies on histologic measurements of proliferative index (Ki67 and mitotic index). More indolent tumors are often well differentiated based on proliferative rate and reflect a good prognosis. More aggressive tumors are often poorly differentiated [62]. Therefore, nonfunctional tumors tend to

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have a worse prognosis as they are diagnosed at a later stage than functional tumors, and the fiveyear survival ranges from 27–62% [63]. The average age of patients diagnosed with NETs is 60, with a slightly greater prevalence in men than women [64]. Most NETs are sporadic, but approximately 10% are associated with hereditary endocrinopathies including multiple endocrine neoplasia type 1 (MEN1), von HippelLindau disease (VHL), neurofibromatosis type 1 (NF1), and tuberous sclerosis (TSC). Of these hereditary etiologies, approximately 80–100% of patients with MEN1, 20% with VHL, 10% with NF1, and 1% with TSC will develop NETs during their lifetime [64]. Clinical symptoms are variable and depend on functionality. With insulinomas, for example, hypoglycemia may be observed. Interestingly, insulinomas may be associated with weight gain due to the patient’s learned behavior to eat excessively in an effort to prevent symptoms of hypoglycemia. Gastrinomas, meanwhile, present with abdominal pain and diarrhea. VIPomas present with watery diarrhea. Glucagonomas present with glucose intolerance, necrolytic migratory erythema, and stomatitis. Somatostatinomas present with steatorrhea and cholelithiasis due to its inhibitory effects on bile formation and secretion. Nonfunctioning NETs have nonspecific symptoms including abdominal pain, weight loss, and nausea [65]. Diagnostic workup can include laboratory studies such as chromogranin A, neuron-specific enolase, and pancreatic polypeptide, which can be seen in both functional and nonfunctional NETs [66]. Imaging characteristics are detailed below.

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General Considerations for Diagnosis of a Pancreatic Mass

1. Is the lesion solid, cystic, or a combination of both? 2. What are worrisome radiographic features of various pancreatic masses? 3. What is the best strategy to work up radiographic findings to secure a correct and timely diagnosis?

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The differential diagnoses of a pancreatic lesion are refined depending on the lesion’s characteristics – size, shape, appearance, ductal communication, and presence of fluid component. However, clinical history is essential to the proper diagnosis, as lesions can either be cystic degeneration of a solid mass, or a malignant transformation (i.e., mass formation) of a cystic neoplasm. Depending on clinical presentation, anatomic variation (i.e., obesity/presence of intervening bowel gas), operator experience, and location of the lesion, a transabdominal ultrasound may occasionally offer useful information as part of the diagnostic workup [67]. For instance, in the properly selected patient, a pancreatic cyst will appear anechoic with posterior acoustic enhancement, similar to what is seen on an EUS. Similarly, a transabdominal ultrasound may reveal clues that suggest CP, including atrophic parenchyma and pancreatic calcifications with post-acoustic shadowing. However, there is a uniformly poor performance of transabdominal ultrasound when attempting to interrogate the pancreatic head, due to its deep retroperitoneal location. For example, in situations of obstructive jaundice, the transabdominal ultrasound will typically only reveal a dilated common bile duct (CBD), but will be unable to visualize the pancreatic/periampullary region. In fact, a transabdominal ultrasound is not even considered as part of the diagnostic algorithm of pancreatic masses in a recent Cochrane review on the topic [68]. Therefore, for most practical purposes, CT scans are often the first study ordered for further characterization of a pancreatic mass. Although definitive diagnosis of a pancreatic mass in 2020 typically benefits from a comprehensive multimodality evaluation, some general patterns can be gleaned based on tomographic appearance. For instance, PDAC (discussed in detail in a separate ▶ Chaps. 25, “Evaluation and Management of the Patient with a Pancreatic Cyst”, ▶ 27, “Pathogenesis, Epidemiology, and Prognosis of Pancreatic Adenocarcinomas”) may appear as an hypoattenuating mass with ill-defined borders, as well as upstream pancreatic duct dilatation [69]. A dual-phase CT (arterial and portal phase) is particularly useful, not only to define the tumor, but

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also to assess for vascular involvement. Typically, the arterial phase of the study is taken approximately 30 s after intravenous (IV) contrast administration; the portal phase approximately 60 s after IV contrast. Because a focal pancreatic mass may not be visualized up to 10% of the time in situations of an isoattenuating mass, other indirect tomographic clues are essential to the correct diagnosis, including abnormal pancreas contour (shape), loss of peripancreatic fat plane with soft tissue around key vasculature (suggestive of vascular encasement), vessel deformity or thrombosis, or upstream pancreatic +/ biliary ductal dilation [69]. Although serologic markers such as CA 19-9 should not be relied upon for the initial diagnosis of PDAC (not only due to its elevation in nonmalignant disease such as chronic pancreatitis, cirrhosis, and cholangitis, but also due to the 10% of patients who do not express the Lewis blood group antigen and hence have unmeasurable CA 19-9 levels), it may be useful to monitor response to treatment in tissue-proven PDAC [70]. MRI, meanwhile, can be seen as complementary to CT – this modality, for instance, has superior contrast resolution and offers 5–10% higher accuracy compared with CT at detection of pancreatic adenocarcinoma, and performs superiorly in detection of cystic components through the T2 sequences. Additionally, through advanced application of MRI modalities such as diffusionweighted imaging, a distinction can be made between PDAC and focal pancreatitis [71]. However, MRI offers lower spatial resolution compared with CT [67], and is generally less accessible than CT scans (not only in terms of exam times, but also limited availability of MRI machines compared with CT scanners, as well as various limitations such as individuals with metal implants and claustrophobia). EUS, meanwhile, offers still more complementary information to the two aforementioned modalities – not only can it detect diminutive mass lesions as small as 0.2 cm, but can also adjudicate whether a lesion is solid, cystic, or mixed. Additionally, EUS-guided biopsy now allows for tissue acquisition not only to secure a diagnosis, but also with the advent of reliable fine

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needle biopsy (FNB) devices, next-generation genomic testing for precision medicine can be performed. However, the primary limitations of EUS are its relatively limited availability (although this is less of an issue in 2020, with many community practices having established referral patterns to tertiary referral centers), and more importantly, the modality’s steep learning curve. In fact, EUS is no longer recommended as a routine staging tool based on the 2020 NCCN guidelines [72]. In contrast, NETs more often have a distinct round appearance with well-circumscribed borders (Fig. 6). The CT appearance of NETs depend in part on its proliferative index – while typically hyperattenuating in appearance due to its vascularity. NETs with high proliferative index (Ki-67 > 50%) may instead appear hypoattenuating with necrosis, similar to PDAC [67]. The role of positron emission tomography/computed tomography (PET-CT) scan is well established in the evaluation of NET. Two radiotracers are now in clinical use – 18-fluorodeoxyglucose (18-FDG) and [68]Gallium ( [68]Ga) dotatate. Although FDG-PET has low clinical specificity for NET due to its inability to separate neoplasm from inflammation and other hypermetabolic situations, it may be useful for following a NET response to chemotherapy. On the other hand, it is now demonstrated that [68]Ga-DOTA performs even better than octreotide scans for NET. Thus, the combination of [68]Ga-DOTA and

Fig. 6 NET in tail of pancreas showing the typical round and well-circumscribed mass

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18-FDG may actually be a useful combination, where the former confirms the diagnosis, and the latter confirms low metabolic activity (and hence can act as a surrogate for low Ki-67 mitotic index) [67]. As in the case of PDAC, MRI can offer complementary information for the diagnosis of NET but remains a second-line investigative technique. Although specialized strategies such as T1 sequence, fat suppression technique, and diffusion weighted images can be used to detect NET and grade, in other clinical scenarios MRI detection can perform poorly compared with CT scan or even transabdominal ultrasound with IV contrast [67]. In general, EUS performs well in the detection of NETs. One systematic review of over 600 patients, for instance, found a 26% incremental benefit of EUS in detecting NETs over standard CT scan (95% CI, 17–37%) [73]. In general, NETs appear as solid, homogeneous, well-demarcated lesions on EUS. Approximately half of NETs are hypervascular on MRI, and this phenomenon of increased vascularity of NET is also observed on EUS exams; in fact, this may be useful to distinguish NETs from PDAC [74]. SPENs, typically seen in young females, are often large and well encapsulated; they can have a radiographic appearance of either a solid to partially cystic mass depending on whether intratumoral bleeding has occurred. The diagnosis can be secured with EUS-guided biopsy demonstrating myxoid stroma with branching papillae. CP, though often showing pathognomonic findings such as dilation of main and side branch pancreatic ducts (PD) as well as diffuse parenchymal calcification and gland atrophy [75], can manifest as focal mass-like lesions, which is clinically worrisome because CP itself is a risk factor for PDAC, with a 5% risk over 20 years. One strategy to distinguish PDAC and CP is the presence of a “duct penetrating sign,” wherein a smooth or even normal PD traverses the mass, which is more often associated with CP than PDAC [67]. Although AIP often has a prototypical appearance of a “sausage shaped” gland with peripancreatic halo, it can also present as a focal mass lesion. Depending on location in the

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pancreas, this can also present as painless jaundice, and can be very difficult to distinguish from PDAC. One strategy is to look for delayed contrast uptake in late sequences, which helps distinguish focal AIP from PDAC. However, in routine clinical practice, an EUS-FNA or FNB is often requested for histologic confirmation, with resultant histologic findings of cancer cells or findings suggestive of AIP. For type I AIP which is more commonly seen in elderly men, for instance, there can be widespread extra-pancreatic involvement; elevated serum IgG4 concentration; and on pancreatic biopsy, evidence of extensive lymphoplasmacytic infiltration of IgG4-positive cells, obliterative phlebitis, and storiform fibrosis. For type II AIP, which is usually in younger patients without sex predilection, the histologic pattern is one of granulocytic epithelial involvement of the pancreatic duct with little to no IgG4positive plasma cells. Collectively, these features are components of the HISORt criteria. Because the sensitivity of EUS-FNA can be somewhat disappointing (approximately 40%) [76], if malignancy has been reasonably excluded or even in atypical AIP cases, it may be reasonable to consider a course of steroids for diagnostic and therapeutic purposes, particularly if a radiographic response occurs [77]. In contrast to NETs, pancreatic cysts (which is afforded a whole chapter unto itself within this reference book “Approach to the Patient with a Pancreatic Mass”) are often well characterized with MRI pancreas protocol, due to MRI’s superior performance in not only detecting cystic components (via T2 intensity), but also due to its ability to characterize ductal communication and presence of solid components which may signify malignant transformation. In fact, a 2015 comparative study among 148 patients undergoing pancreatectomy for pancreatic cystic neoplasms revealed that MRI pancreas protocol yielded the highest diagnostic accuracy (80/92, or 86%), followed by CT (76/94, or 81%), followed by EUS (103/138, or 74%) [78]. The role of EUS-FNA and biochemical analysis (e.g., cyst fluid CEA) will be covered in detail in a subsequent chapter “Approach to the Patient with a Pancreatic Mass”.

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D. Lew et al. Clinical presentation, history, and physical

Imaging, preferably contrast-enhanced1

Indeterminate or solid-cysc pancreac lesion

Solid pancreac lesion

Cysc pancreac lesion

Multidisciplinary review2

NET, PDAC, CP, AIP, metastases, lymphoma, other2? (based on multidisciplinary review)

Possibility of mucinous cystic lesion (IPMN, MCN)?

Possible PDAC / NET

Possible AIP

Possible lymphoma3

All others (CP, etc)

Yes / Indeterminate

Follow published guidelines 4

Advanced imaging as indicated (e.g. CT 3 phase pancreas, MRI/MRCP, octreotide scan, PET/CT, 68Ga-DOTA, others) Follow HISORt criteria

If sampling indicated: EUS with FNA or FNB5

Unlikely

Further management with guidance from gastroenterology

Addional subspecialist referral(s) as indicated: HPB surgeon, radiaon oncologist, medical oncologist

1 – depending on situation and local availability. Options include contrast-enhanced CT, or transabdominal ultrasound in select circumstances 2 – ideally, a “tumor board” including a hepatopancreaticobiliary (HPB) surgeon, a body radiologist, and an interventional gastroenterologist 3 – ensure proper workflow including availability of FNB to achieve core tissue, availability of proper transport media including RPMI / Hank’s solution, access to flow cytometry, and access to hematopathologist 4 – options include the 2015 AGA Institute Guidelines, 2017 updated international consensus Fukuoka guidelines, and 2018 ACG Clinical Guidelines 5 – increasingly, tumors may benefit from core biopsy to facilitate testing for cancer genomics and immunotherapy biomarkers such as PD-L1, MSI, ALK, ROS1, EGFR, and others AIP – autoimmune pancreatitis; ALK - Anaplastic Lymphoma Receptor Tyrosine Kinase Gene; CP – chronic pancreatitis; CT – computed tomography; EGFR – epidermal growth factor receptor; EUS with FNA or FNB – endoscopic ultrasound with fine needle aspiration or fine needle biopsy; 68Ga-DOTA – 68-Gallium Dotatate; HISORt – Histology, Imaging, Serology, Other organ involvement, Response to treatment; HPB – hepatopancreaticobiliary surgeon, also known as surgical oncologist; IPMN – intraductal papillary mucinous neoplasm; MCN – mucinous cystic neoplasm; MRI/MRCP – magnetic resonance imaging/magnetic resonance cholangiopancreatography; MSI – microsatellite instability; NET – neuroendocrine tumor; PDAC – pancreatic ductal adenocarcinoma; PET/CT – positron emission tomography/computed tomography; ROS1 – Repressor of Silencing 1 gene; RPMI – Roswell Park Memorial Institute

Fig. 7 Suggested algorithm for systematic management of focal pancreatic lesions

Lastly, despite the multitude of diagnostic options available for workup of pancreatic masses, in certain situations a lesion may elude multiple efforts at proper diagnosis, even after several attempts at EUS-FNA or FNB (e.g., intra-pancreatic metastasis of renal cell carcinoma). Recent meta-analyses evaluated the utility of repeating EUS-FNA of pancreatic masses after initial nondiagnostic or inconclusive results, and concluded that a repeat EUS-FNA increased the diagnostic accuracy with 77% sensitivity, 98% specificity, positive predictive value of 99%, and negative predictive value of 61% [79]. Thus, there is utility to repeat EUS-FNA if the initial biopsies were inconclusive and the clinical suspicion is still high. However, it may be inevitable to undergo an exploratory laparotomy with resection if the clinical suspicion remains high of a malignant disease despite multiple negative biopsy results [80].

immediately applicable into the practicing gastroenterologist (see Figure 7 for algorithm). The first step in the decision tree is to identify whether the lesion is solid, cystic, or indeterminate. This is ideally determined with a contrast-enhanced cross-sectional imaging study. The lesion’s solid or cystic characteristics has direct implications on whether one needs to pursue additional enhanced imaging, to engage in multidisciplinary “tumor board” review, or to follow international consensus guidelines on mucin-producing cystic neoplasms. The next step is typically to proceed with acquiring further information – generally, histology via EUS-guided FNA or FNB. Lastly, with the combination of imaging and histologic criteria, a proper determination can be made as to the proper subspecialist referral (a hepatopancreaticobiliary (HPB) surgeon, a radiation oncologist, or a medical oncologist).

5 4

Conclusion

Algorithm

Due to the broad differential diagnosis of pancreatic lesions, it is important to have a comprehensive yet easy-to-use algorithm which can be

As is apparent by this point in the chapter, the differential diagnosis of pancreatic lesions is quite expansive. However, a logical, algorithmic approach which takes into consideration multiple

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Approach to the Patient with a Pancreatic Mass

data points (taking the correct history, ordering the proper imaging studies, obtaining a tissue biopsy, and reviewing challenging cases in a multidisciplinary fashion) remains the cornerstone to proper and timely management of various pancreatic lesions.

References 1. Basturk O, Askan G. Benign tumors and Tumorlike lesions of the pancreas. Surg Pathol Clin. 2016;9(4): 619–41. 2. Sachs T, Pratt WB, Callery MP, Vollmer CM Jr. The incidental asymptomatic pancreatic lesion: nuisance or threat? J Gastrointest Surg. 2009;13(3):405–15. 3. Lee KS, Sekhar A, Rofsky NM, Pedrosa I. Prevalence of incidental pancreatic cysts in the adult population on MR imaging. Am J Gastroenterol. 2010;105(9): 2079–84. 4. Hart PA, Zen Y, Chari ST. Recent advances in autoimmune pancreatitis. Gastroenterology. 2015;149(1): 39–51. 5. O’Reilly DA, Malde DJ, Duncan T, Rao M, Filobbos R. Review of the diagnosis, classification and management of autoimmune pancreatitis. World J Gastrointest Pathophysiol. 2014;5(2):71–81. 6. Sugumar A, Takahashi N, Chari ST. Distinguishing pancreatic cancer from autoimmune pancreatitis. Curr Gastroenterol Rep. 2010;12(2):91–7. 7. Wakabayashi T, Kawaura Y, Satomura Y, et al. Clinical and imaging features of autoimmune pancreatitis with focal pancreatic swelling or mass formation: comparison with so-called tumor-forming pancreatitis and pancreatic carcinoma. Am J Gastroenterol. 2003;98(12): 2679–87. 8. Ghazale A, Chari ST, Smyrk TC, et al. Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer. Am J Gastroenterol. 2007;102(8):1646–53. 9. Chari ST, Smyrk TC, Levy MJ, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol. 2006;4(8):1010–6. quiz 934 10. Sandanayake NS, Church NI, Chapman MH, et al. Presentation and management of post-treatment relapse in autoimmune pancreatitis/immunoglobulin G4-associated cholangitis. Clin Gastroenterol Hepatol. 2009;7(10):1089–96. 11. Shimosegawa T, Chari ST, Frulloni L, et al. International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas. 2011;40(3):352–8. 12. Kirkegard J, Mortensen FV, Cronin-Fenton D. Chronic pancreatitis and pancreatic cancer risk: a systematic review and meta-analysis. Am J Gastroenterol. 2017;112(9):1366–72.

411 13. Raimondi S, Lowenfels AB, Morselli-Labate AM, Maisonneuve P, Pezzilli R. Pancreatic cancer in chronic pancreatitis; aetiology, incidence, and early detection. Best Pract Res Clin Gastroenterol. 2010;24 (3):349–58. 14. Ballehaninna UK, Chamberlain RS. The clinical utility of serum CA 19-9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: an evidence based appraisal. J Gastrointest Oncol. 2012;3 (2):105–19. 15. Forsmark CE. Management of chronic pancreatitis. Gastroenterology. 2013;144(6):1282–91 e3. 16. Wolske KM, Ponnatapura J, Kolokythas O, Burke LMB, Tappouni R, Lalwani N. Chronic pancreatitis or pancreatic tumor? A problem-solving approach. Radiographics. 2019;39(7):1965–82. 17. Yamada Y, Mori H, Matsumoto S, Kiyosue H, Hori Y, Hongo N. Pancreatic adenocarcinoma versus chronic pancreatitis: differentiation with triple-phase helical CT. Abdom Imaging. 2010;35(2):163–71. 18. Tajima Y, Kuroki T, Tsutsumi R, Isomoto I, Uetani M, Kanematsu T. Pancreatic carcinoma coexisting with chronic pancreatitis versus tumor-forming pancreatitis: diagnostic utility of the time-signal intensity curve from dynamic contrast-enhanced MR imaging. World J Gastroenterol. 2007;13(6):858–65. 19. Kim JK, Altun E, Elias J Jr, Pamuklar E, Rivero H, Semelka RC. Focal pancreatic mass: distinction of pancreatic cancer from chronic pancreatitis using gadolinium-enhanced 3D-gradient-echo MRI. J Magn Reson Imaging. 2007;26(2):313–22. 20. Adler DG, Diehl DL. Missed lesions in endoscopic ultrasound. Endoscopic Ultrasound. 2015;4(3):165–7. 21. Ardengh JC, Lopes CV, Campos AD, Pereira de Lima LF, Venco F, Modena JL. Endoscopic ultrasound and fine needle aspiration in chronic pancreatitis: differential diagnosis between pseudotumoral masses and pancreatic cancer. JOP. 2007;8(4):413–21. 22. de la Fuente SG, Ceppa EP, Reddy SK, Clary BM, Tyler DS, Pappas TN. Incidence of benign disease in patients that underwent resection for presumed pancreatic cancer diagnosed by endoscopic ultrasonography (EUS) and fine-needle aspiration (FNA). J Gastrointest Surg. 2010;14(7):1139–42. 23. Bournet B, Souque A, Senesse P, et al. Endoscopic ultrasound-guided fine-needle aspiration biopsy coupled with KRAS mutation assay to distinguish pancreatic cancer from pseudotumoral chronic pancreatitis. Endoscopy. 2009;41(6):552–7. 24. Xu WSJ, Li X, et al. Endoscopic ultrasound elastography for differentiation of benign and malignant pancreatic masses: a systemic review and metaanalysis. Eur J Gastroenterol Hepatol. 2013;25(2): 218–24. 25. Gong TTHD, Zhu Q. Contrast-enhanced EUS for differential diagnosis of pancreatic mass lesions: a metaanalysis. Gastrointest Endosc. 2012;76:301–9. 26. Yamashita YST, Napoleon B, et al. Value of contrastenhanced harmonic endoscopic ultrasonography with

412 enhancement pattern for diagnosis of pancreatic cancer: a meta-analysis. Dig Endosc. 2019;31(2):125–33. 27. Harmsen F-JR, Domagk D, Dietrich CF, Hocke M. Discriminating chronic pancreatitis from pancreatic cancer: contrast-enhanced EUS and multidetector computed tomography in direct comparison. Endoscopic ultrasound. 2018;7(6):395–403. 28. Rückert F, Brussig T, Kuhn M, et al. Malignancy in chronic pancreatitis: analysis of diagnostic procedures and proposal of a clinical algorithm. Pancreatology. 2013;13(3):243–9. 29. American Cancer Society Cancer Facts and Figures. Atlanta. GA: American Cancer Society; 2020. p. 2020. 30. Siegel RMK, Jemal A. Cancer statistics, 2020. CA Cancer J Lin. 2020;70(1):7–30. 31. Howlader N, Noone AM, Krapcho M, et al. SEER cancer statistics review, 1975–2017. Bethesda, MD: National Cancer Institute; 2020. 32. Decker GA, Batheja MJ, Collins JM, et al. Risk factors for pancreatic adenocarcinoma and prospects for screening. Gastroenterol Hepatol (N Y). 2010;6(4): 246–54. 33. Porta M, Fabregat X, Malats N, et al. Exocrine pancreatic cancer: symptoms at presentation and their relation to tumour site and stage. Clin Transl Oncol. 2005;7(5): 189–97. 34. Matsuyama M, Ishii H, Kuraoka K, et al. Ultrasoundguided vs endoscopic ultrasound-guided fine-needle aspiration for pancreatic cancer diagnosis. World J Gastroenterol. 2013;19(15):2368–73. 35. Hruban RH, Klimstra DS. Adenocarcinoma of the pancreas. Semin Diagn Pathol. 2014;31(6):443–51. 36. Lanke G, Ali FS, Lee JH. Clinical update on the management of pseudopapillary tumor of pancreas. World J Gastrointest Endosc. 2018;10(9):145–55. 37. Romics L Jr, Olah A, Belagyi T, Hajdu N, Gyurus P, Ruszinko V. Solid pseudopapillary neoplasm of the pancreas – proposed algorithms for diagnosis and surgical treatment. Langenbeck’s Arch Surg. 2010;395(6): 747–55. 38. Cai H, Zhou M, Hu Y, et al. Solid-pseudopapillary neoplasms of the pancreas: clinical and pathological features of 33 cases. Surg Today. 2013;43(2):148–54. 39. Jiang L, Cui L, Wang J, Chen W, Miao L, Jia J. Solid pseudopapillary tumors of the pancreas: findings from routine screening sonographic examination and the value of contrast-enhanced ultrasound. J Clin Ultrasound. 2015;43(5):277–82. 40. Holen KD, Klimstra DS, Hummer A, et al. Clinical characteristics and outcomes from an institutional series of acinar cell carcinoma of the pancreas and related tumors. J Clin Oncol. 2002;20(24):4673–8. 41. Mortenson MM, Katz MH, Tamm EP, et al. Current diagnosis and management of unusual pancreatic tumors. Am J Surg. 2008;196(1):100–13. 42. Zundler S, Erber R, Agaimy A, et al. Pancreatic panniculitis in a patient with pancreatic-type acinar cell carcinoma of the liver – case report and review of literature. BMC Cancer. 2016;16:130.

D. Lew et al. 43. Chiou YY, Chiang JH, Hwang JI, Yen CH, Tsay SH, Chang CY. Acinar cell carcinoma of the pancreas: clinical and computed tomography manifestations. J Comput Assist Tomogr. 2004;28(2):180–6. 44. Tatli S, Mortele KJ, Levy AD, et al. CT and MRI features of pure acinar cell carcinoma of the pancreas in adults. Am J Roentgenol. 2005;184(2):511–9. 45. Klimstra DS. Nonductal neoplasms of the pancreas. Mod Pathol. 2007;20(Suppl 1):S94–112. 46. Nishimura R, Takakuwa T, Hoshida Y, Tsujimoto M, Aozasa K. Primary pancreatic lymphoma: clinicopathological analysis of 19 cases from Japan and review of the literature. Oncology. 2001;60(4):322–9. 47. Sadot E, Yahalom J, Do RK, et al. Clinical features and outcome of primary pancreatic lymphoma. Ann Surg Oncol. 2015;22(4):1176–84. 48. Koniaris LG, Lillemoe KD, Yeo CJ, et al. Is there a role for surgical resection in the treatment of early-stage pancreatic lymphoma? J Am Coll Surg. 2000;190(3): 319–30. 49. Merkle EM, Bender GN, Brambs HJ. Imaging findings in pancreatic lymphoma: differential aspects. AJR Am J Roentgenol. 2000;174(3):671–5. 50. Nagtegaal ID, Odze RD, Klimstra D, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020;76(2):182–8. 51. Nayer H, Weir EG, Sheth S, Ali SZ. Primary pancreatic lymphomas: a cytopathologic analysis of a rare malignancy. Cancer. 2004;102(5):315–21. 52. Salman B, Brat G, Yoon YS, et al. The diagnosis and surgical treatment of pancreatoblastoma in adults: a case series and review of the literature. J Gastrointest Surg. 2013;17(12):2153–61. 53. Montemarano H, Lonergan GJ, Bulas DI, Selby DM. Pancreatoblastoma: imaging findings in 10 patients and review of the literature. Radiology. 2000;214(2):476–82. 54. Ohike N, La Rosa S. Pancreatoblastoma. In: WHO Classification of Tumours Editorial Board, editor. WHO classification of tumors: digestive system tumours. 5th ed. Lyon: International Agency for Research on Cancer; 2019. p. 337. 55. Adsay NV, Andea A, Basturk O, Kilinc N, Nassar H, Cheng JD. Secondary tumors of the pancreas: an analysis of a surgical and autopsy database and review of the literature. Virchows Arch. 2004;444(6):527–35. 56. Adler H, Redmond CE, Heneghan HM, et al. Pancreatectomy for metastatic disease: a systematic review. Eur J Surg Oncol. 2014;40(4):379–86. 57. Wente MN, Kleeff J, Esposito I, et al. Renal cancer cell metastasis into the pancreas: a single-center experience and overview of the literature. Pancreas. 2005;30(3): 218–22. 58. Triantopoulou C, Kolliakou E, Karoumpalis I, Yarmenitis S, Dervenis C. Metastatic disease to the pancreas: an imaging challenge. Insights Imaging. 2012;3(2):165–72. 59. van der Pol CB, Lee S, Tsai S, et al. Differentiation of pancreatic neuroendocrine tumors from pancreas renal

24

Approach to the Patient with a Pancreatic Mass

cell carcinoma metastases on CT using qualitative and quantitative features. Abdom Radiol (NY). 2019;44 (3):992–9. 60. Fesinmeyer MD, Austin MA, Li CI, De Roos AJ, Bowen DJ. Differences in survival by histologic type of pancreatic cancer. Cancer Epidemiol Biomark Prev. 2005;14(7):1766–73. 61. Kasumova GG, Tabatabaie O, Eskander MF, Tadikonda A, Ng SC, Tseng JF. National Rise of primary pancreatic carcinoid tumors: comparison to functional and nonfunctional pancreatic neuroendocrine tumors. J Am Coll Surg. 2017;224(6):1057–64. 62. Philips P, Kooby DA, Maithel S, et al. Grading using Ki-67 index and mitotic rate increases the prognostic accuracy of pancreatic neuroendocrine tumors. Pancreas. 2018;47(3):326–31. 63. Fraenkel M, Kim MK, Faggiano A, Valk GD. Epidemiology of gastroenteropancreatic neuroendocrine tumours. Best Pract Res Clin Gastroenterol. 2012;26(6):691–703. 64. Grozinsky-Glasberg S, Mazeh H, Gross DJ. Clinical features of pancreatic neuroendocrine tumors. J Hepatobiliary Pancreat Sci. 2015;22(8):578–85. 65. Madura JA, Cummings OW, Wiebke EA, Broadie TA, Goulet RL Jr, Howard TJ. Nonfunctioning islet cell tumors of the pancreas: a difficult diagnosis but one worth the effort. Am Surg. 1997;63(7):573–7; discussion 7–8 66. Eriksson B, Oberg K, Stridsberg M. Tumor markers in neuroendocrine tumors. Digestion. 2000;62(Suppl 1): 33–8. 67. Guarneri G, Gasparini G, Crippa S, Andreasi V, Falconi M. Diagnostic strategy with a solid pancreatic mass. Presse Med. 2019;48(3 Pt 2):e125–e45. 68. Best LM, Rawji V, Pereira SP, Davidson BR, Gurusamy KS. Imaging modalities for characterising focal pancreatic lesions. Cochrane Database Syst Rev. 2017;4(4):Cd010213. 69. Tummala MP, Rao MS, Agarwal MB. Differential diagnosis of focal non-cystic pancreatic lesions with and without proximal dilation of pancreatic duct noted on CT scan. Clin Transl Gastroenterol. 2013;4(11):e42.

413 70. Macgregor-Das A, Goggins M. Diagnostic biomarkers. In: Neoptolemos JP, Urrutia R, Abbruzzese JL, Büchler MW, editors. Pancreatic cancer. New York, Springer; 2018. p. 659–80. 71. Zhang TT, Wang L, Liu HH, et al. Differentiation of pancreatic carcinoma and mass-forming focal pancreatitis: qualitative and quantitative assessment by dynamic contrast-enhanced MRI combined with diffusion-weighted imaging. Oncotarget. 2017;8(1): 1744–59. 72. Network NCC. Pancreatic adenocarcinoma (Version 1.2020). 2020. 73. James PD, Tsolakis AV, Zhang M, et al. Incremental benefit of preoperative EUS for the detection of pancreatic neuroendocrine tumors: a meta-analysis. Gastrointest Endosc. 2015;81(4):848–56 e1. 74. Jeon SK, Lee JM, Joo I, et al. Nonhypervascular pancreatic neuroendocrine tumors: differential diagnosis from pancreatic ductal adenocarcinomas at MR imaging-retrospective cross-sectional study. Radiology. 2017;284(1):77–87. 75. Al-Hawary MM, Kaza RK, Azar SF, Ruma JA, Francis IR. Mimics of pancreatic ductal adenocarcinoma. Cancer Imaging. 2013;13(3):342–9. 76. Iwashita T, Yasuda I, Doi S, et al. Use of samples from endoscopic ultrasound-guided 19-gauge fine-needle aspiration in diagnosis of autoimmune pancreatitis. Clin Gastroenterol Hepatol. 2012;10(3):316-22. 77. Matsubayashi H, Ishiwatari H, Imai K, et al. Steroid therapy and steroid response in autoimmune pancreatitis. Int J Mol Sci 2019; 21(1). 78. Duconseil P, Turrini O, Ewald J, et al. ‘Peripheric’ pancreatic cysts: performance of CT scan, MRI and endoscopy according to final pathological examination. HPB (Oxford). 2015;17(6):485–9. 79. Lisotti A, Frazzoni L, Fuccio L, et al. Repeat EUS-FNA of pancreatic masses after nondiagnostic or inconclusive results: systematic review and metaanalysis. Gastrointest Endosc. 2020;91(6):1234–41.e4. 80. Kersting S, Janot MS, Munding J, et al. Rare solid tumors of the pancreas as differential diagnosis of pancreatic adenocarcinoma. JOP. 2012;13(3):268–77.

Evaluation and Management of the Patient with a Pancreatic Cyst

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Suut Go¨ktu¨rk, Thiruvengadam Muniraj, and Harry R. Aslanian

Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416 1.1 Types of Pancreatic Cysts (Classification of Pancreatic Cysts) . . . . . . . . . . . . . . . . . . 416 1.2 Non-neoplastic Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417 2 2.1 2.2 2.3

Pancreatic Pseudocysts (PPs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management of Pancreatic Pseudocysts (PPs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pancreatic Cystic Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intraductal Papillary Mucinous Neoplasms (IPMNs) . . . . . . . . . . . . . . . . . . . . . . . . . . . .

417 419 420 420

3

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421

4

Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422

5

Surveillance of Mucinous Cysts (IMPN and MCN) . . . . . . . . . . . . . . . . . . . . . . . . . . . 423

6

Mucinous Cystic Neoplasms (MCNs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425

7

Serous Cystic Neoplasms (SCNs): Serous Cystadenoma (SCA) . . . . . . . . . . . . . 426

8

Solid Pseudopapillary Neoplasms (SPNs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426

9

Cystic Pancreatic Neuroendocrine Tumors (cPNETs) . . . . . . . . . . . . . . . . . . . . . . . . 427

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428

Abstract

Pancreas cysts are frequently incidentally detected on cross-sectional imaging. This

review presents an approach to the diagnosis and management of pancreas cysts, including pancreas pseudocysts, serous cystadenomas and mucinous cysts, which include mucinous cystadenomas and intraductal papillary neoplasms

S. Göktürk Brooklyn Hospital Center, Brooklyn, NY, USA

Keywords

T. Muniraj · H. R. Aslanian (*) Section of Digestive Diseases, Yale University, New Haven, CT, USA e-mail: [email protected]; [email protected]

Pancreas cyst · Mucinous cystadenoma · Serous cystadenoma · Intraductal papillary mucinous neoplasm

© Springer Nature Switzerland AG 2022 C. Doria, J. N. Rogart (eds.), Hepato-Pancreato-Biliary Malignancies, https://doi.org/10.1007/978-3-030-41683-6_27

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1

Introduction

Pancreatic cysts (PCs) are often detected on abdominal imaging obtained for indications unrelated to the pancreas. The frequency of diagnosis is increasing due to improved imaging technologies, increased awareness, and the aging population [1]. Most pancreatic cysts are asymptomatic at the time of diagnosis [2]. The incidence of PCs in the USA is estimated to be between 3% and 15% [3]. In an autopsy series, PCs were found in 24.3% (73 of 300) of cases [4]. PCs were incidentally detected in 3% of computed tomography (CT) and 20% of magnetic resonance imaging (MRI) exams. The prevalence of PCs increases with advancing age, approaching 10– 40% by age 80. A review of abdominal MRIs performed for non-pancreatic indications in patients over the age of 70 showed a 40% incidence of incidental pancreatic cysts [3, 5–7]. Most pancreatic cysts are small at the time of diagnosis, often 2 cm was only 0.8% [8, 9]. The risk of malignant transformation is difficult to precisely quantify; however, when considering all individuals with pancreatic cysts, the risk of pancreatic malignancy is higher than the general population [10]. The incidental finding of a pancreatic cyst can cause significant anxiety for patients and their medical providers. A recent systematic review and meta-analysis of 3,236 patients categorized intraductal papillary mucinous neoplasms (IPMNs) into low and high risk, the latter being defined as the presence of a mural nodule or dilated main pancreatic duct. They reported a pooled cumulative incidence of highgrade dysplasia or pancreatic cancer of 0.02% at 1 year, 3.12% at 5 years, and 7.77% at 10 years for low-risk IPMNs and 1.95% at 1 year, 9.77% at 5 years, and 24.68 at 10 years for high-risk IPMNs [8, 11]. The risks and benefits of evaluation of PCs for diagnosis, surveillance, and potential therapy must be carefully balanced. Management decisions must take into account the low risk of malignancy, the frequent detection of PCs, and the significance of other patient comorbidities. The cost of PC analysis and imaging-based

surveillance is high, while the benefit related to cancer prevention and longevity is largely unproven. While some progress has been made in developing endoscopic therapeutic approaches to neoplastic pancreatic cysts, the efficacy of these therapies remains suboptimal, and surgical resection remains the standard therapy. The goal of diagnosis and surveillance is to identify high-risk neoplastic cysts that would benefit from surgical resection while in a benign or localized condition, thus preventing the development of malignancy. Surgical resection may be associated with significant morbidity and mortality. A recent review of the literature suggests that the mortality rate from pancreatic resection for pancreatic cysts is approximately 2.1%, with a morbidity rate of 30% [8, 9]. For surveillance to be effective, the clinician requires accurate tools to identify highrisk patients who are most likely to benefit from surgical resection of a neoplastic pancreatic cyst. This chapter will discuss the major types of PCs, diagnostic and surveillance strategies, and treatment options.

1.1

Types of Pancreatic Cysts (Classification of Pancreatic Cysts)

Cystic lesions of the pancreas have an extensive differential diagnosis (Table 1), but can be divided into a few main categories, including nonneoplastic and neoplastic cystic lesions. Neoplastic cysts or pancreatic cystic neoplasms (PCNs) are commonly subcategorized into mucinous and Table 1 Classification of pancreatic cysts Neoplastic (with malignant potential) Mucinous IPMN, main-duct, side-branch, and mixed Mucinous cystadenoma Cystic PNET Solid and papillary neoplasm Neoplastic (very low malignant potential) Serous cystadenoma Non-neoplastic cysts Pseudocyst Lymphoepithelial cyst

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non-mucinous cystic lesions. Accurate cyst diagnosis and categorization is important to dedicate surveillance resources and consider surgical resection in the highest-risk groups while avoiding unnecessary testing and anxiety among low-risk patients with non-neoplastic cysts. Diagnosis of cyst type requires consideration of the clinical presentation, imaging features, and cyst fluid analysis. Even with this information available, correct classification of cyst type is often challenging. Cystic lesions with malignant potential include IPMNs, MCNs, solid pseudopapillary tumors, and pancreatic neuroendocrine tumors.

1.2

Non-neoplastic Cysts

Non-neoplastic cysts of the pancreas are benign lesions without malignant potential. It may be challenging to differentiate them from PCNs, and the imaging appearance alone is not diagnostically accurate. Pancreatic pseudocysts (PPs) are the most common. These post-inflammatory cysts develop after more severe episodes of acute pancreatitis and have a fibrous, non-epithelial wall. Epithelial non-neoplastic cysts are very rare and are listed in Table 1.

2

Pancreatic Pseudocysts (PPs)

A pseudocyst is a collection of inflammatory pancreatic fluid, outside the ductal system, that is enclosed by a fibrous tissue membrane. As the fluid cavities are not lined with an epithelium, pseudocysts are not true cysts and are, instead, surrounded by chronic reactive granulation tissue [12]. PPs almost always develop as a complication of acute pancreatitis [12]. Approximately 10% of patients with acute pancreatitis develop PPs. PPs may also arise in the setting of chronic pancreatitis as well as trauma, developing due to alteration of the pressure dynamics or leak of the pancreatic duct [12, 13]. The Atlanta classification of acute pancreatitis revised the terminology to define inflammatory pancreatic fluid collections in 2016. They were categorized as acute peri-pancreatic fluid

417

collections, acute necrotic collections, PPs, and walled-off necrosis [14]. The development of a well-defined wall with granulation or fibrous tissue distinguishes a pseudocyst from other focal fluid collections, and the formation usually requires 4 or more weeks from the onset of acute pancreatitis. Among interstitial edematous pancreatitis cases, collections 4 weeks are defined as pseudocysts. In the presence of necrosis, early collections 4 weeks), they are defined as walled-off necrosis [15]. PPs are usually single solitary cysts ranging from 2 to 20 cm in size but can be multiple in approximately 10% of cases. They are commonly round or oval, but some may be multilocular and irregular in shape. They are more common in adult men than women [1, 3]. A PP should be suspected when abdominal pain does not subside completely or serum amylase or lipase levels remain elevated after clinical improvement of acute pancreatitis. The most common symptoms are recurrent abdominal pain, nausea, and vomiting. The larger the PP, the more likely it is to cause pain or obstruction due to compression of adjacent structures. Patients may have early satiety, abdominal fullness, and weight loss due to gastric dysmotility or gastric or duodenal compression when the size of the cyst is very large. Icterus, pruritus, and dark urine may be seen in 10% of patients as a result of bile duct compression. Presence of fever should raise the suspicion of an occult infection of the pseudocyst which is presumed to be due to the migration of enteric organisms from the intestinal tract. Other rare complications of PPs include digestion of an adjacent vessel wall leading to the formation of a pseudoaneurysm, which can produce massive gastrointestinal bleeding, bleeding into the pancreatic duct (hemosuccus pancreaticus), splenic vein thrombosis due to splenic vein compression, pancreatic pleural effusion, and pancreatic ascites. Pancreatic ascites and pleural effusions result from disruption of the pancreatic duct, leading to fistula formation to the abdomen or chest, or may be due to rupture of a pseudocyst with tracking of pancreatic fluid into the peritoneal cavity or pleural space. Analysis of fluid obtained at

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paracentesis or thoracentesis is diagnostic, with a very high lipase or amylase concentration (typically >1000 IU/L) [1, 8, 15–17]. Diagnosis of PPs is usually based on the patient history and clinical presentation. In some cases, the acute episode of pancreatitis may not be apparent, or the pseudocyst may be due to underlying chronic pancreatitis. PP is the most common complication of chronic pancreatitis, occurring in up to 25% of cases [12]. If the pain does not improve or amylase levels remain high after an acute pancreatitis episode, imaging with abdominal US, CT, or MRI can be utilized to evaluate for complications [1]. PPs appear as anechoic structures with acoustic enhancement on US. Abdominal CT has a sensitivity of 90–100% for detection of PPs. A round, fluid-filled lesion surrounded by a thick, dense wall adjacent to the pancreas on CT in a patient with recent history of pancreatitis is highly consistent with a diagnosis of PP [16]. PPs are typically located in the pancreas, but large lesions rarely may be seen in the mediastinum or pelvis [18]. PPs may contain debris, blood, or infection, which will appear as high-attenuation areas within the fluid-filled cavity. MRI and magnetic resonance cholangiopancreatography (MRCP) usually give similar results to CT [1, 19]. It is important to differentiate pseudocysts from PCNs since PPs have no malignant potential and do not require surveillance or treatment when small and asymptomatic (Fig. 1).

It is important to keep in mind that a cystic neoplasm may rarely cause pancreatitis, due to obstruction of the pancreatic duct due to compression or the passage of mucin. This may be a cause of idiopathic acute pancreatitis in up to 20% of individuals over the age of 40. A careful history and consideration of prior abdominal imaging can be important. If the cyst was present prior to or at the initial onset of an initial episode of acute pancreatitis, it increases the likelihood of being a cystic neoplasm, as pseudocysts usually take several weeks to develop after the onset of an at least moderately severe episode of acute pancreatitis. Additional investigations including endoscopic ultrasound (EUS) with pancreatic fluid aspiration and analysis [8, 15] may be helpful to distinguish PPs from other neoplastic pancreatic cysts when faced with diagnostic uncertainty [20]. Peripheral calcifications in a cyst wall are more commonly seen with a mucinous cystadenoma rather than a pseudocyst. Fine-needle aspiration (FNA) can differentiate PPs and PCNs in more than 90% of patients [1]. PP cyst fluid is characterized by a high amylase level and low carcinoembryonic antigen (CEA), while the opposite [high CEA (>192 ng/mL) and low amylase] is typically seen in the fluid of mucinous neoplastic cysts (Table 2). A high concentration of amylase in fluid is indicative of communication with the main pancreatic duct and is seen with PPs due to the leakage of fluid from the pancreatic duct. Very low levels of amylase (6 cm was commonly used as a “rule of thumb”) is not an indication for drainage, unless symptoms are present [15]. Small PPs, less than 4 cm in diameter, usually are not symptomatic and are often gradually resorbed or stabilize. It is rare that an asymptomatic pseudocyst benefits from drainage. Before considering drainage of a pseudocyst, good-quality contrast-enhanced crosssectional imaging should be performed to exclude the presence of a pseudoaneurysm. If a pseudoaneurysm is present, embolization by interventional radiology should be pursued, prior to any other intervention. It is also important to consider the contents of a pseudocyst. Thin fluid may be easily drained with smaller caliber stents, while multiloculated collections and those with large amounts of debris or solid material (characteristic of walled-off necrosis) will require larger caliber drains and may require multiple interventions to achieve adequate drainage. Once a fluid collection is instrumented, drainage must be maintained and the collection adequately cleared, as the cavity is exposed to bacteria and predisposed to infection if drainage is incomplete. Options for drainage of PPs include percutaneous, endoscopic, or surgical approaches [15, 18, 23]. Local expertise, patient anatomy, and the characteristics of the pancreas fluid collection on the spectrum between pseudocyst and walled-off necrosis require consideration. Complex fluid collections are typically best managed with multidisciplinary review between gastroenterology, radiology, and surgery. Endoscopic drainage of PPs is frequently the preferred approach for most patients who require drainage. Endoscopic approaches include transmural-EUS guided (typically through the stomach or duodenum) alone or in combination with an ERCP-based trans-papillary approach. Transmural

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drainage requires abutment or close approximately between the cyst and the gastric or duodenal wall without intervening vessels and a larger cyst size that can accommodate transmural stent placement [15, 24–26]. A trans-papillary approach with ERCP may be considered when a pseudocyst is located in the head of the pancreas, is of smaller size, and communicates with the main pancreatic duct [27]. An ongoing pancreatic duct leak or obstruction may be suggested by imaging of the pancreatic duct showing stone, stricture, or dilation and the recurrence of a pancreatic cyst after removal of transmural drains or high output via percutaneous drains. An ongoing leak or obstruction is an indication to pursue ERCP with the placement of a pancreatic duct stent across any identified pancreatic duct stricture or leak. The overall complication rate of elective endoscopic drainage is 13%, with success rates of more than 90% and recurrence rates of less than 10% [28] (Fig. 2a, b).

Fig. 2 (a) Cystogastrostomy: CT abdomen with pigtail stents within a lumen apposing metal stent (LAMS). (b) Cystogastrostomy endoscopic image: LAMS in the gastric body

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Percutaneous drainage of pancreatic pseudocysts may be performed under US or CT guidance [1]. Percutaneous drainage may be a particularly good option when the cyst is anatomically not amenable to an endoscopic approach. Some studies have shown endoscopic drainage to have higher rates of treatment success, lower rates of re-intervention, and shorter lengths of hospital stay [15]. Surgical drainage may be performed laparoscopically and typically involves the creation of a cyst-gastrostomy or video-assisted retroperitoneal debridement (VARD). A step-up approach, based on local expertise, utilizing endoscopic or percutaneous approaches has become favored. Other non-neoplastic pancreatic cysts include a variety of very rare cysts that are often asymptomatic and do not require resection. These include true cysts, retention cysts, mucinous non-neoplastic cysts, and lymphoepithelial cysts. They are typically diagnosed after surgical resection of a lesion that was thought to be a pancreatic cystic neoplasm (PCN) preoperatively. Retention cysts: Retention cysts are small dilated pancreatic duct side branches arising due to obstruction. They are usually found incidentally and have little clinical significance. Retention cysts can be congenital or secondary to ductal obstruction with mucin or calculi or related to chronic pancreatitis. These cysts are usually small in size, and their wall is covered with normal ductal epithelium, which is similar to mucinous cysts. In addition, communication with the main pancreatic duct (MPD) may be observed, which makes the differentiation from an IPMN difficult [3]. Mucinous non-neoplastic cysts: Mucinous non-neoplastic cysts have recently been described and are difficult to differentiate from PCNs. Like PCNs, mucinous non-neoplastic cysts are lined with a mucinous lining, but they lack any neoplastic features or ductal communication [29]. Lymphoepithelial cysts: Lymphoepithelial cysts (LEC) are rare, usually asymptomatic, benign cystic lesions. These lesions are lined by mature keratinizing squamous epithelium surrounded by a distinct layer of lymphoid tissue. EUS-FNA may be required to differentiate a LEC

from a PCN. Cyst fluid analysis may not be helpful as LEC may also have elevated CEA and mucin similar to mucinous PCN. FNA cytology usually reveals characteristic epithelial cells and small, mature lymphocytes in a background of keratinaceous debris, anucleate squamous cells, and multinucleated histiocytes. Resection is only recommended in symptomatic cases [30, 31].

2.2

Pancreatic Cystic Neoplasms

Pancreatic cystic neoplasms (PCNs) are grossly classified as mucinous and non-mucinous lesions according to the epithelial lining of the cyst (Table 1). Mucinous cystic lesions include intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs). They both produce mucin and have malignant potential. Non-mucinous neoplasms include serous cystic neoplasms (SCNs), solid pseudopapillary neoplasms (SPNs), and pancreatic neuroendocrine tumors (PNETs) [32]. IPMNs account for 27% to 48%, MCNs for 11% to 23%, SCNs for 13% to 23%, PNETs for 4% to 7%, and SPNs for 2% to 5%, of series of resected pancreatic cystic neoplasm [3]. IPMNs are divided into main-duct and sidebranch categories. Side-branch IPMN is the most common incidentally detected pancreatic cyst [32].

2.3

Intraductal Papillary Mucinous Neoplasms (IPMNs)

IPMNs are the most commonly diagnosed and resected type of pancreatic cystic neoplasms. IPMNs are mucinous cystic lesions of the pancreas characterized by the development of neoplastic, mucin-secreting, papillary cells on the pancreatic ductal surface [1, 32]. IPMNs are frequently located in the head of the pancreas as a solitary lesion, but are multifocal in approximately 30% of cases. In 5–10% of cases, they may involve the pancreas diffusely [33, 34]. IPMNs have clinical importance due to their frequent identification and malignant potential. Factors influencing their increased incidence include aging of the population and increased use of

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Evaluation and Management of the Patient with a Pancreatic Cyst

cross-sectional imaging in clinical practice. The mean age at diagnosis is 65 years, and the male gender is more common. IPMNs are usually asymptomatic and diagnosed incidentally on routine imaging obtained for other indications. The presence of symptoms is more common with advanced main-duct IPMN or the progression to malignancy [16]. Patients who develop invasive malignancy may present with weight loss, new-onset diabetes mellitus, and symptoms of biliary compression including pruritus and jaundice. Both side-branch and mainduct IPMNs may rarely give rise to pancreatitis, likely due to thick mucin occluding the pancreatic duct orifice [38]. IPMNs can originate from the main pancreatic duct (MD-IPMN) or side branches (BD-IPMN) or have mixed origins (mixed duct IPMN) [35]. Small BD-IPMNs are the most common incidentally detected cyst [36] (Fig. 3a, b). Although mucin-producing cysts have malignant

potential, the vast majority of side-branch IPMNs will not progress to pancreatic cancer. The overall estimated risk of malignancy is only 0.25% per year [9]. Main-duct IPMN is much less common and has a much higher risk of malignancy than side-branch IPMN, with 38–68% of main-duct IPMNs harboring high-grade dysplasia or pancreatic cancer in resected specimens [37]. IPMNs may also be classified into gastric, intestinal, pancreaticobiliary, and oncocytic type, based on the predominant cell type, which may have prognostic significance. For example, typically gastric-type IPMN is more commonly seen with BD-IPMN and can develop into a tubular type of invasive cancer. Alternatively, the intestinal-type IPMN is more commonly seen in MD-IPMN, which may progress to a colloid variety of invasive IPMN. Patients with gastric-type IPMN have the lowest risk of malignant progression, while increased risk has been associated with intestinal and pancreato-biliary type [1, 35].

3

Fig. 3 (a) MRI abdomen of branch-duct IPMN in the pancreas uncinate (b) MRI abdomen of branch-duct IPMN in the neck of the pancreas.

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Diagnosis

Routine blood tests such as complete blood count, basic metabolic panel, liver function tests, and pancreatic enzymes are usually normal and not helpful for diagnosis. Serum CEA and CA19-9 do not have any diagnostic value and are not expected to be elevated in the absence of invasive malignancy [1]. PCNs are detected by conventional imaging techniques including US, CT, and MRI, usually performed for unrelated conditions (Fig. 3a, b). Imaging helps characterize the type of cyst and can assess for high-risk cyst features or an associated solid mass lesion [8]. The anatomic locations, size, number, degree of septation and calcification, pancreatic duct dilation, and appearance of cysts on imaging can help differentiate cyst type [1]. The American College of Gastroenterology (ACG) guidelines recommend MRI or MRCP as the first choice to assess PCNs as a non-invasive test without radiation exposure that can assess for communication with the main pancreatic duct (which is characteristic of BD-IPMN) [8]. Pancreatic protocol CT and EUS are excellent

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alternatives in patients who are unable to undergo MRI. The accuracy of MRI/MRCP in differentiating between a benign and malignant cyst has ranged from 55% to 76% with up to 96% sensitivity for detecting an IPMN [39, 40]. MRI is better than CT for depicting the internal morphology of the cyst. MRI, however, has lower spatial resolution, is insensitive for identifying calcification, and can be affected by motion artifact [8]. Both CT and MRI can detect metastases in cases of invasive carcinoma associated with IPMN [1, 41, 42]. High-risk stigmata for increased risk of malignancy with IPMN include cyst size >3 cm, main pancreatic duct diameter >5–10 mm, a solid component or mural nodule, and a thickened or enhancing cyst wall [43] (Table 3). ERCP has a limited role, other than evaluating the extent/location of main-duct IPMN involvement [8]. EUS is particularly useful when the diagnosis is uncertain with cross-sectional imaging modalities, for evaluation of cysts with high-risk features and assessment of malignancy before consideration of surgery [32]. Main IPMN may lead to obstruction of the main pancreatic duct with mucus, resulting in diffuse parenchymal changes mimicking chronic pancreatitis [35]. BD-IPMNs may have the appearance of an anechoic “cluster of grapes” on EUS, due to the tortuous side branches distended with mucin. EUS imaging alone (without cyst fluid evaluation) is 65–96% accurate for distinguishing a benign from a malignant cyst [39]. This is similar to the accuracy of MRI and CT scan. EUS is more accurate for the identification of a mural nodule [44]. EUS-guided aspiration (EUS-FNA) can be performed to obtain cyst fluid for biochemical analysis, cytology, and DNA analysis and to obtain cells from the cyst wall and nodules for cytology that may aid in the diagnosis of the cyst type and differentiation between low- and high-risk cysts. With IPMN and mucinous cystadenoma, the fluid is highly Table 3 High-risk features of neoplastic pancreatic cysts Main pancreas duct dilation (>5 mm) Cyst wall nodularity, thickening, or enhancement Cyst size >3 cm

viscous, the CEA level is high (>192 ng/ml), the amylase level may be elevated (due to cyst communication with pancreatic ductal system) or normal, and cytology may identify mucinous epithelium (Table 2). Elevated cyst fluid CEA identifies mucinous cysts with a sensitivity of 64–100% and a specificity of 60–98% [1, 3, 8, 33, 35]. The most commonly used CEA level cutoff threshold of 192 ng/mL has a reported sensitivity of 73% and a specificity of 84% [45]. Among all the cyst fluid parameters, CEA concentration alone is the most accurate test for the diagnosis of cystic mucinous neoplasms [3]. Other cyst fluid protein biomarkers have been examined, including CA72-4, CA125, CA19-9, or CA15-3, but were found to have a lower accuracy than CEA and are, therefore, not routinely used [21]. Pancreatic cyst fluid typically has a low level of cells, and cytology is infrequently diagnostic unless a thickened cyst wall, mural nodule, or mass is targeted during the EUS fine-needle aspiration [46]. DNA analysis of pancreatic cyst fluid may include evaluation of KRAS and GNAS mutations. KRAS mutation is highly specific (96%) for mucinous cysts and is positive in 80% of IPMNs (and 14% of MCNs). In one study, GNAS mutation was present in 66% of IPMNs, and either KRAS or GNAS mutations were identified in 96% of IPMNs. Positive KRAS or GNAS mutations and elevated cyst fluid CEA suggest the lesion is most likely a mucinous cyst but unfortunately do not differentiate benign from malignant lesions or predict future cancer risk [47–49].

4

Treatment

In asymptomatic patients who are not medically fit for surgery, consideration should be given to not pursue further evaluation of incidentally found pancreatic cysts, irrespective of cyst size [8]. Patients with multiple comorbidities have a high risk of dying from causes unrelated to IPMN and are unlikely to benefit from further investigation [36, 50, 51]. The decision whether or not to resect a cystic lesion is best determined by a pancreatic multidisciplinary team that integrates multiple different factors, such as patient comorbidities and life

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expectancy, the type of surgery required to remove the lesion, and the estimated morbidity and mortality associated with surgery. In addition, it is essential to include the patient in the decisionmaking process. Patients should understand the potential risks and benefits of surgery and surveillance [8]. MD-IPMNs have higher predisposition for malignant transformation, compared with BD-IPMNs, as demonstrated in a longitudinal study, wherein the 5-year actuarial risk of progression to high-grade dysplasia among MD-IPMNs was of 63% in contrast to 15% in the BD-IPMNs [52]. Hence, if accurately diagnosed, MD-IPMN is considered a surgical disease requiring resection due to the high risk of invasive malignancy [35]. If the margin is positive for high-grade dysplasia, additional resection should be attempted to obtain at least moderate-grade dysplasia at the surgical margin [1]. BD-IPMNs mostly occur in elderly patients, and the annual malignancy rate is low (2–3%), so a variety of guidelines have evolved to help decide which patients should have surgery and which can be safely surveyed [1, 35]. According to the most recent revised Fukuoka guidelines and the European consensus guidelines, features favoring surgical management include cysts with obstructive jaundice and those with enhancing mural nodules >5 mm or main pancreatic duct diameter > 10 mm [53], whereas worrisome or relative features favoring further investigation with EUS include cysts >3 cm, enhancing mural nodules 5 mm/2 years or > 10 mm during the follow-up [35]. In patients who refuse surgery or are high-risk surgical candidates, EUS-guided cyst ablation with ethanol and a cytotoxic agent (paclitaxel) has been introduced as an alternative treatment. Reported results have been promising but variable, with cyst resolution reported in 33–79% of cases [8]. The reported rate of adverse events (~12%) is higher than that for routine EUS-FNA (1–2%), and adverse events include fever, abdominal pain,

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pancreatitis, peritonitis, and splenic and portal vein thrombosis. Radiofrequency ablation (RFA) of PCNs has been recently described in a pilot study of six patients. Post-procedure imaging at 3–6 months showed complete resolution of the cysts in two patients, while in three patients, there was 48.4% reduction in size [54]. Initial results suggest that the procedure is technically easy and safe. To date, it has not been shown that decreasing cyst size in IPMNs or MCNs eradicates the risk of progression to high-grade dysplasia or pancreatic cancer, with one report of pancreatic cancer developing following alcohol ablation [55]. Furthermore, patients with IPMNs are at increased risk of pancreatic cancer at a site separate from the cyst, and thus ablation does not remove the need for surveillance. There is insufficient evidence to support the routine use of cyst ablation; however, it may be considered in patients who refuse or are not candidates for surgery.

5

Surveillance of Mucinous Cysts (IMPN and MCN)

Before embarking on cyst surveillance, the physician should review the patient’s risk of developing pancreatic malignancy, their approximate life expectancy, their comorbid conditions, and whether they are a surgical candidate. Cyst surveillance should be offered to surgically fit candidates with asymptomatic cysts that are presumed to be IPMN or MCNs [8]. In a recently published retrospective, large long-term study of patients with branch-duct IPMNs, the 5-year incidence rate of pancreatic malignancy was found to be 3.3%, reaching 15.0% at 15 years after IPMN diagnosis. There are currently no prospective studies documenting that cyst surveillance alters mortality. IPMNs and MCNs are, however, typically present in a benign condition for many years before some progress to pancreatic cancer. Patients who undergo surgery for high-grade dysplasia or very early pancreatic cancer arising from PCNs may undergo curative resection and have been shown to have improved survival rates relative to patients with typical pancreas adenocarcinoma [56, 57] (Tables 4 and 5). After resection,

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Table 4 History and initial evaluation of a patient with a pancreatic cyst Does the patient have symptoms? Jaundice, weight loss, abdominal pain History of acute pancreatitis? Pseudocyst vs mucinous cyst causing pancreatitis Family history of gastrointestinal malignancy? Initial imaging: Why was cross-sectional imaging performed? Assess the quality of the imaging Was IV contrast used? Could this be a solid lesion?

Table 5 Initial and surveillance imaging of pancreatic cysts Initial imaging: Determine if cyst has malignant potential Identify neoplastic, mucinous cysts. Determine if the cyst has high-risk features Is EUS- FNA needed? Is surgical consultation needed? Surveillance imaging: Is performed to identify the development of high-risk features and lesions that would benefit from surgical resection The ultimate goal of cyst surveillance is to prevent death from pancreas cancer

the overall recurrence rate of IPMNs varies from 7% to 30%, and regular follow-up and monitoring of disease for recurrence is needed. MRI/MRCP is the primary surveillance modality. The frequency of surveillance imaging takes into consideration the cyst size, years of stability, and the presence of any high-risk stigmata and may also consider a family history of pancreatic cancer and the growth rate of the cyst. For cysts, 1 cm or less with no high-risk stigmata, imaging is typically performed at 1–2-year intervals and at 1-year intervals for cysts over 2 cm. The presence of high-risk stigmata requires consideration of more frequent surveillance and consideration of EUS-FNA, particularly to target mural nodules or wall thickening (Fig. 4a, b). A recent retrospective study was performed of 722 patients with pancreatic cysts who underwent EUS for suspected neoplastic pancreatic cysts; 87 of 722 patients (12%) underwent surgical resection within the first 5 years of

Fig. 4 (a) MRI abdomen of a cystic lesion in the tail of the pancreas with a solid component. (b) EUS-FNA of a cystic lesion in the tail of the pancreas with a hypoechoic solid component, found to be a side-branch IPMN with malignant transformation

surveillance. Among resected patients, 68 (78%) had malignancy [58]. International guidelines have suggested followup of patients with BD-IPMNs 5 mm, a focal dilation of the pancreatic duct concerning for main-duct IPMN or an obstructing lesion, IPMNs or MCNs measuring 3 cm in diameter, or rapid increase in the size of cyst (IV) The presence of high-grade dysplasia or pancreatic cancer on cytology [8] (Table 3) There are very little data to evaluate whether surveillance intervals can be extended or whether surveillance should be discontinued if cysts are stable after a specified time period. The 2015 AGA guidelines recommend discontinuing surveillance for pancreatic cysts without high-risk features after 5 years of demonstrated stability based on “very-low-quality evidence” [9]. 2012 radiology guidelines recommended suspending surveillance after 2 years of stability [59]. The ACG guideline suggested that surveillance intervals may be increased for cysts with no concerning features that are stable in size [8]. Currently, there appears to be insufficient evidence to broadly support discontinuing surveillance after 5 years in patients who are still surgically fit. It is appropriate to stop surveillance when the patient is no longer a surgical candidate because of comorbid conditions.

6

Mucinous Cystic Neoplasms (MCNs)

MCNs are composed of columnar, mucinproducing ductal epithelium with an underlying ovarian-type stroma [60]. Most patients are symptomatic (70%), most commonly presenting with nonspecific abdominal pain [3]. MCNs are typically unilocular cysts (Fig. 5). They are much more common in women (>90%) of middle age and are located in the body and tail of the pancreas in more than 97% of cases [3]. MCNs lack

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Fig. 5 CT abdomen of a MCN in the tail of the pancreas

communication with pancreatic ducts and do not recur post-resection [35]. MCNs harbor a risk of malignancy, with estimates ranging from 10% to 50%. KRAS mutations are observed in benign, borderline, and malignant MCNs with increasing frequency correlating with the extent of dysplasia, whereas p53 overexpression is typically only seen in invasive MCNs [61]. More recently, investigators have shown loss of DPC4 in 85% of invasive MCN specimens but none of the benign MCNs examined [62]. Risk factors for the presence of malignancy include larger tumor size, associated mass or mural nodule, and advanced age [1]. A recent review of 90 resected MCNs found that only 10% of them contained either high-grade dysplasia or pancreatic cancer [63]. In this study, and a large review of 344 MCNs, there were no cases of high-grade dysplasia or pancreatic cancer in MCNs less than 3 cm in size with a normal serum CA19-9 and no concerning features [64]. On imaging studies, MCNs may contain calcification at the edge of the cyst in 15% of MCNs, in contrast to SCNs, in which calcification may be seen at the center [35, 65]. As described above, the cyst fluid analysis and characteristics of MCNs are identical to that for IPMNs [35]. MCN and IPMN make up the category of “mucinous cystic neoplasm” and are typically considered similar entities in patient evaluation. Current guidelines favor resection of MCNs over surveillance because these lesions typically occur in the tail of the pancreas (resected with a distal

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pancreatectomy) in young women, and resection is considered curative (whereas IPMN may recur and are considered a “field defect” of the pancreas) [60]. Outcomes following resection of non-invasive MCNs are uniformly excellent. Distant recurrence is common in patients with invasive MCNs, and 5-year disease-specific survival is reported to be 57%, highlighting the importance of resection prior to the development of invasive disease [66].

7

Serous Cystic Neoplasms (SCNs): Serous Cystadenoma (SCA)

Serous cystadenomas are non-mucinous, almostalways benign cystic neoplasms. Malignant cases of serous cystadenocarcinoma are extremely rare, with only about 25 malignant cases reported [1, 3]. SCNs arise from centro-acinar cells and (typically) have septations lined with cuboidal, glycogen-rich epithelial cells, containing a strawcolored serous fluid [1]. Morphologically, SCA typically have a micro-cystic, “honeycomb”-like appearance. There is a variant of SCN, macrocystic serous cystadenoma, which may be unilocular and mimic the appearance of a mucinous cystic neoplasm. SCA may grow to a large diameter despite their benign nature. They occur more frequently in the body or tail of the pancreas. 70% of serous cystadenomas have a mutation in the VHL gene (and nearly 90% of von Hippel-Lindau (VHL) syndrome patients develop SCNs). Most patients have no symptoms. On cross-sectional imaging, a dense fibronodular scar with calcification often located in the center of the lesion can be seen in 30% of patients (this is considered pathognomonic for SCN). If the initial imaging shows classic findings of a SCA- microcystic changes with a central scar, (Fi no further evaluation is typically warranted, given the very low risk of malignancy [8]. It is frequent, however, that distinction between mucinous cysts (including side-branch IPMN and MCN) may be difficult on imaging. Aspirated cyst fluid has characteristic features of a very low CEA (less than 5.0 in 95% of cases). The gross appearance of

Fig. 6 (a) MRI abdomen of a serous cystadenoma. (b) EUS of a serous cystadenoma demonstrating the typical honeycomb/microcystic appearance

the fluid is typically watery (non-viscous) and may be blood-tinged related to the numerous, thin vascular thin septations. The yield of cytology with EUS-FNA is poor; however, PAS-positive small cuboidal cells rich in glycogen are specific to SCAs [67, 68]. Although large size does not predict malignancy, large SCNs are reported to grow at a faster rate and are more likely to be symptomatic [1] (Fig. 6a, b).

8

Solid Pseudopapillary Neoplasms (SPNs)

SPNs are rare neoplasms of the pancreas, which most commonly develop in young women (10:1), 20–30 years of age [3]. They can occur in any part of the pancreas. SPNs are low-grade malignant neoplasms composed of monomorphic epithelial cells that form solid and pseudopapillary

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Evaluation and Management of the Patient with a Pancreatic Cyst

structures. Macroscopically, SPNs are large, round, solitary masses which frequently undergo hemorrhagic cystic degeneration [69], giving them a heterogeneous appearance. Molecular aberrations including CTNNB1 sequence variations and Wnt/β-catenin pathway activations have been identified [3]. Malignant behavior, including local invasion, nodal or liver metastases, or local or distant recurrence after resection, is seen in 10–20% of cases [70–72]. Abdominal pain, vomiting, and jaundice are the most common presenting symptoms [3]. Approximately one-third of patients are asymptomatic [73]. On CT or MRI, SPNs appear as wellcircumscribed and encapsulated masses with varying soft tissue and necrotic foci areas. The capsule is usually thick and enhancing. Peripheral calcification has been reported in up to 30% of patients [74]. On EUS, SPNs are usually welldefined hypoechoic, heterogeneous masses often with a cystic component. EUS-FNA has a diagnostic yield of more than 80%. The cyst fluid is usually hemorrhagic and highly cellular with a low CEA level [75] (Fig. 7a, b). Surgical resection of SPNs is recommended surgery because of their malignant potential and is curative in 85–95% of patients. The overall 5-year survival rate is 95%; however, after 5 years, SPNs recur in approximately 10% of patients; therefore, surveillance imaging is necessary.

9

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Cystic Pancreatic Neuroendocrine Tumors (cPNETs)

Pancreatic neuroendocrine tumors (PNETs) are rare and usually non-functioning [8]. They may be solid or cystic. cPNETs account for 10–18% of resected PNETs and 7–10% of all pancreatic neoplasms [76]. Most PNETs are sporadic, but they can be associated with hereditary endocrinopathies involving loss of a tumor-suppressor gene, including multiple endocrine neoplasia type 1 (MEN1), von Hippel-Lindau (VHL) syndrome, neurofibromatosis type I (NF1), and tuberous sclerosis. Approximately 80–100% of the patients with MEN1, up to 20% of the patients with VHL, 10% of the patients with NF1, and 1% of the patients with tuberous sclerosis will develop a PNET [77]. They are equally common in women and men with peak presentation in the sixth decade. Most cPNETs are asymptomatic, non-functioning, and often diagnosed incidentally [3]. The clinical presentation varies depending on size, whether the tumor is functional or not, and which hormones are produced. An increasing percentage of tumors are detected incidentally in asymptomatic patients who undergo diagnostic evaluations for unrelated conditions. Most PNETs are relatively indolent, but ultimately malignant, except for insulinomas, which are predominantly benign (and most commonly functional) [77].

Fig. 7 (a) MRI abdomen of a large SPN in the head of the pancreas. (b) EUS of large SPN in the head of the pancreas

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Imaging of cPNETs reveals a well-circumscribed multi- or unilocular cyst, typically surrounded by a thick fibrous capsule. Debris within the cyst is common, while communication with the main pancreatic duct is rare [3]. Wall thickening, low CEA levels, and diagnostic cytologic features are found significantly more frequently in patients with cPNETs than in patients with mucinous cysts. Targeted cyst wall puncture and aspiration during EUS-FNA increases the diagnostic yield [76]. The recommended treatment for clinically active cPNETs is complete resection. Asymptomatic cPNETs below 1 cm are managed with surveillance or resection. Patients with resected cPNETs have an excellent prognosis [78–80].

References 1. Brugge WR. Diagnosis and management of cystic lesions of the pancreas. J Gastrointest Oncol. 2015;6(4):375–88. 2. Yoon WJ, Brugge WR. Pancreatic cystic neoplasms: diagnosis and management. Gastroenterol Clin N Am. 2012;41:103–18. 3. Basar O, Brugge WR. My treatment approach: pancreatic cysts. Mayo Clin Proc. 2017;92(10):1519–31. 4. Kimura W, Nagai H, Kuroda A, Muto T, Esaki Y. Analysis of small cystic lesions of the pancreas. Int J Pancreatol. 1995;18(3):197–206. 5. Laffan TA, Horton KM, Klein AP, et al. Prevalence of unsuspected pancreatic cysts on MDCT. AJR Am J Roentgenol. 2008;191(3):802–7. 6. Lee KS, Sekhar A, Rofsky NM, Pedrosa I. Prevalence of incidental pancreatic cysts in the adult population on MR imaging. Am J Gastroenterol. 2010;105(9): 2079–84. 7. Matsubara S, Tada M, Akahane M, et al. Incidental pancreatic cysts found by magnetic resonance imaging and their relationship with pancreatic cancer. Pancreas. 2012;41(8):1241–6. 8. Elta GH, Enestvedt BK, Sauer BG, Lennon AM. ACG clinical guideline: diagnosis and management of pancreatic cysts. Am J Gastroenterol. 2018;113(4): 464–79. 9. Scheiman JM, Hwang JH, Moayyedi P. American Gastroenterological Association technical review on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology. 2015;148(4): 824–48. 10. Gardner TB, Glass LM, Smith KD, et al. Pancreatic cyst prevalence and the risk of mucin-producing adenocarcinoma in US adults. Am J Gastroenterol. 2013;108:1546–50.

S. Go¨ktu¨rk et al. 11. Choi SH, Park SH, Kim KW, et al. Progression of unresected intraductal papillary mucinous neoplasms of the pancreas to cancer: a systematic review and metaanalysis. Clin Gastroenterol Hepatol. 2017;15:1509–20. 12. Muniraj T, Aslanian HR, Farrell J, Jamidar PA. Chronic pancreatitis, a comprehensive review and update. Part II: diagnosis, complications, and management. Dis Mon. 2015;61(1):5–37. 13. Aghdassi A, Mayerle J, Kraft M, et al. Diagnosis and treatment of pancreatic pseudocysts in chronic pancreatitis. Pancreas. 2008;36:105–12. 14. Foster BR, Jensen KK, Bakis G, Shaaban AM, Coakley FV. Revised Atlanta classification for acute pancreatitis: a pictorial essay. Radiographics. 2016;36(3):675–87. 15. Muniraj T, Jamidar PA, Nealon WH, Aslanian HR. Endoscopic management of pancreatic fluid collections. J Clin Gastroenterol. 2017;51(1):19–33. 16. Habashi S, Draganov PV. Pancreatic pseudocyst. World J Gastroenterol. 2009;15:38–47. 17. Cannon JW, Callery MP, Vollmer CM Jr. Diagnosis and management of pancreatic pseudocysts: what is the evidence? J Am Coll Surg. 2009;209:385–93. 18. Ortiz V, Yousaf MN, Muniraj T, Jamidar P, Aslanian HR. Endoscopic management of pancreatic duct disruption with large mediastinal pseudocyst. VideoGIE. 2018;3(5):162–5. 19. Garcea G, Ong SL, Rajesh A, et al. Cystic lesions of the pancreas. A diagnostic and management dilemma. Pancreatology. 2008;8:236–51. 20. Brugge WR. The use of EUS to diagnose cystic neoplasms of the pancreas. Gastrointest Endosc. 2009;69: S203–9. 21. Van der Waaij LA, van Dullemen HM, Porte RJ. Cyst fluid analysis in the differential diagnosis of pancreatic cystic lesions: a pooled analysis. Gastrointest Endosc. 2005;62:383–9. 22. Pitman MB, Lewandrowski K, Shen J, et al. Pancreatic cysts: preoperative diagnosis and clinical management. Cancer Cytopathol. 2010;118:1–13. 23. Turner BG, Brugge WR. Pancreatic cystic lesions: when to watch, when to operate, and when to ignore. Curr Gastroenterol Rep. 2010;12:98–105. 24. Varadarajulu S, Christein JD, Tamhane A, et al. Prospective randomized trial comparing EUS and EGD for transmural drainage of pancreatic pseudocysts (with videos). Gastrointest Endosc. 2008;68:1102–11. 25. Panamonta N, Ngamruengphong S, Kijsirichareanchai K, et al. Endoscopic ultrasound-guided versus conventional transmural techniques have comparable treatment outcomes in draining pancreatic pseudocysts. Eur J Gastroenterol Hepatol. 2012;24:1355–62. 26. Park DH, Lee SS, Moon SH, et al. Endoscopic ultrasound-guided versus conventional transmural drainage for pancreatic pseudocysts: a prospective randomized trial. Endoscopy. 2009;41:842–8. 27. Samuelson AL, Shah RJ. Endoscopic management of pancreatic pseudocysts. Gastroenterol Clin N Am. 2012;41:47–62.

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Evaluation and Management of the Patient with a Pancreatic Cyst

28. Brugge WR. Endoscopic approach to the diagnosis and treatment of pancreatic disease. Curr Opin Gastroenterol. 2013;29:559–65. 29. Kosmahl M, Egawa N, Schröder S, et al. Mucinous nonneoplastic cyst of the pancreas: a novel nonneoplastic cystic change? Mod Pathol. 2002;15:154. 30. Ramsden KL, Newman J. Lymphoepithelial cyst of the pancreas. Histopathology. 1991;18:267. 31. Nasr J, Sanders M, Fasanella K, et al. Lymphoepithelial cysts of the pancreas: an EUS case series. Gastrointest Endosc. 2008;68:170. 32. Farrell JJ, Fernández-del CC. Pancreatic cystic neoplasms: management and unanswered questions. Gastroenterology. 2013;144(6):1303–15. 33. Farrell JJ, Brugge WR. Intraductal papillary mucinous tumor of the pancreas. Gastrointest Endosc. 2002;55(6):701–14. 34. Sahani DV, Lin DJ, Venkatesan AM, et al. Multidisciplinary approach to diagnosis and management of intraductal papillary mucinous neoplasms of the pancreas. Clin Gastroenterol Hepatol. 2009;7:259–69. 35. Farrell JJ. Intraductal papillary mucinous neoplasm to pancreas ductal adenocarcinoma sequence and pancreas cancer screening. Endosc Ultrasound. 2018;7(5):314–8. 36. Muniraj T, Aslania HR. Awash in a multitude of pancreas cysts: can we stop looking? Clin Gastroenterol Hepatol. 2016;14(6):872–4. 37. Stark A, Donahue TR, Reber HA, et al. Pancreatic cyst disease: a review. JAMA. 2016;315:1882–93. 38. Sahora K, Ferrone CR, Brugge WR, et al. Effects of comorbidities on outcomes of patients with intraductal papillary mucinous neoplasms. Clin Gastroenterol Hepatol. 2015;13:1816–23. 39. Tirkes T, Aisen AM, Cramer HM, et al. Cystic neoplasms of the pancreas; findings on magnetic resonance imaging with pathological, surgical, and clinical correlation. Abdom Imaging. 2014;39:1088–101. 40. Jones MJ, Buchanan AS, Neal CP, et al. Imaging of indeterminate pancreatic cystic lesions: a systematic review. Pancreatology. 2013;13:436–42. 41. De Jong K, Van Hooft JE, Nio CY, et al. Accuracy of preoperative workup in a prospective series of surgically resected cystic pancreatic lesions. Scand J Gastroenterol. 2012;47:1056–63. 42. Khashab MA, Kim K, Lennon AM, et al. Should we do EUS/FNA on patients with pancreatic cysts? The incremental diagnostic yield of EUS over CT/MRI for prediction of cystic neoplasms. Pancreas. 2013;42:717–21. 43. Tanaka M, Fernández-del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology. 2012;12:183–97. 44. Kamata K, Kitano M, Omoto S, et al. Contrastenhanced harmonic endoscopic ultrasonography for differential diagnosis of pancreatic cysts. Endoscopy. 2016;48:35–41. 45. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of pancreatic cystic neoplasms: a report

429

of the cooperative pancreatic cyst study. Gastroenterology. 2004;126(5):1330–6. 46. Maker AV, Carrara S, Jamieson NB, et al. Cyst fluid biomarkers for intra-ductal papillary mucinous neoplasms of the pancreas: a critical review from the international expert meeting on pancreatic branchduct-intra-ductal papillary mucinous neoplasms. J Am Coll Surg. 2015;220:243–53. 47. Farrell JJ, Al-Haddad MA, Jackson SA, Gonda TA. Incremental value of DNA analysis in pancreatic cysts stratified by clinical risk factors. Gastrointest Endosc. 2019;89(4):832–841.e2. 48. Majumbar S, Aslanian HR, Farrell JJ, et al. Novel methylated DNA markers discriminate advanced neoplasia in pancreatic cysts: marker discovery, tissue validation, and cyst fluid testing. Am J Gastroenterol. 2019;114(9):1539–49. 49. Dal Molin M, Matthaei H, Wu J, et al. Clinicopathological correlates of activating GNAS mutations in intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Ann Surg Oncol. 2013;20:3802–8. 50. Kawakubo K, Tada M, Isayama H, et al. Risk for mortality from causes other than pancreatic cancer in patients with intraductal papillary mucinous neoplasm of the pancreas. Pancreas. 2013;42:687–91. 51. Charlson M, Szatrowski TP, Peterson J, et al. Validation of a combined comorbidity index. J Clin Epidemiol. 1994;47:1245–51. 52. Lévy P, Jouannaud V, O’Toole D, et al. Natural history of intraductal papillary mucinous tumors of the pancreas: actuarial risk of malignancy. Clin Gastroenterol Hepatol. 2006;4:460–8. 53. Kim TH, Song TJ, Hwang JH, et al. Predictors of malignancy in pure branch duct type intraductal papillary mucinous neoplasm of the pancreas: a nationwide multicenter study. Pancreatology. 2015;15: 405–10. 54. Pai M, Senturk H, Lakhtakia S, et al. 351 endoscopic ultrasound guided radiofrequency ablation (EUS-RFA) for cystic neoplasms and neuroendocrine tumors of the pancreas. Gastrointest Endosc. 2013;77:AB143–4. 55. Gomez V, Takahashi N, Levy MJ, et al. EUS-guided ethanol lavage does not reliably ablate pancreatic cystic neoplasms (with video). Gastrointest Endosc. 2016;83: 914–20. 56. Oyama H, Tada M, Takagi K, et al. Long-term risk of malignancy in branch-duct intraductal papillary mucinous neoplasms. Gastroenterology. 2020;158:226–37. 57. Muniraj T, Aslanian HR. Long-term follow-up of low-risk branch duct IPMNs of the pancreas: watch for main pancreatic duct dilatation, and for how long? Clin Transl Gastroenterol. 2018;9:198. 58. Kwong WT, Hunt GC, Fehmi SM, et al. Low rates of malignancy and mortality in asymptomatic patients with suspected neoplastic pancreatic cysts beyond 5 years of surveillance. Clin Gastroenterol Hepatol. 2016;14:865–71. 59. Berland LL, Silverman SG, Megibow AJ, et al. Managing incidental findings on abdominal CT: white

430 paper of the ACR incidental findings committee. J Am Coll Radiol. 2010;7:754–73. 60. Chandwani R, Allen PJ. Cystic neoplasms of the pancreas. Annu Rev Med. 2016;67:45–57. 61. Jimenez RE, Warshaw AL, Z’Graggen K, et al. Sequential accumulation of K-ras mutations and p53 overexpression in the progression of pancreatic mucinous cystic neoplasms to malignancy. Ann Surg. 1999;230:501–9. 62. Iacobuzio-Donahue CA, Wilentz RE, Argani P, et al. Dpc4 protein in mucinous cystic neoplasms of the pancreas: frequent loss of expression in invasive carcinomas suggests a role in genetic progression. Am J Surg Pathol. 2000;24:1544–8. 63. Park JW, Jang JY, Kang MJ, et al. Mucinous cystic neoplasm of the pancreas: is surgical resection recommended for all surgically fit patients? Pancreatology. 2014;14:131–6. 64. Goh BK, Tan YM, Chung YF, et al. A review of mucinous cystic neoplasms of the pancreas defined by ovarian-type stroma: clinicopathological features of 344 patients. World J Surg. 2006;30:2236–45. 65. Procacci C, Carbognin G, Accordini S, et al. CT features of malignant mucinous cystic tumors of the pancreas. Eur Radiol. 2001;11:1626–30. 66. CrippaS SR, Warshaw AL, et al. Mucinous cystic neoplasm of the pancreas is not an aggressive entity: lessons from 163 resected patients. Ann Surg. 2008;247: 571–9. 67. Procacci C, Graziani R, Bicego E, et al. Serous cystadenoma of the pancreas: report of 30 cases with emphasis on the imaging findings. J Comput Assist Tomogr. 1997;21:373–82. 68. Belsley NA, Pitman MB, Lauwers GY, et al. Serous cystadenoma of the pancreas: limitations and pitfalls of endoscopic ultrasound-guided fine-needle aspiration biopsy. Cancer. 2008;114:102–10. 69. Papavramidis T, Papavramidis S. Solid pseudopapillary tumors of the pancreas: review of 718 patients reported in English literature. J Am Coll Surg. 2005;200:965–72.

S. Go¨ktu¨rk et al. 70. Butte JM, Brennan MF, Gönen M, et al. Solid pseudopapillary tumors of the pancreas: clinical features, surgical outcomes, and long-term survival in 45 consecutive patients from a single center. J Gastrointest Surg. 2011;15(2):350–7. 71. Bhatnagar R, Olson MT, Fishman EK, Hruban RH, Lennon AM, Ali SZ. Solid-pseudopapillary neoplasm of the pancreas: cytomorphologic findings and literature review. Acta Cytol. 2014;58(4):347–55. 72. Reddy S, Cameron JL, Scudiere J, et al. Surgical management of solid-pseudopapillary neoplasms of the pancreas (Franz or Hamoudi tumors): a large singleinstitutional series. J Am Coll Surg. 2009;208(5): 950–7; discussion 957–959 73. Law JK, Ahmed A, Singh VK, et al. A systematic review of solid-pseudo-papillary neoplasms: are these rare lesions? Pancreas. 2014;43:331–7. 74. Hoi JY, Kim MJ, Kim JH, et al. Solid pseudopapillary tumor of the pancreas: typical and atypical manifestations. AJR Am J Roentgenol. 2006;187:W178–86. 75. Jani N, Dewitt J, Eloubeidi M, et al. Endoscopic ultrasound-guided fine-needle aspiration for diagnosis of solid pseudopapillary tumors of the pancreas: a multicenter experience. Endoscopy. 2008;40:200–3. 76. Li-Geng T, Cai G, Aslanian HR. EUS diagnosis of cystic pancreatic neuroendocrine tumors. VIDEOGIE. 2018;3(3):106–108. 77. Muniraj T, Vignesh S, Shetty S, Thiruvengadam S, Aslanian HR. Pancreatic neuroendocrine tumors. Dis Mon. 2013;59:5–19. 78. Kunz PL, Reidy-Lagunes D, Anthony LB, North American Neuroendocrine Tumor Society, et al. Consensus guidelines for the management and treatment of neuroendocrine tumours. Pancreas. 2013;42(4):557–77. 79. Boninsegna L, Partelli S, D’Innocenzio MM, et al. Pancreatic cystic endocrine tumors: a different morphological entity associated with a less aggressive behavior. Neuroendocrinology. 2010;92(4):246–51. 80. Gaujoux S, Tang L, Klimstra D, et al. The outcome of resected cystic pancreatic endocrine neoplasms: a casematched analysis. Surgery. 2012;151(4):518–25.

Diagnosis and Evaluation of Pancreatic and Periampullary Adenocarcinoma

26

Daniel Lew and Karl Kwok

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432

2 2.1 2.2

Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 PDAC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 Ampullary Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434

3 3.1 3.2 3.3

Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PDAC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inherited Cancer Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ampullary Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4 4.1 4.2

Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438 PDAC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438 Ampullary Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438

5

Diagnostic Workup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439

6

Labs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439

7 7.1 7.2

Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440 Transabdominal Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440 Computed Tomography (CT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440

434 434 437 438

Supplementary Information: The online version of this chapter (https://doi.org/10.1007/978-3-030-41683-6_29) contains supplementary material, which is available to authorized users. D. Lew Kaiser Permanente, Baldwin Park Medical Center, Baldwin Park, CA, USA e-mail: [email protected] K. Kwok (*) Division of Gastroenterology, Kaiser Permanente, Los Angeles Medical Center, Los Angeles, CA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2022 C. Doria, J. N. Rogart (eds.), Hepato-Pancreato-Biliary Malignancies, https://doi.org/10.1007/978-3-030-41683-6_29

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432

D. Lew and K. Kwok 7.3 7.4

Magnetic Resonance Imaging (MRI) and Magnetic Resonance Cholangiopancreatography (MRCP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441 Position Emission Tomography (PET) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442

8 8.1 8.2 8.3

Endoscopic Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Esophagogastroduodenoscopy (EGD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endoscopic Retrograde Cholangiopancreatography (ERCP) . . . . . . . . . . . . . . . . . . . Endoscopic Ultrasound (EUS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

442 442 442 442

9 9.1 9.2 9.3 9.4 9.5 9.6

Tissue Acquisition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PDAC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ampullary Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Interventional Radiology (IR)-Guided Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . EGD with Biopsies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ERCP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endoscopic Ultrasound (EUS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

444 444 445 445 446 446 448

10 10.1 10.2

Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449 PDAC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449 Ampullary Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452

11

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453

Abstract

Due to the serious nature of the disease, both pancreatic and periampullary cancers warrant heightened radiographic suspicion when signs and symptoms point to the disease. However, because the two diseases have separate biologies and significant differences in prognosis (in general, stage for stage, patients with ampullary cancers demonstrate longer survival rates compared with pancreatic cancers), it is incumbent upon the physician to make a timely, accurate diagnosis. Therefore, the objectives of this chapter are several fold. First, it aims to summarize the symptoms and risk factors of each disease, including a review of hereditary cancer syndromes. Next, it guides the reader into selecting the optimal diagnostic modality for each disease. Additionally, comparative effectiveness data comparing various types of biopsy modalities is presented. Finally, data on performance of staging CT/ MRI/EUS is presented.

Keywords

Pancreatic Intraepithelial Neoplasia · PanIN · Pancreatic Cancer · Pancreatic Ductal

Adenocarcinoma · PDAC · Ampullary Cancer · FAMMM · Familial Atypical Multiple Mole Melanoma · hereditary breastovarian cancer syndrome · HBOC · PeutzJeghers Syndrome · PJS · Hereditary Non Polyposis Colorectal Cancer · HNPCC · Pancreatic Exocrine Insufficiency · PEI

1

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the tenth most common cancer diagnosis annually in the United States with an estimated 57,600 cases in 2020, with an approximately 0.3–0.7% yearover-year increase in incidence [1]. Furthermore, with a 5-year relative survival rate of only 9%, it is the fourth most deadly cancer (over 47,000 deaths estimated in 2020) [2]. One possible explanation for the lethality of PDAC is that its progenitor lesion, the pancreatic intraepithelial neoplasia (PanIN), is not a mass-forming lesion, nor is its evolutionary timeline into PDAC well defined. However, if there is an extremely high index of suspicion, despite the lack of focal mass lesions with conventional diagnostic approaches (e.g., cross-sectional imaging including CT pancreas

26

Diagnosis and Evaluation of Pancreatic and Periampullary Adenocarcinoma

protocol, endoscopic ultrasound), surgical resection of a high-grade PanIN may yield 5-year survival rates of over 85% [3, 4]. Less is known about ampullary cancer due to its relative rarity, but this disease carries a much better survival rate at early (T1) stages. For instance, in a 20-year population-based study, the age-standardized rates were 3.8 males per 1,000,000, and 2.7 females per 1,000,000. Fiveyear relative rates of survival were as high as 72.8% for stage I, but as low as 6.6% for stage IV ampullary cancers [5]. This is the framework upon which the chapter is based – namely, to offer the reader a compendium of clinical and radiographic presentations through which one should have a heightened suspicion of PDAC and ampullary cancers and furthermore methods to maximize the likelihood of timely diagnosis of PDAC and ampullary cancers.

2

Symptoms

2.1

PDAC

The most common symptoms of PDAC seen in 80% of patients include generalized fatigue, weight loss, and abdominal pain [6]. Other symptoms that can be seen with PDAC include the following: jaundice (56%), nausea/vomiting (33%), steatorrhea (25–33%), Courvoisier’s sign (nontender but palpable distended gallbladder at the right costal margin) (13%), and thrombophlebitis (3%) [6]. While the presentation of “painless jaundice” has been associated with PDAC, 80% of patients present with pain. Jaundice typically occurs with tumors located in the head because of biliary obstruction. Signs of metastatic disease can include ascites, Virchow’s node (left supraclavicular lymphadenopathy), and Sister Mary Joseph’s node (palpable periumbilical mass) [7].

2.1.1 Pain The pain associated with PDAC can be described as having an insidious onset, usually present for a few weeks to a few months, and has a gnawing visceral quality with possible burning and sharp

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sensations as well. It is generally located in the upper abdomen, epigastric region, and can radiate to the back. Pain is usually worse postprandially. On occasion, sharp, persistent epigastric pain can occur, which can be a result of an episode of acute pancreatitis from tumor occlusion of the main pancreatic duct [8]. Two main mechanisms to explain the pain associated with PDAC: ductal obstruction and pancreatic neuropathy [9]. Ductal obstruction blocks the flow of pancreatic enzymes, which can lead to increased interstitial and intraductal pressures. There is increased parenchymal edema, decreased blood flow to the pancreas, which results in ischemic pain. Pancreatic neuropathy occurs as a result of change or damage to pancreatic nerves within the celiac plexus, and the mechanism of pain includes nerve density and hypertrophy from cytokines and local inflammation, perineural invasion from the tumor, and altered expression of nociceptors [9].

2.1.2 Weight Loss Significant weight loss is a common symptom found in patients with PDAC. Cachexia, defined as unintentional weight loss of greater than 5% within 6 months, is seen in up to 80% of patients with PDAC [10]. Cachexia in PDAC patients can be broken down into three main categories: anorexia, hypercatabolism, and malabsorption. Anorexia or decreased nutritional intake is a component of both mechanical factors (from a large obstructing tumor) and immunomodulating factors (cytokines released by the tumor). A large, obstructing tumor in the head of the pancreas can lead to patients having abdominal pain, nausea, and vomiting from gastric outlet obstruction secondary to duodenal stenosis. This can result in poor nutritional intake. Patients can exhibit early satiety and bloating from decreased gastric accommodation and gastroparesis as a result of paraneoplastic gastrointestinal immotility or tumor infiltration and damage to the celiac plexus or vagus nerve [11]. Cytokines released by the tumor, such as interleukin-1 and tumor necrosisfactor alpha, have been found to be upregulated in PDAC patients. These cytokines can act on the hypothalamus to decrease satiety and nutritional intake [12]. Additionally, cytokines can lead to a

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hypercatabolic state by increasing lipid mobilizing factor and proteolysis-induced factor to cause fat and protein loss [13]. Malabsorption is another main cause of weight loss and is a result of maldigestion of fat-soluble vitamins from pancreatic exocrine insufficiency (PEI), which leads to steatorrhea. Steatorrhea is characterized by oily and greasy stool. Malabsorption and PEI are a result of obstruction of the pancreatic duct and inhibition of the normal secretion of pancreatic enzymes [14].

2.1.3 Diabetes Mellitus Development of diabetes mellitus can occur as a result of PDAC and is distinct from type 1 and type 2 diabetes mellitus. Diabetes due to diseases of the exocrine pancreas are known as type 3c diabetes and are caused by chronic pancreatitis (79%), PDAC (8%), hemochromatosis (7%), cystic fibrosis (4%), and previous pancreas surgeries (2%) [15]. The underlying mechanism of the development of diabetes from PDAC is likely due to a paraneoplastic effect due to mediators and cytokines released from the tumor that causes insulin resistance and beta-cell dysfunction [16]. Studies have shown that ~80% of patients 50 years and older with PDAC have abnormal fasting glucose or glucose intolerance regardless of tumor size or stage and 75–80% of patients reported the onset of diabetes to occur 24–36 months before the diagnosis of PDAC [16].

seen in up to 33% of cases. This finding is likely due to blood loss from the tumor and is seen more commonly than PDAC because ampullary cancers protrude into the gastrointestinal lumen [18].

3

Risk Factors

3.1

PDAC

Overall, the risk of developing PDAC increases with age with 80% of cancers occurring between the ages of 60 and 80 years old. Although there is no gender predilection, African Americans seem to have a higher risk compared to the white population. The development of PDAC can be broken down into three main categories: sporadic, familial, and inherited cancer syndromes. Sporadic PDAC accounts for 90% of cases and include environmental risk factors such as smoking, alcohol, diabetes, pancreatitis, and diet. Familial PDAC accounts for 7% of cases and is defined by having at least two first-degree relatives. Inherited cancer syndromes account for 3% of cases and include the following: hereditary pancreatitis, Peutz-Jeghers syndrome (PJS), familial atypical melanoma mole syndrome (Familial Atypical Multiple Mole Melanoma Syndrome), hereditary breast-ovarian cancer (HBOC) syndrome, and hereditary non-polyposis colorectal cancer (HNPCC) syndrome [19, 20].

3.1.1

2.2

Ampullary Cancer

Presenting symptoms in patients with ampullary cancer are largely similar to patients with PDAC where the cancer is located in the head of the pancreas. Symptoms include painless jaundice (80%), abdominal pain (45%), and weight loss (40%) [17]. Additionally, patients can also present with steatorrhea secondary to PEI from ductal obstruction and occasionally, nausea/vomiting secondary to gastric outlet obstruction. An interesting clinical symptom that is unique to patients with ampullary cancer is melena, which can be

Pancreatic Intraepithelial Neoplasia (PanIN) Pancreatic intraepithelial neoplasia (PanIN) is widely recognized as a precursor lesion to PDAC. According to the Japan Pancreas Society, these lesions are exclusively intraductal, with duct ectasia up to 5 mm in diameter. Depending on the degree of papillary growth and atypia, such lesions are classified as low-grade PanIN or high-grade PanIN [4]. It is now known that the majority high-grade PanIN contain somatic mutations such as K-ras mutations or loss of p16/CDKN2A, often at an early stage of carcinogenesis [21, 22]. Furthermore, the degree of high-grade PanIN correlates

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Diagnosis and Evaluation of Pancreatic and Periampullary Adenocarcinoma

with increasing severity of disease – in one study, with high-grade PanIN occurrence in up to 82% of PDAC [23]. Unfortunately, due to the lack of mass formation, such lesions are exceedingly difficult to detect in the early stages. However, one of the earliest clues to the presence of such lesions may be the presence of unexplained pancreatic duct dilation or even duct cutoff [24].

3.1.2 Smoking Tobacco smoking is considered to be the most important risk factor for the development of PDAC, not only because of its implicated role in 20–30% of PDAC cases but also because it is a modifiable risk factor for PDAC [25]. In a metaanalyses of ten population-based cohort studies, current smokers had a pooled relative risk of PDAC of 1.66 (95% CI 1.38–1.98) when compared to never smokers ( p < 0.05). Furthermore, increased cigarette consumption was found to have an increased risk of PDAC with a pooled relative risk of 1.62 (95% CI 1.51–1.75) for 20 cigarettes per day when compared to 1 cigarette per day ( p < 0.05) [26]. Studies have also evaluated former smokers and their risk for PDAC and have found that there is a decreased risk for former smokers when compared to current smokers. In the same meta-analyses as above, the pooled relative risk was 1.40 (95% CI 1.16–1.67) for former smokers compared to never smokers ( p < 0.05), showing a 22% decreased risk of PDAC for former smokers compared to current smokers. Additional studies have found a complete resolution of risk when quitting smoking for 10 years [26]. The mechanism of smoking in causing PDAC seems to be multifactorial through acinar cell loss and alterations of the immune microenvironment within the pancreas [27]. There seems to be a synergistic effect among alcohol and smoking. In a population-based cohort study evaluating the risk of alcohol and smoking on PDAC, the relative risk for current smokers and heavy alcohol users (
3 drinks/day) was 1.54, while the relative risk for current smokers without drinking was 1.37 [28].

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3.1.3 Alcohol Alcohol also has been independently shown to be a risk factor for PDAC. Heavy drinkers (
3 drinks/day) were found to have a relative risk of 1.29 (95% CI 1.20–1.38) compared to non-drinkers ( p < 0.05). Similar to smoking, the mechanism of PDAC development with alcohol consumption is through alterations of the immune microenvironment within the pancreas to promote cancer progression and fibrosis [27]. There does not seem to be good data on the effects of alcohol cessation on risk reduction of PDAC. Given that smoking cessation decreases the risk of PDAC, and that alcohol and smoking have similar mechanisms of PDAC development, it seems logical that alcohol cessation will lead to a decreased risk of PDAC. 3.1.4 Diet Studies have shown positive associations between meat and total fat intake, as well as grilled and fried meat intake, and the subsequent risk of PDAC [29, 30]. In a large prospective cohort of 322,846 patients older than 50 years old, total meat, red meat, high-temperature cooked meat, grilled/barbeque meat, well/very well-done meats, and heme iron from red meat were all significantly associated with PDAC development [31]. However, other studies were unable to show any association [32, 33]. The inconsistent findings are likely explained by the difficulty in controlling these dietary risk factors in a population-based recall study, which is subject to recall bias. Furthermore, confounders such as smoking were likely present, and recall bias likely occurred. Theories behind potential dietary associations and PDAC development include the overstimulation and premature activation of pancreatic lipase in the pancreatic ducts to high fat intake. High fat intake leads to increased stimulation and replication of the ductal cells to produce lipase, and the lipase may prematurely act on the cell membranes within the ducts, since the cell membranes contain cholesterol esters and other lipids [30]. Another theory behind the possible association of diet and PDAC development is that the process of grilling and frying meats can lead to the

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development of carcinogens including heterocyclic amines and polycyclic hydrocarbons [29]. Lastly, the association between heme iron intake and PDAC is likely explained through the promotion of oxidative stress including formation of N-nitroso compounds and malondialdehyde, which are known carcinogens that promote DNA damage and inflammation [31].

release insulin into the intrapancreatic portal circulation, which provides blood to the acinar and ductal cells. The increased insulin leads to persistent stimulation of IGF-1 receptors, which promote survival and proliferation [37]. Other possible mechanisms include a pro-inflammatory state, for instance, in obesity given its strong association with type 2 diabetes [16].

3.1.5 Obesity Obesity has been shown to be an independent risk factor for PDAC with approximately 10% or greater increased risk for a 5 kg/m2 unit increase in body mass index (BMI), or a 20–50% increased risk among obese relative to normal BMI patients [34]. Beyond obesity, waist circumference has also been associated with an increased risk for PDAC with an 11% increased risk with every 10 cm increase in waist circumference. Waist-hip ratio has also been examined and found to be significantly associated with PDAC risk. Every increase in 0.1 waist-hip ratio was significantly associated with 19% risk of PDAC. Potential mechanisms of the increased risk of PDAC are through obesity causing a chronic low-grade inflammatory state. Obese individuals have been shown to have increased concentrations of tumor necrosis factor-alpha and other cytokines, and this chronic inflammation can promote carcinogenesis. Another potential mechanism is through insulin resistance, which increases production of insulin hormone and promoting cell growth [35].

3.1.7 Pancreatitis Pancreatitis, both acute and chronic, have been shown to be risk factors for PDAC. The progression from chronic pancreatitis to PDAC is more well-established and is theorized to occur likely through chronic inflammatory processes that promote metaplasia and neoplastic transformation [38]. A meta-analysis published in 2017 found a 16-fold, 8-fold, and 3.5-fold increased risk of PDAC within 2 years, 5 years, and 9 years of chronic pancreatitis diagnosis, respectively [39]. Despite the known risk of progression from chronic pancreatitis to PDAC, only 5–10% of patients with chronic pancreatitis will develop PDAC over a 20-year period [38]. Acute pancreatitis itself has been shown to be a risk factor for PDAC, especially in patients 40 years or older with their first episode of acute pancreatitis. The highest risk for PDAC appears to occur within the first 2 months (170-fold) to the first year (7-fold) of being diagnosed with acute pancreatitis, but the risk also extends to 10 years (1.62-fold) [8]. The most likely mechanism is ductal obstruction from underlying tumor, and not necessarily acute pancreatitis leading to the development of PDAC. It is recommended by the American College of Gastroenterology to evaluate for PDAC in patients over 40 years old who have an episode of acute idiopathic pancreatitis [40]. During an episode of acute pancreatitis, the inflammation surrounding the pancreas makes it difficult to distinguish an underlying tumor; therefore, the inflammation needs to resolve before performing an imaging study. There currently is not a set recommendation on how long to wait for the inflammation to resolve, but usually patients are advised to wait 4-8 weeks after an episode of acute pancreatitis before screening for underlying malignancy [8].

3.1.6 Diabetes In addition to new-onset diabetes as a presenting symptom of PDAC, long-standing type 2 diabetes has also been shown to be a risk factor for the development of PDAC. Meta-analyses have reported 1.5–2 times increased risk of PDAC in patients with long-standing (>5 years) diabetes [36]. A potential mechanism behind type 2 diabetes as a risk factor for PDAC is through the increased intrapancreatic insulin levels. There is a long period where the beta cells of the pancreas are producing high levels of insulin to overcome the insulin resistance and maintain glucose homeostasis. Beta cells

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Diagnosis and Evaluation of Pancreatic and Periampullary Adenocarcinoma

3.1.8 Familial Familial PDAC accounts for 7% of cases and is defined by at least two first-degree relatives. The lifetime risk for patients with two first-degree relatives is 8–12% and increases to 40% with three first-degree relatives [41]. The incidence tends to occur between 45 and 65 years of age, which is about 20 years younger compared to the sporadic PDAC cases. Cigarette smoking also acts synergistically to increase the risk of PDAC in patients at risk for familial PDAC with a standardized incidence ratio of 19.2 in smokers and a standardized incidence ratio of 6.25 in non-smokers [42].

3.2

Inherited Cancer Syndromes

3.2.1 Hereditary Pancreatitis Hereditary pancreatitis is a rare inherited disorder characterized by recurrent acute pancreatitis in childhood with the development of chronic pancreatitis. Most mutations are from the PRSS1 gene, which is a gain-of-function mutation in a cationic trypsinogen gene leading to premature trypsin activation and autodigestion of the pancreas. It is transmitted by autosomal dominance with incomplete penetrance. Other mutations include mutations in SPINK1 and CFTR, which are inherited in an autosomal recessive pattern. SPINK1 mutations lead to a loss-of-function mutation where there is loss of the inhibitor protein that prevents premature activation of trypsin. CFTR mutation is more commonly associated with cystic fibrosis, but pancreas manifestations can also be seen through obstruction of the pancreatic duct secondary to thick and excessive secretions [43]. The lifetime risk for PDAC development in inherited cancer syndromes is 35–40% [44]. Smoking increases the risk by twofold and can decrease the age of onset by 20 years [45]. 3.2.2 Peutz-Jeghers Syndrome (PJS) Peutz-Jeghers syndrome is a polyposis syndrome characterized by numerous hamartomatous polyps throughout the gastrointestinal tract and

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mucocutaneous pigmentation. Peutz-Jeghers syndrome is caused by a mutation in the STK11/LKB1 tumor suppressor gene, which is inherited in an autosomal dominant and high penetrance pattern [46]. The life-time risk for PDAC development in PJS is 36%. Beyond PDAC, patients with this syndrome have risks for many other cancers including esophageal, stomach, small intestine, colon, breast, lung, ovarian, cervical, uterine, and testicular cancers [47].

3.2.3

Familial Atypical Malignant Mole and Melanoma Syndrome Familial atypical malignant mole and melanoma (FAMMM) syndrome is characterized by multiple benign melanocytic nevi, dysplastic nevi, and melanoma. FAMMM is caused by a mutation in the p16/CDKN2A gene and is inherited in an autosomal dominant with variable penetrance pattern [48]. The lifetime risk for PDAC development is 10–30%. Beyond PDAC, patients with this syndrome have risks for other cancers including sarcomas and endometrial, breast, and lung cancers [49]. 3.2.4

Hereditary Breast and Ovarian Cancer (HBOC) Syndrome Hereditary breast and ovarian cancer (HBOC) syndrome is primarily characterized by high risk for early development of breast and ovarian cancers. HBOC syndrome is caused by mutations in tumor suppressor genes, BRCA1, BRCA2, or PALB2, which are inherited in an autosomal dominant pattern [50]. The lifetime risk for PDAC development varies for the specific tumor suppressor gene inherited with 5–10% risk for BRCA2 and PALB2 and 3% for BRCA1 [51, 52]. 3.2.5

Hereditary Non-polyposis Colorectal Cancer (HNPCC) Hereditary non-polyposis colorectal cancer (HNPCC) syndrome is primarily characterized by early-onset colorectal cancer. HNPCC is caused by mutations in mismatch repair genes: MLH1, MSH2, MSH6, and PMS2 [53].

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The lifetime risk for PDAC development is 5– 10%. Beyond PDAC and colorectal cancer, patients have risks for other cancers including uterine, ovarian, brain, and urinary tract cancers [54].

3.3

Ampullary Cancer

In general, ampullary cancers are uncommon, with one population-based study noting approximately six cases per million inhabitants [5]. A notable exception, however, are patients with either HNPCC or familial adenomatous polyposis (FAP). In this cohort, the risk of ampullary neoplasm is 100x to as much as 300x that of the general population [55, 56]. With the widespread adoption of prophylactic colectomy in FAP patients, periampullary cancers have become one of the leading causes of death in this population. Currently, it is understood that true ampullary cancers follow the pathway of intestinal cancers, rather than pancreatic cancers, including the adenoma to carcinoma sequence, the early mutation of K-ras, and overall more favorable long-term survival of ampullary cancers as compared with PDAC. For instance, in a 7-year study of 77 ampullary and 148 head of pancreas cancers, a significant survival advantage was noted for ampullary cancers as compared with head of pancreas cancers (5.05 years vs. 2.43 years, p ¼ 0.01) [57].

4

Screening

4.1

PDAC

relative low incidence of 3% and lack of inexpensive, noninvasive screening modalities [59]. In 2012, an international group of physicians from many different fields (epidemiology, genetics, gastroenterology, radiology, oncology, surgery, and pathology) gathered for the Cancer of the Pancreas Screening (CAPS) consortium [60]. During this consortium, it was agreed upon to screen high-risk individuals for PDAC. High-risk individuals (HRI) included anyone with greater than 5% lifetime risk for PDAC development and included patients with familial pancreatic cancer and inherited cancer syndromes. Ever since the initial publication which was largely based on expert opinion, multiple studies have been published to show efficacy of PDAC screening in this population [61, 62]. In 2016, a multicenter European prospective study (Germany, the Netherlands, and Spain) published their results of PDAC screening in HRI. A surveillance program of annual imaging studies was implemented. The study found a resection rate of 75% and 5-year survival of 24% [62]. In 2018, a multicenter study from the CAPS consortium revealed resection rate of 90% and 3-year survival of 85% [61]. Given these findings, the CAPS consortium met in 2018 to update its recommendations and re-affirmed their stance on PDAC screening in HRI [20]. While positive findings for PDAC screening have been shown, there is still much more that can be done to optimize the screening process through further enrichment of the screening population and development of inexpensive, noninvasive screening modalities.

4.2 Pancreatic ductal adenocarcinoma has a dismal 5-year survival rate of 6–8%. There is potential for curative resection if diagnosed early, but 75% of patients are found to have advanced disease on initial diagnosis [58]. Therefore, there is a crucial need for PDAC screening in the hopes of identifying patients at a stage where curative resection is possible. However, PDAC screening in the general population is currently not feasible due to the

Ampullary Cancer

Screening for ampullary carcinoma occurs in patients with FAP and HNPCC. The median interval between colectomy for FAP and the development of upper gastrointestinal cancer is 22 years [63]. Endoscopically visible duodenal adenomas occur in more than half of FAP patients, and approximately half of duodenal cancers are ampullary/periampullary [64]. Furthermore, as

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Diagnosis and Evaluation of Pancreatic and Periampullary Adenocarcinoma

cancer development follows the adenoma to carcinoma sequence, screening can be beneficial to detect early-stage disease. As such, current recommendations from the American College of Gastroenterology is to start screening for gastric and small bowel tumors in FAP patients at 25– 30 years old with surveillance varying from every 0.5 to 4 years depending on the adenoma stage [65].

5

Diagnostic Workup

The diagnosis of PDAC and ampullary cancer is similar and requires a combination of symptoms, labs, imaging, and potentially biopsies. While the clinical presentation can be suggestive of an underlying malignancy, further diagnostic workup is needed to conclusively make the diagnosis. A study evaluating the diagnostic accuracy for PDAC based on symptoms alone revealed that 57% of patients had other disease processes such as pancreatitis, irritable bowel syndrome, or other malignancies [66].

6

Labs

The initial diagnostic workup usually begins with basic laboratory tests including complete blood count and basic metabolic panel. A complete blood count can show evidence of microcytic anemia, and a subsequent iron panel with ferritin should be performed to evaluate for chronic iron deficiency anemia. Further laboratory tests should be drawn based on the signs and symptoms of the patient. The majority of patients present with epigastric pain and jaundice, so aminotransferases, bilirubin, alkaline phosphatase, lipase, and amylase should be tested. Cholestatic liver enzymes are not pathognomonic for the diagnosis of PDAC or ampullary cancer but can give information of an underlying obstructive process such as a pancreatic head mass or ampullary mass obstructing the common bile duct. Lipase and amylase levels are checked to evaluate for underlying acute pancreatitis. They are not specific to patients with

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PDAC or ampullary cancer and the levels may not be elevated [67]. Hemoglobin A1c can be checked to evaluate for new-onset diabetes seen in patients with PDAC. Patients with weight loss and steatorrhea can be evaluated for fat malabsorption and pancreatic exocrine insufficiency with fecal elastase or quantitative/qualitative stool fat. Elastase is a protein produced by the pancreas and is not readily absorbed as it passes through the gastrointestinal tract. In a healthy pancreas, there should be adequate levels of elastase in the stool, while low levels are seen in patients with pancreatic exocrine insufficiency. Fecal elastase has a reported sensitivity of 100% and specificity of 93% in patients with severe pancreatic exocrine insufficiency [68]. Fecal fat can also be checked, but it is not as specific for pancreatic exocrine insufficiency. In general, a qualitative stool fat is first checked, and if positive or the clinical suspicion is high, then a 72-hour quantitative stool fat is checked [69]. Tumor markers can also be checked to aid in the diagnosis of PDAC and ampullary cancer with more extensive investigations focused on PDAC. There have been numerous tumor markers studied for diagnosis of PDAC, but poor sensitivity and high false-positive rates have limited the utility of most tumor markers with the exception of CA 19-9 [70]. CA 19-9 has been studied extensively in screening and diagnosis of PDAC. In asymptomatic individuals undergoing CA 19-9 testing, the positive predictive value (PPV) for elevated CA 19-9 (>37 U/mL) ranges from 0.5% to 0.9% likely due to the low prevalence of PDAC in the general population. In symptomatic individuals characterized by weight loss, epigastric pain, and jaundice, CA 19-9 performs much better with a reported sensitivity of 79–81%, specificity of 82– 90%, PPV of 72%, and negative predictive value (NPV) of 81% [71]. CA 19-9 can be elevated in non-malignant situations such as cholangitis and jaundice, leading to false-positive results in 10– 60%. Furthermore, a small number of patients with a negative Lewis blood group phenotype (Le[a-], Le[b-]) do not express the CA 19-9 antigen, which leads to false-negative results in 5– 10% of cases [72].

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Imaging

The mainstay of diagnosis is imaging studies, which can help diagnose PDAC and ampullary cancers or reveal a separate intra-abdominal disease process.

7.1

Transabdominal Ultrasound

Transabdominal ultrasound (US) is often the firstline imaging modality used in patients presenting with jaundice or abdominal pain given its noninvasive nature, lack of radiation, and costeffectiveness. Transabdominal ultrasound can be helpful to evaluate for common bile duct dilatation and pancreatic duct dilatation, also known as the “double duct” sign, which is suggestive of an obstructive process compressing the common bile duct and pancreatic duct that can occur secondary to a pancreatic head mass or ampullary mass. Transabdominal ultrasound is also useful to exclude other causes of pain and jaundice such as cholelithiasis, choledocholithiasis, cholecystitis, but its role in the diagnosis of PDAC and ampullary cancer is limited. The pancreas is situated in the retroperitoneal space, and overlying bowel gas often limits the utility of US in evaluating the pancreas, particularly the pancreatic head/periampullary area. The sensitivity of US in detecting PDAC has a wide range from 50 to 90%. If seen on US, a hypoechoic area within the pancreas is suggestive of PDAC, but this finding is not specific and can be seen in chronic pancreatitis or neuroendocrine tumor [73]. The diagnostic accuracy for ampullary cancer has been reported to be a dismal 15% [74]. Therefore, cross-sectional imaging is often needed for a comprehensive evaluation of the pancreas.

7.2

pancreas (can be isoattenuating in 11% of patients), associated mass effects including the “double duct” sign, atrophic distal parenchyma, and a sharp transition in the pancreatic duct [73] (Fig. 1). The sensitivity and specificity of a standard helical contrast-enhanced CT scan for the diagnosis of PDAC ranges from 70 to 97% and 75% to 100%, respectively [75]. The development of multiple-detector CT (MDCT) improves upon the diagnostic accuracy. Multiple-detector CT uses a multiple-row detector with narrow detector collimation, wide X-ray beam, and rapid table translation, which improves the images of a standard helical CT by offering faster acquisition and thinner image slices [76]. MDCT includes a delayed arterial (pancreatic) phase, which allows for improved evaluation of the parenchyma and spread to local and regional arteries, and a portal phase, which allows for assessment of venous and peritoneal involvement. The sensitivity and specificity of MDCT for diagnosis of PDAC has been reported to range from 94 to 95% and 90 to 93%, respectively [77]. The main additional benefits of MDCT over a standard helical CT are determination of staging and resectability. Multiple-detector CT can more accurately detect vascular invasion compared to standard CT. Overall, CT is the most commonly used imaging test for diagnosis of PDAC with relatively good accuracy. However, CT is not as accurate in detecting small tumors ( 100 U/mL with unresectable disease (PPV 88–91%) [72]. While

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these findings may suggest CA 19-9 as a relatively good tool to determine staging, it should be noted that 10–15% of patients with low or normal levels will have unresectable disease and 5–10% of elevated CA 19-9 levels will have resectable disease [172]. Therefore, the value of CA 19-9 should be used as an adjunctive test to aid in staging and resectability and should not be used as the sole criteria given its inherent limitations as discussed previously. In summary, the standard helical CT has relatively good accuracy for staging purposes but is improved with MDCT, which is usually the first imaging modality for staging purposes and determining resectability. MRI has been shown to have similar diagnostic accuracies to MDCT and can be an alternative. Endoscopic ultrasound can serve as a complementary role for lesions not clearly detected on MDCT/MRI, especially to evaluate for small liver metastasis and small primary tumor size (less than 3 cm) with vascular invasion that may be missed with MDCT/MRI. Factors including local resource availability and expertise will need to be taken into consideration when deciding on the imaging modality to be used. Furthermore, it may be important to perform multidisciplinary evaluation (e.g., tumor board discussion and two or more study modalities) to more accurately determine resectability.

10.2

Ampullary Cancer

Staging for ampullary cancer also follows the TNM staging system [173]. The criteria for resectability in ampullary cancer is similar to PDAC in that encasement of the major blood vessels preclude resectability. Fortunately for patients with ampullary cancer, 81% of patients are considered resectable at time of diagnosis [174]. Tumor size and intraductal extension are a unique feature to ampullary cancer that can dictate subsequent management. Traditionally, ampullary cancers have been managed through surgical resection, but with advances of endoscopy, endoscopic ampullectomy has been performed for management of small ampullary cancers. While there is not a strict criterion, consideration for endoscopic

ampullectomy includes tumor size 30 pg/mL). Given the high likelihood of metastatic disease at the time of presentation (70–92% of pancreatic somatostatinomas), somatostatin analogs such as octreotide are most often the treatment modality of choice for both somatostatinomas and somatostatinoma syndrome. For solitary tumors identified without the presence of metastases, surgical resection can be pursued [48].

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GRFomas

GRFomas are neuroendocrine tumors that secrete growth hormone, leading to acromegaly. They are predominantly seen in the lung; however, 29–30% can be found in the pancreas and are present in only 6 cm) and include liver metastases at the time of presentation. Symptoms are secondary to acromegaly or mass effect from the tumor itself [48]. The diagnosis is made with elevated GRF and GH plasma levels. Generally, GRF levels >300 pg/ mL in addition to elevated IGF-1 to the degree seen in acromegaly are observed [19]. Treatment is via

surgical resection if there is no metastatic disease; otherwise, long-acting somatostatin analogs such as octreotide or lanreotide are first-line therapies with response in up to 75–100% of patients [48].

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Nonfunctional Pancreatic Neuroendocrine Tumors (NF-pNETs)

Nonfunctional pancreatic NETs are pancreatic neoplasms that do not secrete any biologically active products nor secrete products that have an associated clinical syndrome. Around 60–90% of all pancreatic neuroendocrine tumors are nonfunctioning, and most are asymptomatic and incidentally discovered [11]. When symptoms are present, they generally include abdominal pain, jaundice, weight loss, fatigue, or increased bleeding and arise from the tumor’s location, mass effect, and/or metastases [9, 19]. These symptoms can mimic those of pancreatic adenocarcinomas [10]. Examples of NF-pNET products include pancreatic polypeptide, chromogranin A, chromogranin B, alpha-HCG, beta-HCG, and neuron-specific enolase as well as ghrelin, neurotensin, calcitonin, and other GI hormones or neurotransmitters. NF-pNETs are often large (>5 cm), invasive, and metastatic to the liver at the time of presentation as symptoms generally don’t develop until more advanced stages of the disease. Most are solitary tumors and found in the pancreatic head, with the exception being multiple tumors in association with MEN1 [48]. Diagnosis of nonfunctional pancreatic neuroendocrine tumors is usually incidental as most patients remain asymptomatic; however, once identified, they can be challenging to differentiate from functional pancreatic NETs as well as exocrine pancreatic masses. Histology is useful for confirming the diagnosis as is the absence of elevated hormone levels associated with a functional NET. Plasma pancreatic polypeptide can aid in the differentiation of pancreatic malignancies as it is elevated in nonfunctional pNETs but not in the setting of pancreatic adenocarcinomas; however, it can also be elevated in the setting of renal failure, old age, EtOH abuse, pancreatitis, inflammatory conditions, hypoglycemia, and diabetes. Somatostatin receptor scans are useful to

34 Diagnosis and Management of Pancreatic Neuroendocrine Tumors and Other Rare. . .

identify pNETs and NF-pNETs compared to exocrine pancreatic masses as the former tend to overexpress somatostatin receptors in the primary tumors and their metastases. The only curative treatment for NF-pNETs is surgical resection (via Whipple procedure or distal pancreatectomy); however, around 80% of symptomatic patients present with advanced metastatic disease limiting the effectiveness of surgical intervention. As a result, the 5-year survival is 30–63% with a median survival of 6 years. Tumors less than 1 cm tend to be closely monitored, whereas those larger than 2 cm or that are rapidly growing within 3–6 months are typically resected. For tumors between 1 and 2 cm, surgical resection is more controversial as the risk of malignant progression is low [8, 48].

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Other Rare Pancreatic NETs

Additional rare pancreatic neuroendocrine tumors include ACTHoma, present in 4–16% of all ectopic Cushing’s syndromes. It can also be found in sporadic gastrinomas as well as serve as a poor prognostic indicator in patients with liver metastases. PTHrP producing pNETs have been identified and are often large with liver metastases. Case reports also describe rare pNETs with products such as renin (hypertension), luteinizing hormone (masculinization, decreased libido), erythropoietin (polycythemia), IGF-II (hypoglycemia), enteroglucagon (small intestine hypertrophy, stasis, malabsorption), and cholecystokinin (CCKoma, similar presentation to ZES but with normal gastrin levels). Other proposed but debatable pNETs include those producing calcitonin, neurotensin, PP, and ghrelin, although all are associated with significant false positive rates [48].

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MEN1

Multiple endocrine neoplasia type 1 (MEN1) is associated with a high rate of developing pancreatic neuroendocrine tumors, among other endocrine tumors of the parathyroid and pituitary gland. Most pancreatic neuroendocrine tumors associated with MEN1 are nonfunctional pNETs;

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however, 40–60% of patients with MEN1 will develop gastrinomas, 20–30% will develop insulinomas, and 3–5% will develop one of the other functional pNETs such as VIPomas, glucagonomas, or somatostatinomas [10]. In the past, complications secondary to gastric acid hypersecretion were the leading cause of death in MEN1 patients. This is rarely a cause of death for patients these days, however, with the advances in oral acid suppression and subsequent widespread use of PPIs and H2 blockers [11]. Despite improved gastric acid control, one large study of MEN1 patients found two-thirds of patients died from MEN1-related causes, 40–45% of which were attributed directly to pancreatic neuroendocrine tumors [53]. Imaging with MRI or EUS is typically performed on initial evaluation given the characteristic small and multiple nature of associated pNETs. Surgical treatment of pNETs in the setting of MEN1 remains controversial. Whipple procedures have been performed with curative intent but are associated with both short- and long-term complications. Recent data has found MEN1 patients with pancreatic neuroendocrine tumors smaller than 2 cm have survival rates up to 100% at 15 years, suggesting surgical intervention may not be necessary for small pNETs [10]. For larger tumors greater than 2 cm, enucleation or local resection is often the choice to preserve as much pancreatic function as possible. Pancreaticoduodenectomy is generally reserved for specific cases. Furthermore, symptomatic control with acid suppressing medications allows for sufficient medical management in many cases [9].

32

Pancreatic Cystic Neoplasms

Cystic neoplasms of the pancreas account for 1% of all pancreatic neoplasms and include intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms, serous cyst adenomas, and solid pseudopapillary neoplasms. Diagnosis can be made with CT or MRI; however, EUS with FNA of cystic fluid is often helpful in identifying the cystic neoplasm using analysis of cells and tumor markers such as CEA [54]. IPMNs are the most common pancreatic cystic neoplasm and arise from pancreatic ductal

618

cells. They are equally prevalent in men and women and occur predominantly in the head of the pancreas. Patients may remain asymptomatic or present with abdominal pain, pancreatitis, or symptoms of mass effect. Cystic fluid contains large amounts of mucin and CEA. IPMNs can be further divided into three types based on their involvement of the pancreatic ducts (main duct IPMN, branch duct IPMN, or mixed IPMN). Malignant potential is determined by its type, with the highest risk of malignant potential seen in main duct IPMNs. Five-year survival rates are good for benign, borderline, and carcinoma in situ IPMNs but range from 30 to 75% in invasive, malignant IPMNs [55, 56]. Treatment is with surgical resection. Mucinous cystic neoplasms make up around 20% of these cystic neoplasms and occur primarily in middle-aged women. They range from benign to malignant depending on their degree of dysplasia and are most often found in the body or tail of the pancreas. Cystic fluid is generally thick with a large amount of mucin and elevated CEA levels. Imaging shows no communication between the neoplasm and the pancreatic ducts, differentiating it from IPMNs. Eggshell calcifications are associated with malignant progression. They are often incidentally found; however, when symptoms are present, they generally arise from mass effect. Treatment is with surgical excision (commonly via distal pancreatectomy) and is associated with an excellent 5-year survival rate (>95% for benign and borderline, 50–75% for malignant with negative margins) [55]. Serous cyst adenomas are the second most common pancreatic cystic neoplasm, again most common in women, and are found predominantly in the body or tail of the pancreas. These cystic lesions have a very low malignant potential and are often incidentally discovered, with symptoms present from mass effect. The characteristic CT finding is a “sunburst” due to a central scar, found in less than 30% of patients. Cystic fluid is high in glycogen, with low viscosity and low CEA levels. Treatment is with surgical excision for rapidly growing cyst adenomas; otherwise, observation is appropriate for asymptomatic patients [57]. Solid pseudopapillary neoplasms are rare (around 5% of pancreatic cystic lesions), most often seen in young women, and can

A. Foong and J. Buxbaum

be found throughout the pancreas but more often in the body and tail. They possess low malignant potential (10–15% malignant), and diagnosis is incidental or from symptoms secondary to mass effect. Surgical excision is generally curative, with 5-year survival rates >98% [55–57].

33

Squamous and Adenosquamous Cell Carcinomas

Squamous cell carcinomas and adenosquamous cell carcinomas are rare exocrine tumors of the pancreas. They are both more aggressive than pancreatic adenocarcinomas, with the former arising from squamous cells and the latter displaying characteristics of both adenocarcinomas and squamous cell carcinomas. Squamous cell carcinomas account for 0.5–5% of all exocrine pancreatic neoplasms; however, the pathogenesis is still poorly understood as squamous cells are not normally found in the pancreas [58, 59]. Chemotherapy with gemcitabine or 5-FU and platinum agents has been used in addition to surgical resection; however, prognosis remains poor, with a median survival of 7 months according to a recent meta-analysis [59]. Adenosquamous cell carcinomas comprise 1–4% of all exocrine pancreatic neoplasms and must include at least 30% of the squamous component for classification [60]. They are more likely to be found in the body or tail of the pancreas and tend to be larger, higher grade, and with positive lymph nodes compared to adenocarcinomas. Chemotherapy and surgical resection have been used for treatment; however, these malignancies are still associated with a very poor prognosis, with median survival ranging from 5 to 7 months [61, 62].

34

Acinar Cell Carcinoma

Acinar cell carcinoma accounts for less than 1% of all pancreatic cancers. They express many pancreatic enzymes in high levels such as lipase, amylase, trypsin, elastase, and chymotrypsin; however, tumor markers such as CEA and CA

34 Diagnosis and Management of Pancreatic Neuroendocrine Tumors and Other Rare. . .

19-9 are often not useful in their diagnosis or management [56, 63]. Lipase has historically been used to follow disease progression or response to therapy. CT images of acinar cell carcinoma appear with intermediate density, and most respond well to chemotherapy with 5-FU and oxaliplatin [63]. They also tend to be larger but less aggressive than adenocarcinomas, presenting at a younger age but more amenable to curative resection [64].

35

Pancreatic Lymphoma

Lymphomas can be present in the pancreas and comprise less than 1% of all pancreatic neoplasms. They generally present as large masses, often with extrapancreatic extension. Associated lymphadenopathy may or may not be present. Treatment is with chemotherapy and radiation, in addition to pancreaticoduodenectomy in some cases, with generally good prognosis [65].

36

Pancreatic Schwannoma

Pancreatic schwannomas are very rare, benign forms of pancreatic cancer arising from neural crest cells. They are most often encapsulated and may be diagnosed with CT or MRI. Surgical resection is usually curative with a good prognosis following resection [66].

37

Pancreatoblastoma

Almost exclusive to the pediatric population, pancreatoblastomas can be seen in adults in rare cases. Its precise pathogenesis is currently unknown. They can be found throughout the pancreas and are often large, well-defined masses with cystic and solid components. Surgical resection is the only curative treatment; however, in the setting of metastatic disease, chemotherapy and/or radiation may be employed. According to one study, the median survival with unresected tumors was 5 months but improved to 20 months with chemoradiation and surgical resection [67, 68].

38

619

Conclusion

The field of pancreatic neuroendocrine tumors and other rare pancreatic malignancies has been rapidly changing, accelerating over the past several years. As more patients present with these less commonly encountered tumors, the onus is on medical professionals to develop better diagnostic tests and additional treatment options in an effort to improve morbidity and mortality. The new advances in both diagnosis and management of pancreatic neuroendocrine and rare pancreatic exocrine tumors as described in this chapter are promising with vast potential; however, there is still much to be learned and studied. It is only with a dedication to ongoing assessment, improvement, and innovation will we continue to make great strides in the field of rare pancreatic tumors.

References 1. American Cancer Society. Cancer facts & figures 2020. Atlanta: American Cancer Society; 2020. 2. Rahid L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–21. 3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34. https://doi.org/10. 3322/caac.21551. 4. Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467(7319):1114–7. https://doi. org/10.1038/nature09515. 5. Cives M, Strosberg J. Treatment strategies for metastatic neuroendocrine tumors of the gastrointestinal tract. Curr Treat Options Oncol. 2017;18:1. 6. Basuroy R, Srirajaskanthan R, Ramage JK. Neuroendocrine Tumors. Gastroenterol Clin N Am. 2016;45(3): 487–507. https://doi.org/10.1016/j.gtc.2016.04.007. 7. Dickson PV, Behrman SW. Management of pancreatic neuroendocrine tumors. Surg Clin N Am. 2013;93: 675–91. 8. Kulke MH, Shah MH, Benson AB, Bergsland E, Berlin JD, Blaszkowsky LS, Emerson L, Engstrom PF, Fanta P, Giordano T, Goldner WS, Halfdanarson TR, Heslin MJ, Kandeel F, Kunz PL, Kuvshinoff BW, Lieu C, Moley JF, Munene G, Pillarisetty VG, Saltz L, Sosa J, Strosberg JR, Vauthey J, Wolfgang C, Yao JC, Burns J, FreedmanCass D. Neuroendocrine tumors, Version 1.2015. J Natl Compr Canc Netw. 2015;13(1):78–108. Retrieved August 14, 2020, from https://jnccn.org/view/journals/ jnccn/13/1/article-p78.xml

620 9. McKenna LR, Edil BH. Update on pancreatic neuroendocrine tumors. Gland Surg. 2014;3:258–75. 10. Amin S, Kim MK. Islet cell tumors of the pancreas. Gastroenterol Clin N Am. 2016;45(1):83–100. https:// doi.org/10.1016/j.gtc.2015.10.00. 11. Falconi M, Eriksson B, Kaltsas G, et al. ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology. 2016;103(2):153–71. 12. Frilling A, Modlin IM, Kidd M, et al. Recommendations for management of patients with neuroendocrine liver metastases. Lancet Oncol. 2014;15:e8–21. 13. Sundin A. Radiological and nuclear medicine imaging of gastroenteropancreatic neuroendocrine tumours. Best Pract Res Clin Gastroenterol. 2012;26:803–18. 14. Worhunsky DJ, Krampitz GW, Poullos PD, et al. Pancreatic neuroendocrine tumours: hypoenhancement on arterial phase computed tomography predicts biological aggressiveness. HPB (Oxford). 2014;16:304–11. 15. Wang Y, Chen ZE, Yaghmai V, et al. Diffusionweighted MR imaging in pancreatic endocrine tumors correlated with histopathologic characteristics. J Magn Reson Imaging. 2011;33:1071–9. 16. Ito T, Jensen RT. Molecular imaging in neuroendocrine tumors: Recent advances, controversies, unresolved issues, and roles in management. Curr Opin Endocrinol Diabetes Obes. 2017;24:15. 17. Anderson MA, Carpenter S, Thompson NW, et al. Endoscopic ultrasound is highly accurate and directs management in patients with neuroendocrine tumors of the pancreas. Am J Gastroenterol. 2000;95:2271–7. 18. Rösch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med. 1992;326:1721–6. 19. Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology. 2008;135:1469–92. 20. Jürgensen C, Schuppan D, Neser F, et al. EUS-guided alcohol ablation of an insulinoma. Gastrointest Endosc. 2006;63:1059–62. 21. Kim MK. Endoscopic ultrasound in gastroenteropancreatic neuroendocrine tumors. Gut Liver. 2012; (6):405–10. 22. Gupta N, Kankotia R, Sahakian A, et al. Endoscopic ultrasound assessment of pancreatic duct diameter predicts neuroendocrine tumors and other pancreas masses. Pancreas. 2019;48(1):66–9. https://doi.org/ 10.1097/MPA.0000000000001200. 23. Kitano M, Kudo M, Yamao K, et al. Characterization of small solid tumors in the pancreas: the value of contrast-enhanced harmonic endoscopic ultrasonography. Am J Gastroenterol. 2012;107(2):303–10. https:// doi.org/10.1038/ajg.2011.354. 24. Gibril F, Reynolds JC, Chen CC, Yu F, Goebel SU, Serrano J, Doppman JL, Jensen RT. Specificity of somatostatin receptor scintigraphy: a prospective study and effects of false-positive localizations on management in patients with gastrinomas. J Nucl Med. 1999;40(4):539–53.

A. Foong and J. Buxbaum 25. Bajetta E, Ferrari L, Martinetti A, et al. Chromogranin A, neuron specific enolase, carcinoembryonic antigen, and hydroxyindole acetic acid evaluation in patients with neuroendocrine tumors. Cancer. 1999;86:858–65. 26. Paik WH, Ryu JK, Song BJ, et al. Clinical usefulness of plasma chromogranin A in pancreatic neuroendocrine neoplasm. J Korean Med Sci. 2013;28:750–4. 27. Yang X, Yang Y, Li Z, et al. Diagnostic value of circulating chromogranin a for neuroendocrine tumors: a systematic review and meta-analysis. PLoS One. 2015;10:e0124884. 28. Crippa S, Boninsegna L, Partelli S, et al. Parenchymasparing resections for pancreatic neoplasms. J Hepatobiliary Pancreat Sci. 2010;17:782–7. 29. Chua TC, Yang TX, Gill AJ, Samra JS. Systematic review and meta-analysis of enucleation versus standardized resection for small pancreatic lesions. Ann Surg Oncol. 2016;23(2):592–9. https://doi.org/10. 1245/s10434-015-4826-3. 30. Cusati D, Zhang L, Harmsen WS, Hu A, Farnell MB, Nagorney DM, Donohue JH, Que FG, Reid-Lombardo KM, Kendrick ML. Metastatic nonfunctioning pancreatic neuroendocrine carcinoma to liver: surgical treatment and outcomes. J Am Coll Surg. 2012;215(1): 117–24.; discussion 124–5. https://doi.org/10.1016/j. jamcollsurg.2012.05.002. 31. Sarmiento JM, Heywood G, Rubin J, Ilstrup DM, Nagorney DM, Que FG. Surgical treatment of neuroendocrine metastases to the liver: a plea for resection to increase survival. J Am Coll Surg. 2003;197(1):29–37. https://doi.org/10.1016/S1072-7515(03)00230-8. 32. Gurusamy KS, Pamecha V, Sharma D, et al. Palliative cytoreductive surgery versus other palliative treatments in patients with unresectable liver metastases from gastro-entero-pancreatic neuroendocrine tumours. Cochrane Database Syst Rev. 2009:CD007118. 33. Lesurtel M, Nagorney DM, Mazzaferro V. When should a liver resection be performed in patients with liver metastases from neuroendocrine tumours? A systematic review with practice recommendations. HPB (Oxford). 2015;17:17–22. 34. Gurusamy KS, Ramamoorthy R, Sharma D, et al. Liver resection versus other treatments for neuroendocrine tumours in patients with resectable liver metastases. Cochrane Database Syst Rev. 2009:CD007060. 35. Fiore F, Del Prete M, Franco R, et al. Transarterial embolization (TAE) is equally effective and slightly safer than transarterial chemoembolization (TACE) to manage liver metastases in neuroendocrine tumors. Endocrine. 2014;47:177–82. 36. Kouvaraki MA, Ajani JA, Hoff P, et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004;22: 4762–71. 37. Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011;117:268–75.

34 Diagnosis and Management of Pancreatic Neuroendocrine Tumors and Other Rare. . . 38. Fine RL, Gulati AP, Krantz BA. Capecitabine and temozolomide (CAPTEM) for metastatic, welldifferentiated neuroendocrine cancers: the Pancreas Center at Columbia University experience. Cancer Chemother Pharmacol. 2013;71:663–70. 39. Kunz PL, Catalano PJ, Nimeiri H, et al. A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: a trial of the ECOG-ACRIN Cancer Research Group (E2211). J Clin Oncol. 2018;36:4004. 40. Mohamed A, Blanchard M, Albertelli M, Barbieri F, Brue T, Niccoli P, Delpero J, Monges G, Garcia S, Ferone D, Florio T, Enjalbert A, Moutardier V, Schonbrunn A, Gerard C, Barlier A, Saveanu A. Pasireotide and octreotide antiproliferative effects and sst2 trafficking in human pancreatic neuroendocrine tumor cultures. Endocrine-Related Cancer. 2014;21(5):691–704. Retrieved August 12, 2020, from https://erc-bioscientifica-com.libproxy2.usc.edu/ view/journals/erc/21/5/691.xml 41. Wolin EM, Jarzab B, Eriksson B, Walter T, Toumpanakis C, Morse MA, et al. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Des Devel Ther. 2015;9:5075–86. 42. Detjen KM, Welzel M, Farwig K, Brembeck FH, Kaiser A, Riecken EO, et al. Molecular mechanism of interferon alfa-mediated growth inhibition in human neuroendocrine tumor cells. Gastroenterology. 2000;118: 735–48. 43. Capdevila J, Salazar R, Halperin I, et al. Innovations therapy: mammalian target of rapamycin (mTOR) inhibitors for the treatment of neuroendocrine tumors. Cancer Metastasis Rev. 2011;30:27–34. 44. Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016;387:968–77. This is the first phase III trial to demonstrate that everolimus is active in gastrointestinal and lung NETs 45. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501–13. 46. Hobday TJ, Rubin J, Holen K, et al. Mco44h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): a phase II consortium (P2C) study. J Clin Oncol. 2007:S4504. 47. Villard L, Romer A, Marincek N, et al. Cohort study of somatostatin-based radiopeptide therapy with [(90)YDOTA]-TOC versus [(90)Y-DOTA]-TOC plus [(177) Lu-DOTA]-TOC in neuroendocrine cancers. J Clin Oncol. 2012;30:1100–6. 48. Jensen RT. Neuroendocrine tumors of the gastrointestinal tract and pancreas. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill.

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49. Shibata C, Kakyo M, Kinouchi M, et al. Criteria for the glucagon provocative test in the diagnosis of gastrinoma. Surg Today. 2013;43:1281–5. 50. Norton JA, Alexander HR, Fraker DL, Venzon DJ, Gibril F, Jensen RT. Comparison of surgical results in patients with advanced and limited disease with multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome. Ann Surg. 2001;234(4):495–506. https:// doi.org/10.1097/00000658-200110000-00009. 51. Kulke MH, Hörsch D, Caplin ME, Anthony LB, Bergsland E, Öberg K, et al. Telotristat Ethyl, a Tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome. J Clin Oncol. 2017;35(1):14–23. This phase III study provides evidence that the new serotonin synthesis inhibitor telotristat ethyl is effective for diarrhea palliation in patients with poorly controlled carcinoid syndrome 52. Pavel M, Gross D, Benavent M, Caplin M, Perros P, Srirajaskanthan R, et al. Efficacy and safety results of telotristat ethyl in patients with carcinoid syndrome during the double-blind treatment period of the TELECAST phase 3 clinical trial. Abstract presented at NANETS 2016, Jackson Hole, WY, USA. 53. Ito T, Igarashi H, Uehara H, et al. Causes of death and prognostic factors in multiple endocrine neoplasia type 1: a prospective study: comparison of 106 MEN1/Zollinger-Ellison syndrome patients with 1613 literature MEN1 patients with or without pancreatic endocrine tumors. Medicine (Baltimore). 2013;92:135–81. 54. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, Centeno BA, Szydlo T, Regan S, del Castillo CF, Warshaw AL. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology. 2004;126(5):1330–6. https:// doi.org/10.1053/j.gastro.2004.02.013. 55. McNabb-Baltar J, Swanson R. Tumors of the pancreas. In: Greenberger NJ, Blumberg RS, Burakoff R. eds. CURRENT diagnosis & treatment: gastroenterology, hepatology, & endoscopy, 3e. McGraw-Hill; https:// accessmedicine-mhmedical-com.libproxy2.usc.edu/con tent.aspx?bookid¼1621§ionid¼105184911 56. Luo G, Fan Z, Gong Y, Jin K, Yang C, Cheng H, Huang D, Ni Q, Liu C, Yu X. Characteristics and outcomes of pancreatic cancer by histological subtypes. Pancreas. 2019;48(6):817–22. https://doi.org/10.1097/ MPA.0000000000001338. 57. Elta GH, Enestvedt BK, Sauer BG, Lennon AM. ACG clinical guideline: diagnosis and management of pancreatic cysts. Am J Gastroenterol. 2018;113(4):464– 79. https://doi.org/10.1038/ajg.2018.14. 58. Makarova-Rusher OV, Ulahannan S, Greten TF, Duffy A. Pancreatic squamous cell carcinoma: a populationbased study of epidemiology, clinicopathologic characteristics and outcomes. Pancreas. 2016;45(10):1432–7. https://doi.org/10.1097/MPA.0000000000000658. 59. Ntanasis-Stathopoulos I, Tsilimigras DI, Georgiadou D, Kanavidis P, Riccioni O, Salla C, Psaltopoulou T, Sergentanis TN. Squamous cell carcinoma of the pancreas: a systematic review and pooled

622 survival analysis. Eur J Cancer. 2017;79:193–204. https://doi.org/10.1016/j.ejca.2017.04.006. 60. Okabayashi T, Hanazaki K. Surgical outcome of adenosquamous carcinoma of the pancreas. World J Gastroenterol. 2008;14(44):6765–70. https://doi.org/ 10.3748/wjg.14.6765. 61. Boyd CA, Benarroch-Gampel J, Sheffield KM, Cooksley CD, Riall TS. 415 patients with adenosquamous carcinoma of the pancreas: a populationbased analysis of prognosis and survival. J Surg Res. 2012;174(1):12–9. https://doi.org/10.1016/j.jss.2011. 06.015. 62. Hester CA, Augustine MM, Choti MA, Mansour JC, Minter RM, Polanco PM, Porembka MR, Wang SC, Yopp AC. Comparative outcomes of adenosquamous carcinoma of the pancreas: an analysis of the National Cancer Database. J Surg Oncol. 2018;118(1):21–30. https://doi.org/10.1002/jso.25112. 63. Kruger S, Haas M, Burger PJ, Ormanns S, Modest DP, Westphalen CB, Kleespies A, Angele MK, Hartwig W, Bruns CJ, Kirchner T, Werner J, Heinemann V, Boeck S. Acinar cell carcinoma of the pancreas: a rare disease with different diagnostic and therapeutic implications than ductal adenocarcinoma. J Cancer Res Clin Oncol.

A. Foong and J. Buxbaum 2016;142(12):2585–91. https://doi.org/10.1007/ s00432-016-2264-7. 64. Wisnoski NC, Townsend CM Jr, Nealon WH, Freeman JL, Riall TS. 672 patients with acinar cell carcinoma of the pancreas: a population-based comparison to pancreatic adenocarcinoma. Surgery. 2008;144(2):141–8. https://doi.org/10.1016/j.surg.2008.03.006. 65. Battula N, Srinivasan P, Prachalias A, Rela M, Heaton N. Primary pancreatic lymphoma: diagnostic and therapeutic dilemma. Pancreas. 2006;33(2):192–4. https:// doi.org/10.1097/01.mpa.0000227910.63579.15. 66. Wang S, Xing C, Wu H, Dai M, Zhao Y. Pancreatic schwannoma mimicking pancreatic cystadenoma: a case report and literature review of the imaging features. Medicine (Baltimore). 2019;98(24):e16095. https://doi.org/10.1097/MD.0000000000016095. 67. Vilaverde F, Reis A, Rodrigues P, Carvalho A, Scigliano H. Adult pancreatoblastoma – case report and review of literature. J Radiol Case Rep. 2016;10 (8):28–38. https://doi.org/10.3941/jrcr.v10i8.2737. 68. Omiyale AO. Clinicopathological review of pancreatoblastoma in adults. Gland Surg. 2015;4(4): 322–8. https://doi.org/10.3978/j.issn.2227-684X. 2015.04.05.

Epidemiology, Pathogenesis, and Prognosis of Pancreatic Neuroendocrine Tumors

35

Tara Keihanian and Mohamed Othman

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624

2

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624

3 Classification: Functional Versus Nonfunctional Tumors . . . . . . . . . . . . . . . . . . . . 625 3.1 Functional Pancreatic NETs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625 4

Grading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628

5 5.1 5.2 5.3

Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chromatin Remodeling Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . TP53/Rb Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PI3K/AKT/mTOR Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

628 629 629 629

6 Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1 AJCC Eighth Staging for Pancreatic NETs AJCC Eighth Staging for G3 Pancreatic NETs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2 AJCC Eighth and Pancreatic G1-G2 NET Prognostic Stage Groups . . . . . . . . . . . . 6.3 AJCC Eighth and Pancreatic G3 NET Prognostic Stage Groups . . . . . . . . . . . . . . . . 6.4 Validation of the Eighth AJCC Guideline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

630

7 7.1 7.2 7.3 7.4 7.5

Survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metastatic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tumor Functionality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tumor Location . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Age of Onset . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of mTOR Inhibitor in Survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

632 632 632 633 634 634

8

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634

631 631 631 631

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634

Abstract

T. Keihanian · M. Othman (*) Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX, USA e-mail: [email protected]

Pancreatic neuroendocrine tumors (NETs) account for 7% of pancreatic tumors. Most cases of NETs are sporadic. Pancreatic NETs are classified clinically into two groups: functional and nonfunctional. Patients with

© Springer Nature Switzerland AG 2022 C. Doria, J. N. Rogart (eds.), Hepato-Pancreato-Biliary Malignancies, https://doi.org/10.1007/978-3-030-41683-6_36

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functional tumors present with variety of symptoms as the result of hormone or active peptides production. Among functional NETs, insulinoma is the most common type; the majority of tumors are benign; however, lesions larger than 2 cm carry higher malignant potential. Gastrinoma is the second most common functional NET, and up to 90% of the tumors are malignant. The three most common impaired signaling pathways in pancreatic NETs include the PI3K/AKT/mechanistic target of rapamycin (mTOR) pathway, T53/Rb pathway, and chromatin remodeling pathway. Due to advances in diagnostic modalities and utility of endoscopic ultrasound, there has been an increase in early detection of pancreatic NETs. Treatment of pancreatic NETs is tailored based on tumor grade (tumor Ki-67 proliferation index and mitotic index) and stage (tumor size, lymph node involvement, and metastasis). Lymphovascular invasion, perineural invasion, higher tumor grade, advanced tumor stage, distant metastasis, and older age at the time of diagnosis are considered poor prognostic factors for disease-free survival. Considering mTOR pathway plays a crucial role in pathogenesis of NETs, mTOR inhibitor for management of pancreatic NETs has been shown beneficial. Keywords

Pancreatic neuroendocrine · Epidemiology · Pathogenesis · Prognosis · Tumor stage · Tumor grade

1

Introduction

Pancreatic neuroendocrine tumors (NETs) originate from the islet cells in the pancreas and account for 7% of pancreatic tumors [1] and 2% of primary pancreatic malignancies [2]. Pancreatic neuroendocrine tumors are classified to functional and nonfunctional tumors; functional tumors produce hormone and active peptides and result in nine syndromes. The different hormonal syndromes with their associated presenting

symptoms are discussed in detail in this chapter. Tumor next-generation sequencing has led to great advances in developing knowledge of underlying pathogenesis of pancreatic NETs. The three most common impaired signaling pathways in pancreatic NETs include the PI3K/AKT/ mTOR pathway, T53/Rb pathway, and chromatin remodeling pathway [44]. The importance of each pathway in progression and development of NETs also will be addressed in this chapter. Prognosis and survival of patients with pancreatic NETs depends on variety of factors such as tumor grade, tumor stage, location, genetic mutation, and age of onset. The main focus of this chapter is to discuss epidemiology, pathogenesis, and prognosis of pancreatic NETs.

2

Epidemiology

According to the American Cancer Society prediction in 2018, over 4000 individuals are estimated to be diagnosed with pancreatic neuroendocrine tumor in the USA by 2020 [1]. Although total detection rate of pancreatic NETs has increased from 2.48 to 5.86 per 100,000 per year, the overall incidence of metastatic disease has remained the same [3]. Improvement in diagnostic imaging modalities and utility of endoscopic ultrasound resulted in higher detection rates of pancreatic NETs, especially earlier stage tumors, within the last two decades [3]. Pancreatic NETs commonly occur in the fourth to sixth decade of life [1]. Annual incidence of pancreatic NETs is slightly higher in males [4]. Most cases of pancreatic NETs are sporadic; however, a higher incidence rate has been reported in inherited disorders such as multiple neuroendocrine neoplasia type 1 (MEN1) [80–100%], von HippelLindau disease (VHL) [10–17%], neurofibromatosis 1 (NF-1) [0–10%], and tuberous sclerosis [17 mcIU/ml, proinsulin >100 pmol/L, and C-peptide >3.6 ng/ml could be used as criteria to differentiate benign and malignant

insulinomas [26]. This may be explained by larger tumors and higher tumor burden in malignant lesions [26]. In comparison with benign lesions, malignant insulinoma are larger in size [4.2  3.2 vs. 1.8  0.8 cm] [20]. More than 80% of benign insulinoma are less than 2 cm in size [27]. It has been proposed that 2 cm can be used as a cutoff to predict malignant potential of insulinoma in the early stage of diagnosis [20, 27]. II. Gastrinoma (Zollinger-Ellison syndrome): Gastrinoma is the second most common functional pancreatic NET. The annual incidence of gastrinoma is between 0.5 and 2 per million population. Gastrinoma results in gastrin secretion and subsequently leads to hyperplasia of the fundic parietal cell and high gastric acid output. The excess acid can result in mucosal ulceration and inactivation of the pancreatic digestive enzymes with subsequent diarrhea and malabsorption. The most common presenting symptoms are abdominal pain, heartburn, diarrhea, and duodenal or prepyloric ulcer. Although less common, gastrinomas can also present with ulcer complications such as bleeding (1–17%), perforation (0–5%), and obstruction (0–5%) [28]. Zollinger-Ellison refers to clinical manifestation of the disease and gastrinoma refers to the pancreatic NET. Almost 75–80% of gastrinomas are sporadic, and 20–30% are associated with MEN-1. A recent meta-analysis was remarkable for a higher frequency of gastrinomas in men in the setting of MEN1 (61 vs. 54%) [29]. Gastrinoma can be located anywhere in the upper GI tract, but 60% of cases are located in the pancreas and 30% in the duodenum [28]. Pancreatic gastrinomas are generally large in size (mean 3.8 cm, 6% 500 pg/mL are suggestive of gastrinoma, and levels >1000 pg/mL are highly suggestive of gastrinoma [28]. The diagnosis can be confirmed with a secretin stimulation test, with an increase in circulating gastrin levels of >200 pg/ml above baseline after intravenous administration of 1–2 μg/kg of body weight of secretin [33]. It is highly important to keep in mind that gastrin level can be falsely elevated in the setting of PPI use; gastrin level should be checked 1 week after patient has remained off of proton pump inhibitor therapy. If the diagnosis of gastrinoma is established, the tumor localization can be achieved via abdominal multiphasic CT/MRI, SSRbased imaging or EUS. Considering pancreatic gastrinomas are usually larger than duodenal lesions, sensitivity of EUS for detecting pancreatic gastrinomas has been reported close to 100% in the literature [34] (Fig. 1). It is highly important to screen for MEN1 in patients with gastrinoma and properly address the expected concurrent syndromes such as hyperparathyroidism. III. Glucagonoma: Glucagonoma is a rare pancreatic NET with annual incidence of almost 0.01–0.1 per 1 million population per year. There is usually a delay in diagnosis (average time between symptoms and diagnosis of glucagonoma of 31.4 months), and 50–80% of patients present with malignant

Fig. 1 Gastrinoma sampled by using endoscopic ultrasound fine needle aspiration

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glucagonoma [30, 35]. The most common metastasis sites are the liver (~80%), followed by the LN and bone [35]. Glucagonoma is usually sporadic; however, it has been associated with MEN1 in almost 20% of cases [30]. Tumor produces glucagon and usually originates from the alpha cell in the pancreas located mainly in the pancreatic tail. The most common symptoms are rash called migratory necrolytic erythema, diabetes/glucose intolerance, weight loss, anemia, and thromboembolic disease [28]. Considering glucagonoma is extremely rare, most recently a review paper was published on 216 patients on long-term follow-up diagnosed since 1998 [35]. Glucagonomas are usually larger than 3 cm with average of 5 cm in reported cases [35]. Initial workup to establish diagnosis entails checking glucagon level (levels higher than 500–1000 pg/ml are diagnostic) followed by tumor localization using CT/MRI or SSR-based imaging modalities. IV. Vasoactive intestinal peptide (VIP)oma: The annual incidence of VIPoma is 0.05–2 per 1 million population per year. Ninety percent originates from the pancreas, and very rarely only in 6% of cases of VIPoma is seen in MEN1 [30]. Fifty to 80% present with malignant lesions (commonly metastasis to regional lymph nodes and liver [36]), and the most common symptoms are severe watery diarrhea (90–100%), dehydration/ hypokalemia (45–95%), hyperglycemia (20–50%), hypercalcemia (25–50%), and hypochlorhydria (35–76%) [28]. The diagnosis of VIPoma should be suspected in individuals with high output secretory diarrhea. The diagnosis can be established with measurement of serum VIP concentration, and if the value is >75 pg/mL, diagnosis can be established. V. Somatostatinoma: Somatostatinoma is an extremely rare tumor with overall incidence of 1 per 40 million persons [37]. This tumor originates from the D-cell in the pancreas, with malignant tumor in >70% of cases with reported association with MEN1 in 45% [30]. Somatostatinoma can also be

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VI.

VII.

VIII.

IX.

4

T. Keihanian and M. Othman

associated with neurofibromatosis type 1 (NF1) and von Hippel-Lindau syndrome; however, the tumor is originally located within the duodenum in these syndromes. Somatostatinoma represents 5% pancreatic NETs [38]. As somatostatin inhibits endocrine secretion and the motility of the stomach and gallbladder, the most common symptoms are diabetes mellitus (60–90%), cholelithiasis (65–90%), and steatorrhea (35–90%) [30]. Growth hormone releasing hormone (GRH) oma: Growth hormone releasing hormone producing tumor is extremely rare with >60% presenting with malignant lesions and is associated with MEN1 in 16% [30]. The most common initial symptom is acromegaly. Diagnosis starts with an elevated growth hormone releasing factor >300 pg/mL. GRH suppression test can be used to establish diagnosis. ACTH producing tumor/Cushing syndrome: It is most commonly (>95%) malignant and presents with Cushing syndrome [30]. It is highly important to rule out pituitary lesions producing ACTH before establishing the diagnosis [36]. Pancreatic NET causing carcinoid syndrome: It produces serotonin, 5hydroxyindoleacitic acid, and tachykinins, rare with only few reported cases. It presents similar to carcinoid syndrome: diarrhea, bronchospasm, skin flushing, and cardiac valvular fibrosis [30, 36]. Parathyroid hormone releasing peptide (PTHrp)-oma: This extremely rare pancreatic neuroendocrine tumor produces PTHrp, and 84% of the tumors are malignant at the time of diagnosis. The most common symptoms are hypercalcemia and abdominal pain due to hepatic metastases [30].

Grading

The World Health Organization (WHO) released an updated guideline regarding grading and classification of pancreatic NETs. Depending on tumor Ki-67 proliferation index and the mitotic

index, tumors are classified as well differentiated (pancreatic neuroendocrine tumor), poorly differentiated (pancreatic neuroendocrine carcinoma), and mixed neuroendocrine-non-neuroendocrine tumors [39]. Well-differentiated pancreatic NETs are graded as 1, 2, and 3. Ki-67 proliferation index is 20% in G1, G2, and G3, respectively. Mitotic index is 20% in G3 [39]. Poorly differentiated pancreatic NETs have >20% Ki-67 proliferation index and >20 mitotic index, divided into small and large cell types [39]. The difference between well-differentiated and poorly differentiated G3 is based on Ki-67 index, morphological appearance, and immunohistochemical (IHC) staining. Almost 15% of pancreatic NETs are neuroendocrine carcinomas (NECs) [40]. Pancreatic NECs are highly aggressive tumors in comparison with well-differentiated pancreatic NETs with an indolent coarse and different therapeutic approach and long-term prognosis among these two entities. Poorly differentiated NETs are reported mainly to occur in the head of the pancreas [41, 42]. In general, the higher the Ki-67 index, the more likelihood of carcinogenesis. Poorly differentiated tumors usually have higher index of Ki-67 (55%) and respond well to platinum-based chemotherapy [43]. On the contrary, patients with Ki-67 indices 5% [59]. Loss of PTEN expression has been reported in 29% of pancreatic NETs [60]. Data is remarkable for loss of PTEN correlating with the positive expression of phosphorylated AKT (pAKT) [61]. Loss of PTEN and increased pAKT expression are associated with metastatic potential in low-grade neuroendocrine tumors [61]. Low PTEN expression/p-mTOR-positive tumors have a higher Ki-67 index and 5-year overall survival rate (79 vs. 100%) [60]. A low cytoplasmic PTEN (negative to weak staining) level was also associated with a functional status and more aggressive tumors and correlated with shorter disease-free survival [59]. In an observational study by Dalai et al., no distant metastasis was detected in patients with normal expression of TSC2 and PETN; however, neither was an independent prognostic factor [59]. Somatostatin receptor 2 (SSTR2) expression is low in functional tumors compared with nonfunctional tumors [59]. Upregulated expression of fibroblast growth factor 13 (FGF13) was seen more in metastatic and more aggressive tumors (Ki-67% >5%) and correlated with shorter disease-free survival [59]. Overexpression of BCL-2 protein is not unique; it has been seen more frequently in pancreatic NECs in comparison with welldifferentiated NETs, and its presence correlates directly with higher mitotic rate and Ki-67 proliferation index [42].

T. Keihanian and M. Othman

The relationship between poorly differentiated pancreatic neuroendocrine carcinoma and pancreatic ductal carcinoma is not well understood. Presence of SMAD4/DPC4 and KRAS, which are more commonly seen in pancreatic ductal adenocarcinoma, has been shown in only a few patients with pancreatic NECs, speculating the idea that pancreatic NECs do not usually rise from preexisting ductal lesions [42]. Alteration in MEN1 tumor suppressor gene and p16INK4a/CDKN2A tumor suppressor gene can occur in gastrinoma [62, 63]. Goebel et al. studied the correlation between MEN1 gene mutation in 51 patients with sporadic gastrinomas [62]. MEN1 gene mutation was seen in almost 31% of sporadic gastrinomas, and mutations were clustered between amino acids 66 and 166 [62]. Presence of MEN1 did not correlate with disease activity behavior [62]. In patients with MEN1, mutation occurs throughout the gene. There is no known correlation between alteration of p16INK4a/CDKN2A tumor suppressor gene and tumor behavior pattern, stage, or prognosis [63].

6

Staging

In order to stratify pancreatic NETs, various classification and histopathological grades have been proposed and updated over the years. The first classification was released by the European Neuroendocrine Tumor Society (ENETS) based on grading and tumor node metastasis (TNM) in 2006 [64]. The American Joint Committee on Cancer (AJCC) seventh edition endorsed pancreatic NETs as a separate entity of pancreatic exocrine neoplasm and released its first staging system in the WHO 2010 staging manual. AJCC released an updated eighth edition in 2017 for staging pancreatic NETs, different from the pancreatic exocrine tumor TNM staging. The new guideline emphasizes that the newly defined TNM staging only applies to G1 and G2 pancreatic NETs, and staging for G3 pancreatic neuroendocrine carcinoma should be according to the pancreatic exocrine adenocarcinoma (PEA) staging [64]. In the new edition, the size of the tumor was updated with a new cutoff of 4 cm. M1 was

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Epidemiology, Pathogenesis, and Prognosis of Pancreatic Neuroendocrine Tumors

also categorized into three different groups: liver, extrahepatic, or both [65]. In patients with stage IV M1 pancreatic neuroendocrine neoplasm, 82.4% of pancreatic NETs and 70.8% of pancreatic NECs have evidence of liver metastasis [66]. In terms of extrahepatic metastasis, the most common metastasis sites for pancreatic neuroendocrine tumors were the bone, followed by the distant lymph node, lung, and brain. The lung was the most common site of extrahepatic metastasis in pancreatic neuroendocrine carcinoma, followed by the distant lymph node, bone, and brain [66].

M1a

M1b

M1c

Metastasis confined to the liver Metastasis in at least one extrahepatic site (lung, ovary, nonregional lymph node, peritoneum, and bone) Both hepatic and extrahepatic metastases

6.2 6.1

T1

T2

T3

T4

N0 N1

AJCC Eighth Staging for Pancreatic NETs AJCC Eighth Staging for G3 Pancreatic NETs Tumor limited to the pancreas, 4 cm, or invading the duodenum or common bile duct Tumor invades adjacent structures (stomach, spleen, colon, adrenal gland, or the wall of large vessels) (celiac axis or the superior mesenteric artery) No regional lymph node metastasis Regional lymph node metastasis

T3

T2

T4

M1

No distant metastasis Distant metastasis

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

Stage I IIA IIB IIIA IIIB IV

6.3

Stage I Stage II Stage III

N0 N1

N2

M0

Tumor 2 cm or less in greatest dimension Tumor more than 2 cm but no more than 4 cm in greatest dimension Tumor more than 4 cm in greatest dimension

M0 M1

No regional lymph node metastasis Metastases in one to three regional lymph nodes Metastases in four or more regional lymph nodes No distant metastasis Distant metastasis (continued)

Stage IV

6.4

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AJCC Eighth and Pancreatic G1-G2 NET Prognostic Stage Groups [65] T T1 T2 T3 T4 Any T Any T

N N0 N0 N0 N0 N1 Any N

M M0 M0 M0 M0 M0 M1

AJCC Eighth and Pancreatic G3 NET Prognostic Stage Groups [65] (A) T1 N0 M0 (B) T2 N0 M0 (A) T3 N0 M0 (B) Any T N1 M0 Any T N2 M0 T4 Any N M0 Any t Any N M1

Validation of the Eighth AJCC Guideline

Since the release of AJCC eighth edition, there are multiple published studies evaluating the validity of the new guidelines. You et al. studied 472 patients who underwent surgery for

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pancreatic NETs and were enrolled in the Korean nationwide surgery database. They focused on comparing ENETS and AJCC seventh edition with the new updated AJCC eighth edition [67]. According to this cohort, the 5-year and 10-year cumulative overall survival rate was as follows: IA (97.4% and 97.4%), IB (95.1% and 75.2%), IIA (90.0% and 72.7%), IIB (83.2% and 61.5%), III (100% and 0%), and IV (69.9% and 69.9%) [67]. This was one of the first studies demonstrating the higher efficacy and sensitivity of the eighth edition AJCC guidelines for long-term prognosis of the pancreatic NETs. In a SEER-based study, individuals with well- and moderately differentiated stage I pancreatic NETs, according to AJCC eighth edition staging, were followed from 2007 to 2015 [68]. Overall, the observed 5-year survival rates were 56% in the nonsurgical patients in comparison with 92% in the surgical group; however, both cohorts had similar cancer-specific survival rates of 94% vs. 98% in 5 years [68]. Surgical resection, sex, and age were not predictors of improved cancer-specific survival in this study [68]. One may hypothesize that the observed higher overall survival in the surgical group can be the result of selection bias in choosing individuals with superior health for surgical resection in comparison with those with multiple comorbidities. Although poorly differentiated G3 was excluded from the new edition of AJCC guidelines, survival of patients with G3 pancreatic neuroendocrine carcinoma has been demonstrated in many trials. In the first published trial by Yang et al., 104 patients from west China were enrolled. When applying the AJCC eighth pancreatic exocrine adenocarcinoma (EAC) staging to G3 pancreatic NETs, the estimated 3-year survival for stage I, II, III, and IV was 86.7%, 76.0%, 44.5% and 20.7%, respectively [64]. However, according to the AJCC eighth edition pancreatic G1-G2 NET staging, the survival rate for stage I, II, III, and IV was 100.0%, 83.6%, 47.1%, and 20.7%. Advanced analysis by Yang et al. demonstrated that pancreatic EAC had a higher diagnostic validity for overall survival [64].

T. Keihanian and M. Othman

7

Survival

Survival of pancreatic NETs differs based on tumor aggressive behavior, genetic mutation, tumor stage, and therapeutic interventions. Current data is remarkable for an association between an improved overall survival and surgical resection of small and localized pancreatic NETs [69]. Lymphovascular invasion, perineural invasion, and grade are considered independent prognostic factors for disease-free survival [67]. Independently, lymph node involvement is also an indicator of poor prognosis [70, 71]. In a SEER-based study from 1973 to 2000, in the era prior to utilizing newer staging systems, advanced stage, higher grade, and age were the strongest predictors of worse survival. Patients with functional tumors had better outcomes than patients with nonfunctional tumors [4].The better prognosis observed in functional tumors can most probably be explained by hormonal syndrome and earlier detection prior to advanced findings in imaging modalities.

7.1

Metastatic Disease

Patients with advanced stage tumors may have worse prognosis. In a Wen et al. trial consisting of 1371 stage patients with stage IV pancreatic neuroendocrine neoplasm, the overall 5-year survival rate of patients with M1a, M1b, and M1c stage was 44.15, 53.32, and 19.70%, respectively. The multivariate analysis also was remarkable for identifying age at diagnosis and the number of distant metastatic sites as independent prognostic factors for metastatic disease [66].

7.2

Tumor Functionality

In a recent study from the west China hospital database, nonfunctional pancreatic NETs and functional pancreatic NETs other than insulinoma had a worse prognosis [16]. Disease-free survival, overall survival, and disease-specific survival appear to be longer in metastatic M0 insulinoma than other types of functional pancreatic NETs

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Epidemiology, Pathogenesis, and Prognosis of Pancreatic Neuroendocrine Tumors

and nonfunctional pancreatic NETs (overall survival: 183 months vs. 87 and 109 months) [58]. However, M1 metastatic insulinoma had shorter disease-specific survival in comparison with other types of functional pancreatic NETs (31 months vs. 61 months), while similar survival rate was observed in nonfunctional pancreatic NETs [58]. In a Cao et al. study, there was a positive linear relation between the Ki-67 index and recurrence for metastatic non-insulinoma functional pancreatic NETs and nonfunctional pancreatic NETs [58]. Patients with insulinrelated metachronous hormonal syndrome had a lower survival rate [17]. The 5-year survival rate of patients with pancreatic or periampullary somatostatinoma is 60–100% with localized disease and 15–60% with metastatic disease [72]. Malignant insulinoma has worse 5-year survival rate in comparison with benign insulinoma. Malignant insulinoma is a rare entity; we have limited information about its long-term prognosis. According to a recent SEER-based study, 5-year and 10-year survival rates were 58% and 55% in patients with malignant insulinoma [26]. A higher survival rate was seen in patients who had surgical resection: 84% 5-year overall survival versus 14% 5-year overall survival for the surgery and no-surgery groups, respectively [26]. However, a recent single-center study from Mayo Clinic found the 5-year survival rate of stage I and II malignant insulinoma is 100%, almost similar to 95% 5-year survival of benign lesions [20]. The 5-year survival rate decreased to 89% for stage III and 50% for stage IV [20]. In a SEER-based study following up patients from 1973 to 2015, the median survival time for insulinomas, gastrinoma, glucagonoma, and VIPoma was 12.7, 10.2, 7.7, and 7.9 years, respectively [73]. The independent factors associated with prolonged survival were histology (insulinoma, gastrinoma, and VIPoma), absence of distant metastases, age 5% and weight loss at diagnosis [75]. In the same trial, treatment with long acting octreotide correlated with disease stabilization and good quality of life in almost 40% of patients [75].

7.3

Tumor Location

In a recent SEER-based study of 3011 patients from 2004 to 2016, 63% and 38% of tumors were located in the body/tail and head of the pancreas, respectively [76]. Tumors located in the head were larger, with higher LN involvement and distant metastasis [76]. LN metastasis worsens overall survival of patients with low-grade pancreatic body/tail NETs, while it had no effect on the tumor originating from the head of the pancreas. The overall survival of nonfunctional NETs located in the body/tail was higher [76].

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T. Keihanian and M. Othman

Age of Onset

Although it is unclear whether age is an independent risk factor, in a recent study of 6259 patients diagnosed with pancreatic NETs from 2004 to 2016, 27% had young onset pancreatic NETs (age 4 cm (32% vs. 27%)) and a higher stage (15% vs. 11%) than patients over 50 years old. In this cohort, the most common mutations were MEN1 (young onset vs. adult onset: 26% vs. 56%), DAXX ( 26% vs. 36%), TSC2 ( 24% vs. 16%), ATRX ( 13% vs. 21%), and TP53 ( 13% vs. 14%) [77]. The overall 5-year survival was higher in patients with young onset of pancreatic NET ( 20

Differentiation refers to morphology of tumor cells. Welldifferentiated is defined as tumor cell in similar morphology to normal, non-cancerous cells. Poorly differentiated bear no resemblance to normal, non-cancerous cells and divide and grow more rapidly. Specifically, in neuroendocrine tumors, poorly differentiated tumors can be sorted into small and large cell subtypes

and surgical management have contributed to increasing rates of survival alongside early detection and diagnosis. Medical management is the treatment of choice for symptom control, those who are awaiting an operation, or patients who are not surgical candidates due to medical comorbidities, metastasis, or recurrent tumor burden. Three main groups of therapy are available for the control of tumor growth and include somatostatin analogs, molecular-targeted treatment, and chemotherapy (Fig. 1). Imaging techniques have led to a significant increase in the diagnosis and identification of PNETs. In clinical practice, over 50% are incidentally discovered as asymptomatic, and up to 90% are non-functioning tumors. At presentation, 65% of patients have unresectable or metastatic disease. The 5-year survival rate of patients with metastatic disease is 30–40%. PNETs are often slow growing, and so laboratory and imaging modalities are used to follow tumor size and growth. The optimal management of PNETs is dependent on the tumor size, grade, stage, rate of progression, and association with genetic syndromes. A patient’s functional status and medical comorbidities also have a significant impact on deciding treatment options. While surgical excision is the primary decision for localized disease, it may not be feasible for all patients and is associated with significant adverse events. Due to metastatic disease, tumor bulk, or local extension of disease, surgery is often non-curative. In advanced cases, debulking surgery may be used to reduce symptoms related to tumor burden and hormone production. For those who cannot undergo surgery, symptom control,

suppressing tumor growth, and disease progression are the primary focus of treatment. For functioning PNETs, the goal of treatment is to control hormonal hypersecretion and achieve symptom resolution. Medical therapies and management of excessive hormone secretion have allowed for improvement in the control of these tumors. Given the low malignant potential of these tumors, there is no need for complete resection of the tumor. Insulinomas are the most common F-PNETs. Currently available studies have shown significant resolution of clinical symptoms in patients with insulinomas with medical management. The impact of medical therapy on other functioning tumors has also improved and allowed for improvement in symptom control. The decision for surgical versus medical management for NF-PNETs is more complex. NF-PNETs have a worse diagnosis than F-PNETs, likely as a result of late diagnosis. Clinicians must balance the risk of overtreatment for patient with a benign disease course versus undertreatment in those with undetected metastatic disease. Several studies suggest surgical resection of all NF-PNETs to prevent growth and progression of disease. However, studies have suggested comparable outcomes in patients who underwent nonoperative approach. Serial imaging with a more conservative approach can be a reasonable alternative when no growth or suspicious features are identified. Active surveillance is plausible in certain cases such as small (