Malignant Liver Tumors, Third Edition: Current and Emerging Therapies

Malignant Liver Tumors Current and Emerging Therapies THIRD EDITION E D I T E D BY Pierre-Alain Clavien, MD, PhD, FACS...

Author: Pierre-Alain Clavien | Stefan Breitenstein | Jacques Belghiti | Ravi S. Chari | Josep M. Llovet | Chung-Mau Lo | Michael A. Morse | Tadatoshi Takayama | Jean-Nicolas Vauthey

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Malignant Liver Tumors Current and Emerging Therapies THIRD EDITION E D I T E D BY

Pierre-Alain Clavien, MD, PhD, FACS, FRCS Professor and Chairman Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

D E P U T Y E D ITOR

Stefan Breitenstein, MD Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

ASS O CI AT E E D I T O R S

Jacques Belghiti,

MD

Professor of Surgery Department of Hepatobiliary Surgery Hospital Beaujon Clichy, France

Ravi S. Chari,

MD, MBA

Professor of Surgery and Cancer Biology Vanderbilt University Medical Center Nashville, TN, USA

Josep M. Llovet,

MD

Associate Professor of Medicine Liver Cancer Program Division of Liver Diseases Mount Sinai School of Medicine New York, New York, USA; Professor of Research – ICREA BCLC Group, IDIBAPS, Liver Unit Hospital Clinic Barcelona, Spain

Chung-Mau Lo,

MS, FRCS (Edin),

FRACS, FACS Professor Divisions of Hepatobiliary/Pancreatic Surgery and Liver Transplantation Departments of Surgery The University of Hong Kong Queen Mary Hospital Hong Kong, China

Michael A. Morse,

MD, MHS

Associate Professor of Medicine Division of Medical Oncology, GI Oncology Molecular Therapeutics Program Duke University Medical Center Durham, NC, USA

A John Wiley & Sons, Ltd., Publication

Tadatoshi Takayama,

MD, PhD

Professor Department of Digestive Surgery Nihon University School of Medicine Tokyo, Japan

Jean-Nicolas Vauthey,

MD, FACS

Professor of Surgery Liver Service Department of Surgical Oncology The University of Texas M.D. Anderson Cancer Center Houston, TX, USA

Malignant Liver Tumors Current and Emerging Therapies

Third Edition

Malignant Liver Tumors Current and Emerging Therapies THIRD EDITION E D I T E D BY

Pierre-Alain Clavien, MD, PhD, FACS, FRCS Professor and Chairman Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

D E P U T Y E D ITOR

Stefan Breitenstein, MD Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

ASS O CI AT E E D I T O R S

Jacques Belghiti,

MD

Professor of Surgery Department of Hepatobiliary Surgery Hospital Beaujon Clichy, France

Ravi S. Chari,

MD, MBA

Professor of Surgery and Cancer Biology Vanderbilt University Medical Center Nashville, TN, USA

Josep M. Llovet,

MD

Associate Professor of Medicine Liver Cancer Program Division of Liver Diseases Mount Sinai School of Medicine New York, New York, USA; Professor of Research – ICREA BCLC Group, IDIBAPS, Liver Unit Hospital Clinic Barcelona, Spain

Chung-Mau Lo,

MS, FRCS (Edin),

FRACS, FACS Professor Divisions of Hepatobiliary/Pancreatic Surgery and Liver Transplantation Departments of Surgery The University of Hong Kong Queen Mary Hospital Hong Kong, China

Michael A. Morse,

MD, MHS

Associate Professor of Medicine Division of Medical Oncology, GI Oncology Molecular Therapeutics Program Duke University Medical Center Durham, NC, USA

A John Wiley & Sons, Ltd., Publication

Tadatoshi Takayama,

MD, PhD

Professor Department of Digestive Surgery Nihon University School of Medicine Tokyo, Japan


MD, FACS

Professor of Surgery Liver Service Department of Surgical Oncology The University of Texas M.D. Anderson Cancer Center Houston, TX, USA

This edition first published 2010, © 2010 by Blackwell Publishing Ltd Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley-Blackwell. Registered office: John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www. wiley.com/wiley-blackwell The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Malignant liver tumors : current and emerging therapies / edited by Pierre-Alain Clavien ; deputy editor, Stefan Breitenstein ; associate editors, Jacques Belghiti . . . [et al.]. – 3rd ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4051-7976-8 1. Liver–Cancer–Treatment. I. Clavien, Pierre-Alain. [DNLM: 1. Liver Neoplasms–therapy. WI 735 M251 2010] RC280.L5L578 2010 616.99′436–dc22 2009029874 ISBN: 9781405179768 A catalogue record for this book is available from the British Library. Set in 9/12 pt Meridien by Toppan Best-set Premedia Limited Printed and bound in Singapore 1

2010

Contents

Contributors, vii Preface, xi

9 Modalities for Imaging Liver Tumors, 76 Dominik Weishaupt and Thomas F. Hany

Acknowledgments, xiii Abbreviations, xiv

Section 1 Introduction, 1

Section 3 Systemic and Regional Therapies, 103 Introduction, 105 Ravi S. Chari

1 From Promethean to Modern Times, 3 Kuno Lehmann, Stefan Breitenstein, and Pierre-Alain Clavien

10 Systemic Treatment of Hepatobiliary Tumors, 107 Panagiotis Samaras, Michael A. Morse, and Bernhard C. Pestalozzi

2 Hepatic Anatomy and Terminology, 11 Steven M. Strasberg

11 External Beam Radiation Therapy for Liver Tumors, 122 Rakesh Reddy and A. Bapsi Chakravarthy

Section 2 Epidemiology and Diagnosis, 27 Introduction, 29 Chung-Mau Lo 3 Histology and Pathology of Normal and Diseased Liver, 30 Valérie Paradis and Achim Weber 4 Pathology of Primary and Secondary Malignant Liver Tumors, 40 Kay Washington 5 Epidemiology, Etiology, and Natural History of Hepatocellular Carcinoma, 52 Wei-Chen Lee and Miin-Fu Chen 6 Epidemiology, Etiology, and Natural History of Cholangiocarcinoma, 56 Peter Neuhaus, Ulf P. Neumann, and Daniel Seehofer 7 Epidemiology, Etiology, and Natural History of Colorectal Liver Metastases, 64 Robert J. Porte 8 Tumor Markers in Primary and Secondary Liver Tumors, 69 Ketsia B. Pierre and Ravi S. Chari

12 Internal Radiation Therapy for Liver Tumors, 131 Ahsun Riaz, Laura Kulik, Michael Abecassis, and Riad Salem 13 Transarterial Embolization for Patients with Hepatocellular Carcinoma, 139 Jordi Bruix, Carmen Ayuso, and Maria I. Real 14 Selective Continuous Intra-arterial Chemotherapy for Liver Tumors, 151 Fidel D. Huitzil-Melendez, Stefan Breitenstein, and Nancy Kemeny 15 Isolated Hepatic Perfusion and Percutaneous Hepatic Perfusion, 164 Charles K. Heller, III, James F. Pingpank, and Steven K. Libutti

Section 4 Resection, Ablation or Transplantation for Liver Tumors, 173 Introduction, 175 Jean-Nicolas Vauthey and Tadatoshi Takayama 16 Liver Resection of Primary Tumors: Hepatocellular Carcinoma, Cholangiocarcinoma, and Gallbladder Cancer, 177 Tadatoshi Takayama and Masatoshi Makuuchi

v

Contents 17 Liver Resection of Colorectal Liver Metastases, 192 Daria Zorzi, Yun Shin Chun, and Jean-Nicolas Vauthey 18 Laparoscopic Liver Resection, 203 Luca Viganò and Daniel Cherqui 19 Repeat Resection for Liver Tumors, 216 Mickael Lesurtel and Henrik Petrowsky 20 Cryoablation of Liver Tumors, 227 Sivakumar Gananadha and David L. Morris 21 Thermal Ablation of Liver Tumors by Radiofrequency, Microwave, and Laser Therapy, 244 M. B. Majella Doyle and David C. Linehan 22 Ethanol and Other Percutaneous Injection Modalities in the Treatment of Liver Tumors, 266 Michael A. Heneghan and Andrew D. Yeoman 23 Transplantation for Liver Tumors, 281 François Durand, Claire Francoz, and Jacques Belghiti 24 Preventing Recurrence of Hepatocellular Carcinoma after Curative Resection, 296 Stefan Breitenstein, Dimitris Dimitroulis, and Beat Müllhaupt

Section 5 Guidelines for Liver Tumor Treatment, 305 Introduction, 307 Stefan Breitenstein and Pierre-Alain Clavien 25 Strategies for Safer Liver Surgery, 308 Philipp Dutkowski, Olivier de Rougemont, and Pierre-Alain Clavien 26 Hepatocellular Carcinoma, 317 Tadatoshi Takayama 27 Cholangiocarcinoma, 324 Jacques Belghiti and Charles B. Rosen 28 Gallbladder Cancer, 333 Juan Hepp and Chung-Mau Lo 29 Colorectal Liver Metastases, 342 Phuong L. Doan, Jean-Nicolas Vauthey, Martin Palavecino, and Michael A. Morse

Section 6 Emerging Therapies, 347

31 Signaling Pathways and Rationale for Molecular Therapies in Hepatocellular Carcinoma, 368 Augusto Villanueva, Clara Alsinet, and Josep M. Llovet 32 Novel Therapies Targeted at Signal Transduction in Liver Tumors, 382 Fidel D. Huitzil-Melendez, Ghassan K. Abou-Alfa, and Michael A. Morse 33 Induction of Apoptosis in Liver Tumors, 393 Markus Selzner and Pierre-Alain Clavien 34 Antiangiogenic Agents for Liver Tumors, 400 Mathijs Vogten, Emile E. Voest, and Inne H.M. Borel Rinkes 35 Integrative Oncology: Alternative and Complementary Treatments, 414 Barrie R. Cassileth and Jyothirmai Gubili

Section 7 Special Tumors, Population, and Special Considerations, 421 Introduction, 423 Stefan Breitenstein and Pierre-Alain Clavien 36 Liver Metastases from Endocrine Tumors, 424 Clayton D. Knox and C. Wright Pinson 37 Uncommon Primary and Metastatic Liver Tumors, 439 Stefan Breitenstein, Ashraf Mohammad El-Badry, and Pierre-Alain Clavien 38 Liver Tumors in Special Populations, 454 Tadahiro Uemura, Akhtar Khan, and Zakiyah Kadry 39 Malignant Liver Tumors in Children, 475 Xavier Rogiers and Ruth De Bruyne 40 Liver Tumors in Asia, 487 Norihiro Kokudo, Sumihito Tamura, and Masatoshi Makuuchi 41 Liver Tumors in South America, 500 Lucas McCormack and Eduardo de Santibañes 42 Liver Tumors in Africa, 509 Michael C. Kew 43 Anesthetic Management of Liver Surgery, 519 Marco P. Zalunardo 44 Qualitative and Economic Aspects of Liver Surgery, 531 René Vonlanthen, Ksenija Slankamenac, and Christian Ernst

Introduction, 349 Michael A. Morse and Josep M. Llovet 30 Viral-Based Therapies for Primary and Secondary Liver Cancer, 352 Menghua Dai, Lorena Gonzalez, and Yuman Fong

vi

Index, 539

Contributors

Stefan Breitenstein,

Michael Abecassis,

Yun Shin Chun,

MD Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

MD Professor Division of Organ Transplantation Department of Surgery Northwestern University Chicago, IL, USA

MD Department of Surgical Oncology The University of Texas M.D. Anderson Cancer Center Houston, TX, USA

Pierre-Alain Clavien, Ghassan K. Abou-Alfa,

MD

Department of Medicine Division of Gastrointestinal Oncology Memorial Sloan-Kettering Cancer Center New York, NY, USA

Clara Alsinet,

PhD Barcelona-Clinic-Liver-Cancer (BCLC) Group, Institut d’ Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Centro de Investigaciones Biomédicas en Red (CIBEREHD) Liver Unit, Hospital Clínic Barcelona, Spain

Carmen Ayuso,

MD Senior Consultant Barcelona-Clinic-Liver-Cancer (BCLC) Group Department of Radiology Hospital Clínic, University of Barcelona Centro de Investigaciones Biomédicas en Red Institut d’ Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona, Spain

Jordi Bruix,

MD

Senior Consultant Barcelona-Clinic-Liver-Cancer (BCLC) Group Liver Unit Hospital Clínic, University of Barcelona Centro de Investigaciones Biomédicas en Red Institut d’ Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona, Spain

Barrie R. Cassileth,

MS, PhD Integrative Medicine Service Memorial Sloan-Kettering Cancer Center New York, NY, USA

A. Bapsi Chakravarthy,

MD

Associate Professor Department of Radiation Oncology Vanderbilt University Nashville, TN, USA

Inne H.M. Borel Rinkes, Professor of Surgery Department of Surgery University Medical Center Utrecht, The Netherlands

Menghua Dai,

MD Department of Surgery Memorial Sloan-Kettering Cancer Center New York, NY, USA

Olivier de Rougemont,

MD

Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

Eduardo de Santibañes,

MD Professor of Surgery and Cancer Biology Vanderbilt University Medical Center Nashville, TN, USA

MD, PhD, FACS Professor of Surgery Hepatobiliopancreatic and Liver Transplant Unit Hospital Italiano Buenos Aires, Argentina

Miin-Fu Chen,

MD, FACS Department of General Surgery Chang-Gung Memorial Hospital Chang-Gung University Medical School Taoyuan, Taiwan

Ruth De Bruyne,

Daniel Cherqui,

Dimitrios Dimitroulis,

Ravi S. Chari,

Jacques Belghiti,

MD Professor of Surgery Department of Hepatobiliary Surgery Hospital Beaujon Clichy, France

MD, Phd Professor Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

MD Department of Pediatrics Section of Pediatric Gastroenterology University Medical Center Ghent Ghent, Belgium

MD, PhD MD Professor of Surgery Chief Department of Digestive and Hepatobiliary Surgery Hôpital Henri Mondor – Université Paris Créteil, France


vii

Contributors

Phuong L. Doan,

MD Department of Medicine Division of Medical Oncology Duke University Medical Center Durham, NC, USA

Jyothirmai Gubili,

MS, FACS Integrative Medicine Service Memorial Sloan-Kettering Cancer Center New York, NY, USA

Thomas F. Hany, M.B. Majella Doyle,

MD

Assistant Professor of Surgery Washington University School of Medicine Department of Surgery Section of Liver Transplant and Hepatobiliary Surgery St Louis, MO, USA

François Durand,

MD Hepatology and Liver Intensive Care Hospital Beaujon Clichy, France

Philipp Dutkowski,


Ashraf Mohammad El-Badry MB.BCh, MCh, MD Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

Christian Ernst,

Prof Dr Economics and Management of Social Services University Hohenheim Stuttgart, Germany

Yuman Fong,

MD Murray F. Brennan Chair in Surgery Memorial Sloan-Kettering Cancer Center New York, NY, USA

MD Department of Nuclear Medicine University Hospital Zurich Zurich, Switzerland

Charles K. Heller III,

Sivakumar Gananadha Senior lecturer Department of Surgery The Canberra Hospital Australian National University Medical School Canberra, Australia

Lorena Gonzalez,

MD Department of Surgery Memorial Sloan-Kettering Cancer Center New York, NY, USA

viii

MD, FACS Assistant Professor of Surgery Division of Transplantation Department of Surgery Penn State Milton S. Hershey Medical Center Hershey, PA, USA

Clayton D. Knox,

MD, MBA Vanderbilt University School of Medicine Nashville, TN, USA

DO

Norihiro Kokudo,

MD, PhD Hepato-Biliary-Pancreatic Surgery Division Department of Surgery University of Tokyo Tokyo, Japan

Surgery Branch National Cancer Institute National Institutes of Health Bethesda, MD, USA

Michael A. Heneghan,

MD,

MMedSc, FRCPI Consultant Hepatologist & Lead Clinician for Hepatology Institute of Liver Studies King’s College Hospital London, UK

Juan Hepp,

MD, FACS Professor of Surgery Clínica Alemana – Universidad del Desarrollo School of Medicine Department of Surgery Clínica Alemana Santiago Santiago, Chile

Laura Kulik,

MD Assistant Professor Division of Hepatology Department of Medicine Robert H. Lurie Comprehensive Cancer Center Northwestern University Chicago, IL, USA

Wei-Chen Lee,

MD Department of General Surgery Chang-Gung Memorial Hospital Chang-Gung University Medical School Taoyuan, Taiwan

Kuno Lehmann,

MD Departamento de Hematología y Oncología Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán” Mexico, D. F. Mexico


Zakiyah Kadry,

MD, FACS Professor of Surgery Division of Transplantation Department of Surgery Penn State Milton S. Hershey Medical Center Hershey, PA, USA

Mickael Lesurtel,

MD, PhD Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

Nancy Kemeny,

Steven K. Libutti,

Michael C. Kew,

David C. Linehan,

Fidel D. Huitzil-Melendez,

Claire Francoz,

MD Hepatology and Liver Intensive Care Hospital Beaujon Clichy, France

Akhtar Khan,

MD Memorial Sloan-Kettering Cancer Center Professor of Medicine Weill Medical College of Cornell University New York, NY, USA MD University of Cape Town; Emeritus Professor and Honorary Professor University of the Witwatersrand Johannesburg, South Africa

MD, FACS Professor of Surgery, Department of Surgery Montefiore Medical Center/Albert Einstein College of Medicine New York, NY, USA MD Section of Hepatobiliary, Pancreatic and Gastrointestinal Surgery Washington University School of Medicine Saint Louis, MO, USA

Contributors

Josep M. Llovet,

MD Associate Professor of Medicine Liver Cancer Program, Division of Liver Diseases Mount Sinai School of Medicine New York, New York, USA; Professor of Research – ICREA Barcelona-Clinic-Liver-Cancer (BCLC) Group Institut d’ Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Centro de Investigaciones Biomédicas en Red (CIBEREHD) Liver Unit, Hospital Clínic Barcelona, Spain

Ulf P. Neumann,

Martin Palavecino,


FRACS, FACS Department of Surgery The University of Hong Kong Queen Mary Hospital Hong Kong, China

Valérie Paradis, MD, PhD Department of Pathology Beaujon Hospital Clichy, France INSERM U773 Centre de Recherche Bichat Beaujon Paris, France

Masatoshi Makuuchi,

Bernhard C. Pestalozzi,

Chung-Mau Lo,

MS, FRCS (Edin),

MD, PhD Department of Hepato-Biliary-Pancreatic Surgery President Japanese Red Cross Medical Center Tokyo, Japan

Maria I. Real,

MD Department of General, Visceral and Transplantation Surgery Charité – Universitätsmedizin Berlin Campus Virchow-Klinikum Berlin, Germany

MD Barcelona-Clinic-Liver-Cancer (BCLC) Group Department of Radiology Hospital Clínic, University of Barcelona Centro de Investigaciones Biomédicas en Red Institut d’ Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona, Spain

Rakesh Reddy,

MBBS Department of Radiation Oncology Vanderbilt University Nashville, TN, USA

Ahsun Riaz,

MD Section of Interventional Radiology Department of Radiology Robert H. Lurie Comprehensive Cancer Center Northwestern University Chicago, IL, USA MD, PhD Department of General and Hepatobiliary Surgery Transplantation Center University Medical Center Ghent Ghent, Belgium

Henrik Petrowsky,

MD The Dumont-UCLA Transplant Center Ronald Reagan Medical Center David Geffen School of Medicine at UCLA Los Angeles, CA, USA

Charles B. Rosen,

Professor of Surgery UNSW Department of Surgery St George Hospital Sydney, Australia

Ketsia B. Pierre,

Riad Salem,

Michael A. Morse,

James F. Pingpank,

Lucas McCormack,

MD

Xavier Rogiers,

Department of Oncology Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

MD

Liver Transplant Program General Surgery Service Hospital Aleman Buenos Aires, Argentina

MD Professor of Surgery Division of Transplantation Surgery Mayo Clinic Rochester, MN, USA

David Lawson Morris

MD, MHS Associate Professor of Medicine Division of Medical Oncology, Gl Oncology Molecular Therapeutics Program Duke University Medical Center Durham, NC, USA

Beat Müllhaupt,

MD Department of Gastroenterology and Hepatology Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

Peter Neuhaus,


MD, MSCI Department of Surgery Vanderbilt University Medical Center Nashville, TN, USA MD

Associate Professor of Surgery Department of Surgery University of Pittsburgh Pittsburgh, PA, USA

C. Wright Pinson

MD, MBA H. William Scott Professor of Surgery Deputy Vice-Chancellor for Health Affairs Vanderbilt University Medical Center Nashville, TN, USA

MD, MBA Professor Interventional Oncology Section of Interventional Radiology Department of Radiology Robert H. Lurie Comprehensive Cancer Center Northwestern University Chicago, IL, USA

Panagiotis Samaras,

MD Department of Oncology Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

Daniel Seehofer, Robert J. Porte,

MD, PhD

Professor of Surgery Department of Surgery Section Hepatobiliary Surgery and Liver Transplantation University Medical Center Groningen University of Groningen Groningen, The Netherlands


ix

Contributors

Markus Selzner,

MD Department of Surgery Multiorgan Transplant Program Toronto General Hospital Toronto, Ontario, Canada

MD Department of Hepatobiliary and Digestive Surgery Ospedale Mauriziano “Umberto I” Torino, Italy

Ksenija Slankamenac,

Augusto Villanueva,


Steven M. Strasberg,

MD Pruett Professor of Surgery Section of Hepatobiliary-Pancreatic Surgery Washington University in Saint Louis Saint Louis, MO, USA

Luca Viganò,

MD Barcelona-Clinic-Liver-Cancer (BCLC) Group Institut d’ Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Centro de Investigaciones Biomédicas en Red (CIBEREHD) Liver Unit, Hospital Clínic Barcelona, Spain

Emile E. Voest,

MD, PhD Department of Medical Oncology University Medical Center Utrecht, The Netherlands

Tadatoshi Takayama,

MD, PhD Professor of Surgery Department of Digestive Surgery Nihon University School of Medicine Tokyo, Japan

Sumihito Tamura,

MD, PhD Hepato-Biliary-Pancreatic Surgery Division Department of Surgery University of Tokyo Tokyo, Japan

J. Mathijs Vogten


MD, FACS Professor of Surgery Liver Service Department of Surgical Oncology The University of Texas M.D. Anderson Cancer Center Houston, TX, USA

x

Dominik Weishaupt,

Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

Kay Washington, MD, PhD Department of Pathology Vanderbilt University Medical Center Nashville, TN, USA

MD

Division of Radiology Triemli Hospital Zurich Zurich, Switzerland

Andrew D. Yeoman,

MB BCh,

MRCP Institute of Liver Studies King’s College Hospital London, UK MD

Institute of Anesthesiology University Hospital of Zurich Zurich, Switzerland

Daria Zorzi, MD

Tadahiro Uemura,

MD, Assistant Professor of Surgery Division of Transplantation Department of Surgery Penn State Milton S. Hershey Medical Center Hershey, PA, USA

MD Department of Pathology Institute of Surgical Pathology Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

Marco P. Zalunardo, MD, PhD

Department of Surgery University Medical Center Utrecht, The Netherlands

René Vonlanthen,

Achim Weber,


Preface

Very few areas in medicine offer as many controversies as the management of liver tumors. Since the publication of the first two editions of the book, in 1999 and 2004 respectively, many novel diagnostic and therapeutic tools have become available. This has brought tremendous excitement and hope for curing previously lethal diseases. However, the recent proliferation of innovative and competitive approaches, often marketed prior to conclusive demonstration of their efficacy, has also brought confusion about which therapeutic modalities to select for a particular case [1]. Today, the success of treating a patient with hepatic malignancy is often linked to the appropriate use of various treatments, combining neoadjuvant and adjuvant modalities with surgery. Thus, the best approach for a patient with an hepatic tumor is achieved by a multidisciplinary team comprising a medical oncologist, hepatologist, hepatic surgeon, radiotherapist, and interventional radiologist. The availability of such specialists in a center per se is not enough for success. Of vital importance is the daily interaction of those specialists, which is mandatory in order to provide optimal treatment for each patient presenting with a complex liver malignancy [2]. Since most innovative approaches are still experimental and often technically demanding, patients presenting with hepatic tumors should optimally be managed in centers with a strong commitment to research. Patients often need to travel long distances to reach such centers. Therefore, for adequate long-term management of these patients, it is imperative to establish a close collaboration between specialized centers and local oncologists, as well as other physicians. To this end, the third edition of Malignant Liver Tumors has been extensively revised compared to the two previous editions, including a new format, new associate editors, and 16 new chapters containing guidelines for the treatment of each specific type of malignancy. However, the goal remains similar in providing a comprehensive and critical approach to current and established therapeutic modalities, while critically evaluating promising new avenues. The book was written by a multidisciplinary panel of international

experts, each with extensive experience in this population of patients. Each chapter was reviewed by the Editor, Deputy Editor, two Associate Editors, and at least one external reviewer to achieve comprehensive and balanced coverage of each topic, to minimize redundancy among chapters, and to provide appropriate cross-references. While each chapter can be read separately, the book was written with the intention that the chapters be read sequentially. The first and second editions received many positive comments published in several surgical, oncologic, and gastrointestinal journals, testifying to the interdisciplinary interest in the field. Besides many eulogistic comments, such as “best book in the area” [3], the most relevant criticism of the second edition appeared in the New England Journal of Medicine: “If I were a physician who was consulting this book for advice on how to treat my patient, I would be impressed by how many treatment options my patient had, but I would have no idea how to pick up the best one” [4]. To address this pertinent comment we added an entire new section (Section 5) on “Guidelines for liver tumor treatment,” covering the most common liver malignancies: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), gallbladder cancer, and colorectal liver metastases. These guidelines were prepared by the Associate Editors, taking into account other guidelines prepared by international or national societies, which should now offer a specific strategy to treat a patient with a specific condition through algorithms. Each chapter has been updated, often by the original authors. Sixteen new chapters have been added. The book starts with a new chapter (Chapter 1) on the history of liver tumors and their therapies. The next chapter (Chapter 2) is also new, covering the liver anatomy and the consensus terminology for the various types of liver resection. A new emphasis is also given to histologic changes in the liver related to underlying conditions such as steatosis and cirrhosis, as well as neoadjuvant chemotherapies, which are increasingly used in clinical practice (Chapter 4). Three new chapters (Chapters 5–7) cover the epidemiology and the natural history of HCC, CC, and colorectal liver metastases, respectively. Novel developments have occurred in the field of internal radiation therapy of liver tumors, which is

xi

Preface covered in Chapter 12. Strategies for liver resection are newly covered in two separate chapters (Chapters 16 and 17), one for HCC and gallbladder cancer, and another for colorectal metastases. Among the emerging therapies, novel therapies, targeted at specific signaling pathways, appear to be the most promising, and a new chapter has been included which covers relevant signaling pathways in liver tumors (Chapter 31). Finally, a new chapter has been included to cover the economic aspects of the treatment of liver tumors (Chapter 44). This book also has an important educational purpose, and therefore we include 5–10 questions after each chapter. This will enable the reader to test his or her understanding of the main information in each chapter. I hope that this third edition of Malignant Liver Tumors: Current and Emerging Therapies will prove useful, and will

xii

provide timely information and guidelines for the management of this difficult population of patients. P.-A.C.

References 1 Clavien PA, Petrowsky H, deOliveira ML, Graf R. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med 2007;356:1545–59. 2 Clavien PA, Mullhaupt B, Pestalozzi B. Do we need a center approach to treat patients with liver diseases? Forum on Liver Transplantation. J Hepatol 2006;44:639–42. 3 Morris DL. Book review. Br J Surg 2000;87:1117. 4 Di Bisceglie AM. Book review. N Engl J Med 2004;350:203.

Acknowledgments

Madeleine Meyer, assistant to the Editor, deserves special thanks for her enthusiasm and tireless work to get each initial and revised chapter in on time. A hearty thanks goes to all authors who often served as reviewers of other chapters, and in particular to the Associate Editors, Jacques

Belghiti, Ravi Chari, Chung-Mau Lo, Josep Llovet, Michael Morse, Tadatoshi Takayama, and Jean-Nicolas Vauthey, as well as the Deputy Editor, Stefan Breitenstein, who despite their busy schedules have dedicated a large amount of their time to the success of this book.

xiii

Abbreviations

5-FU AFLD AFP AFU AIDS Akt APAF-1 ASH ATP BMI BSC CAG CASH CBA CC CEA CEUS CGH CK CLM CRC CSI CT CTAP

5-fluorouracil alcoholic fatty liver disease alpha-fetoprotein alpha-L-fucosidase acquired immunodeficiency syndrome protein kinase B apoptosis protease activating factor alcoholic steatohepatitis adenosine triphosphate body mass index best supportive care chronic atropic gastritis chemotherapy-associated steatohepatitis cost-benefit analysis cholangiocarcinoma cost-effective analysis contrast-enhanced ultrasound comparative genomic hybridization cytokeratin colorectal liver metastasis colorectal cancer chemical shift imaging computed tomography computed tomography during arterial portography CTHA computed tomography during hepatic arteriography CTNNB1 catenin (cadherin-associated protein), beta CTV clinical target volume CUA cost-utility analysis CEA, carcinoembryonic antigen CUSA cavitron ultrasonic surgical aspiration CyA cyclosporin A DFS disease-free survival DRG diagnosis-related group ECC extrahepatic cholangiocarcinoma ECM extracellular matrix EGF epidermal growth factor EGFR epidermal growth factor receptor ERC endoscopic retrograde cholangiography

xiv

ERCP ERK FDG FLR FNH FSE FUDR GRE GSK-3β GTV H&E HAC HAI HBV HCC HCG HCV HEHE HNPCC HIV HPB HSC IAP ICC ICER ICG IGF IHP IL IMTP IOUS ITV IVC LDLT LMET LOH LSF MAPK MDCT

endoscopic retrograde cholangiopancreatography extracellular signal-regulated kinase fluoro-2-deoxy-D-glucose future liver remnant focal nodular hyperplasia fast spin echo floxuridine gradient recalled echo glycogen synthase kinase 3 beta gross tumor volume hematoxylin and eosin hepatic artery chemotherapy hepatic arterial infusion hepatitis B virus hepatocellular carcinoma human chorionic gonadotropin hepatitis C virus hepatic epithelioid hemangioendothelioma hereditary nonpolyposis colorectal cancer human immunodeficiency virus hepato-pancreatico-biliary hepatic stellate cell inhibitor of apoptosis protein intrahepatic cholangiocarcinoma incremental cost-effectiveness ratio indocyanine green insulin-like growth factor isolated hepatic perfusion interleukin intensity modulated radiation therapy intraoperative ultrasound internal target volume inferior vena cava living donor liver transplantation liver metastases from endocrine tumor loss of heterozygosity lung shunt function mitogen-activated protein kinase multidetector-row computed tomography

Abbreviations MEK MELD MEN MIP MMAC MMF MNET MRC MRCP MRI mTOR MWA NAFLD NASH NCNEM NET NIH NO NSF OLT PAAI PAS PEI PET PFS PHoT PHP PI3K PKC PSC PTC

mitogen-activated protein kinase model for end-stage liver disease multiple endocrine neoplasia maximum intensity projections mutated in multiple advanced cancer mycophenolate mofetil metastatic neuroendocrine tumor magnetic resonance cholangiography magnetic resonance cholangiopancreatography magnetic resonance imaging mammalian target of rapamycin microwave ablation nonalcoholic fatty liver disease nonalcoholic steatohepatitis noncolorectal nonendocrine metastases neuroendocrine tumor National Institutes of Health nitric oxide nephrogenic systemic sclerosis orthotopic liver transplantation percutaneous acetic acid injection periodic acid–Schiff percutaneous ethanol injection positron emission tomography progression free survival percutaneous hot saline therapy percutaneous hepatic perfusion phosphoinositid-3-kinase protein kinase C primary sclerosing cholangitis percutaneous transhepatic cholangiogram

PTEN PTV PVE PVT QALY RAD RECIST RFA RILD RLN RTK SBRT SEER SIRT SMA SNP STAT TACE TAE TART TGF TKR TLV TNF TNM TPP UPA VEGF VOD ZES

phosphatase and tensin homolog planning target volume portal vein embolization portal vein thrombosis quality adjusted life year radiation absorbed dose response evaluation criteria in solid tumor radiofrequency ablation radiation-induced liver disease regional lymph node receptor tyrosine kinase stereotactic body radiotherapy surveillance epidemiology and end results selective internal radiation therapy superior mesenteric artery single nucleotide polymorphism signal transducers and activators of transcription transarterial chemoembolization transarterial embolization transarterial radionuclide therapy transforming growth factor tyrosine kinase receptor total liver volume tumor necrosis factor tumor/node/metastasis time to progression urokinase-type plasminogen activator vascular endothelial growth factor veno-occlusive disease Zollinger−Ellison syndrome

xv

1

Introduction

1

From Promethean to Modern Times Kuno Lehmann, Stefan Breitenstein, and Pierre-Alain Clavien Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland

From myths to mysteries In the dark ages of our ancestors, liver surgery was inexistent and the organ was a source for myths, legends, and spirituality. During the Babylonian era (∼3000–1500 BC), the liver was thought to bear the soul. Priests used hepatoscopy in animal livers as a tool for divine connection, predicting the future. Clay models of sheep livers, probably used for teaching or divination, still exist from this period. The famous legend of Prometheus was written by Hesiod (750–700 BC), recounting very ancient times (Figure 1.1). Prometheus stole fire from Zeus, the godfather of ancient Greece, and gave it to mankind. For this infringement, the angry Zeus chained him to a rock and sent an eagle to devour his liver. Prometheus was captured in eternal pain. The liver regenerated and gained its normal size overnight, and the hungry eagle returned daily to its victim. Over 2000 years later, the amazing regenerative capacity of the liver is no longer a mystical tale, but the basis for current hepatobiliary surgery and a promising topic of surgical research [1]. Probably the first anatomist to describe the liver was the Alexandrian Herophilus (330–280 BC). Although his written work has not survived, another famous scientist cited him. This was the Greek Galen (130–200 AD), who dominated medical literature for the following centuries. He made accurate descriptions of the lobar anatomy and the vasculature, interpreting the liver as the source of blood. In contrast to his empirical anatomic insights, he propagated a humoral basis of medicine. Originating from the theories of Hippocrates (460–380 BC), diseases were based on an imbalance of the four humors: black and yellow bile, blood and phlegm. However, in the following years and centuries of the Middle Ages, theories became traditions and knowledge moved forward very little. Brilliant exceptions were Leonardo da Vinci’s drawings of the extra- and intra-hepatic portal and venous vessels.

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

In 1640, Johannis Walaeus, from Leiden, Netherlands, reported a common tunic, surrounding the branches of the choledochal duct, the celiac artery, and the portal vein. In 1654, Francis Glisson, from Cambridge, England removed the liver parenchyma by cooking the organ in hot water and explored the hepatic blood flow with colored milk [2]. He discussed the intrahepatic anatomy and topography of the vasculature (Figure 1.2). The growing knowledge of liver anatomy was one of the substantial preconditions for the development of liver surgery. However, this was still far from realization, and the liver remained a fragile bleeding mystery. We would like to refer to the comprehensive overview by McClusky et al for the fruitful interaction between anatomists and pioneers of liver surgery [3].

Of inquisitive anatomists and courageous surgeons In 1842, Crawford W. Long used ether as a surgical anesthetic for the first time in the United States. This was a fundamental step in the development of abdominal surgery. In 1867, Joseph Lister from Glasgow, Scotland, introduced antiseptic techniques against bacterial infections after Louis Pasteur, from Paris, France, had discovered the dangers of bacteria. Before this period, only anecdotal records exist of descriptions about the removal of protruding liver tissue after trauma. Among these surgeons were Ambroise Paré from Paris, France, J.C. Massie from the United States, Victor von Bruns from Germany, and many others. However, liver trauma at this time was generally managed without operation. It took many years before any courageous surgeon was successful in the first attempt of a planned liver resection. Carl Langenbuch from Berlin, Germany (Figure 1.3), who was among those to perform the first cholecystectomy, reported the first elective and successful hepatic resection in 1888 [4]. William W. Keen from Philadelphia performed the first liver resection in the United States in 1891. He used the “finger-fracture” technique to divide the liver parenchyma. By 1899, the first case series were being reported in the

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Introduction

Figure 1.1 Prometheus bound to a rock, with an eagle eating out his liver. 550 BC. Figure 1.3 Carl Langenbuch (1846–81).

Figure 1.2 Intrahepatic vasculature as illustrated in Francis Glisson’s Anatomia Hepatis (1654). (Reproduced from Glisson [2], with permission.)

United States [5]. The most striking challenge at this time was the control of intraoperative bleeding. In 1896, Michel Kousnetzoff and Jules Pensky introduced a continuous mattress suture above the resection line for bleeding control [6]. In 1908, J. Hogarth Pringle from Glasgow, Scotland described a method of temporary compression of the portal ligament in a small series of patients [7]. However, it took 70 years before tolerance of this maneuver – exceeding 20 min – was shown [8].

4

Bleeding control remained a major limiting factor in the development of hepatic surgery for many years. The fine work of anatomists provided the key insights to overcome major bleeding. In 1888, Hugo Rex from Germany [9], and in 1897 James Cantlie from Liverpool, England [10], revisited the accepted anatomic division of the liver by the falciform ligament. Using corrosion studies, they separated the liver by the branches of the portal vein and defined an avascular plane through the gallbladder bed. Today, the plane passing through the gallbladder bed towards the vena cava and through the right axis of the caudate lobe along the middle hepatic vein is known as the Rex–Cantlie line. Walter Wendell from Magdeburg, Germany [11] and Hans von Haberer from Graz, Austria [12] were the first surgeons at the beginning of the 20th century to apply resections along this anatomic plane. Following World War II, Carl-Herman Hjortsjo from Lund, Sweden [13] and John E. Healey from Huston, United States [14] further refined hepatic anatomy by their description of the intrahepatic biliary duct system and the vascular tree. In 1954, Claude Couinaud from Paris, France (Figure 1.4) published his seminal work on the segmental architecture of the liver [15, 16]. Based on the branches of the portal vein, he separated the liver into eight well-described segments. Before this time, liver resections were mostly performed in a “blindly manner.” The findings of Carl-Herman Hjortsjo, John Healey, and Claude Couinaud had a major impact on surgical technique and related mortality. The rapidly evolving era of liver surgery had begun.

CHAPTER 1

In 1950, Ichio Honjo from Kyoto, Japan reported the first “anatomic” liver resection [17]. Jean-Louis LortatJacob from Paris, France in 1952 [18], followed by Julian. K. Quattlebaum, from Georgia, United States in 1953 [19], reported the first resections in Europe and the United States. Subsequent, descriptions of the procedure were provided by Alexander Brunschwig [20] and George T. Pack [21] in New York, United States, and later by William P. Longmire and Samuel A. Marable [22] in Los Angeles, United States. At this time, George T. Pack documented the regenerative potential of the human liver after a major hepatectomy [23]. A few years later, Tien-Yu Lin and Chiu-Chiang Chen from Taipei, Taiwan described the decrease of regenerative capacity of the cirrhotic liver [24]. The knowledge about liver regeneration in humans was preceded by animal experiments years before. In 1879, Hermann Tillmanns from Leipzig, Germany [25] demonstrated regeneration in rabbit livers. In 1883, Themisocles Gluck from Berlin [26], and later Emil Ponfick from Breslau, Germany, demonstrated liver regeneration after major resections in animals. In the 1960s, perioperative mortality rates up to 50% were common after right hemihepatectomy. Furthermore, serious concern was growing over hepatic nomenclature, and notably, liver surgeons throughout the world used different, sometimes confusing, terms [27]. In 2000, a group of international liver surgeons proposed a standardized nomenclature, which was introduced at the bi-annual

Figure 1.4 Claude Couinaud working with his collection of liver casts at the School of Medicine in Paris, 1988.

From Promethean to Modern Times

meeting of the International Hepato-Pancreato-Biliary Association (IHPBA) in Brisbane, Australia. The terminology for hepatic anatomy was subsequently called the Brisbane nomenclature [28]. Nomenclature in hepatic surgery is discussed in detail in Chapter 2. Over the years, growing anatomic and physiologic knowledge, and ongoing specialization in experienced centers, have significantly lowered mortality from liver resections to below 5% [29]. We would like to refer to the comprehensive overviews by Joseph G. Fortner and Leslie H. Blumgart [30], and James H. Foster [31], for an in-depth coverage of liver surgery in the 20th century.

The era of liver transplantation A giant leap forward and a driving force in the rapid development of hepatobiliary surgery was the onset of the transplantation era. In 1955, Cristopher S. Welch from Albany, United States, published the first heterotopic liver transplantation in a dog [32]. Others, such as J. A. Cannon, Thomas E. Starzl, and Francis D. Moore, followed with orthotopic liver transplantations (OLT), also in dogs, and established the basis for transplantation in humans [33]. In 1963, Thomas E. Starzl (Figure 1.5) made the first attempt to transplant a human liver in Denver, United States [34]. However, the patient died during the operation. Another attempt by Francis D. Moore in Boston also did not succeed

Figure 1.5 Thomas E. Starzl has the honor of the first pitch at the Three Rivers Stadium in 1983, Pittsburgh. (Reproduced from the Pittsburgh Post-Gazette.)

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Introduction

[35]. The first series of successful OLTs was reported in 1968 by Thomas E. Starzl [36]. A year later, Sir Roy Calne performed the first OLT in Europe in Cambridge, England [37]. However, although many patients initially tolerated the transplantation well, most did not survive OLT longer than a few weeks or months. Another quantum leap was the discovery of cyclosporine A (CyA) by Hartmann F. Stähelin and Jean-Francois Borel from Basel, Switzerland, in 1972. Seven years later, Sir Roy Calne reported the first use of CyA in OLT patients with a dramatic improvement in long-term survival [38]. Before the introduction of CyA, 5-year survival after OLT was less than 20% and improved to 60% or more with the introduction of CyA [39]. In the late 1980s, Thomas E. Starzl introduced FK-506 (tacrolimus) as a new and promising immunosuppressant at the University of Pittsburgh. The introduction of effective immunosuppressants such as polyclonal antilymphocyte antibodies, anti-CD3 antibodies in the 1980s, or mycophenolate mofetil (MMF) in the early 1990s, and rapamycin in the late 1990s offered further alternatives in the management of patients after OLT. Already in the early stage of solid organ transplantation, it was recognized, that success could only be achieved with adequate preservation of the organs. Cold preservation was described as early as 1912 by the French surgeon Alexis Carell, who preserved and transplanted vessels, skin, and connective tissues in dogs [40]. Together with the famous aviator and engineer Charles A. Lindberg, he constructed a perfusion pump and successfully preserved thyroid glands [41]. Years later, in the era of liver transplantation, the relevance of cooling the donor organ was recovered during animal experiments by Francis D. Moore [33]. Lawrence Brettschneider from Denver, United States used cooling of the animal donor organ and intraportal infusion with a balanced, cooled electrolyte solution, buffered to pH. The organ was additionally perfused after harvesting, but this technique was much too complex for clinical application [42]. For many years, storage in cold Collins solution was the standard for organ procurement [43]. A landmark advance was the development of the University of Wisconsin (UW) solution by Folkert O. Belzer and James H. Southard in 1988 [44], representing an important growth of knowledge in the pathophysiology of ischemia/reperfusion injury. This solution contains colloids to prevent cell swelling, the oxygen scavengers allopurinol and glutathione, and adenosine to facilitate adenosine triphosphate (ATP) production. In 1983, a National Institutes of Health (NIH) Consensus Conference considered liver transplantation as an accepted therapy for patients with end-stage liver disease. The consequence of this statement was a rapid increase in the numbers of patients on waiting lists in the following years, resulting in a dramatic shortage of available donor organs for trans-

6

Figure 1.6 Henri Bismuth.

plantation. The development of new concepts was therefore crucial. The shortage of size-matched liver donors for pediatric patients was responsible for a high death rate on the cadaveric pediatric waiting list. This stimulated the development of technical innovations based on the segmental anatomy of the liver. Reduced liver graft, split graft, and living donor liver transplantation were such innovative techniques. In 1984, Henri Bismuth (Figure 1.6) from Paris, France, performed the first OLT using a left hemiliver [45]. In 1988, Rudolf Pichlmayr from Hannover, Germany extended the concept of partial liver graft transplantation and published in 1988 a report of a split graft, where the right hemiliver was transplanted to an adult, and the left to a child [46]. Two years later, Christoph E. Broelsch published the first patient series of split liver transplantation in Chicago, United States [47]. The introduction of living donors was a critical step in the further evolution of liver transplantation [48]. In 1989, Silvano Raia from Sao Paulo, Brazil [49], and one year later Russell W. Strong from Brisbane, Australia [50], reported the first living donor liver transplantations using the left hemiliver. In 1994, Yoshio Yamaoka from Kyoto, Japan used the right hemiliver for transplantation, expanding this procedure also for adults [51]. The first series of patients was published by Christoph E. Broelsch in Chicago [52], later by Chung-Mau Lo in Hong Kong [53]. Nowadays, patient survival after one year has reached 80–90% in many contemporary series of OLT [54]. Conse-

CHAPTER 1

quently, donor criteria are still expanding under the pressure of an insufficient donor pool. Beside end-stage liver disease and acute liver failure, selected patients with primary liver cancer [55] and early stage hilar cholangiocarcinoma [56] have become accepted indications for OLT (see also Chapter 26 for indications of OLT in treatment of liver tumors). A potential approach to solve the shortage of donor organs was the use of steatotic donor organs and this was shown to have a favorable outcome by McCormack et al [57]. Donor risk scores and appropriate matching to selected recipients may further improve the outcome [58]. Thus, extending donor criteria, improvement of allocation procedures, and finally, translation of knowledge from basic research about donor organ protection into clinical application, may help to overcome the problem of donor organ shortage in the near future.

Surgical oncology: breaking down the limits Parallel to the progress in the field of liver transplantation, liver surgery, mostly for oncologic diseases, became more sophisticated. In 1983, William P. Longmire from Los Angeles, California, published the results of 138 patients after major resections with a 30-day mortality of 10% [59]. In the 1990s, Jacques Belghiti from Paris, France reported – in a large series of 747 patients – a mortality of 1% in patients with normal liver parenchyma [60]. Leslie H. Blumgart from New York, United States [61] and Sheung Tat Fan from Hong Kong [62] published similar results. However, the presence of cirrhosis [63], portal hypertension [64], and liver steatosis [65] were identified as important risk factors for perioperative morbidity and mortality. An important step for the improved outcomes was the understanding that these complex diseases must be treated in specialized, interdisciplinary centers [66]. A higher caseload in such hepato-pancreatico-biliary (HPB) centers translates into more experience, an important factor for favorable outcomes [67, 68]. In the last decades, basic research provided new insights into liver physiology and pathophysiology [69–71]. Interleukin-6 [72], tumor necrosis factor α [73], platelet-derived serotonin [74], and bile salts [75] were identified as central mediators of liver regeneration. Explorations of mechanisms of ischemic damage and cell death provided novel perceptions of liver injury [76–79]. However, only few new strategies, such as ischemic preconditioning, made the transition into clinical practice [80]. Diagnostic accuracy improved due to the availability of computed tomography (CT) scans and magnetic resonance (MR) tomography. Masatoshi Makuuchi, from Tokyo, Japan, introduced the concept of routine intraoperative


ultrasonography for liver surgery [81]. He was also among the first to use portal vein embolization to increase the future liver remnant prior to major resection [82], although the mechanism of selective portal occlusion and subsequent contralateral hypertrophy was already known since 1920 [83]. For the treatment of unresectable tumors, radiofrequency was introduced as an alternative treatment [84–86]. The complex treatment strategies for metastatic liver disease are illustrative examples of the progress of HPB surgery [1]. In 1940, Richard B. Cattell, in Boston, United States, performed the first resection of a metastatic tumor [87], although resection of colorectal liver metastases remained controversial until the early 1980s. The survival of patients after resection was 21%, but the operative mortality still reached 17% [88]. Today, resection for liver metastasis, especially of colorectal origin, provides favorable outcomes compared to the natural history [89]. In a series of 1001 consecutive patients, the 5-year survival rate was 37% [1, 90]. In selected patients with unresectable and multifocal metastases, a two-stage hepatectomy combined with chemotherapy was recognized as an effective and safe treatment strategy [91]. In 2004, promising survival rates for patients treated with two-stage procedures, combined with portal vein ligation, were published [92]. Down-staging of previously unresectable colorectal liver metastases could also be achieved by portal vein ligation combined with intraarterial chemotherapy [93]. Multistage procedures are currently recognized as effective strategies for patients with otherwise unresectable tumors [1]. In conclusion, liver surgery has enjoyed a dramatic development during the last three decades. Surgical experience and outcomes after major surgery improved as a result of progress in many fields. Furthermore, multidisciplinary patient management became a mainstay of care in recognized HPB centers. Today, liver surgery no longer carries the high risk that it did in its infancy. In experienced hands, liver surgery became reliable and effective, and consequently saved the lives of many patients.

Self-assessment questions 1 Name the surgeon who performed the first successful liver resection. 2 Name the surgeons who performed the first major liver resections. 3 What was a prerequisite for safe major liver surgery? 4 What was the major innovation making OLT a successful treatment? 5 A great problem was the availability of size-matched donor organs for children. Who found the solution, which had also a major impact on later developments?

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Introduction

References 1

2 3

4 5

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9 10 11 12 13 14

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patients from a prospective database. Ann Surg 2004;240:698– 708; discussion 708–10. Nagasue N, Yukaya H, Ogawa Y, Kohno H, Nakamura T. Human liver regeneration after major hepatic resection. A study of normal liver and livers with chronic hepatitis and cirrhosis. Ann Surg 1987;206:30–9. Bruix J, Castells A, Bosch J, et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 1996;111:1018–22. McCormack L, Petrowsky H, Jochum W, Furrer K, Clavien PA. Hepatic steatosis is a risk factor for postoperative complications after major hepatectomy: a matched case-control study. Ann Surg 2007;245:923–30. Clavien PA, Mullhaupt B, Pestalozzi BC. Do we need a center approach to treat patients with liver diseases? J Hepatol 2006;44:639–42. Dimick JB, Wainess RM, Cowan JA, Upchurch GR, Jr, Knol JA, Colletti LM. National trends in the use and outcomes of hepatic resection. J Am Coll Surg 2004;199:31–8. Glasgow RE, Showstack JA, Katz PP, Corvera CU, Warren RS, Mulvihill SJ. The relationship between hospital volume and outcomes of hepatic resection for hepatocellular carcinoma. Arch Surg 1999;134:30–5. Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology 2006;43(Suppl 1):S45–53. Michalopoulos GK, DeFrances MC. Liver regeneration. Science 1997;276:60–6. Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol 2004;5:836–47. Cressman DE, Greenbaum LE, DeAngelis RA, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 1996;274:1379–83. Yamada Y, Kirillova I, Peschon JJ, Fausto N. Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor. Proc Natl Acad Sci U S A 1997;94:1441–6. Lesurtel M, Graf R, Aleil B, et al. Platelet-derived serotonin mediates liver regeneration. Science 2006;312:104–7. Huang W, Ma K, Zhang J, et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 2006;312:233–6. Clavien PA, Harvey PR, Sanabria JR, Cywes R, Levy GA, Strasberg SM. Lymphocyte adherence in the reperfused rat liver: mechanisms and effects. Hepatology 1993;17:131–42. McKeown CM, Edwards V, Phillips MJ, Harvey PR, Petrunka CN, Strasberg SM. Sinusoidal lining cell damage: the critical injury in cold preservation of liver allografts in the rat. Transplantation 1988;46:178–91. Otto G, Wolff H, David H. Preservation damage in liver transplantation: electron-microscopic findings. Transplant Proc 1984;16:1247–8. Caldwell-Kenkel JC, Thurman RG, Lemasters JJ. Selective loss of nonparenchymal cell viability after cold ischemic storage of rat livers. Transplantation 1988;45:834–7. Clavien PA, Selzner M, Rudiger HA, et al. A prospective randomized study in 100 consecutive patients undergoing major liver resection with versus without ischemic preconditioning. Ann Surg 2003;238:843–50; discussion 851–2.

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81 Makuuchi M, Hasegawa H, Yamazaki S. Intraoperative ultrasonic examination for hepatectomy. Ultrasound Med Biol 1983;(Suppl 2):493–7. 82 Makuuchi M, Thai BL, Takayasu K, et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery 1990;107:521–7. 83 Rous P, Larimore L. Relation of the portal blood to liver maintenance. J Exp Med 1920;31:609–70. 84 Curley SA, Izzo F, Delrio P, et al. Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies: results in 123 patients. Ann Surg 1999;230:1–8. 85 Elias D, Debaere T, Muttillo I, Cavalcanti A, Coyle C, Roche A. Intraoperative use of radiofrequency treatment allows an increase in the rate of curative liver resection. J Surg Oncol 1998;67:190–1. 86 Siperstein AE, Rogers SJ, Hansen PD, Gitomirsky A. Laparoscopic thermal ablation of hepatic neuroendocrine tumor metastases. Surgery 1997;122:1147–54; discussion 1154–5. 87 Cattell R. Successful removal of a liver metastasis from carcinoma of the rectum. Lahey Clin Bull 1940;2:7–11. 88 Foster JH. Survival after liver resection for secondary tumors. Am J Surg 1978;135:389–94. 89 Wagner JS, Adson MA, Van Heerden JA, Adson MH, Ilstrup DM. The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Ann Surg 1984;199:502–8. 90 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;230:309–18; discussion 318–21. 91 Adam R, Laurent A, Azoulay D, Castaing D, Bismuth H. Two-stage hepatectomy: A planned strategy to treat irresectable liver tumors. Ann Surg 2000;232:777–85. 92 Jaeck D, Oussoultzoglou E, Rosso E, Greget M, Weber JC, Bachellier P. A two-stage hepatectomy procedure combined with portal vein embolization to achieve curative resection for

10

initially unresectable multiple and bilobar colorectal liver metastases. Ann Surg 2004;240:1037–49; discussion 1049–51. 93 Selzner N, Pestalozzi BC, Kadry Z, Selzner M, Wildermuth S, Clavien PA. Downstaging colorectal liver metastases by concomitant unilateral portal vein ligation and selective intraarterial chemotherapy. Br J Surg 2006;93:587–92.

Self-assessment answers 1 Carl Langenbuch, a German surgeon, performed the first successful liver resection in 1888 in Berlin. 2 Ichio Honjo reported the first “anatomic” liver resection in 1950 in Kyoto, Japan. In 1952, Jean-Louis LortatJacob from Paris, France reported the first resection in Europe, followed by Julian K. Quattlebaum from Georgia, who reported the first resections in the United States in 1953. 3 The fine work of Carl-Herman Hjortsjo from Lund, Sweden, John E. Healey from Huston, United States and Claude Couinaud from Paris, France revealed the complex anatomy of intrahepatic structures, a fundamental basis for safe liver surgery. 4 Before the advent of cyclosporine A, discovered in 1972 by Hartmann F. Stähelin and Jean-Francois Borel from Basel, Switzerland, the prognosis after OLT was poor. Cyclosporine A improved the outcome of these patients significantly. 5 The segmental anatomy of the liver was the key to the problem. Henri Bismuth from Paris, France performed the first OLT using a left hemiliver in 1984. Later, Rudolf Pichlmayr from Hannover, Germany performed a split graft, where the right hemiliver was transplanted to an adult, and the left to a child. This principle was also the basis for living related liver transplantation.

2

Hepatic Anatomy and Terminology Steven M. Strasberg Section of Hepatobiliary-Pancreatic Surgery, Washington University in Saint Louis, Saint Louis, MO, USA

Overview A clear understanding of hepatic anatomy is critical to the planning and conduct of liver surgery. The branching pattern of the hepatic artery and bile ducts within the liver is regular and virtually identical to each other, unlike for the portal vein. Consequently the Brisbane 2000 Terminology of Hepatic Anatomy and Resections of the International Hepatobiliary Pancreatic Association (IHBPA) [1] (Members of the Committee of the Brisbane Classification: Strasberg SM, Belghiti J, Clavien PA, Gadzijev E, Garden JO, Lau W, Makuuchi M, Strong RW) is based on the anatomy of the hepatic artery and bile duct. The IHBPA terminology has now been adopted by most major textbooks of hepatic anatomy and surgery. In this chapter the most common anatomic pattern is referred to as the “prevailing pattern.” All other patterns are “anomalies” and they need not be rare.

Anatomic basis of the Brisbane 2000 Terminology: Division of the liver based on the hepatic artery and bile ducts The primary (first-order) division of the proper hepatic artery is into the right and left hepatic arteries (Figure 2.1). These branches supply arterial blood to the right and left hemilivers or livers (Figure 2.2). The plane between two distinct zones of vascular supply is called a watershed. The watershed of the first-order division intersects the gallbladder fossa and the fossa for the inferior vena cava (Figure 2.2). It is called the mid-plane of the liver. The second-order division (Figures 2.1 and 2.3) of the hepatic artery is into four sectional arteries, two on the right and two on the left (Figure 2.1). On the right side, the right anterior sectional artery and the right posterior sectional hepatic artery supply arterial blood to the right anterior section and the right posterior section (Figure 2.3). The plane between these sections is the right intersectional plane, which does not have


any markings on the surface of the liver to indicate its position. On the left, the left medial sectional hepatic artery and a left lateral sectional hepatic artery (Figure 2.1) supply arterial blood to the left medial section and the left lateral section (Figure 2.3). The plane between these sections is the left intersectional plane, which does have surface markings indicating its position. These are the umbilical fissure and the line of attachment of the falciform ligament to the anterior surface of the liver. The third-order division of the hepatic artery is into segmental arteries (Figure 2.1) and divides the liver into seven segments (segments (Sg) 2–8) (Figures 2.1 and 2.4). Each of the segments has its own feeding segmental artery. The left lateral section is divided into Sg 2 and Sg 3. The pattern of ramification of vessels within the left medial section does not permit subdivision of this section into segments, each with its own arterial blood supply. Therefore, the right medial section and Sg 4 are synonymous. However, Sg 4 is arbitrarily divided into superior (4a) and inferior (4b) parts without an exact anatomic plane of separation based on internal ramification of vessels. Note then that Sg 4 and the right medial section are identical. The right anterior section is divided into two segments, Sg 5 and Sg 8. The right posterior section is divided into Sg 6 and Sg 7. The planes between segments are referred to as intersegmental planes. The ramification of the bile ducts is identical to that described for the arteries and the zones of the liver drained by the ducts are identical to the zones supplied by the respective arteries. Sg 1 (caudate lobe) is a distinct portion of the liver, separate from the right and left hemilivers (Figure 2.5). It consists of three parts, the bulbous left part (Spiegelian lobe), hugging the left side of the vena cava and readily visible through the lesser omentum; the paracaval portion, anterior to the vena cava; and the caudate process, on the right, merging indistinctly with the right hemiliver. It lies posterior to the hilum and the portal veins and its upper extent is limited by the hepatic veins, which lie anterior and superior to the paracaval portion of the caudate lobe [2, 3] (Figure 2.5). It receives vascular supply from both right and left hepatic arteries (and portal veins). Caudate bile ducts drain

11

SECTION 1

Introduction into both right and left hepatic ducts [2, 3]. The caudate lobe is drained by several short caudate veins that enter the inferior vena cava (IVC) directly from the caudate lobe. Their number and size is variable. On occasion caudate veins are quite short and wide, and therefore must be isolated and divided cautiously. Commonly, these veins enter the IVC on either side of the midplane of the vessel, an anatomic feature which normally allows passage of a clamp behind the liver on the surface of the IVC without encountering the caudate veins.

8 7

3

4 e c d

2 f

B A

Terminology of liver resections Terminology of resections is based upon anatomic terminology. Resection of one side of the liver is called a hepatectomy or hemihepatectomy (Figure 2.2). Resection of the right side of the liver is a right hepatectomy or hemihepatectomy, and resection of the left side of the liver is a left hemihepatectomy or hepatectomy. Resection of a liver section is referred to as a sectionectomy (Figure 2.3). Resection of the liver to the left side of the umbilical fissure is referred to as a left lateral sectionectomy. The other sectionectomies are named accordingly: left medial sectionectomy, right anterior sectionectomy, and right posterior sectionectomy. Resection of three contiguous sections is referred to as a trisectionectomy. When the sections are right posterior section, right anterior section, and right medial section (right liver plus Sg 4), this is referred to as a right trisectionectomy (Figure 2.3). Similarly, resection of the two sections of the left hemiliver plus the right anterior section is referred to as a left trisectionectomy (Figure 2.3). Resection of one of the numbered segments is referred to as a segmentectomy (Figure 2.4). Resection of the caudate lobe can be referred to as a caudate lobectomy or resection of Sg 1. It is always appropriate to refer to a resection by the numbered segments. For instance, it would be appropriate to call a left lateral sectionectomy a resection of Sg 2 and Sg 3.

5 6

Figure 2.1 Prevailing pattern of branching of the hepatic artery. The proper hepatic divides into the right (A) and left (B) hepatic arteries, which supply the right and left hemilivers (see Figure 2.2) respectively. The right hepatic artery divides into anterior (c) and posterior (d) sectional arteries, which supply the right anterior and right posterior sections (see Figure 2.3). The right anterior sectional artery divides into two segmental arteries, which supply Sg 5 and Sg 8 (see Figure 2.4) and the right posterior sectional artery divides into arteries that supply Sg 6 and Sg 7. The left hepatic artery (B) also divides into two sectional arteries, the left medial (e) and left lateral (f). The former supplies the left medial section (see Figure 2.3) also called Sg 4, while the latter supplies the left lateral section. The left lateral sectional artery divides into segmental arteries to Sg 2 and Sg 3 (see Figure 2.4). The caudate lobe (Sg 1 and Sg 9) are supplied by branches from A and B. Bile duct anatomy and nomenclature are similar to those of the hepatic artery. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

Anatomic term

Couinaud segments referred to

Term for surgical resection

Diagram (pertinent area is shaded) 2

Right hemiliver or right liver

Sg 5–8 (±Sg 1)

Right hepatectomy or right hemihepatectomy (stipulate ±Sg 1)

8

4

7 6

3

5

2 Left hemiliver or left liver

12

Sg 2–4 (±Sg 1)

Left hepatectomy or left hemihepatectomy (stipulate ±Sg 1)

8 7 6

5

4

3

Figure 2.2 Nomenclature for first-order division anatomy (hemilivers) and resections. The border or watershed of the first-order division which separates the two hemilivers is a plane which intersects the gallbladder fossa and the fossa for the inferior vena cava (IVC) and is called the midplane of the liver. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

CHAPTER 2

Anatomic term


Hepatic Anatomy and Terminology


Diagram (pertinent area is shaded) 2

Right anterior section

Sg 5,8

Add (-ectomy) to any of the anatomic terms as in right anterior sectionectomy

8 7 6

Right posterior section

Sg 6,7

Right posterior sectionectomy

Sg 4

Left lateral section

Sg 2,3

(a)

Figure 2.3 Nomenclature for (a) secondorder division anatomy (sections, based on bile ducts and hepatic artery) and (b) other “sectional” liver resections, including extended resections. The borders or watersheds of the sections are planes referred to as the right and left intersectional planes. The left intersectional plane passes through the umbilical fissure and the attachment of the falciform ligament. There is no surface marking on the right intersectional plane. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

Sg 4–8 (±Sg 1)

Sg 2,3,4,5,8 (±Sg 1)

(b)

Surgical anatomy for liver resections Hepatic arteries In the prevailing anatomic pattern, the celiac artery terminates by dividing into common hepatic and splenic arteries. Rarely the hepatic artery arises directly from the aorta (Figure 2.6). The common hepatic artery runs for 2–3 cm anteriorly and to the right to ramify into gastroduodenal and proper hepatic arteries. The proper hepatic artery enters the hepatoduodenal ligament, normally runs for 2–3 cm along the left side of the common bile duct, and terminates by

Left medial sectionectomy or Resection segment 4 (also see third order) or Segmentectomy 4 (also see third order)

Left lateral sectionectomy or Bisegmentectomy 2,3 (also see third order)

2 3

4

2 3

4

2 3

4

2 3

4

2 3

5

8 7 5

8 7 6

Right trisectionectomy (preferred term) or Extended right hepatectomy 7 or Extended right hemihepatectomy 6 (stipulate ±Sg 1) Left trisectionectomy (preferred term) or Extended left hepatectomy or Extended left hemihepatectomy (stipulate ±Sg 1)

4

7

6

5

8 5

8 7 6

3

5

8

6 Left medial section

4

5

dividing into the right and left hepatic arteries, the right artery immediately passing behind the common hepatic duct. The four sectional arteries arise from the right and left arteries 1–2 cm from the liver. The preceding description is the prevailing pattern but variations are very common (Figure 2.7). The surgeon is wise not to make assumptions regarding hepatic arteries based on size or position, but to rely instead on exposure, trial occlusions, and radiologic support. “Replaced” arteries are surgically important anomalies. “Replaced” means that the artery supplying a particular part of the liver is in an unusual location and also that it provides

13

SECTION 1

Introduction

Anatomic term



Sg 1–8

Any one of Sg 1–8

Segmentectomy (e.g. segmentectomy 6)

Diagram (pertinent area is shaded) 2 8

4

7 6

3

5

2 Two contiguous segments

Any two of Sg 1–8 in continuity

Bisegmentectomy (e.g. bisegmentectomy 5,6)

8 7 6

5

4

3

Figure 2.4 Nomenclature for third-order division anatomy (segments) and resections. The borders or watersheds of the segments are planes referred to as intersegmental planes. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

MHV

IVC

LHV

RHV

SL PC CP LPV

RPV

PV

IVC

Figure 2.5 Schematic representation of the anatomy of the caudate lobe. The caudate lobe consists of three parts, the caudate process (CP) on the right, the paracaval portion anterior to the vena cava (PC), and the bulbous left part (Spiegelian lobe, SL). IVC, inferior vena cava; PV, portal vein; RHV, MHV, LHV, right hepatic, middle hepatic and left hepatic veins, respectively; RPV, LPV, left and right portal vein, respectively (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

the sole blood supply to that part of the liver. “Aberrant” means the structure is in an unusual location. While the definition of “aberrant” does not state whether the structure provides sole supply, it is usually considered to be synonymous with “replaced” in respect to these arteries. “Accessory” refers to an artery which is additional, i.e. is present in addition to the normal structure and as a result is not the

14

Figure 2.6 CT scan of patient with absent celiac artery. Hepatic artery (HA), splenic artery (SA) (labeled “b” in sagittal view, inset) and left gastric artery (labeled “a” in sagittal view, inset) arise independently from the aorta. Superior mesenteric artery is labeled “c” in inset. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

sole supply to a volume. Consequently, ligation of an accessory artery does not cause ischemia. Approximately 25% of patients have a replaced hepatic artery. A replaced right hepatic artery arises from the superior mesenteric artery and runs from left-to-right behind the lower end of the common bile duct to emerge and course on its right posterior border. It may supply a segment, section, or the entire right hemiliver. Rarely its supplies the whole liver and then it is called a replaced hepatic artery. A replaced left hepatic artery arises from the left gastric artery and courses in the lesser omentum with vagal branches to the liver. It may also supply a segment, section, hemiliver, or very rarely the whole liver. Sometimes left hepatic arteries arising from the left gastric artery are actually accessory, and exist in conjunction with normally situated left hepatic

CHAPTER 2

arteries. Replaced arteries may confer an advantage during surgery. For instance, when a replaced left artery supplies the left lateral section, it is possible to resect the entire proper hepatic artery when performing a right trisectionectomy for hilar cholangiocarcinoma. In performing hepatectomies by the standard technique of isolating individual structures instead of pedicles, it is necessary to correctly identify the particular artery(ies) supplying the volume of liver to be resected. A helpful rule is

Figure 2.7 A dangerous anomaly. In this patient the right hepatic artery (RHA) came off the gastroduodenal artery (GDA). The common hepatic artery (CHA) divided into the left hepatic artery (LHA) and the GDA. There was no proper hepatic artery. The LHA could easily be mistaken for the proper hepatic artery. Ligation of the GDA could lead to arterial devascularization of the right liver. Note early branching of the RHA into anterior and posterior sectional branches. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

B8 B7

Right posterior sectional bile duct Right anterior sectional bile duct Right bile duct

B8

B7

Correct


that an artery located to the right side of the bile duct always supplies the right side of the liver, but arteries found on the left side of the bile duct may supply either side of the liver. Therefore, when using the individual vessel ligation method, it is important to determine the position of the common hepatic duct.

Bile ducts Prevailing pattern and variations of bile ducts draining the right hemiliver Normally the right hepatic duct is a short structure with only about 1 cm in an extrahepatic position. The prevailing pattern of bile duct drainage is shown in Figure 2.8a. The segmental ducts from Sg 6 and Sg 7 (called B6 and B7) unite to form the right posterior sectional bile duct and the segmental ducts from Sg 5 and Sg 8 (B5 and B8) unite to form the right anterior sectional bile duct (Figure 2.8a). The sectional ducts unite to form the right hepatic duct, which unites with the left hepatic duct at the confluence to form the common hepatic duct. There are two important sets of biliary anomalies on the right side of the liver. In the first, a right sectional bile duct joins the left hepatic duct. This is a common anomaly. The right posterior sectional duct inserts into the left hepatic duct in 20% of individuals (Figure 2.8b) and the right anterior bile duct does so in 6% (Figure 2.8c). A right sectional bile duct inserting into the left hepatic duct may be injured during left hepatectomy if the left duct is divided close to the midplane of the liver (Figure 2.8b, “incorrect”). The left hepatic duct should be divided close to the umbilical fissure to avoid this injury (Figure 2.8b, “correct”). The second important anomaly is insertion of a right bile duct into the biliary tree at a lower level than the prevailing site of confluence. Low union may affect the right hepatic duct, a sectional right duct (usually the anterior one), a segmental duct, or a subsegmental duct. The duct will unite with the common hepatic duct well below the prevailing site of confluence in about 2% of individuals. In some it first

B8 B7

Incorrect

B6 B5

B6

(a)

(b)

B5

B6

(c)

B5

(d)

Figure 2.8 Variations in formation of the right hepatic ducts. (a) Prevailing pattern and (b–d) some variations of bile ducts draining the right hemiliver (see text). (b,c) Separate entry of right anterior and right posterior sectional ducts (no right duct). (d) Shifting of entry of a right bile duct inferiorly. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

15

SECTION 1

Introduction

unites with the cystic duct and then with the common hepatic duct. The right posterior sectional duct normally hooks over the origin of the right anterior sectional portal vein (“Hjortsjo’s crook”) [4], where it is in danger of being injured if the right anterior sectional pedicle is clamped too close to its origin (Figure 2.9).

Prevailing pattern and important variations of bile ducts draining the left hemiliver The prevailing pattern of bile duct drainage from the left liver is shown in Figure 2.10a, and is present in only 30% of individuals, i.e. anomalous patterns are present in the majority of individuals. In the prevailing pattern the segmental ducts from Sg 2 and Sg 3 (B2 and B3) unite to form the left lateral sectional bile duct. This duct passes behind the umbilical portion of the portal vein and unites with the duct from Sg 4 (B4) (also called the left medial sectional duct RASBD

Hjortsjo’s crook

RPSBD

Figure 2.9 Hjortsjo’s crook. Note that the right posterior sectional bile duct (RPSBD) crosses the origin of the right anterior sectional portal vein. RASBD, right anterior sectional bile duct. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

B4

B4

B3

Prevailing pattern of bile ducts draining the caudate lobe (Sg 1) Two to three caudate ducts normally enter the biliary tree. Their orifices are usually located posteriorly on the left duct, right duct, or right posterior sectional duct [2, 3].

B3 B4

B2 Left lateral sectional bile duct

B4

B3

Combined B3, B4 duct

B4

B3 B2

B2

B2 Left lateral sectional bile duct

Left lateral sectional duct

Left bile duct

(a)

since section and segment are synonymous for this volume of liver). The union of these ducts to form the left hepatic duct occurs about one-third of the distance between the umbilical fissure and the confluence of left and right bile ducts at the midplane of the liver. The left hepatic duct continues from this point for 2–3 cm along the base of Sg 4 to its termination. Note that it is in an extrahepatic position and that it has a much longer extrahepatic course than the right bile duct. The extrahepatic position of the left hepatic duct is a key anatomic feature, which makes this section of duct the prime site for high biliary–enteric anastomosis. The left hepatic duct runs at a variable angle. In some individuals it is almost horizontal but in others it runs sharply upward. It is much easier to expose a long length of duct in the former type. The major anomalies of the left ductal system involve variations in site of insertion of B4 (Figure 2.10b), multiple ducts coming from B4 (Figure 2.10c), and primary union of B3 and B4 with subsequent union of B2 (Figure 2.10d). B4 may join the left lateral sectional duct to the left or right of its point of union in the prevailing pattern (Figure 2.10b); in the former case the insertion of B4 is at the umbilical fissure, and in the latter it may occur at any place to the right of the usual point of insertion up to the site where the left lateral sectional duct unites with the right hepatic duct. Rarely the left lateral sectional duct and the duct to B4 do not unite before a confluence with the right hepatic duct. In these cases the confluence of the three ducts forms the common hepatic duct and there is no left hepatic duct. The bile duct to Sg 3 has been used to perform biliary bypass and can be isolated by following the superior surface of the ligamentum teres to the portal pedicle for Sg 3. The technique is less commonly used now that internal endoscopic bypass has been developed.

Left hepatic duct

(b)

(c)

(d)

Figure 2.10 Variations in formation of the left hepatic ducts. (a) Prevailing pattern and (b–d) some variations of bile ducts draining the left hemiliver. (b) Insertion of B4 shifted to right or left. (c) Multiple ducts draining B4. (d) B3, B4 form a common channel before insertion of B2. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

16

CHAPTER 2

Portal veins The portal vein divisions on the right side of the liver correspond exactly to those of the hepatic artery and bile duct, and they supply the same hepatic volumes. There is a right portal vein which supplies the entire right hemiliver and it divides into two sectional portal veins and four segmental portal veins (Figure 2.11) supplying the same sections and segments as the respective right hepatic arteries. On the left side of the liver, however, the left portal vein is quite unusual because of the fact that its structure was adapted to function in utero as a conduit between the umbilical vein and the ductus venosus, whereas postnatally the direction of flow is reversed. The left portal vein consists of a horizontal or transverse portion, which is located under Sg 4, and a vertical part or umbilical portion, located in the umbilical fissure (Figure 2.11). Unlike the right portal vein, neither portion of the left portal vein actually enters the liver substance, but rather lies directly on the surface. The umbilical portion is usually hidden by a bridge of tissue passing between left medial and lateral sections. This bridge of liver tissue may be as thick as 2 cm or only be a fibrous band. The junction of the transverse and umbilical portions of the left portal vein is marked by the attachment of a stout cord – the ligamentum venosum. This structure, the remnant of the fetal ductus venosus, runs in the groove between the left lateral section and the caudate lobe, and attaches to the left hepatic vein–IVC junction.

8


The transverse portion of the left portal vein sends no or only a few small branches to Sg 4. Large branches from the portal vein to the left liver arise exclusively beyond the attachment of the ligamentum venosum, i.e. from the umbilical part of the vein [5]. These branches come off both sides of the vein; those arising from the right side pass into Sg 4 and those from the left supply into Sg 2 and Sg 3. There is usually only one branch to Sg 2 and one to Sg 3, but often there is more than one branch to Sg 4. The left portal vein terminates in the ligamentum teres at the free edge of the left liver. Note that the umbilical portion of the left portal vein has a unique pattern of ramification with multiple branches emanating from its sides as it narrows to terminate blindly in the ligamentum teres (Figures 2.11 and 2.12). This unusual branching pattern of the umbilical portion of the left portal vein represents both an opportunity and a danger for the hepatic surgeon. The portal vein branches to Sg 4 may be isolated in the umbilical fissure on the right side of the umbilical portion of the left portal vein. The veins here become associated with the bile ducts and the arteries and enter Sg 4 within a segmental fibrous sheath. Isolation of these structures in this location may provide an extra tissue margin when resecting a tumor in Sg 4 that impinges upon the umbilical fissure. Also, by dividing these branches, the portal vein may be rolled to the left to allow exposure of an extra length of left lateral sectional bile ducts in operations for hilar cholangiocarcinoma. The danger of dissection

LT

7

3 4 2

U c d

T A LV

5 6

Figure 2.11 Ramification of the portal vein in the liver. The portal vein divides into right (A) and left (T) branches. The right portal vein divides into anterior (c) and posterior (d) sectional arteries. The branches in the right liver correspond to those of the hepatic artery and bile duct (see Figure 2.1). The branching pattern on the left is unique. The left portal vein has transverse (T) and umbilical portions (U). The transition point between the two parts is marked by the attachment of the ligamentum venosum (LV). All major branches come off the umbilical portion (see text). The vein ends blindly in the ligamentum teres (LT). (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

Figure 2.12 Ramification of the left portal vein as seen on computed tomography. Note the branches to Sg 2–4 and the ligamentum teres (LT). The arrowhead points to the groove between the left lateral section and the caudate lobe. This is also the site of origin of the ligamentum venosum, where the transverse portion of the portal vein becomes the umbilical portion of the vein, proving conclusively that the branch to Sg 2 is not part of a terminal division of the transverse portion of the vein as might be concluded from cast studies. (See also ref. [5]). (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

17

SECTION 1

Introduction

in the umbilical fissure is that injury to the portal vein in this position could deprive Sg 2 and Sg 3 of portal vein supply, as well as Sg 4. It is also is possible to isolate the portal vein branches going into Sg 2 and Sg 3 in the umbilical fissure in order to extend a margin when resecting a tumor in the left lateral section. In order to access the portal vein in the umbilical fissure it is usually necessary to divide the bridge of liver tissue, between the left medial and lateral sections. This is done by passing a blunt instrument behind the bridge before dividing it, usually with cautery. Note that arteries and bile ducts passing to the left lateral section are in danger of being injured as the most posterior–superior portion of the bridge is isolated. Although the anatomy of the portal vein is unusual, it is uncommon to have variations. The most common variation is absence of the right portal vein. In these cases the right posterior and right anterior sectional veins originate independently from the main portal vein; the anterior sectional vein is not readily visible because of it high position in the porta hepatis. An unsuspecting surgeon may divide the posterior sectional vein thinking that it is the right portal vein and become confused when the anterior sectional vein is come upon during hepatic transection. Rarely there is no extrahepatic left portal vein. Failure to recognize this anomaly may lead to a catastrophic complication. The apparent right vein is really the main portal vein, a structure which enters the liver, gives off branches to the right liver, and then loops back within the liver substance

to supply the left side (Figure 2.13). The vein looks like a right vein in terms of position but it is larger. Transection results in total portal vein disconnection from the liver. This anomaly should always be searched for on computed tomography (CT) scans as right hepatectomy is not usually possible when it is present. The presence of the umbilical portion of the left vein in the umbilical fissure on CT scan precludes the presence of this problem.

Hepatic veins and liver resection (Figure 2.14) Normally there are three large hepatic veins. Respectively, these run in the midplane of the liver (middle hepatic vein), the right intersectional plane (right hepatic vein), and the left intersectional plane (left hepatic vein). The left hepatic vein actually begins in the intersegmental plane between Sg 2 and Sg 3, and travels in that plane for most of its length. It becomes quite a large vein even in that location. About 1 cm from its termination in the IVC, it enters the left intersectional plane, where it receives the “umbilical vein” from Sg 4 (Figures 2.14–2.16). The latter tributary of the left hepatic vein normally drains the most leftward part of Sg 4 [6, 7]. (It is important not to confuse the “umbilical vein” with the “umbilical portion of the left portal vein.”) The length of the left hepatic vein in the left intersectional plane is short. It lies between the point where it receives the umbilical vein and the IVC, a distance of only about 1–2 cm (see both the 3D radiograph in Figure 2.15 and the operative picture in Figure 2.16). The left and middle hepatic veins

IVC R

L UV

7 8

M

2

4

5 3 6

Figure 2.13 Absent extrahepatic left portal vein, a rare and very dangerous anomaly. Three-dimensional reconstruction of CT scan. Note that main portal vein (MPV) enters the right liver, gives off the right posterior sectional portal vein (RPSPV) and some branches to the right anterior section, and then proceeds to the left as an internal left portal vein (LPV). (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

18

Figure 2.14 Hepatic veins. There are normally three hepatic veins: right (R), middle (M), and left (L). Note the segments drained. The umbilical vein (UV) normally drains part of Sg 4 into the left hepatic vein. The latter is proof that the terminal portion of the left vein lies in the intersectional plane of the left liver. IVC, inferior vena cava. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

CHAPTER 2

Figure 2.15 Three-dimensional reconstruction of CT scan showing prevailing pattern of the umbilical vein (UV). The UV receives tributaries form Sg 4 and Sg 3 and travels in the plane of the umbilical fissure (left intersectional plane) to join the left hepatic vein (LPV). The LPV continues in the same plane for 1–2 cm before joining the middle hepatic vein and entering the IVC. This shows that a major hepatic vein can lie in the same plane as a major portal vein (left portal vein which also lies in this plane; see also Figure 2.16). The pattern shown in this figure is the prevailing pattern, but the UV is not usually this prominent. RHV, MHV, LHV, right hepatic, middle hepatic and left hepatic veins, respectively; IVC, inferior vena cava. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

Figure 2.16 Operative photograph at completion of left lateral sectionectomy in which the side of left hepatic vein (LHV) was cleared. Note that the terminal 2 cm of the LHV lie in the same plane as the umbilical portion of the left portal vein (UPLPV). The umbilical vein (UV) from Sg 4 can be seen entering the side of the LHV. HPL, hepatoduodenal ligament; ALHA, aberrant left hepatic artery off the left gastric artery; RL, round ligament; IVC, inferior vena cava. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)


usually fuse at a distance of about 1 cm from the IVC, so that when viewed from within the IVC there are only two hepatic vein openings, the right and the combined left/middle vein openings. Rarely hepatic veins join the IVC above the diaphragm. Note that the termination of the left hepatic vein lies in the plane of the umbilical fissure (left intersectional plane) at the point it receives tributaries from Sg 4. This is an apparent contradiction of the contention of Couinaud regarding separation of planes of portal and hepatic veins and another example of the unusual venous anatomy on the left side of the liver. In about 10% of individuals there is more than one large right hepatic vein. In addition to the right superior hepatic vein (normally called the right hepatic vein), which enters the IVC just below the level of the diaphragm, there is a right inferior hepatic vein which enters the IVC 5–6 cm below this level. In the presence of this vein resections of Sg 7 and Sg 8 may be performed, including resection of the right superior vein without compromising the venous drainage of Sg 5 and Sg 6. As noted above, the caudate lobe is drained by its own veins – several short veins that enter the IVC directly from the caudate lobe. When performing a classical right hepatectomy, caudate veins are divided in the preliminary portion of the dissection. As dissection moves up the anterior surface of the vena cava to isolate the right hepatic vein, a bridge of tissue lateral to the IVC is encountered, referred to as the “inferior vena caval ligament” [7]. It connects the posterior portion of the right liver to the caudate lobe behind the IVC. This bridge of tissue usually consists of fibrous tissue, but occasionally is a bridge of liver. It limits exposure of the right side of the IVC at a point just below the right hepatic vein and must be divided in order to isolate the right hepatic vein. This must be done with care as the ligament may contain a large vein and forceful dissection of the ligament may also result in injury to the right lateral side of the IVC. Isolation of the right hepatic vein is also aided by clearing the areolar tissue between the right and middle hepatic veins down to the level of the IVC when exposing these veins from above. Another approach to right hepatectomy is to leave division of the caudate and right hepatic veins until after the liver is transected. In this case a clamp may be passed up along the anterior surface of the vena from below to emerge between the right and middle hepatic veins. By passing an umbilical tape the liver may be hung to facilitate transection (“hanging maneuver”) [8]. This is possible since caudate veins usually lie lateral to the midplane of the vena cava, as noted above. The left and middle veins can also be isolated prior to division of the liver. There are several ways to achieve this anatomically. One method is to divide all the caudate veins as well as the right hepatic vein. This exposes the entire anterior surface of the retrohepatic vena cava and leaves the liver attached to the vena cava only by the middle and left

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Introduction

hepatic veins, which are then easily isolated. This is suitable when performing a right hepatectomy or extended right hepatectomy, especially when the caudate lobe is also to be resected. The advantage of having control of these veins during operations on the right liver is that total vascular occlusion is possible without occlusion of the IVC, and hemodynamically the effect is not much different from occlusion of the main portal pedicle alone (Pringle maneuver). A different anatomic approach to isolation of the left and middle hepatic veins is required when performing a left hepatectomy since the right hepatic vein is conserved (Figure 2.17). The veins may be isolated from the left side by dividing the ligamentum venosum where it attaches to the left hepatic vein, then dividing the peritoneum at the superior tip of the caudate lobe and gently passing an instrument on the anterior surface of the vena cava to emerge between the middle and right veins (Figure 2.17) and/or between the left and middle veins. Again care needs to be applied when performing this maneuver in order to avoid injury to the structures. Isolation of the vena cava above and below the hepatic veins is also a technique that should be in the armamentarium of surgeons performing major hepatic resections, although it is not required routinely. Isolation of the vena

Sg 8 Sg 4

cava superior to the hepatic veins is done by dividing the left triangular ligament and the lesser omentum, being careful to first look for a replaced left hepatic artery. Next the peritoneum on the bulbous superior border of the caudate lobe is divided and a finger is passed behind the vena cava to come out just inferior to the crus of the diaphragm. Isolation of the vena cava below the liver is more straightforward but awareness of the position of the adrenal vein is needed. Finally, the surgeon should be aware that during transection of the liver large veins will be encountered in certain planes of transection. For instance, in its passage along the midplane, the middle hepatic vein usually receives two large tributaries, one from Sg 5 inferiorly and the other from Sg 8 superiorly (Figure 2.14). Both are routinely encountered in performing right hepatectomy. The venous drainage of the right side of the liver is variable and additional large veins, including one from Sg 6, may also enter the middle hepatic vein.

Plate/sheath system of the liver The plate/sheath system was originally described by Waleaus and Glisson in the 17th century and was clarified in modern times by Couinaud [3]. Understanding this complicated anatomy is essential to performing pedicle isolation. The analogy of a shirt with the front cut away to leave only the back and the sleeves is helpful (Figure 2.18 inset) [9]. If the shirt were made of fibrous tissue, its back would be a plate and the sleeves would be sheaths. The true plate/sheath

LHV MHV

Sheath

RHV

LV

Sheath Plate 4

Sg 1

IVC

Cystic

Umbilical 3

4 Hilar 8 Figure 2.17 Isolation of left and middle hepatic veins (LHV/MHV). Isolation of these veins may be accomplished from the left side of the liver by opening the triangular space between the left hepatic vein, the inferior vena cava (IVC) and the underside of Sg 4. This is facilitated by dividing the ligamentum venosum and dividing the peritoneum at the superior border of the caudate. Gentle dissection in this space on the IVC with a blunt clamp is aimed at the space between the right hepatic vein (RHV) and MHV to isolate the MHV and LHV. LV, ligamentum venosum. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

20

2

7 5

6 Arantian 1

1

Figure 2.18 Plate/sheath system of the liver with inset showing a schematic of a plate with two sheaths. (Redrawn with permission from the Journal of the American College of Surgeons.)

CHAPTER 2


Right anterior sectional pedicle Figure 2.19 Isolation of right portal pedicle and sectional pedicles using the technique of dissection on the surface of pedicles. No inflow occlusion or separate hepatotomies are used (see ref. [10]). The umbilical tape in the upper right of the photograph is around the bridge of liver tissue over the umbilical fissure. (Reproduced with permission from the Journal of the American College of Surgeons.)

Right posterior sectional pedicle

system is more complex. There are four plates (hilar, cystic, umbilical, and arantian) and several sheaths [3] (Figure 2.18). The hilar plate is the most important plate in liver surgery. It is a mostly flat structure, which lies principally in the coronal plane, posterior to the main bilo-vascular structures in the porta hepatis. However, its upper border is curved, so that it has the shape of a toboggan when viewed in the sagittal plane (Figure 2.18). This upper curved edge lies superior to the right and left bile ducts, the most superior structures in the porta hepatis. It is this taut, firm, upper curved edge of the hilar plate which is dissected free from the underside of the liver when “lowering the hilar plate.” The sheath of the right portal pedicle extends off the hilar plate like a sleeve in the “shirt” analogy. It carries into the liver surrounding the portal structures, i.e. portal vein hepatic artery and bile duct. The combined structure consisting of a hepatic artery, bile duct, and portal vein surrounded by its fibrous sheath is referred to as a “portal pedicle.” As the right portal pedicle enters the liver, it divides into a right anterior and right posterior portal pedicle supplying the respective sections and then into segmental pedicles supplying the four segments. On the left side, only the segmental structures are sheathed. There is no sheathed main portal pedicle because the main portal vein, proper hepatic artery, and common hepatic duct are not close enough to the liver to be enclosed in a sheath. The cystic plate is the ovoid fibrous sheet on which the gallbladder lies (Figure 2.18). In its posterior extent the cystic plate narrows to become a stout cord which attaches to the anterior surface of the sheath of the right portal pedicle. The latter is a point of anatomic importance for the surgeon wishing to expose the anterior surface of the right portal pedicle, because this cord must be divided to do so, as we have described [10]. The other plates are the umbilical and arantian, which underlie the umbilical portion of the left portal vein and the ligamentum venosum, respectively (Figure 2.18). The other sheaths carry segmental bilo-vascular pedicles of the left liver and caudate lobe.

In performing a right hepatectomy, isolation of the right portal pedicle can be performed by making hepatotomies above the right portal pedicle in Sg 4 and in the gallbladder fossa after removing the gallbladder. A finger is passed through the hepatotomy to isolate the right portal pedicle. This technique usually requires inflow occlusion. It can also be done without inflow occlusion by lowering the hilar plate and coming around the right portal pedicle directly on its surface, as we have recently described (Figure 2.19) [9]. It is advisable to divide caudate veins in the area below the vena caval ligament before performing pedicle isolation, since hemorrhage from these veins can be considerable if they are injured during isolation of the right portal pedicle. The advantage of pedicle isolation over isolation of individual vessels and the bile duct is that true anatomic sectional and segmental resections require isolation of pedicles (Figure 2.18) [9]. Furthermore, pedicle isolation is much easier to do laparoscopically than by individual structure isolation.

Liver capsule and attachments The liver is encased in a thin fibrous capsule which covers the entire organ except for a large bare area posteriorly where the organ is in contact with the IVC and with the diaphragm to the right of the IVC. The bare area stretches anterosuperiorly to include the termination of the three hepatic veins and ends in a point anterior to the veins. This point corresponds to the highest point of attachment of the falciform ligament. The limit of the bare area, where the peritoneum passes from the body wall to the liver surface, is called the coronary ligament. It is one of three structures that connect the liver to the abdominal wall “dorsally,” the other two being the right and left triangular ligaments. The liver also has another bare area, best thought of as a bare crease, where the hepatoduodenal ligament and the lesser omentum attach on the “ventral” surface. It is through this crease that the portal structures enter the liver at the hilum (hilum means “a crease on a seed”).

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The other ligamentous structures of interest to surgeons are the ligamentum teres, falciform ligament, and ligamentum venosum. The ligamentum teres (teres means “round”) is the obliterated left umbilical vein and it runs in the free edge of the falciform ligament from the umbilicus to the termination of the umbilical portion of the left portal vein. The falciform (falciform means “scythe shaped”) is the filmy fold that runs between the anterior abdominal wall above the umbilicus and attaches to the anterior surface of the liver between the left medial and left lateral sections. The ligamentum venosum marks the transition from the transverse portion of the left portal vein to the umbilical portion of the vein. It runs from that point to insert at the junction of the left hepatic vein and IVC. Note that its origin on the left portal vein is 1–2 cm proximal to the takeoff of the vein to Sg 2, which proves that the vein to Sg 2 is a branch of the umbilical portion of the portal vein [5] and not a terminal branch of the horizontal portion of the vein as claimed by Couinaud. Its surgical importance lies in the isolation of the left and middle hepatic veins as described above.

Surface anatomy Numerous terms for surface anatomy exist. They are of minimal surgical importance. Since the term “lobe” has been used in different ways by various anatomists and surgeons, it is best avoided except in reference to the caudate lobe. Fissure and scissure or scissura are similarly confusing terms since they apply only to clefts in casts of the liver. The shape of the liver is variable, especially the right liver, which may have a long inferior extension (Riedel’s lobe). Consideration of liver shape is important in determining whether all hepatic ducts are seen on a cholangiogram. Using CT images as a guide, and thereby reconciling the cholangiogram to the shape of the liver, is helpful [10].

Pathologic conditions Pathologic conditions may distort or alter the position of normal hepatic structures. Tumors may push vessels so that they are stretched and curved over the surface of the tumor, narrowing or occluding them by direct pressure. Tumors may partially or completely occlude vessels by mural invasion, inducing bland thrombi, or entering the lumen and producing tumor thrombi. They may cause bile ducts to dilate to a size many times normal. Atrophy of a liver volume will be induced by processes that occlude either the portal vein or bile duct. Since the liver will undergo hyperplasia to maintain a constant volume of liver cells, atrophy of one part of the liver is usually accompanied by growth of another. If the right portal vein is occluded by a tumor, the right liver will atrophy and the left liver will grow. When seen from below, this process will exert a counter-clockwise rotational effect on the porta hepatis, rotating the bile duct posteriorly, the hepatic artery to the right, and the portal vein to the left and anteriorly.

22

Gallbladder and extrahepatic bile ducts and arteries Gallbladder The gallbladder lies on the cystic plate (see above). The edge of the gallbladder forms one side of the hepatocystic triangle. The other two sides are the right side of the common hepatic duct and the liver. Eponyms covering this anatomy (e.g. Calot and Moosman) are confusing and should be abandoned. The hepatocystic triangle contains the cystic artery, cystic node, and a portion of the right hepatic artery, as well as fat and fibrous tissue. Clearance of this triangle along with isolation of the cystic duct and elevation of the base of the gallbladder off the lower portion of the cystic plate gives the “critical view of safety” that we have described for identification of the cystic structures during laparoscopic cholecystectomy [11]. The following are anomalies of importance to the surgeon: • Agenesis of the gallbladder. Agenesis is rare (1 in 8000 births) and can be difficult to recognize. An ultrasonographer may describe a “shrunken” gallbladder. When agenesis is suspected it may be confirmed by axial imaging. If doubt remains, laparoscopy is definitive. • Double gallbladder. This is also a very rare anomaly but can be the cause of persistent symptoms after resection of one gallbladder. A gallbladder may also be bifid, which usually does not cause symptoms, or have an hourglass constriction, which may cause symptoms due to obstruction of the upper segment.

Cystic duct This structure is normally 1–2 cm in length and 2–3 mm in diameter. It joins the common hepatic duct at an acute angle to form the common bile duct. The cystic duct normally joins the common hepatic duct approximately 4 cm above the duodenum. However, the cystic duct may enter at any level from the right hepatic duct to the ampulla. In fact the cystic duct may also join the right hepatic duct either when the right duct is in its normal position or in an aberrant location. There are three patterns of confluence of the cystic duct and common hepatic duct (Figure 2.20). In the 20% of patients in which there is a parallel union, the surgeon approaching the common hepatic duct by dissecting the cystic duct is prone to injure the side of the former structure (Figure 2.20). Although a gallbladder with two cystic ducts has been described, the author has not seen convincing proof that this anomaly actually occurs. If it does, it must be an anomaly of extreme rarity. When two “cystic ducts” are identified, it is likely that the cystic duct is congenitally short or has been effaced by a stone and that the two structures thought to be dual cystic ducts are, in fact, the common bile duct and the common hepatic duct.

CHAPTER 2

(a)

(b)

(c)

Figure 2.20 The three types of cystic duct/common hepatic duct confluence: (a) angular (75%), (b) parallel (20%), and (c) spiral (5%). Dissection of the parallel union confluence (b, arrow) may lead to injury of the side of the common hepatic duct. During laparoscopic cholecystectomy this is often a cautery injury. (Adapted from Warrren et al. In: Irvine WT, ed. Modern Trends in Surgery. London: Butterworth, 1966, with permission from Washington University, Saint Louis, MO, USA.)

Cystic artery The cystic artery is about 1 mm in diameter and normally arises from the right hepatic artery in the hepatocystic triangle in the prevailing pattern (85%). The cystic artery may also arise from a right hepatic artery that runs anterior to the common hepatic duct, or from the right hepatic artery on the left side of the common hepatic duct and run anterior to this duct, while the right hepatic artery runs behind it. Such cystic arteries tend to tether the gallbladder and make dissection of the hepatocystic triangle more difficult. The cystic artery may arise from an aberrant right hepatic artery coming off the superior mesenteric artery (SMA). In this case the cystic artery and not the cystic duct tends to be in the free edge of the fold leading from the hepatoduodenal ligament to the gallbladder. This should be suspected whenever the “cystic duct” looks smaller than the “cystic artery.” Normally the cystic artery runs for 1–2 cm to meet the gallbladder superior to the insertion of the cystic duct. The artery ramifies into an anterior and posterior branch at the point of contact with the gallbladder and these branches continue to divide on their respective surfaces. Sometimes the cystic artery divides into branches before the gallbladder edge is reached. In that case the anterior branch may be mistaken to be the cystic artery proper and the posterior branch will not be discovered until later in the dissection when it may be inadvertently divided. The artery may ramify into several branches before arriving at the gallbladder giving the impression that there is no cystic artery. The anterior and posterior branches may arise independently from the right hepatic artery, giving rise to two distinct cystic arteries.


Multiple small cystic veins drain into intrahepatic portal vein branches by passing into the liver around or through the cystic plate. Sometimes there are cystic veins in the hepatocystic triangle that run parallel to the cystic artery to enter the main portal vein. The cystic plate has been described above. Small bile ducts may penetrate the cystic plate to enter the gallbladder. These “ducts of Luschka” are very small, usually submillimeter accessory ducts. However, if divided during a cholecystectomy postoperative biloma may result. Bilomas and hemorrhage may also be caused by penetration of the cystic plate during dissection. In about 10% of patients there is a large peripheral bile duct immediately deep to the plate, disruption of which will cause copious bile drainage. The origin of the middle hepatic vein is also in this location, and if it is injured massive hemorrhage may ensue.

Extrahepatic bile ducts The common hepatic duct is a structure formed by the confluence of left and right ducts (see above). The union normally occurs at the right extremity of the base of Sg 4, anterior and superior to the bifurcation of the portal vein. The common hepatic duct travels in the right edge of the hepatoduodenal ligament for 2–3 cm, and then it joins the cystic duct to form the common bile duct. The latter has a supraduodenal course of 3–4 cm and then passes behind the duodenum to run in or occasionally behind the pancreas to enter the second portion of the duodenum. The external diameter of the common bile duct varies from 5 to 13 mm when distended to physiologic pressures. However, the duct diameter at surgery, i.e. in fasting patients with low duct pressures, may be as small as 3 mm. Radiologically, the internal duct diameter is measured on fasting patients. Under these conditions the upper limit of normal is about 8 mm. Size should never be used as a sole criterion for identifying a bile duct. Although the cystic duct may be enlarged due to passage of stones, the surgeon should take extra precautions before dividing a “cystic duct” that is greater than 2 mm in diameter because the common bile duct can be 3 mm in diameter and aberrant ducts may be smaller.

Anomalies of extrahepatic bile ducts As already noted there are biliary anomalies of the right and left ductal systems that can affect outcome of hepatic surgery. The same is true for biliary surgery. The most important clinical anomaly is low insertion of right hepatic ducts. In approximately 2% of patients, one of the right hepatic sectional ducts, usually the posterior, joins the common hepatic duct at a level close to the point where the cystic duct normally enters the common hepatic duct. Sometimes the aberrant duct is a segmental duct and rarely it is the main right hepatic duct itself. Its low location means it may be mistaken for the cystic duct and be injured. This is even more likely

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Introduction

to occur when the cystic duct unites with an aberrant duct as opposed to joining the common hepatic duct. An extremely rare (if it exists at all) and even more hazardous anomaly occurs when an aberrant right hepatic duct joins the infundibulum of the gallbladder. This anomaly will in most instance not be recognized and lead to an injury of the duct. In most cases this appearance is probably due to a Mirizzi syndrome of the type in which the anterior wall of the common hepatic duct has been destroyed, giving the appearance that the right hepatic duct enters the gallbladder. Left hepatic ducts can also join the common hepatic duct at a low level. They are less prone to be injured since the dissection during cholecystectomy is on the right side of the biliary tree.

Extrahepatic arteries The course of these arteries has been described above. Anomalies of the hepatic artery may be important in gallbladder surgery. Normally the right hepatic artery passes posterior to the bile duct (80%) and gives off the cystic artery in the hepatocystic triangle. However, in 20% of cases the right hepatic artery runs anterior to the bile duct. The right hepatic artery may lie very close to the gallbladder and chronic inflammation can draw the right hepatic artery directly onto the gallbladder where it lies in an inverse Uloop and is prone to injury. Sometimes the right hepatic artery makes a “hairpin” turn in the triangle of Calot. This variation results in the appearance the right hepatic artery is the cystic artery, especially if the latter is narrow in caliber (Figure 2.21). In the “classical injury” in laparoscopic cholecystectomy in which the common bile duct is mistaken for the cystic duct, an associated right hepatic artery injury is very common, since the right hepatic artery is considered to be the cystic artery.

Blood supply of bile ducts Bile ducts receive supply only from the hepatic artery and this is axial [12]. Inferiorly the common bile duct receives supply from the retroduodenal arteries, branches of the gastroduodenal arcade. These arteries pass onto the bile duct at the 3 o’clock and 9 o’clock positions and run upward along the common bile duct. Superiorly, branches pass from the proper, right, and left hepatic arteries onto the common hepatic duct at the level of the confluence of the right and left bile ducts (Figure 2.22). Arteries pass onto the bile duct at the 3 o’clock and 9 o’clock positions, run downward along the common bile duct, and anastomose with the longitudinal arteries coming up from below. The arteries which pass onto the bile duct form a plexus – the epicholedochal plexus, which covers the entire surface of the common bile duct, common hepatic duct, and the right and left bile ducts. The uppermost part of the plexus has been referred to as the hilar plexus. The hilar communicating artery is a marginal artery like the 3 o’clock and 9 o’clock arteries, but lies on

24

Figure 2.21 A dangerous anatomic variant – the “hairpin” right hepatic artery (RHA). Note that the RHA (enlarged in inset) enters the triangle of Calot and gives off two cystic arteries then takes a U-turn towards the liver. The artery is parallel to and about the same size as the cystic duct (CD). This artery is in danger of being mistaken for a cystic artery if dissection of the triangle of Calot is incomplete. CHD, common hepatic duct. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

top of the confluence of the right and left ducts, and forms part of the hilar plexus. There is a watershed of arterial blood supply on the bile duct. If the common hepatic bile duct is transected at a high level, i.e. close to the confluence, the arterial blood supply to the inferior cut edge of the common hepatic duct will come from the retroduodenal arteries through the longitudinal vessels running along the supraduodenal bile duct to the level of transection – a distance of several centimeters. Consequently, ischemia of the inferior cut edge of the bile duct is possible (Figure 2.22a). Similarly, if the bile duct is transected at the level of the duodenum, the upper cut edge of the common bile duct may be ischemic (Figure 2.22b). The clinical implication is that whenever hepatico-jejunostomy is performed, the bile duct should be divided close to its upper end to assure good blood supply, e.g. 1–2 cm below the normal site of confluence of left and right ducts. A corollary is that choledocho-choledochototomy is inherently risky because of the potential for one or other of the cut ends to be ischemic depending on the level of transection. When either the right or left hepatic arteries are occluded, there is usually little clinical effect because of rapid reflow

CHAPTER 2

Figure 2.22 Blood supply to the bile ducts. Longitudinal 3 o’clock and 9 o’clock arteries are enlarged. 1. Transection 1 cm below confluence. Blood supply at the lower cut margin is tenuous. 2. Transection 1 cm below confluence. Blood supply at the upper cut margin is tenuous. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

from the artery of the nonoccluded side through the hilar plexus.

Self-assessment questions 1 The anatomic basis of The Brisbane 2000 Terminology of Hepatic Anatomy and Resections is based on divisions of which of the following? (more than one answer is possible) A Hepatic vein B Hepatic artery C Bile ducts D Plate/sheath system E Portal vein


1

2

4 Which of the following statements are true? (more than one answer is possible) A The transverse portion of the left portal vein provides a large branch to segment 4 B Segmental branches of the left portal vein may be isolated in the umbilical fissure C The right portal vein has a long extrahepatic course D The left portal vein enters the liver substance at the base of the umbilical fissure E The branches of the left portal vein combine with hepatic arteries and bile duct to enter segmental sheaths

2 Which of the following are correct terms for hepatic resections? (more than one answer is possible) A Right hepatic lobectomy B Right trisectionectomy C Left lateral segmentectomy D Left lateral sectionectomy E Resection segments 5 and 6

5 Which of the following statements are true? (more than one answer is possible) A The termination of the left hepatic vein lies in the plane of the umbilical fissure B The middle hepatic vein drains segments 4, 5, and 8 C The right hepatic vein drains segments 5–8 D The umbilical vein drains blood from the umbilicus through the round ligament E The inferior right hepatic vein drains the caudate lobe.

3 After division of the apparent right hepatic artery and the right portal vein, failure of the entire right liver to demarcate might be due to which of the following? (more than one answer is possible) A Failure to occlude the caudate veins B Presence of a replaced artery supplying part of the right liver C Presence of steatosis D Absence of the right portal vein with failure to appreciate a separate right anterior sectional portal vein E Hypoxia

6 When transecting the liver during a right hepatectomy the surgeon encounters a large venous structure. Which of the following structures might this be? (more than one answer is possible) A Umbilical vein B Right anterior sectional vein in a case of absent right portal vein C Left hepatic vein coursing through the interior of the liver in a case of absent extrahepatic left portal vein D Hepatic vein from segment 5 E Hepatic vein from segment 8

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Introduction

7 Which of the following statements are true? (more than one answer is possible) A All arteries to the left of the common hepatic duct supply the left liver B All arteries to the right of the common hepatic duct supply the right liver C The cystic artery may arise from an artery on the left side of the bile duct D The right hepatic artery lies superior to the right hepatic duct in the porta hepatic E Rarely, an artery arising from the left gastric artery may supply the right liver 8 Which of the following statements are false? (more than one answer is possible) A The cystic duct is uniformly smaller than the common hepatic duct B The cystic duct may enter the left side of the bile duct C The cystic duct may enter the right hepatic duct. D Double cystic ducts are common but double gallbladders never occur E The cystic plate connects to the sheath of the right portal pedicle 9 A 59-year-old male with a large central tumor has had resection of segments 2–5 and 8. What is this operation called? A Left trisegmentectomy B Right trisegmentectomy C Central hepatectomy plus left lateral sectionectomy D Left trisectionectomy E Right trisectionectomy 10 The right lobe of the liver consists of which of the following? A Segments 5-8 B Segments 4-8 C Segments 4-8 and the caudate process D The right hemiliver plus segment 4 E “Lobe” is a confusing term and should be abandoned except for caudate lobe

References 1 Terminology Committee of the IHPBA. The Brisbane 2000 Terminology of Liver Anatomy and Resections. HPB Surg 2000;2:333–9.

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2 Healey JE, Schroy PC. Anatomy of the biliary ducts within the human liver; Analysis of the prevailing pattern of branchings and the major variations of the biliary ducts. Arch Surg 1953; 66:599–616. 3 Couinaud C. Le Foie. Etudes Anatomiques et Chirugicales. Paris: Masson & Cie, 1957. 4 Hjortsjo C-H. The topography of the intrahepatic duct systems. Acta Anat 1951;11:599–615. 5 Botero AC, Strasberg SM. Division of the left hemiliver in man – segments, sectors, or sections. Liver Transplant Surg 1998; 4:226–31. 6 Masselot R, Leborgne J. Anatomical study of hepatic veins. Anat Clin 1978;1:109–125. 7 Makuuchi M, Yamamoto J, Takayama T, et al. Extrahepatic division of the right hepatic vein in hepatectomy. Hepatogastroenterology 1991;38:176–9. 8 Belghiti J, Guevara OA, Noun R, Saldinger PF, Kianmanesh R. Liver hanging maneuver: a safe approach to right hepatectomy without liver mobilization. J Am Coll Surg 2001;193:109–11. 9 Strasberg SM, Linehan DC, Hawkins WG. Isolation of right main and right sectional portal pedicles for liver resection without hepatotomy or inflow occlusion. J Am Coll Surg 2008;206: 390–6. 10 Strasberg SM, Picus DD, Drebin JA. Results of a new strategy for reconstruction of biliary injuries having an isolated rightsided component. J Gastrointest Surg 2001;5:266–74. 11 Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of biliary injury during laparoscopic cholecystectomy. J Am Coll Surg 1995;180:101–25. 12 Northover JM, Terblanche J. A new look at the arterial supply of the bile duct in man and its surgical implications. Br J Surg 1979;66:379–84.

Self-assessment answers 1 2 3 4 5 6 7 8 9 10

B, C B, D, E B, D B, E A, B, C B, C, D, E B, C, E A, D D E

2

Epidemiology and Diagnosis

Introduction Chung-Mau Lo Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Malignant liver tumors are among the most dismal of all cancers. While primary liver cancer is the sixth most common cancer worldwide, it is the third most common cause of cancer death with a mortality-to-incidence ratio exceeding 0.9. The liver is also a common site of metastases, notably from primaries arising from the gastrointestinal tract. Colorectal cancer in particular is one of the most common malignancies and over 50% of cases will eventually develop liver metastases. Although liver metastases are usually regarded as part of systemic metastasis and the prognosis is poor, isolated colorectal liver metastases are currently managed as locoregional disease with surgical resection for cure similar in many ways to that for primary liver cancer. This section focuses on the pathology, epidemiology, natural history, and diagnosis of various liver cancers. It starts with a comprehensive review of the pathology of benign and malignant liver disease, followed by the epide-

miology, etiology, and natural history of different liver cancers. There is a striking variation in the risk of different kinds of liver cancer in different geographic areas, suggesting that various lifestyle and environment factors have a role in the etiology, and that a better understanding of the epidemiology provides excellent opportunity for prevention. For example, chronic hepatitis B is a major risk factor for hepatocellular carcinoma and prevention of hepatitis B infection by vaccination of newborns has resulted in a dramatic decrease in the incidence of liver cancer. Knowledge of the epidemiology also allows identification of the high-risk population for screening. Together with the chapters on advances in molecular diagnosis using tumor markers and imaging techniques, this section provides the framework for the recent advances in prevention, early diagnosis, and effective treatment of malignant liver tumors.


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Histology and Pathology of Normal and Diseased Liver Valérie Paradis1 and Achim Weber2 1 Department of Pathology, Beaujon Hospital, Clichy, and INSERM U773, Centre de Recherche Bichat Beaujon, Paris, France 2 Swiss HPB (Hepato-Pancreato-Biliary) Center, Department of Pathology, Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland

Introduction The pathologic analysis of liver background parenchyma is crucial for a better understanding of the development of liver tumors, as well as improvements in the management of patients who are potential candidates for liver surgery. This chapter will describe the normal histology of the liver and review the main pathologic changes observed in the context of malignant tumors. Primary malignant tumors, and especially hepatocellular carcinomas (HCCs), usually develop on already diseased liver parenchyma, since HCC progression follows a multistep process of carcinogenesis. Due to the increase in metabolic syndrome and viral chronic hepatitis worldwide, which represent significant risk factors for HCC, specific interest will be focused on steatosis and liver fibrosis. More recently, specific liver changes, including vascular damage, have been described in the context of liver metastases.

called Kupffer cells. The space between the endothelium and hepatocytes is known as the space of Disse, which contains hepatic stellate cells (HSCs, previously named Ito cells, lipocytes, or fat-storing cells) [1] (Figure 3.2). Such cells account for less than 10% of a normal liver, where they store vitamin A, and may acquire an activated myofibroblast-like phenotype during the fibrogenic process [2]. In normal liver, extracellular matrix (ECM) is restricted to the portal tracts, sinusoid walls, and central veins. Quantitatively, ECM is very limited, accounting for less than 3% of the total area of liver tissue [3]. The most common proteins found in the liver are collagens, with types I, III, IV, and V the most abundant, and display a specific localization and function in the liver [4]. Noncollagenous glycoproteins, such as laminin, fibronectin, tenascin, glycosaminoglycans, and proteoglycans are also constitutive ECM components of the liver [5]. ECM is organized into a complex network that fulfils major functions, such as maintaining mechanical coherence and resistance of the liver, as well as biologic functions, including cell proliferation, migration, differentiation, and gene expression [6].

Histology of normal liver The structural unit of the liver is represented by the hepatic lobule, which is composed of plates of hepatocytes radiating from the periphery to the center of the lobule. A lobule is roughly hexagonal in shape with portal tracts, and contains a bile duct and a terminal branch of the hepatic artery and portal vein at the vertices, and a central vein in the middle (Figure 3.1). The concept of acinus is rather functional, describing three main zones, based on the afferent vascular system. Liver cells are composed of different phenotypic cell populations; among them, the hepatocytes represent the majority, accounting for almost 80% of total resident cells. These hepatocytes make contact with blood in sinusoids, which are vascular channels lined by highly fenestrated endothelial cells and containing liver resident macrophages,


30

Steatosis The adult human liver normally contains up to 5% of its mass as lipid. Steatosis, i.e. an abnormal accumulation of lipids in hepatocytes, results from a variety of different underlying conditions. It is not a mere histologic finding, but rather can point to a potentially progressive liver disease. The clinical impact of the diagnosis of steatosis ranges from a harmless condition to an acutely threatening situation, depending on the amount and kind of fatty change and the clinical context. Steatosis is the basis for fatty liver diseases, which now are a common cause of liver function test elevation, paralleling the worldwide increase in obesity not only in adults but also in children. A major complication of steatosis is the development of steatohepatitis, a chronic inflammatory condition associated with fibrosis and potentially leading to cirrhosis. Alcoholic steatohepatitis (ASH) develops in the context of alcoholic

CHAPTER 3

Histology and Pathology of Normal and Diseased Liver

fatty liver disease (AFLD), which is delineated from nonalcoholic steatohepatitis (NASH) developing in the context of nonalcoholic fatty liver disease (NAFLD) in which patients lack a history of significant alcohol consumption. The latter conditions are considered to be mostly hepatic manifestations of insulin resistance in metabolic syndrome, which has become a major health problem in Western societies, paralleling the increased prevalence of obesity [7, 8]. NAFLD and NASH are associated with central obesity, type 2 diabetes mellitus, and the metabolic syndrome, but also with disorders of lipid metabolism, like hyperlipidemia. Liver biopsy is the current gold standard for diagnosis (or exclusion) of fatty liver disease. It can reveal clinically unsuspected fatty liver, and provide a grading and staging

of the fatty liver disease, evaluating the degree of steatosis, inflammation, liver cell injury, fibrosis, and architectural changes. Histologically, steatosis is described according to the amount of fatty change, the distribution with respect to zones involved, and the dominant kind of lipid drops, discriminating macrovesicular steatosis from microvesicular steatosis. Macrovesicular steatosis, the more common pattern, is characterized by lipid drops which predominantly fill most of the cell and push the nucleus to the periphery (Figure 3.3), whereas in microvesicular steatosis, the fat is finely dispersed in uniform droplets throughout the cytoplasm, and the nucleus remains centrally located. Frequently, steatosis shows a combination of both patterns.

Figure 3.1 Organization of a liver lobule. PT, portal tract; CV, central vein.

Figure 3.2 Hepatic stellate cell. A quiescent stellate cell is present in the space of Disse (arrow, Trichrome staining).

(a)

(b)

Figure 3.3 Features of alcoholic steatohepatitis. (a) Mostly macrovesicular steatosis, extensive hepatocyte ballooning, numerous Mallory bodies, and lobular inflammation including neutrophils. (b) Sirius stain highlights fibrosis with primarily pericellular distribution, extending to portal and perivenular areas.

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(a)

(b)

Figure 3.4 Adenoma and steatosis in the liver from a 19-year-old male with glycogenosis type I. (a) Yellow cut surface of adenoma and nontumorous tissue indicating increased fat content. (b) Histology reveals a mostly macrovesicular steatosis and several neutrophils reflecting “surgical” hepatitis.

Numerous conditions lead to macrovesicular steatosis, including obesity and diabetes mellitus in the context of metabolic syndrome; drugs and toxins, including alcohol, corticosteroids, methotrexate; infections (e.g. particular types of hepatitis C virus); total parenteral and protein– calorie nutrition; as well as (inherited) metabolic disorders, e.g. particular types of glycogen storage diseases (Figure 3.4) or Wilson disease. Among these causes, histology is not uniform, but can point to the underlying condition. For example, whereas steatosis is mostly perivenular, periportal steatosis is observed in parenteral nutrition or acquired immunodeficiency syndrome (AIDS), and glycogenated nuclei can point to diabetes mellitus. The histology of microvesicular steatosis reveals mostly unspectacular changes with swollen hepatocytes containing numerous small vacuoles and centrally located nuclei, and therefore is difficult to diagnose based on hematoxylin and eosin (H&E) staining of paraffin sections alone. In contrast to the generally mild morphologic changes, microvesicular steatosis is usually a clinically more serious condition. It results from mitochondrial damage and impaired βoxidation. Causes are acute fatty liver of pregnancy, Reye syndrome, acute alcohol intoxication, and several hepatotoxic drugs, e.g. valproate and nucleoside analogs given for human immunodeficiency virus (HIV) infection. Liver biopsy remains the gold standard for the diagnosis of steatohepatitis as a complication of AFLD or NAFLD [9, 10]. Histopathologic changes of ASH (Figure 3.3) and NASH are similar, and the two conditions cannot readily be distinguished based on histology alone. Diagnosis of NASH (and also ASH) relies not on a single feature, but rather on a combination of lesions [11]. Morphologic hallmarks of steatohepatitis are – besides steatosis – hepatocellular damage in

32

the form hepatocyte ballooning, formation of Mallory bodies and megamitochondria, liver cell apoptosis, predominantly lobular inflammation, and infiltration by neutrophils, sometimes including satellitosis, as well as fibrosis with primarily pericellular distribution (so-called chicken-wire fibrosis; Figure 3.3b), potentially extending to a portal and perivenular distribution [12, 13]. Based on the criteria of steatosis, lobular inflammation, and hepatocellular ballooning, a semiquantitative scoring system has been developed to score the spectrum of NAFLD, which has mostly been applied to treatment trials [14]. Both ASH and NASH can progress to cirrhosis, and NASH frequently is the reason for “cryptogenic cirrhosis” [15]. Patients are also at risk for liver failure and the development of HCC. Several observations provide evidence that NAFLD also can predispose to the development of HCC, even in the absence of cirrhosis [16]. Finally, histologic evaluation of hepatic steatosis is a wellestablished procedure in the setting of liver transplantation, since significant (macrovesicular) steatosis can cause initial poor liver graft function and therefore result in rejection of a potential donor organ [17, 18].

Fibrosis and cirrhosis Liver fibrosis is the main hallmark of almost all chronic liver diseases, whatever their origin. It is defined by the accumulation of various ECM components in different parts of the liver, mainly sinusoids and portal tracts. Due to its localization, excessive deposits of ECM will have deleterious consequences for liver functions, and may be taken into consideration in the surgical management of patients: the presence of fibrosis may result in significant decrease in liver

CHAPTER 3

function reserve, impairing potential regeneration. However, it is now clear that ECM metabolism is a very dynamic process and deposition of ECM in tissue is much more reversible than was previously thought [19].

Extracellular matrix in fibrotic liver In fibrotic liver, the ECM components are similar to those present in normal liver but are quantitatively increased (three- to five-fold increase) [20]. Importantly, redistribution of the relative amounts of ECM components is also observed. In the setting of chronic liver diseases, liver fibrosis is associated with additional mechanisms, including architectural distortion, liver cell regeneration, and vascular redistribution, that also contribute to the impairment of liver functions. ECM accumulation in sinusoid walls is one of the early changes, leading to sinusoid capillarization and thus strong impairment of exchange between hepatocytes and blood flow [21]. During this process of fibrogenesis, several types of cells are able to produce and secrete ECM components [22]. Besides hepatocytes, HSCs and portal fibroblasts are the major contributors of ECM [23]. A specific interest was shown in HSC activation in this process as HSCs show significant morphologic changes (elongated shape, loss of lipid droplets), phenotypic modifications (de novo expression of intermediate filaments characteristic of a smooth muscular phenotype), and function gains (proliferation, migration, contractility, and protein synthesis) [24]. Via the production of various mediators, including growth factors, HSCs participate in an autocrine and paracrine pathway of regulation. Since these cells are also able to produce specialized enzymes, such as matrix metalloproteases, involved in the remodeling of ECM, HSCs play a key role in the control of both synthesis and destruction of fibrosis [25].

Morphologic patterns of fibrosis For pathologists, the most obvious change in fibrosis is the expansion of ECM from the portal space or central vein. The preferential site for fibrosis to start is related to the mechanism responsible for fibrosis induction and is closely linked to etiology, mainly as follows: central fibrosis for vascular or alcohol/metabolic fibrosis; and portal fibrosis for viral, autoimmune, or biliary diseases. The stellate expansion of fibrous tissue around the portal tract or central vein leads to the development of fibrous connections from one vascular structure to another. At a more advanced stage, when most vascular spaces are interconnected, cirrhosis is constituted. In this new organization, redistribution of incoming liver blood flow is observed, with the blood supply derived mainly from branches of the hepatic artery (arterialization) in association with phenotypic modifications of sinusoid endothelial cells associated with capillarization. In chronic viral and autoimmune hepatitis, the portal area enlarges and extends through zone 1 of the acinus as a broad-based area of fibrosis to create portal–portal bridges. Chronic biliary diseases also


produce periportal injury that leads to fibrosis of acinar zone 1, and further extends along acinar zone 1, usually associated with ductular proliferation. The resulting septa that link adjacent portal tracts produce fairly regular nodules of parenchyma, often with a terminal hepatic venule in the center.

Evaluation and staging of fibrosis As mentioned above, malignant tumors, and especially HCC, arise in the course of chronic liver diseases characterized by the development of liver fibrosis. Therefore, pathologic analysis of nontumoral liver tissue, in that context, aims to assess with accuracy the necroinflammatory grade and stage of fibrosis. This is currently achieved by the development of different scales such as Ishak, Scheuer scores, or the METAVIR system [26–28]. Figure 3.5 is a schematic representation of the METAVIR scoring system. These scores have been fully validated in viral chronic hepatitis. More recently, an additional scoring system has been proposed by Brunt and Kleiner dedicated to AFLD and NAFLD [14]. In scoring systems, fibrosis is categorized into five to six progressive stages, from normal liver to cirrhosis with intermediate stages according to the number and extent of fibrous septa (Table 3.1). Since alcoholic- and nonalcoholic-related fibrosis is characterized by early and prominent sinusoidal fibrosis, fibrosis stage according to Brunt and Kleiner takes into account the degree of sinusoidal fibrosis in the evaluation of liver fibrosis [14]. Although a good to excellent reproducibility was reported in independent studies, especially for the staging of fibrosis, it should be pointed out that assessment of liver fibrosis, which is the main endpoint of chronic liver disease, may be affected by tissue sampling in as much as the tissue sample is provided by needle liver biopsy [29–31]. Further approaches, including immunohistochemistry, may be of significant value in measuring the activity of the profibrogenic state. Such studies allow the demonstration and quantification of activated HSCs by evaluating the expression of various protein markers, including α-smooth muscle actin [32] (Figure 3.6).

Table 3.1 Semiquantitative fibrosis staging systems. Fibrosis

METAVIR

Scheuer

Ishak

Normal Few portal tracts Most portal tracts Rare portal septa Few septa Numerous septa Incomplete cirrhosis Cirrhosis

0 1 1 2 2 3 4 4

0 1 1 2 3 3 4 4

0 1 2 2 3 4 5 6

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Figure 3.5 Schematic representation of the METAVIR system. F1, portal enlargement without septa; F2, few portal septa; F3, numerous fibrous septa; F4, cirrhosis; PT, portal tract; CV, central vein.

Figure 3.7 Hepatocellular carcinoma in a patient with hepatitis C virus infection. A 2-cm encapsulated tumor (early hepatocellular carcinoma) has developed in a cirrhotic liver (macroscopic view).

Figure 3.6 Activated hepatic stellate cell immunostained with α-smooth muscle actin (immunohistochemistry).

“Typical features” of nontumoral liver according to the type of malignant tumor Malignant liver tumors are divided into primary and metastatic tumors. In the group of primary tumors, HCCs and cholangiocarcinomas (CCs) are generally the most frequent.

34

Although cirrhosis is one of the major risk factors for HCC, some variation in incidence of HCC may be observed according to the etiologic cause of chronic liver injury [33]. Hepatitis C virus (HCV) infection is the leading cause of HCC (Figure 3.7) associated with cirrhosis in Western countries and Japan, followed by alcoholic cirrhosis and hereditary hemochromatosis in Europe [34, 35]. In Asia and Africa, the major cause of HCC is related to hepatitis B virus (HBV) infection. It should be pointed out that HCC developing in the context of HBV infection is more often diagnosed at an

CHAPTER 3

(a)


(b)

(c) Figure 3.8 Hepatocellular carcinoma arising in a patient with metabolic syndrome. (a) An encapsulated large heterogeneous tumor with cholestatic areas (macroscopic view). (b) Well-differentiated hepatocellular carcinoma formed of widened cell trabeculae (H&E staining). (c) Nontumoral liver shows marked steatosis (>66%) without any significant fibrosis (H&E staining).

earlier stage than cirrhosis [36]. In addition, several preneoplastic changes may be observed, including cirrhotic macronodules, also called dysplastic nodules, and dysplastic foci, including large and small liver cell changes. Due to the rising incidence of obesity and metabolic syndrome worldwide, NAFLD is now recognized as one of the leading causes of chronic liver disease and then HCC [37, 38]. In that context, histologic analysis of nontumoral liver may reveal a wide spectrum of metabolic fatty liver disorders, including simple steatosis, NASH, fibrosis, and cirrhosis (Figure 3.8). Finally, a distinct subtype of HCC – fibrolamellar HCC, which occurs in a young population without any evidence of chronic liver injury, arises on a quite normal liver parenchyma [39] (Figure 3.9). CCs, the second most common primary malignant tumors of the liver, arising from epithelial biliary cells, occur on

Figure 3.9 Fibrolamellar hepatocellular carcinoma (macroscopic view). A large unencapsulated polychrome tumor with fibrous septa inside.

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SECTION 2


(a)

(b)

Figure 3.10 Cholangiocarcinoma. (a) A white, well-limited tumor surrounded by cholestatic and fibrous liver parenchyma (macroscopic view). (b) Nontumoral liver tissue shows extensive fibrosis with a pattern of biliary fibrosis (Trichrome staining).

(a)

(b)

Figure 3.11 Liver metastasis. (a) One tumoral white unencapsulated nodule developed on a nodular parenchyma without fibrosis (regenerative nodular hyperplasia, macroscopic view). (b) Nontumoral liver tissue and peritumoral liver tissue.

nondiseased liver in most cases. However, cirrhosis carries a 10-fold risk for developing such a tumor [40, 41]. Primary sclerosing cholangitis, HCV infection, and genetic hemochromatosis are the most frequent risk factors encountered in the development of CC in Western countries, whereas parasitic infection and hepatolithiasis are common in Asia [41–43]. A specific pattern of liver damage, including a significant degree of secondary biliary fibrosis and cholestasis, may be observed in cases of hilar CC where the tumor results in the chronic obstruction of the large bile ducts (Figure 3.10).

36

Finally, in cases of liver metastasis, various features of liver damage may be seen, mainly depending on the “liver history” of the patient, such as alcohol consumption, presence of chronic liver disease or metabolic syndrome. Also, it has been recently pointed out that systemic chemotherapy may induce morphologic changes in the nontumoral tissue. Major disorders include vascular lesions, such as sinusoidal obstruction syndrome, steatosis, and even steatohepatitis in some studies [44–46]. Several cases of regenerative nodular hyperplasia also have been reported (Figure 3.11).

CHAPTER 3

Impact of diseased liver on surgical management of patients with malignant liver tumors To be able to determine the pathologic aspect of nontumoral liver tissue is a key point for surgeons who have to manage patients with malignant tumors. Indeed, in order to improve peri- and post-operative care, especially in candidates for extended liver resection, specific procedures may be performed in patients with potentially insufficient hepatic functional reserve. In that setting, a preoperative liver biopsy may be proposed since imaging modalities are insufficiently accurate to date. Noninvasive serum markers, developed for the diagnosis of cirrhosis mainly in chronic viral diseases, have not been validated in the context of malignant liver tumors. For that purpose, the objectives of the liver biopsy are to evaluate the architecture of the liver parenchyma, and to establish the staging of fibrosis, histologic grading of inflammation, and severity of steatosis.

Self-assessment questions 1 Which one of the following statements concerning steatosis is true? A Liver biopsy for the evaluation of steatosis is nowadays replaced by ultrasonography and blood tests B Macrovesicular steatosis is usually a clinically more severe condition than microvesicular steatosis C Mallory bodies are a characteristic histologic finding of alcoholic steatohepatitis (ASH), but not of nonalcoholic steatohepatitis (NASH) D Pericellular fibrosis and ballooned hepatocytes are a characteristic histologic finding of both ASH and NASH E Macrovesicular and microvesicular steatosis are mutually exclusive, and usually do not coexist in the same liver 2 Which one of the following statements regarding evaluation and staging of fibrosis is false? A Scoring systems are based on a semiquantitative assessment of fibrosis B Scoring systems have been mainly validated in viral chronic hepatitis C Different patterns of fibrosis are observed according to the etiology of the liver disease D Sinusoidal fibrosis is a typical feature observed in biliary fibrosis E Specific stains are useful in fibrosis staging


3 Which one of the following statements concerning fibrosis is false? A Fibrosis is defined by production and accumulation of extracellular matrix (ECM) B Definition of cirrhosis is restricted only to fibrosis C Hepatic stellate cells are the main producers of ECM during fibrogenesis D Hepatic stellate cells are able to proliferate during fibrogenesis E In normal liver, hepatic stellate cells contain lipid droplets 4 Which one of the following statements concerning fibrosis is false? A In chronic liver disease, patterns of fibrosis depend on etiology B In biliary fibrosis, ductular proliferation is prominent C Semiquantitative scoring of fibrosis is based on morphometry analysis D Immunohistochemistry may help to identify activated hepatic stellate cells E In alcoholic fatty liver disease and nonalcoholic fatty liver disease the pattern of fibrosis is similar 5 Which one of the following statements concerning hepatocellular carcinomas is false? A Hepatocellular carcinomas (HCCs) are the most frequent tumors to develop in cirrhotic patients B Incidence of HCC varies according to the etiologic cause of chronic liver disease C In alcoholic patients, HCCs are usually diagnosed early in the course of chronic liver disease D HCCs may occur via the development of premalignant changes, including dysplastic cirrhotic nodules E Nonalcoholic steatohepatitis is a clinical condition associated with the development of HCCs 6 Which of the following are true concerning cholangiocarcinomas? (more than one answer is possible) A Cholangiocarcinomas are tumors derived from biliary epithelial cells B Cirrhotic patients do not display an increased risk for developing cholangiocarcinomas C Parasitic infections and hepatolithiasis are risk factors for cholangiocarcinomas D Features of primary sclerosing cholangitis are never observed in the nontumoral liver adjacent to a cholangiocarcinoma E Dilatation of large bile ducts may be related to the presence of hilar cholangiocarcinomas

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7 Which of the following statements concerning metastatic tumors of the liver is false? A Metastatic tumors are the most frequent liver malignancies B Nontumoral liver may be abnormal C Histologic changes of the nontumoral liver tissue may be related to systemic chemotherapy D Fibrosis is the most common pathologic change observed following systemic chemotherapy E Steatosis and vascular lesions are common features on surgical specimens

16

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References

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and risk factors for underlying disease. Hepatology 1999;29: 664–9. Guzman G, Brunt EM, Petrovic LM, Chejfec G, Layden TJ, Colter SJ. Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis? Arch Pathol Lab Med 2008;132:1761–6. McCormack L, Petrowsky H, Jochum W, Furrer K, Clavien PA. Hepatic steatosis is a risk factor for postoperative complications after major hepatectomy: a matched case-control study. Ann Surg 2007;245:923–30. Clavien PA, Petrowsky H, DeOliveira ML, Graf R. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med 2007;356:1545–59. Friedman SL, Arthur MJ. Reversing hepatic fibrosis. Sci Med 2002;8:194–205. Rojkind M, Giambrone MA, Biempica L. Collagen types in normal and cirrhotic liver. Gastroenterology 1985;76:710–19. Schaffner F, Popper H. Capillarization of the sinusoids in man. Gastroenterology 1963;44:239–42. Cassiman D, Libbrecht L, Desmet V, et al. Hepatic stellate cell/ myofibroblast subpopulations in fibrotic human and rat livers. J Hepatol 2002;36:200–9. Knittel T, Kobold D, Saile B, et al. Rat liver myofibroblasts and hepatic stellate cells: different cell populations of the fibroblast lineage with fibrogenic potential. Gastroenterology 1999;117: 1205–21. Friedman SL, Arthur MJ. Activation of cultured rat hepatic lipocytes by Kupffer cell conditioned medium: direct enhancement of matrix synthesis and stimulation of cell proliferation via induction of platelet-derived growth factor receptors. J Clin Invest 1989;84:1780–5. Milani S, Herbst H, Schuppan D, et al. Differential expression of matrix-metalloproteinase-1 and -2 genes in normal and fibrotic human liver. Am J Pathol 1994;144:528–37. Desmet VJ, Gerber M, Hoofnagle JH, et al. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994;19:1513–20. Ishak K, Baptista A, Bianchiu L, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22:696–9. Bedossa P, Poynard T. The French METAVIR Cooperative Study Group. An algorithm for grading activity in chronic hepatitis C. Hepatology 1996;24:298–3. Abdi W, Millan JC, Mezey E. Sampling variability on percutaneous liver biopsy. Arch Intern Med 1979;139:667–9. Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003;38:1449–57. Regev A, Berho M, Jeffers LJ, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002;97:2614–18. Iredale JP, Benyon RC, Pickering J, et al. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 1998;102:538–49. Gines P, Gardenas A, Arroyo V, et al. Management of cirrhosis and ascites. N Engl J Med 2004;350:1646–54. El-Serag HB. Hepatocellular carcinoma and hepatitis C in the United States. Hepatology 2002;36:S74–83. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907–17.

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36 Lam CM, Chan AO, Ho P, et al. Different presentation of hepatitis B-related hepatocellular carcinoma in a cohort of 1863 young and old patients: implications for screening. Aliment Pharmacol Ther 2004;19:771–7. 37 Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001; 50:1844–50. 38 Diehl AM. Nonalcoholic steatohepatitis. Semin Liver Dis 1999;19:221–9. 39 Soreide O, Czeiniak A, Bradpiece H, et al. Characteristics of fibrolamellar carcinoma. Am J Surg Pathol 1986;151:518–23. 40 Sorensen HT, Friis S, Olsen JH, et al. Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark. Hepatology 1998;28:921–925 41 Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004;24:115–25. 42 Watanapa P, Watanapa WB. Liver fluke-associated cholangiocarcinoma. Br J Surg 2002;89:962–70. 43 Donato F, Gelatti U, Tagger A, et al. Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy. Cancer Causes Control 2001;12:959–64. 44 Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemo-


therapy in patients with metastatic colorectal cancer. Ann Oncol 2004;15:460–6. 45 Aloia T, Sebagh M, Plasse M, et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol 2006;24:4983–90. 46 Zorzi D, Laurent A, Pawlik TM, et al. Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br J Surg 2007;94:274–86.

Self-assessment answers 1 2 3 4 5 6 7

B D B C C A, C, D, E D

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4

Pathology of Primary and Secondary Malignant Liver Tumors Kay Washington Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA

Primary Epithelial Tumors of the Liver Hepatocellular carcinoma Gross morphology Hepatocellular carcinomas (HCCs) may be divided into nodular, massive, and diffuse types. The nodular type, the most common, is the type usually seen in cirrhosis, with tumor nodules scattered among regenerating cirrhotic nodules. A dominant tumor nodule may be present. The massive type consists of a large single mass with or without satellite nodules and is usually seen in a noncirrhotic liver. The diffuse type is relatively uncommon and consists of innumerable indistinct small tumor nodules scattered throughout the liver. HCCs are generally soft and variegated in appearance, with color ranging from pale tan or gray to green, reflecting the presence of bile. Invasion and growth into large vessels such as hepatic vein branches and the portal vein is common; invasion of intra- or extra-hepatic bile ducts is seen less often, but occasionally a patient presents with symptoms of large bile duct obstruction from intrabiliary growth of HCC.

the neoplastic cells closely resemble normal hepatocytes, with minimal alterations in nuclear-to-cytoplasmic ratio and chromatin content and distribution. In most tumors, however, the nuclear-to-cytoplasmic ratio is increased and there is some degree of nuclear atypia. Cytoplasm is eosinophilic and slightly granular, and may contain inclusions such as Mallory’s hyaline, α-fetoprotein (AFP), α-1antitrypsin, or bile. The cytoplasm may appear clear due to accumulation of glycogen, and the tumor cells may contain fat. Poorly differentiated tumor cells may be spindle-shaped and have a sarcomatoid appearance. The World Health Organization grading scheme for HCC [1] separates HCCs into four grades, based on resemblance of the tumor cells to normal hepatocytes. Well-differentiated HCCs are usually small early stage lesions; the cells show minimal nuclear atypia. In moderately-differentiated tumors, tumor cells are typically arranged in trabeculae three or more cell layers thick; the nuclear-to-cytoplasmic ratio is higher, and nuclei are more pleomorphic and hyperchromatic than in well-differentiated tumors. Poorly differentiated tumors grow in a solid pattern and are composed of highly pleomorphic cells; multinucleated tumor giant cells are not uncommon. Undifferentiated HCCs are anaplastic and difficult to recognize as hepatocellular.

Histologic types In the most common growth pattern of HCC, tumor cells form trabeculae that vary in width from two to over 20 cells and are separated by sinusoidal-like spaces lined by endothelial cells. Little or no intervening connective tissue stroma is present (Figure 4.1). Other patterns include an acinar or pseudoglandular pattern, in which tumor cells are arranged around a large central bile canalicular structure, and a solid pattern in which the trabeculae are broad and compact, obscuring intervening sinusoidal spaces. Cytologically the cells of HCC display varying degrees of hepatocellular differentiation. In well-differentiated tumors,


40

Precursor lesions The precursor lesion for HCC arising in the cirrhotic liver is considered to be the dysplastic nodule. Nodular lesions arising in the setting of cirrhosis show a wide spectrum of histologic changes, from large macroregenerative nodules without atypical features, to nodules falling just short of the morphologic criteria considered diagnostic of HCC. Although terminology applied to these nodular lesions has been quite varied, the most widely accepted classification scheme is that proposed by the International Working Party [2]. Multiacinar regenerative nodules distinctly larger than the surrounding cirrhotic nodules but lacking cytologic and architectural atypia are termed macrogenerative nodules or large regenerative nodules. A minimum size criterion has not been established but is based upon the size suitable to distinguish the large nodules from background cirrhotic

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Pathology of Primary and Secondary Malignant Liver Tumors

Figure 4.1 The tumor cells in hepatocellular carcinoma are arranged in trabeculae of variable thickness separated by sinusoidal spaces. A few pseudoacinar structures are present.

Figure 4.2 The fibrous stroma in fibrolamellar carcinoma has a characteristic dense lamellar appearance.

nodules. These large regenerative nodules are usually multiple and measure 0.5–1.5 cm, but can be 5 cm or more in diameter. They are found in 15% to nearly 50% of cirrhotic livers and are three to four times more common than dysplastic nodules.

pared to the surrounding liver, and is considered a precursor lesion for HCC [3]. Whether large cell change, characterized by cellular enlargement, nuclear pleomorphism, and hyperchromasia, is a precursor lesion for HCC remains more controversial. While large cell change has been associated with HCC development, it may also be seen in the setting of chronic cholestasis [4] and may not be directly related to hepatocarcinogenesis.

Dysplastic nodules Dysplastic nodules are nodular lesions generally occurring in the setting of cirrhosis and displaying some degree of cytologic or architectural atypia, but lacking definitive histologic features of malignancy. The International Working Party has defined a dysplastic nodule as being 1 mm or more in diameter and having either histologic features indicative of presumed genetic alteration (characterized by “the presence of nuclear or cytoplasmic alterations and the topographic clustering of such variations to form recognizable subpopulations of cells”) or proof of genetic alteration (e.g. clonality) without definitive histologic features of malignancy [2]. Dysplastic nodules are further subdivided into low and high grades, depending on the degree of histologic abnormality, for purposes of risk stratification and clinical utility. Dysplastic changes include architectural aberrations such as focal areas of pseudogland formation and solid areas [2]. If uniformly thick cells plates (three or more cells thick) or large areas of pseudoglandular architecture are encountered, the diagnosis of small HCC should be considered. Two categories of atypical cytologic features are recognized: small cell change and large cell change. Dysplastic foci or nodules often consist of hepatocytes with small cell change, characterized by smaller cell size, a greater nuclearto-cytoplasmic ratio, cytoplasmic basophilia, and denser cellularity in comparison with the surrounding extranodular hepatocytes. Small cell change has been shown to have a higher proliferative rate and a lower apoptotic rate com-

Special variants of hepatocellular carcinoma Fibrolamellar carcinoma The fibrolamellar variant of HCC accounts for less than 5% of HCCs. In contrast to the usual HCC, it occurs in young patients (primarily 5–35 years old). On gross examination, fibrolamellar carcinomas are circumscribed gray or green masses ranging in size from 9 to 14 cm, and are usually single [5]. The tumors are solid, and frequently contain a central fibrous scar reminiscent of focal nodular hyperplasia. The interface of tumor with surrounding liver is scalloped and pushing, rather than infiltrative on gross examination, and the tumor is well circumscribed. The surrounding liver is as a rule not cirrhotic. The microscopic appearance is distinctive, with lamellar bands of collagen separating large polygonal tumor cells with abundant eosinophilic cytoplasm (Figure 4.2). The tumor cells contain single round to oval central nuclei, and the nuclear-tocytoplasmic ratio is relatively low due to the abundant granular cytoplasm, which on ultrastructural examination contains numerous swollen mitochondria. Accumulation of bile within the tumor is common, and cells may contain α-1-antitrypsin, seen as proteinaceous cytoplasmic inclusions, and fibrinogen, seen as pale areas within the cytoplasm known as “pale bodies.” α-Fetoprotein accumulation is not seen.

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(a)

(b)

Figure 4.3 Polyclonal antibodies to carcinoembryonic antigen cross-react with biliary glycoprotein to give a distinctive canalicular staining pattern in normal liver (a) and hepatocellular carcinoma (b).

Table 4.1 Immunohistochemical stains in the diagnosis of malignant tumors in the liver.

Cytokeratins AE1/AE3 CAM 5.2 CK 7/CK 20 HepPar1* MOC-31* α-Fetoprotein Polyclonal CEA* Monoclonal CEA

Hepatocellular carcinoma

Cholangiocarcinoma

Metastatic adenocarcinoma

Negative Positive Negative/negative Positive Negative Positive in 10–50% Canalicular Negative

Positive Positive Positive/negative Negative Positive Negative Cytoplasmic Cytoplasmic

Positive Positive Variable Negative (rare exceptions) Positive Rare Cytoplasmic Cytoplasmic

*Most useful

Sclerosing hepatocellular carcinoma The sclerosing subtype of HCC is a rare variant characterized by the presence of abundant fibrous stroma that lacks the distinctive lamellar quality seen in fibrolamellar carcinoma. The tumor cells are arranged in cords and acinar structures within this diffuse fibrous stroma. While previous reports indicate that sclerosing HCC occurs in older patients and may be associated with hypercalcemia, a more recent study reports a younger mean age (42 years) and normal serum calcium levels in the seven patients studied [6].

Special studies Although most HCCs are readily distinguished from metastatic tumors and other primary malignancies of the liver, their wide range of appearance occasionally overlaps with

42

other tumors. A limited panel of immunohistochemical stains has proven useful in some cases, and ultrastructural analysis may also provide evidence for hepatocellular differentiation. The most useful immunoperoxidase studies for diagnosis of HCC include antibodies to HepPar-1, carcinoembryonic antigen (CEA), and MOC-31 (Table 4.1). The antibody Hep Par 1 is a sensitive and relatively specific marker of hepatocyte differentiation, but may not be detectable in poorly differentiated tumors. Polyclonal antibodies to CEA, but not most monoclonal antibodies, cross-react with a biliary glycoprotein to produce a canalicular staining pattern in 60–90% of HCCs (Figure 4.3). While many adenocarcinomas will display cytoplasmic staining with antibodies to CEA, the canalicular pattern is considered specific for HCC. MOC-31,

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Table 4.2 Staging of hepatocellular carcinoma and intrahepatic cholangiocarcinoma [9] (see Chapter 16). TNM definitions Primary tumor T1 Solitary tumor, without vascular invasion T2 Solitary tumor with vascular invasion or multiple tumors, none >5 cm T3 Multiple tumors >5 cm or tumor involving a major branch of the portal or hepatic vein(s) T4 Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum Regional lymph nodes N0 No regional lymph node metastases N1 Regional lymph node metastases

Figure 4.4 The low pattern appearance of the fetal pattern of hepatoblastoma has a distinctive alternating light and dark appearance, due to accumulation of glycogen in light-staining tumor cells.

Distant metastases M0 No distant metastases M1 Distant metastases

pediatric liver tumors and 25% of all liver tumors in children.

Stage grouping

Gross morphology

Stage Stage Stage Stage Stage Stage

I II IIIA IIIB IIIC IV

T1, N0, M0 T2, N0, M0 T3, N0, M0 T4, N0, M0 Any T, N1, M0 Any T, any N, M1

a cell surface glycoprotein, is generally absent in HCC, but present in almost all cholangiocarcinomas and adenocarcinomas metastatic to the liver [7]. Tumor staining for AFP is relatively specific for HCC; other tumors that may express AFP include germ cell tumors, gastric carcinomas and occasionally other gastrointestinal tract malignancies, and the occasional pancreatic and lung adenocarcinoma. However, AFP is relatively insensitive and positive staining is seen in 50% or less of tumors [8].

Tumor staging The most widely used staging system for HCC, developed by the International Union Against Cancer and the American Joint Committee on Cancer, incorporates tumor size, number of tumor deposits, and vascular invasion [9] (Table 4.2). Several criticisms have been levied against this system, including lack of ability to predict survival. Other schemes have been proposed, such as the Liver Cancer Staging Group of Japan system, but have not been widely adopted [10].

Hepatoblastoma Hepatoblastoma is the most common primary tumor of liver in young children, accounting for over 50% of malignant

Hepatoblastoma is typically a single mass, located in the right lobe in about 60% of cases. The tumors range in size from 6 to over 20 cm, are generally well circumscribed, and may be encapsulated. The cut surface is fleshy, faintly lobulated, pale tan to gray–white, and often variegated because of hemorrhage and necrosis, which may be prominent and more extensive if preoperative chemotherapy has been given [11]. The background liver is generally normal.

Histologic classification Hepatoblastomas are broadly subdivided into epithelial, and mixed epithelial/mesenchymal types. Epithelial hepatoblastomas, the most common type, are further subdivided into fetal, embryonal, macrotrabecular, and small cell undifferentiated patterns. The fetal pattern of hepatoblastoma most closely resembles developing liver. The cells are easily recognized as showing hepatocellular differentiation and are arranged in plates two cell layers thick separated by sinusoids. On low power, zones of pale-staining tumor cells with relatively clear cytoplasm alternate with areas of more deeply eosinophilic cells, imparting a distinctive striped appearance (Figure 4.4). The fetal type is generally divided into mitotically inactive (two or fewer mitotic figures per 10 high power fields) and mitotically active subtypes (more than two mitoses per 10 high power fields) [12]. In the embryonal pattern, the tumor cells are smaller and more primitive in appearance compared to the fetal type cells. These cells are irregular and angulated, with hyperchromatic nuclei and less cytoplasm, and are arranged in sheets, pseudoacini, and ribbons rather than cell plates. The macrotrabecular pattern is distinguished by the presence of large broad trabeculae more than 10 cells thick. The cells may be fetal-

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Table 4.3 Staging of hepatoblastoma. Stage I Stage II Stage III

Stage IV

Complete resection Microscopic residual tumor Gross residual tumor: Primary completely resected, positive lymph nodes Primary incompletely resected Distant metastases

or embryonal-type, or may resemble cells of HCC. The small cell undifferentiated pattern is relatively rare; it is characterized by small primitive cells with scant cytoplasm and hyperchromatic nuclei, growing in loosely cohesive sheets and clusters. Mixed epithelial/mesenchymal hepatoblastomas contain areas of fetal epithelial and embryonal cells admixed with primitive mesenchyme. The mesenchymal cells are elongated, spindle cells resembling fibroblasts; some areas may have a myxoid appearance. Deposition of osteoid-like material is seen in the mixed hepatoblastomas, and cartilage is often present.

Staging and pattern of spread Hepatoblastoma is staged by a scheme used by the Children’s Cancer Study Group Hepatoma Study [13] (Table 4.3). Hepatoblastoma spreads to regional lymph nodes and can disseminate through hematogenous routes as well. Common sites of metastases include adrenal, lung, bone, and brain.

Cholangiocarcinoma Cholangiocarcinomas are the second most frequent primary hepatic malignancy, and make up from 5 to 30% of malignant hepatic tumors. Although several classification schemes for these malignant bile duct tumors have been proposed, the most widely accepted divides these lesions into two broad categories: intrahepatic (peripheral) and extrahepatic, which includes hilar (Klatskin) tumors.

Peripheral or intrahepatic cholangiocarcinomas The Liver Cancer Study Group of Japan has defined peripheral cholangiocarcinoma as cholangiocarcinoma arising in a segmental duct or a more peripheral duct [14]. Intrahepatic cholangiocarcinoma is currently staged using the same tumor/node/metastasis (TNM) classification and stage grouping as HCC [9] (see Table 4.2).

Gross and microscopic features On gross examination, intrahepatic cholangiocarcinomas are generally gray–white to tan masses; larger lesions may contain areas of central necrosis or, less commonly, hemorrhage. Most tumors are firm because of the prominent desmoplastic stroma, which may be gritty because of dystrophic calcifications. In general, the intrahepatic cholangi-

44

Figure 4.5 The neoplastic cells of cholangiocarcinoma form tubules and glands within a prominent fibrous stroma.

ocarcinoma consists of a single nonencapsulated mass in a noncirrhotic liver, although satellite lesions may be present. The margins may be deceptively well circumscribed on gross examination, but microscopic examination shows infiltrative borders. Rarely, involvement of portal or hepatic veins may be seen, and occasionally intraductal growth occurs. Some investigators have subdivided intrahepatic cholangiocarcinomas based on the pattern of growth, and report that tumors without biliary strictures behave more like HCC, in that they are more likely to occur in a diseased liver and have frequent intrahepatic spread without lymph node metastases [14]. Most cholangiocarcinomas are adenocarcinomas; rarely, areas of squamous differentiation may be seen, and sarcomatoid variants have been reported [15]. Other variants include papillary adenocarcinoma, found generally within larger ducts, and signet ring cell carcinoma. The most common microscopic pattern is a well to moderately differentiated adenocarcinoma forming small tubular glands and duct-like structures (Figure 4.5). The tumor cells are low cuboidal to columnar, with clear to eosinophilic cytoplasm and round to oval nuclei. Intracellular mucin production may be scant, but is usually demonstrable with special stains for mucin; typically a mixture of neutral and acidic mucins is found. A desmoplastic stroma is generally prominent, but is not always present. Perineural and lymphovascular invasion is common, and cholangiocarcinomas often involve portal tracts, by spread either within portal vein radicals or within the intrahepatic biliary tree. Bile ducts in adjacent portal tracts may demonstrate varying degrees of epithelial dysplasia; however, it is usually not possible to identify a specific bile duct of origin.

Differential diagnosis The primary challenge for the pathologist in diagnosing most intrahepatic cholangiocarcinomas is distinction from metastatic adenocarcinoma. Primary sites producing tumors with

CHAPTER 4

similar histology include pancreas, extrahepatic biliary tree, breast, and occasionally lung. Immunohistochemical stains are of limited use in distinguishing cholangiocarcinoma from other adenocarcinomas, and mucin stains are helpful only in distinguishing cholangiocarcinoma from HCC. The distinction between cholangiocarcinoma and metastatic adenocarcinoma therefore depends heavily on the exclusion of a primary site elsewhere. Comparative immunohistochemical studies suggest that cytokeratins (CKs) 7 and 20 may be useful in some cases in distinguishing peripheral cholangiocarcinomas, which are generally CK 7+/CK 20–, from colorectal metastases, which are usually CK 7–/CK 20+ [7, 16]. The distinction between HCC and cholangiocarcinoma is usually more straightforward. In problematic cases, a panel of immunohistochemical stains can be employed to distinguish between the two (see Table 4.1).

Extrahepatic cholangiocarcinoma Gross and microscopic features The typical gross appearance of perihilar cholangiocarcinomas is dense white scar infiltrating the hepatic hilum and extending into the adjacent parenchyma. In cases of sclerosing cholangitis, the presence of tumor on gross examination may be obscured by dense fibrosis. The bile duct may be encircled and thickened by dense desmoplastic tumor. In some cases, the tumor is papillary and protrudes into the lumen of the bile duct. In general, the microscopic appearance is similar to that of intrahepatic cholangiocarcinoma, with most of the tumors composed of small well-formed ducts. Desmoplasia is a prominent feature in many perihilar cholangiocarcinomas, and perineural invasion is commonly found. The differential diagnosis includes benign reactive changes and bile ductular proliferation; in patients with biliary stents, diagnosis may be particularly difficult because of the significant degree of cellular atypia associated with reactive change in bile duct epithelium.

Staging Perihilar cholangiocarcinoma can be staged using a TNM classification scheme devised by the American Joint Committee on Cancer (Table 4.4) for staging extrahepatic bile duct carcinomas [9]. For more clinically oriented staging systems see Chapter 16.

Mixed hepatocellular/cholangiocarcinoma Occasional primary epithelial malignancies in the liver will show divergent differentiation, with features of both cholangiocarcinoma and HCC. These tumors assume one of two patterns, termed “collision tumors” and “transition tumors” [15]. In the “collision tumor,” different areas of the neoplasm or separate tumor masses in the liver show different patterns of differentiation, with separate areas of HCC and cholangiocarcinoma. The “transition tumors” show more intermixed patterns. Most cases show the same multiple


Table 4.4 Staging of perihilar cholangiocarcinoma [9]. TNM definitions Primary tumor Tis Carcinoma in situ T1 Tumor confined to the bile duct histologically T2 Tumor invades beyond the wall of the bile duct T3 Tumor invades the liver, gallbladder, pancreas, and/or ipsilateral branches of the portal vein or hepatic artery T4 Tumor invades any of the following: main portal vein or its branches bilaterally, common hepatic artery, or other adjacent structures, such as the colon, stomach, duodenum, or abdominal wall Regional lymph nodes N0 No regional lymph node metastasis N1 Regional lymph node metastases Metastasis M0 M1

No distant metastasis Distant metastasis

Stage grouping Stage Stage Stage Stage Stage

0 IA IB IIA IIB

Stage III Stage IV

Tis, N0, M0 T1, N0, M0 T2, N0, M0 T3, N0, M0 T1, N1, M0 T2, N1, M0 T3, N1, M0 T4, any N, M0 Any T, any N, M1

allelic losses in both tumor components, suggestive of divergent differentiation from a single clone [17]. Metastases maintain the mixed pattern or exhibit hepatocellular differentiation [18].

Biliary cystadenocarcinoma Biliary cystadenocarcinoma is a rare tumor, generally arising in a pre-existing biliary cystadenoma. These tumors arise in adults, and although benign biliary cystadenomas are more common in women, for cystadenocarcinomas the sex ratio is approximately 1 : 1 [15].

Gross morphology Most biliary cystadenocarcinomas are multilocular, although rare unilocular cases have been reported. Cystadenocarcinomas in one series ranged in size from 3 cm to 30 cm, essentially no different in size from benign biliary cystadenomas [15]. The cyst fluid may be clear mucinous, bile-stained, or blood tinged. The cyst lining may contain papillary projec-

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tions into the cyst lumen. Areas of solid thickening and large papillary projections are clues to malignancy.

Microscopic features The epithelial lining of the cysts generally consists of tall columnar cells and should display cytologic features of malignancy. The tumor infiltrates the underlying cyst wall. Most biliary cystadenocarcinomas are well differentiated; the most common patterns are a tubulopapillary or tubular adenocarcinoma. Rarely, the tumor shows adenosquamous differentiation. The stroma is variable in biliary cystadenocarcinomas; mesenchymal ovarian-type stroma is often present in tumors in women; in men, the stroma consists of dense fibrosis.

Determination of malignancy The prediction of behavior from morphologic features is difficult in cystic mucinous neoplasms. Many otherwise benign biliary cystadenomas have areas of nuclear enlargement, crowding, and stratification, considered areas of dysplastic change. Many pathologists reserve the term “cystadenocarcinoma” for cases with frankly invasive adenocarcinoma involving the stroma or adjacent parenchyma. Surgical resection offers the greatest opportunity for cure; long-term survival is relatively high for women with biliary cystadenocarcinomas arising in pre-existing cystadenomas with ovarian-type stroma. Cystadenocarcinomas in men may have a more aggressive course [15].

Primary hepatic sarcomas Angiosarcoma The most common primary sarcoma of the liver is angiosarcoma, occurring in older men (only 25% of patients are women), with a peak incidence in the sixth and seventh decades. It is a rare tumor, accounting for only 25–30 cases per year in the United States. On gross examination, the entire liver is usually involved by angiosarcoma, which appears as gray–white hemorrhagic masses measuring up to 5 cm. The liver is not cirrhotic in most cases. The tumor cells of angiosarcoma are spindle-shaped, with pale cytoplasm with indistinct cell borders. Nuclei are irregular, angulated, enlarged, and hyperchromatic. Angiosarcoma grows in a characteristic pattern by extending along preexisting vascular channels in the liver. With tumor progression the hepatocytes atrophy and disruption of the local architecture by the growing tumor produces larger and larger vascular channels (Figure 4.6). Eventually blood-filled cavitary spaces lined by tumor cells are formed. Thorotrast deposits, if present, appear as coarse brown refractile material in Kupffer cells and the fibrous tissue of portal tracts or Glisson’s capsule.

46

Figure 4.6 Angiosarcoma forms blood-filled channels of varying sizes; tumor cells are plump spindle cells with irregular pleomorphic nuclei.

A variety of immunohistochemical stains may be used to confirm vascular differentiation in hepatic angiosarcomas. The cells are usually positive for Factor VIII-related antigen and Ulex europeus, although staining may be focal and weak in poorly differentiated tumors. Staining for CD34 antigen may be more sensitive than staining for Factor VIIIrelated antigen and is considered more specific than Ulex europeus. Ultrastructural examination shows Weibel-Palade bodies, the characteristic feature establishing endothelial differentiation. Differentiation from other vascular neoplasms may be a problem, but the distinction rests on the presence of malignant cytologic features in angiosarcoma. Overlap with epithelioid hemangioendothelioma may occur. Primary angiosarcoma in the liver must be distinguished from metastatic angiosarcoma on clinical grounds, as the pathologic features are identical.

Epithelioid hemangioendothelioma This tumor occurs in slightly younger patients than angiosarcoma and has a slight female preponderance [19]. Epithelioid hemangioendothelioma is usually multifocal, with firm white–tan sometimes gritty tumor nodules involving both hepatic lobes. Histologically, at the growing edge of tumor nodules, the tumor cells grow along pre-existing sinusoids, and the preservation of the lobular architecture with identifiable residual portal triads may be a clue to diagnosis. Intravascular growth of tumor cells also occurs [15]. Within the tumor nodules the tumor cells grow in small nests surrounded by a distinctive sclerotic or sometimes myxoid stroma (Figure 4.7). Two types of tumor cells are identified: a dendritic type, with irregular cell processes, and an epithelioid type, more rounded, with abundant cytoplasm. The cells of epithelioid hemangioendothelioma contain cytoplasmic vacuoles, which represent intracyto-

CHAPTER 4

Figure 4.7 In epithelioid hemangioendothelioma, the tumor cells are embedded in a sclerotic or myxoid stroma; cytoplasmic vacuoles (arrow) represent intracytoplasmic vascular lumina.

Pathology of Primary and Secondary Malignant Liver Tumors and diastase-resistant. These globules mark variably with immunohistochemical studies for α-1-antitrypsin, α-1chymotrypsin, and albumin but are negative for AFP [15]. Immunohistochemical studies on undifferentiated (embryonal) sarcoma show that the tumor cells stain with a variety of mesenchymal markers; in some cases cytokeratin positivity is reported [20]. These findings are interpreted as evidence of the capability of multipotential differentiation of the primitive tumor cells. The differential diagnosis for undifferentiated (embryonal) sarcoma includes embryonal rhabdomyosarcoma and mesenchymal hamartoma. Embryonal rhabdomyosarcoma occurs as a polypoid mass involving the large bile ducts at the hepatic hilum, and usually is seen in younger children. The cells should demonstrate rhabdomyoblastic differentiation [21]. Mesenchymal hamartoma is regarded by some as the benign counterpart of undifferentiated sarcoma [12]. It is less cellular than undifferentiated sarcoma and the cells do not display cytologic features of malignancy.

Other primary hepatic sarcomas

Figure 4.8 In undifferentiated (embryonal) sarcoma, stellate tumor cells are dispersed in a myxoid background. Large bizarre tumor cells containing eosinophilic proteinaceous droplets (arrow) are common in undifferentiated sarcoma.

This group of tumors is rare as a whole, and includes leiomyosarcoma, malignant fibrous histiocytoma, synovial sarcoma, solitary fibrous tumor, and liposarcoma [15]. Most occur in adults and prognosis is generally poor, except for solitary fibrous tumor, which generally behaves in a benign fashion. Histologically these tumors resemble their soft tissue counterparts in more common locations. Care must be taken to exclude primary sites elsewhere, especially the retroperitoneum, and to exclude metastatic gastrointestinal stromal tumor. Sarcomatoid HCC is also in the differential diagnosis, but can usually be excluded by thorough sampling of the tumor and immunohistochemical studies.

Primary hepatic lymphoma plasmic vascular lumina. High tumor cellularity may indicate a poor prognosis [15].

Undifferentiated sarcoma Although rare, undifferentiated or embryonal sarcoma is the most common hepatic sarcoma in children, and is the third most common malignant liver tumor of childhood, after hepatoblastoma and HCC. On gross examination, these tumors form large, circumscribed, gray–white soft gelatinous masses. Areas of necrosis, hemorrhage, and cystic degeneration are common. Microscopic examination shows pleomorphic stellate tumor cells within a myxoid stroma (Figure 4.8). The tumor cells vary greatly in size, but generally have hyperchromatic irregular nuclei; bizarre multinucleated tumor giant cells are frequently seen. Eosinophilic proteinaceous cytoplasmic globules are present in some tumor cells; these globules are periodic acid-Schiff (PAS)-positive

Although the liver is frequently involved by malignant lymphoma, primary hepatic lymphomas are rare. On gross examination, a single large tumor mass or multiple small masses are seen; diffuse hepatic involvement is present in 5–16% of cases [22]. Most primary hepatic lymphomas are classified as diffuse large cell lymphomas of B-cell lineage, although occasional T-cell malignancies such as gamma delta T-cell lymphoma are seen [23]. The neoplastic cells in most cases involve portal triads and may extend into the parenchyma as destructive tumor nodules. Sinusoidal infiltration is reported with T-cell malignancies. An association of primary hepatic lymphoma with acquired immunodeficiency syndrome (AIDS) has been noted [24], and primary lymphoma of the liver in association with chronic liver disease, including chronic hepatitis B and hepatitis C infection, has been described [25].

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Secondary tumors Metastatic tumors account for 95% of all malignancies involving the liver and for 50% of malignancies in the cirrhotic liver [26]. While the primary tumor site is often known at the time of liver biopsy, carcinomas of the lung and pancreas, and stomach and neuroendocrine tumors not infrequently present with hepatic metastases from previously undetected primaries.

Gross morphology Most metastases to the liver are multiple, but solitary nodules, with or without satellite lesions, do occur. Metastatic tumor can infiltrate the liver as small ill-defined nodules, simulating cirrhosis on gross examination. Size is variable. Most hepatic metastases are gray–white to yellow. Areas of necrosis and hemorrhage are frequently found, and umbilication due to central necrosis is common in colorectal carcinoma metastases. In most cases, the gross morphology is not distinctive, although metastases from malignant melanoma may have a tell-tale dark brown or black hue. Although most hepatic metastases are parenchymal or capsule-based lesions, colorectal carcinoma may rarely metastasize to bile ducts and grow as an intrabiliary tumor [27].

Microscopic features Most metastatic tumors to the liver retain the histologic features of the primary tumor. Sinusoidal growth pattern is often seen at the edge of the tumor mass, particularly in poorly differentiated carcinomas.

Distinction from primary tumors On occasion, distinction of a metastasis from a primary neoplasm of the liver may be difficult. One of the more common problems is distinguishing intrahepatic cholangiocarcinoma from metastatic adenocarcinoma. Histologic features of cholangiocarcinoma and other adenocarcinomas, particularly those from the pancreas and other gastrointestinal sites, may be very similar. Differentiation of metastatic clear cell carcinomas growing in a trabecular pattern, such as renal cell carcinoma, from HCC may be difficult. A limited number of immunohistochemical stains are useful in these situations (see Table 4.1). Expression of prostatic specific antigen and prostatic acid phosphatase is relatively specific; however, since prostatic adenocarcinoma rarely presents as liver metastases, this situation rarely arises in the evaluation of a liver tumor. Thyroglobulin stain may help identify metastatic thyroid carcinoma. Breast carcinoma metastases may theoretically be diagnosed by positive immunohistochemistry for gross cystic disease fluid protein. Caution should be used in interpreting positivity for estrogen and progesterone receptors as indication of origin from breast, as primary liver tumors and other metastatic carcinomas can also express

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Figure 4.9 Metastatic neuroendocrine or carcinoid tumor forms tubular, trabecular, or cribriform structures in the liver, usually associated with desmoplasia. The tumor cells have uniform round to oval nuclei with evenly dispersed chromatin and without prominent nucleoli.

these receptors [28]. The diagnosis of malignant melanoma is usually easily confirmed by using immunohistochemistry for S-100 protein and HMB-45.

The problem of neuroendocrine tumors in the liver Because liver metastases from neuroendocrine tumors may be more indolent than other secondary tumors (Chapter 36), it is important for the pathologist to identify these lesions, although distinction from HCC may be difficult in a small biopsy. Metastatic neuroendocrine tumor should be suspected when the tumor has a nesting, organoid, or trabecular pattern (Figure 4.9), with tumor trabeculae separated by thin connective tissue stroma rather that floating free as in HCC. The chromatin pattern is usually finely granular and nucleoli are inconspicuous, in contrast to the large nucleoli seen in HCC. Immunohistochemistry for chromogranin and other neuroendocrine markers are useful in identifying neuroendocrine tumors. Caution must be used in interpreting the results of immunohistochemical studies, however. While tumors with typical neuroendocrine morphology and prominent positivity for chromogranin are almost always metastatic to the liver, HCC and cholangiocarcinoma may display focal positivity for neuroendocrine markers. Careful correlation of biopsy findings with clinical impression is helpful in problematic cases.

Carcinoma of the gallbladder Gross morphology Carcinoma of the gallbladder may be visible as a solid mass, polypoid mucosal growth, a mucosal plaque, or may cause

CHAPTER 4


Table 4.5 Staging of gallbladder cancer [9]. TNM definitions

Figure 4.10 The histologic appearance of adenocarcinoma of the gallbladder is varied; in this example the tumor is moderately differentiated and associated with calcifications (arrow).

diffuse thickening of the gallbladder wall. Extension into the liver is a common pattern of spread, and these cases may show a concentric ring of tumor growth encasing the gallbladder.

Microscopic appearance Most gallbladder cancers are readily recognizable as adenocarcinomas (Figure 4.10). Many are well differentiated, with variable sized glands lined by columnar or cuboidal cells. The tumor cells have clear to eosinophilic cytoplasm and occasional tumor cells show goblet cell differentiation. Gallbladder carcinomas are associated with a desmoplastic response in most cases. Extension into Rokitansky–Aschoff sinuses should not be confused with tumor invasion. Other histologic patterns include papillary adenocarcinoma, adenosquamous or squamous differentiation, poorly differentiated signet ring cell carcinoma, primary carcinoid tumors, and giant cell carcinoma with osteoclast-like giant cells [29]. Clear cell adenocarcinomas with abundant glycogen accumulation may be confused with metastatic renal cell carcinoma. Small cell undifferentiated carcinoma is usually associated with recognizable adenocarcinoma. Malignant mesenchymal tumors of the gallbladder are quite rare; rhabdomyosarcoma, angiosarcoma, and malignant histiocytoma are among those reported [29].

Staging In the United States, gallbladder cancer is staged using a TNM system (Table 4.5) [9]. The predominant pattern of tumor spread is by direct extension, primarily involving the gallbladder fossa and the liver, followed by involvement of the extrahepatic bile ducts. Duodenum, pancreas, transverse colon, and hepatic artery and portal vein may also be involved by direct extension. Regional lymph nodes are

Primary tumor Tis Carcinoma in situ T1 Tumor invades lamina propria or muscle layer T1a Tumor invades lamina propria T1b Tumor invades muscle layer T2 Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver T3 Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts T4 Tumor invades main portal vein or hepatic artery or invades two or more extrahepatic organs or structures Regional lymph nodes N0 No regional lymph node metastasis N1 Regional lymph node metastasis Metastasis M0 M1

No distant metastasis Distant metastasis

Stage grouping Stage Stage Stage Stage Stage

0 IA IB IIA IIB

Stage III Stage IV

Tis, N0, M0 T1, N0, M0 T2, N0, M0 T3, N0, M0 T1, N1, M0 T2, N1, M0 T3, N1, M0 T4, Any N, M0 Any T, any N, M1

positive in up to 70% of cases. Frequent sites of hematogenous spread include liver, lungs, and bone.

Self-assessment questions 1 Which of the following are considered precursor lesions for hepatocellular carcinoma? (more than one answer is possible) A High grade dysplastic nodule B Focal nodular hyperplasia C Small cell change D Mesenchymal hamartoma E Von Meyenburg complex 2 Which one of the following statements concerning fibrolamellar carcinoma is true?

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A Is associated with hepatitis B infection B Is strongly associated with the use of oral contraceptives C Occurs in the cirrhotic liver D Occurs primarily in young adults E Is associated with a poorer outcome compared to typical hepatocellular carcinoma 3 Immunohistochemistry for α-fetoprotein is the best marker for hepatocellular differentiation in hepatic tumors, because it is the most sensitive and specific test available. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 4 Which of the following are important prognostic indicators for hepatocellular carcinoma? (more than one answer is possible) A Production of bile by tumor cells B Overall TNM stage C Microvascular invasion D Cirrhosis in the background liver 5 Which one of the following statements concerning hepatoblastoma is true? A Is the most common hepatic tumor occurring in teenagers B Is staged using an AJCC/UICC TNM staging system C Is broadly divided into epithelial and mixed epithelial/mesenchymal subtypes on the basis of histologic appearance D The small cell subtype is associated with a better prognosis 6 Intrahepatic cholangiocarcinomas are associated with which of the following conditions? (more than one answer is possible) A Primary sclerosing cholangitis B Liver flukes C Recurrent bacterial cholangitis D Thorotrast 7 The histologic differential diagnosis for intrahepatic cholangiocarcinomas includes metastatic adenocarcinoma, because the typical microscopic appearance for both tumors is that of glandular structures embedded in a desmoplastic stroma. A First part wrong, second part wrong B First part correct, second part wrong

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C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 8 Which of the following statements regarding hepatic sarcomas are true? (more than one answer is possible) A Leiomyosarcoma is the most common primary hepatic sarcoma B Epithelioid hemangioendotheliomas are common neoplasms in elderly men C The most common hepatic sarcoma in children is embryonal or undifferentiated sarcoma D The tumor cells in embryonal sarcoma are small, uniform in cell size, and show little pleomorphism E The differential diagnosis for hepatic sarcomas includes sarcomatoid (spindle cell) hepatocellular carcinoma 9 Metastatic neuroendocrine tumors in the liver may mimic hepatocellular carcinoma in microscopic appearance on small biopsies, because both tumors may exhibit trabecular architecture. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 10 Which one of the following statements regarding gallbladder cancer is true? A Gallbladder carcinoma is commonly associated with diffuse calcification of the gallbladder wall (porcelain gallbladder) B Most gallbladder tumors are sarcomas C DNA content as measured by flow cytometry is an important prognostic indicator D Epithelial dysplasia is considered a precursor lesion for gallbladder carcinoma E Most gallbladder cancers are suspected clinically prior to cholecystectomy

References 1 Hirohashi S, Ishak KG, Kojiro M, et al. Hepatocellular carcinoma. In: Hamilton SR, Aaltonen LA, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System. Lyon: IARC Press, 2000. 2 International Working Party. Terminology of nodular hepatocellular lesions. Hepatology 1995;22:983–93.

CHAPTER 4

3 Hytiroglou P. Morphological changes of early human hepatocarcinogenesis. Semin Liver Dis 2004;24:65–75. 4 Natarajan S, Theise ND, Thung SN, Antonio L, Paronetto F, Hytiroglou P. Large-cell change of hepatocytes in cirrhosis may represent a reaction to prolonged cholestasis. Am J Surgl Pathol 1997;21:312–8. 5 Torbenson M. Review of the clinicopathologic features of fibrolamellar carcinoma. Adv Anat Pathol 2007;14:217–23. 6 Yeh C-N, Hung C-F, Lee K-F, Chen M-F. Sclerosing hepatocellular carcinoma: clinicopathologic features in seven patients from Taiwan and review of the literature. Hepato-Gastroenterology 2005;52:1201–5. 7 Kakar S, Gown AM, Goodman ZD, Ferrell LD. Best practices in diagnostic immunohistochemistry: hepatocellular carcinoma vesus metastatic neoplasms. Arch Pathol Lab Med 2007;131:1648– 54. 8 Varma V, Cohen C. Immunohistochemical and molecular markers in the diagnosis of hepatocellular carcinoma. Adv Anat Pathol 2004;11:239–49. 9 Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual. New York: Springer-Verlag, 2002. 10 Minagawa M, Ikai I, Matsuyama Y, Yamaoka Y, Makuuchi M. Staging of hepatocellular carcinoma: assessment of the Japanese TNM and AJCC/UICC TNM systems in a cohort of 13,772 patients in Japan. Ann Surg 2007;245:909–22. 11 Saxena R, Leake JL, Shafford EA, et al. Chemotherapy effects on hepatoblastoma. A histological study. Am J Surg Pathol 1993;17:1266–71. 12 Finegold MJ. Hepatic tumors in childhood. In: Russo P, Ruchelli eD, Piccoli D, eds. Pathology of Pediatric Gastrointestinal and Liver Disease. New York: Springer-Verlag, 2004, 300–46. 13 Reynolds M. Pediatric liver tumors. Semin Surg Oncol 1999; 16:159–72. 14 Yamanaka N, Okamoto E, Ando T, et al. Clinicopathologic spectrum of resected extraductal mass-forming intrahepatic cholangiocarcinoma. Cancer 1995;76:2449–56. 15 Ishak KG, Goodman ZD, Stocker JT. Tumors of the Liver and Intrahepatic Bile Ducts, 3rd series, fascicle 31 vol. Washington, DC: Armed Forces Institute of Pathology, 2001. 16 Rullier A, Le Bail B, Fawaz R, Blanc JF, Saric J, Bioulac-Sage P. 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;24:870–6. 17 Fujii H, Zhu XG, Matsumoto T, et al. Genetic classification of combined hepatocellular-cholangiocarcinoma. Hum Pathol 2000;31:1011–7. 18 Maeda T, Adachi E, Kajiyama K, Sugimachi K, Tsuneyoshi M. Combined hepatocellular and cholangiocarcinoma: proposed criteria according to cytokeratin expression and analysis of clinicopathologic features. Hum Pathol 1995;26:956–64. 19 Mehrabi A, Kashfi A, Fonouni H, et al. Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive


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review of the literature with emphasis on the surgical therapy. Cancer 2006;107:2108–21. Kiani B, Ferrell LD, Qualman S, Frankel WL. Immunohistochemical analysis of embryonal sarcoma of the liver. Appl Immunohistochem Mol Morphol 2006;14:193–7. Nicol K, Savell V, Moore J, et al. Distinguishing undifferentiated embryonal sarcoma of the liver from biliary tract rhabdomyosarcoma: a Children’s Oncology Group study. Pediatr Dev Pathol 2007;10:89–97. Aozasa K, Mishima K, Ohsawa M. Primary malignant lymphoma of the liver. Leuk Lymphoma 1993;10:353–7. Tamaska J, Adam E, Kozma A, et al. Hepatosplenic gammadelta T-cell lymphoma with ring chromosome 7, an isochromosome 7q equivalent clonal chromosomal aberration. Virchows Archiv 2006;449:479–83. Jacobs SL, Rozenblit A. HIV-associated hypervascular primary Burkitt’s lymphoma of the liver. Clin Radiol 2006;61:453–5. Salmon JS, Thompson MA, Arildsen RC, Greer JP. NonHodgkin’s lymphoma involving the liver: clinical and therapeutic considerations. Clin Lymphoma Myeloma 2006;6:273–80. Melato M, Laurino L, Mucli E, Valente M, Okuda K. Relationship between cirrhosis, liver cancer, and hepatic metastases. An autopsy study. Cancer 1989;64:455–9. Riopel MA, Klimstra DS, Godellas CV, Blumgart LH, Westra WH. Intrabiliary growth of metastatic colonic adenocarcinoma: a pattern of intrahepatic spread easily confused with primary neoplasia of the biliary tract. Am J Surg Pathol 1997;21:1030–6. Nash JW, Morrison C, Frankel WL. The utility of estrogen receptor and progesterone receptor immunohistochemistry in the distinction of metastatic breast carcinoma from other tumors in the liver. Arch Pathol Lab Med 2003;127:1591–5. Albores-Saavedra J, Henson DE, Klimstra DS. Tumors of the Gallbladder, Extrahepatic Bile Ducts, and Ampulla of Vater, 3rd series, fascicle 27 vol. Washington, DC: Armed Forces Institute of Pathology, 2000.


A, C D A B, C, D C A, B, C, D E C, E E D

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5

Epidemiology, Etiology, and Natural History of Hepatocellular Carcinoma Wei-Chen Lee and Miin-Fu Chen Department of General Surgery, Chang-Gung Memorial Hospital, Chang-Gung University Medical School, Taoyuan, Taiwan

Malignant liver tumor ranks the fifth most common cancer in the world and the third most common cause of cancer mortality [1]. This indicates that they are not only common but also very deadly. Among various primary malignant liver tumors, hepatocellular carcinoma (HCC) is the most common and accounts for 80–90% of all malignant liver tumors. This chapter describes the epidemiology, etiology, and natural history of HCC (regarding treatment of HCC please see Chapters 16 and 26).

Epidemiology Geographic area/ethnic group The incidence of HCC is unevenly distributed in the world. Eastern Asia has the highest incidence, followed by middle Africa, South-East Asia, the Pacific Islands, East Africa, West Africa, Southern Europe, Southern Africa, Eastern and Western Europe, South and North Americas, Australia and New Zealand, Northern Europe, and Central America [2]. The three highest incidence rates of HCC are 35.2–48.8 per 100 000 in Eastern Asia, 24.2 per 100 000 in middle Africa, and 18.3 per 100 000 in South-East Asia and the Pacific Islands. The incidence rates in Europe, the Americas, Australia, and New Zealand are all below 10 per 100,000. The two lowest incidence rates are in Northern Europe and Central America, with only 2.6 and 2.1 per 100 000, respectively [2, 3]. The incidence rates among ethnic groups are also varied. In the United States, the incidence rate is twice that in Asians compared to African Americans, and the rate in African Americans is higher than that in the whites [3].

Gender Primary malignant liver tumor ranks the fifth most common cancer for males and the eighth for females, and males also have a higher incidence of HCC than females [1]. The ratio of


52

incidence rates between males and females ranges from 1.3 : 1 to 4 : 1 [3, 4]. The reason why males are more susceptible to this disease than females is not really known. Sex hormones may be an important factor. In a community-based cohort study carried out in Taiwan, serum samples collected from 9691 males showed that 35 newly developed HCC cases were associated with elevated testosterone levels [5].

Age The age distribution of HCC varies around the world and depends on region, sex and etiology. In high-risk areas, the incidence of HCC, increasing with age, reaches its peak at the age of 50 years and plateaus afterwards. In low-risk areas, the incidence of HCC steadily increases with age until 75 years or even older [3]. In regard to the influence of sex on age distribution, males have their peak incidence rate 5 years earlier than females. In regard to the influence of etiology on age distribution, the mean age for hepatitis B-related HCC is 10 years earlier than that for hepatitis C-related HCC. In Japan, for example, most HCC cases are related to hepatitis C and the incidence of HCC reaches a plateau at the age of 65 years, whereas in Korea, where most of the HCC cases are related to hepatitis B, the mean age for HCC onset is 55 years [2]. In a study from Taiwan, clinical diagnosis was made at a mean age of 49 years for hepatitis B-related HCC and 61 years for hepatitis C-related HCC [6].

Etiology Eighty to ninety per cent of all HCC cases develop from underlying chronic liver diseases. Multiple risk factors associated with chronic liver diseases have been identified. These include cirrhosis, hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, alcohol consumption, tobacco consumption, iron overload and hereditary hemochromatosis, obesity, and ingestion of aflatoxin-contaminated food. However, genetic events and cell transformation involved in hepatocarcinogenesis are still poorly understood. There have been recent reports about HCC displaying genomic alterations, which include chromosomal instability, CpG

CHAPTER 5

Epidemiology, Etiology, and Natural History of Hepatocellular Carcinoma

island methylation, DNA rearrangements, and DNA hypomethylation [7]. Nevertheless, the exact mechanism of hepatocarcinogenesis remains an enigma.

Cirrhosis Cirrhosis is a common late-stage development of many liver diseases including chronic viral hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis, hemochromatosis, primary biliary cirrhosis, autoimmune liver diseases, and metabolic disorder diseases. HCC is strongly associated with cirrhosis. Most HCC develops from cirrhosis induced by chronic viral hepatitis, alcoholic liver disease, hemochromatosis, or metabolic disorder diseases. On the other hand, primary biliary cirrhosis and autoimmune liver diseases rarely give rise to HCC [8]. HCC usually develops after many years of chronic hepatitis. Hepatocarcinogenesis is a complex procedure which remains to be unraveled. The procedure involves gene alterations and eventually malignant transformation of hepatocytes. Cirrhosis is the end stage of chronic inflammation, which involves cell damage, cell regeneration, and cell proliferation. During cell damage and cell regeneration, the chronic inflammatory liver may provide an environment for gene mutation or instability, which leads to HCC development [9]. However, as HCC rarely develops in autoimmunity-induced cirrhotic livers, factors other than chronic liver inflammation must contribute to the development of HCC.

Hepatitis B virus Hepatitis B virus infection is a major cause of HCC, especially in Eastern and South-East Asia. Chronic active inflammation of HBV may lead to fibrosis and cirrhosis, which contribute to the development of HCC. Most HBV-related HCC is associated with cirrhosis. However, sometimes HBVrelated HCC also develops in liver without cirrhotic change. In fact, HBV itself is an important factor for HCC. In a study from Taiwan, the risk of HCC development increased 10-fold in males who were positive for HBsAg, and 60-fold for males who were positive for both HBsAg and HBeAg, compared with males who were negative for HBsAg [10]. By measuring the level of HBV DNA, the replication level of HBV can be evaluated. However, using the replication level of HBV to predict HCC development is still controversial. Currently, it is known that HBV DNA sequence can integrate into cellular DNA in HCC tissue or even in the nontumor portion of liver tissue with chronic inflammation. HBV insertion may cause chromosomal deletion at HBV DNA insertion sites and thus increase chromosomal instability. HBV DNA integration may also occur in genes which encode proteins for cell signaling, proliferation, and viability [11]. Cell proliferation brought about by chronic inflammation may cause rearrangement of the sequence of the inserted HBV and induce cell transformation, and hence increase the possibility of HCC development.

That HBV is an important cause of HCC can be further proven by the results of vaccination against HBV. In Taiwan, HBV infection is highly prevalent and most HCC is associated with it. A mass vaccination program against HBV was launched in 1984. Since then, all neonates born to HBVcarrier mothers have been vaccinated against HBV, and the incidence of HCC has declined from 0.52 to 0.13 per 100 000 children aged 6–9 years [12].

Hepatitis C virus Hepatitis C virus infection is another major cause of chronic liver diseases. The clinical course of HCV infection progresses from acute inflammation to fibrosis, and eventually cirrhosis. Although it varies in rate, in most cases the progression from infection to cirrhosis takes more than 20 years. HCC is a complication of HCV-related cirrhosis, particularly in the United States, Europe, Australia, and Japan. The relative risk of HCC among hepatitis C patients ranges from 11.5 to 20 [3, 4, 13]. The annual incidence rate of HCC developing from HCV-related cirrhosis is around 1–4%, but is up to 7% in Japan [3]. Currently, pegylated interferon plus ribavirin is used to treat HCV infection and can achieve a sustained viral response rate of 50–60%. However, whether treatment for HCV infection can reduce HCC development is still controversial. The mechanism of HCV-inducing HCC may be a result of viral cytopathic effects. Chronic liver injury by HCV induces regeneration and proliferation of hepatocytes. Frequent hepatocyte proliferation increases the chance of genetic mutation or instability and accumulation of genetic mutation or instability enhances the possibility of malignant transformation of hepatocytes. A recent study showed that chronic inflammation in hepatitis C-directed hepatic transforming growth factor (TGF)-β signaling to fibrogenesis, accelerating liver fibrosis and so increasing the risk of HCC [14].

Alcohol Most alcohol-related HCC develops in cirrhotic livers resulting from long-term alcohol consumption. The risk of HCC development markedly increases if alcohol consumption exceeds 80 g daily for more than 10 years [15]. In fact, the risk of HCC is proportionate to alcohol consumption. The relative risk of HCC is 1.17 for alcohol consumption at 25 g per day, 1.36 at 50 g per day, and 1.86 at 100 g per day [16]. For patients with hepatitis B or C, alcohol is particularly conducive to HCC. A study from Taiwan showed that the risk of HCC increased three-fold to four-fold in hepatitis B patients who consumed alcohol compared with patients who did not, and two studies from Japan and Taiwan showed that the risk increased two-fold in hepatitis C patients who consumed alcohol compared with patients who did not [15]. The mechanism by which alcohol causes HCC is unknown, yet it has been found in studies on animals that alcohol alone cannot induce HCC. It is postulated

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that the mechanism may involve oxidative stress, DNA methylation, decreased immune surveillance, and genetic susceptibility.

Hemochromatosis Hemochromatosis, whether hereditary hemochromatosis or an iron overload disorder, is a well-known risk factor for HCC. Patients with hereditary hemochromatosis have a relative risk of HCC ranging between 93 and 200 [17, 18]. Iron overload disorders, whether dietary iron overload in Africa or homozygous β-thalassemia, also increase the incidence of HCC. The possible mechanisms of iron-inducing HCC include direct and indirect effects. Cell proliferation and direct damage to DNA resulting in inactivation of tumor suppressor genes, such as p53, have a direct effect in engendering of HCC, while formation of reactive oxygen species in the liver, lipid peroxidation, and acceleration of fibrogenesis lead to HCC indirectly [19, 20].

Obesity Epidemiologic studies have shown that obesity is a significant risk factor for the development of HCC. In a study enrolling 43 965 obese patients from Denmark, the relative risk of HCC development in these patients was 1.9-fold that of the general population [21]. In another study from the United States on the relationship between mortality from cancer and body mass index (BMI), the relative risk of mortality from liver cancer was 4.52-fold for males and 1.68-fold for females having a BMI equal to or greater than 35 kg/m2 compared to the reference groups with a BMI between 18.5 and 24.9 kg/m2 [22]. It is believed that there is a correlation between the development of HCC and the pathophysiologic aspects of nonalcoholic steatohepatitis, including lipid peroxidation, free radical oxidative stress, and oval cell proliferation [23].

398 days with a mean of 136 days [27]. In the study from Italy, 39 patients with asymptomatic small HCC (≤5 cm in diameter) were observed for 92–962 days. The doubling time of the tumors ranged from 27 to 605 days with a mean of 204 days. No correlation between the doubling time and the initial diameter of the tumors was found. The survival rates were 81% at 1 year, 55.7% at 2 years, and 21% at 3 years [28]. In the study from Japan, 30 patients with small HCC (35 kg/m2 markedly increases the risk of HCC development C Obese females and obese males share equal risk of HCC D The mean doubling time of HCC is about 4–7 months E The survival rate at 3 years is 12–21% for small asymptomatic HCC

References 1 Parkin DM, Bray F, Ferlay J, et al. Estimating the world cancer burden: globocan 2000. Int J Cancer 2001;94:153–6. 2 Bosch FX, Ribes J, Diaz M, et al. Primary liver cancer: Worldwide incidence and trends. Gastroenterology 2004;127:S5–S16. 3 El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132:2557–76. 4 Sherman M. Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin Liver Dis 2005;25:143–54. 5 Yu MW, Chen CJ. Elevated serum testosterone levels and risk of hepatocellular carcinoma. Cancer Res 1993;53:790–4. 6 Lee WC, Jeng LB, Chen MF. Hepatectomy for hepatitis B, hepatitis C, and dual hepatitis B- and C-related hepatocellular carcinoma in Taiwan. J Hepatobiliary Pancreat Surg 2000;7: 265–9. 7 Herath NI, Leggett BA, Macdonald GA. Review of genetic and epigenetic alterations in hepatocarcinogenesis. J Gastroenterol Hepatol 2006;21:15–21. 8 Fattovich G, Stroffolini T, Zagni I, et al. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127:S35–S50. 9 Elsharkawy AM, Mann DA. Nuclear factor-kB and the hepatic inflammation-fibrosis-cancer axis. Hepatology 2007;46:590–7. 10 Yang HI, Lu SN, Liaw YF, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 2002;347:168–74. 11 Brechot C. Pathogenesis of hepatitis B virus-related hepatocellular carcinoma: Old and new paradigms. Gastroenterology 2004;127:S56–S61. 12 Chang MH, Chen CJ, Lai MS, et al. Universal Hepatitis B Vaccination in Taiwan and the Incidence of Hepatocellular Carcinoma in Children. N Engl J Med 1997;336:1855–9. 13 Donato F, Boffetta P, Pouti M. A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C

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infections in causing hepatocellular carcinoma. Int J Cancer 1998;75:347–354. Matsuzaki K, Murata, M, Yoshida K, et al. Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor β signaling, promoting cirrhosis and hepatocellular carcinoma. Hepatology 2007;46:48–57. Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology 2004;127:S87–S96. Pelucchi C, Gallus S, Garavello W, et al. Cancer risk associated with alcohol and tobacco use: Focus on upper aero-digestive tract and liver. Alcohol Res Health 2006;29:I93–8. Bradbear RA, Bain C, Siskind V, et al. Cohort study of internal malignancy in genetic hemochromatosis and other chronic nonalcoholic liver diseases. J Natl Cancer Inst 1985;75:81–4. Hsing AW, McLaughlin JK, Olsen JH, et al. Cancer risk following primary hemochromatosis: a population-based cohort study in Denmark. Int J Cancer 1995;60:160–2. Kowdley KV. Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology 2004;127:S79–S86. Kew MC, Asare GA. Dietary iron overload in the African and hepatocellular carcinoma. Liver Int 2007;27:735–41. Moller H, Mellemgaard A, Lindvig K, et al. Obesity and cancer risk: a Danish record-linkage study. Eur J Cancer 1994; 30A:344–50. Calle EE, Rodriguez C, Walker-Thurmond K, et al. Overweight, obesity and mortality from cancer in a prospectively studied cohort of U. S. adults. N Engl J Med 2003;348:1625–38. Caldwell SH, Crespo DM, Kang HS, et al. Obesity and hepatocellular carcinoma. Gastroenterology 2004;127:S97–S103. Ross RK, Yuan JM, Yu MC, et al. Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma. Lancet 1992;339: 943–946. Kensler TW, Egner PA, Wang JB, et al. (2004) Chemoprevention of hepatocellular carcinoma in aflatoxin endemic areas. Gastroenterology 2004;127:S310–S318. Yu MC, Yuan JM. Environmental factors and risk for hepatocellular carcinoma. Gastroenterology 2004;127:S72–S78. Sheu JC, Sung JL, Chen DS, et al. Growth rate of asymptomatic hepatocellular carcinoma and its clinical implications. Gastroenterology 1985;89:259–66. Barbara L, Benzi G, Gaiani S, et al. Natural history of small untreated hepatocellular carcinoma in cirrhosis: a multivariate analysis of prognostic factors of tumor growth rate and patient survival. Hepatology 1992;16:132–7. Ebara M, Hatano R, Fukuda H, et al. Natural course of small hepatocellular carcinoma with underlying cirrhosis. A study of 30 patients. Hepato-Gastroenterology 1998;45:1214–20.

Self-assessment answers 1 2 3 4 5

D D B D C

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Epidemiology, Etiology, and Natural History of Cholangiocarcinoma Peter Neuhaus, Ulf P. Neumann, and Daniel Seehofer Department of General, Visceral and Transplantation Surgery, Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany

Cholangiocarcinomas arise from the extra- or intra-hepatic biliary epithelium. Histologically, adenocarcinomas are seen in more than 90% of cases. The majority of cases (50–60%) are hilar cholangiocarcinomas originating from the bifurcation of the hepatic ducts (Klatskin tumors). About 20–30% of cholangiocarcinomas are situated in the distal common bile duct and only 10–15% arise in peripheral intrahepatic bile ducts. Both forms of cholangiocarcinomas, the extrahepatic cholangiocarcinoma (ECC) and the intrahepatic cholangiocarcinoma (ICC), are distinct clinical entities with significant therapeutic and epidemiologic differences. However, their differentiation is often difficult in clinical and epidemiologic studies. For example, owing to the proximity of hilar tumors to the liver, 92% of hilar cholangiocarcinomas, which are traditionally classified as ECCs, were classified as ICCs in the US National Cancer Institute SEER registry (surveillance epidemiology and end results), which represents more than 10% of the total United States population. In addition, gallbladder carcinoma, which is a clinically and epidemiologically distinct entity, has eventually been included in the ECC subgroup. Therefore, epidemiologic studies have to be compared cautiously. Wherever possible this chapter describes the two forms of cholangiocarcinomas separately, with hilar tumors assigned to the ECCs. Carcinomas of the distal bile duct, which are managed in the same way as pancreatic tumors, are not considered specifically.

Epidemiology Worldwide, cholangiocarcinoma accounts for 3% of all gastrointestinal cancers and for approximately 15% of primary liver cancers. It represents the second most common primary liver malignoma. However, the incidence of primary liver cancers varies enormously in different geographic regions. This reflects the variable distribution of local risk factors and


56

genetic differences among populations. In some regions of Thailand, cholangiocarcinomas are more frequently observed than hepatocellular carcinomas (HCCs). Conversely, in countries with a high incidence of HCC, the proportion of cholangiocarcinomas is much lower, and they account for a mere 2% of liver cancers in parts of Africa and Java. This relation is mainly based on risk factors for the development of HCC, but to a lesser extent also on risk factors for cholangiocarcinoma, as discussed below. In the United States about 5000 cases of cholangiocarcinomas are diagnosed annually, and cases of ICC and ECC are almost equally distributed [1]. However, the overall incidence of cholangiocarcinoma has increased within the last decades in most European countries, the United States, and parts of Asia. Interestingly, the incidence of ICC is considered to be rising, whereas that of ECC is decreasing [2–4]. It has been debated whether the former is a true increase or a statistical phenomenon, caused by changing classifications of the subtypes or increasing diagnosis of earlier stages by means of improved diagnostic methods. Against this theory are the facts that the increased incidence of ICC in several national databases is not associated with an increased number of small and early stage tumors, and that the increase has been delineated in various age groups. As a result, the age-standardized mortality rates for ICC are increasing. Since the overall prognosis for cholangiocarcinomas is relatively poor, mortality data can be considered a good surrogate parameter for tumor incidence. In addition (e.g. in the SEER registry), the rise of ICC is greater than the relative decline of ECC, arguing against a simple phenomenon of altered classification. Therefore, the data may reflect a true increase in the incidence of ICC, although the underlying causes are still unclear.

Intrahepatic cholangiocarcinoma The highest incidence of ICC globally is observed in NorthEast Thailand with 96 and 38 cases per 100 000 men and women, respectively. One of the lowest recorded incidences per 100 000 people is found in Australia; 0.2 in men and 0.1 in women [5]. In most Western countries, incidences range between 0.4 and 1.0 cases per 100 000.

CHAPTER 6

Epidemiology, Etiology, and Natural History of Cholangiocarcinoma

In general, males prevail, but this is less pronounced than in HCC epidemiology. The male-to-female ratio ranges from 1.3 in white Americans to 3.3 in France [5]. No clear racial predisposition has been identified. ICC rarely occurs before the age of 40 years. The average age worldwide is 50 years [6], but in Western countries the maximum incidence is found in people older than 65 years [5]. In the United States, the SEER registry revealed that ageadjusted incidence rates for ICC have increased by 165% from 0.32 per 100 000 in the 1970s to 0.85 per 100 000 in the 1990s [5]. This has been confirmed across all gender, racial, and age groups. Not unexpectedly, the highest increase was observed in those older than 65 years of age. Whereas the incidence in the group aged from 45 to 64 years doubled from the late 1970s to the late 1990s, it increased three-fold in the group over 65 within the same period. In parallel, World Health Organization (WHO) data show a worldwide increase in the age-standardized mortality rate of ICC in both men and women [7]. This is underlined by several national databases in the United States, France, Italy, Australia, the UK, and Japan. For example, the agestandardized mortality rate increased in Japan by 130% and in Australia by 600% [8]. In the United States, mortality from ICC increased 10-fold from 0.07 per 100 000 in 1973 to 0.69 per 100 000 in 1997 [2], reflecting the increasing incidence and overall poor prognosis. This increase in mortality rate was higher in most countries than that for HCC in the same period, leading to more ICC- than HCC-related deaths in countries with a low incidence of HCC, like England and Wales since the mid-1990s [3]. The underlying causes are still unclear. Primary sclerosing cholangitis, as the commonest known predisposing factor in the UK, although associated with only a minority of cases, has not increased in incidence at the same rate as cholangiocarcinoma mortality.

from 0.6 per 100 000 in 1979 to 0.3 per 100 000 in 1998 [2]. Comparable trends have been reported worldwide [10]. However, the decrease in mortality was, for example in England and Wales, more distinctive, with a decline in mortality from 0.80 per 100 000 in 1979 to 0.23 per 100 000 in men [3]. In total, these data have to be interpreted with some caution, since in several databases gallbladder cancer is included in the ECC entity [8]. This might impact the data considerably, because gallbladder cancer has a different clinical course and its incidence is known to be declining, probably as a result of increasing cholecystectomy rates over the past decades.

Etiology In most countries, the known risk factors for cholangiocarcinomas (Table 6.1) account for only a small proportion of the emerging cases, and the etiology in the majority of cases is still unknown. An established risk factor is chronic inflammation of the biliary tract, leading to epithelial damage, cellular proliferation, and increased rate of cellular DNA synthesis. The presence of other cofactors (e.g. chemical carcinogens) eventually induces DNA damage and subsequently malignant

Table 6.1 Factors associated or possibly associated with the development of cholangiocarcinoma and respective incidence in the affected subpopulation.

Strong association

Extrahepatic cholangiocarcinoma Relatively few data exist on the incidence and mortality of ECC. Its incidence in different countries does not show as marked variation as is the case for ICC. The reported incidence varies between 0.53 per 100 000 in the UK to 1.14 per 100 in Manitoba, Canada [9]. In a large analysis from the SEER registry between 1973 and 1987, the age-adjusted incidence was 1.2 per 100 for men and 0.8 per 100 000 for women [9]. In the same registry, ECC was slightly more common in whites than in blacks, and in men than in women. Like for ICC, most ECC patients are older than 65, and the maximum incidence is observed between 70 to 74 years of age. In contrast to ICC, incidence and mortality rates for ECC are declining in many countries. The age-adjusted incidence decreased in the United States from 1.08 per 100 000 in 1979 to 0.82 per 100 000 in 1998 [6]. Accordingly, the age-standardized mortality rate for ECC in the United States halved

Weak association

Possible association

Factor

Incidence (%)

Primary sclerosing cholangitis Thorotrast Choledochal cysts Type I, IV Choledochal cysts Type II, III Caroli syndrome (Todani Type V) Hepatolithiasis Biliary papillomatosis Liver fluke infestation Chronic HCV infection Lynch syndrome (HNPCC) Chronic HBV infection HIV infection Liver cirrhosis of any cause Diabetes mellitus Alcohol abuse Smoking Nitrosamines Organochlorines Dioxins

7–15 10–20 20–30 10–15 7–14 5–10 25–50 ∼1 ∼1 1 cm 54% 5 mm (median) 20 ± 17 mm

NR NR 2-year 75 3-year 87 2-year 89

2-year 67 3-year 51 2-year 83

O’Rourke et al [59] Vibert et al [5] Authors’ series [57] NR, not reported.

[38, 53]. No port site recurrences imputable to laparoscopy were noted. Laparoscopic liver resection of HCC can offer advantages if subsequent liver transplantation is required. Adam et al reported poor outcomes of salvage liver transplant after previous hepatectomy because of adhesions related to primary treatment and increased blood loss [54]. In our center, 12 patients underwent bridge or salvage transplantation after primary laparoscopic resection. When transplantation was performed, they benefitted from the absence of adhesions and, in comparison with 12 transplantations after laparotomic hepatectomies, they had lower operative time, blood loss, and transfusion rate [55]. These preliminary data could enhance the role of laparoscopic liver resection as first-line treatment of HCC.

Colorectal liver metastases Few data are available about laparoscopic liver resections of colorectal liver metastases. About 150 patients have been reported in the literature. Most relevant series are reported in Table 18.5. In 2002 Mala et al [39] compared outcomes of laparoscopic and open liver resections for colorectal liver metastases (15 versus 14). Short-term outcomes and margin width were similar in the two groups. No survival data were reported. The largest series was reported by Vibert et al [5] in 2006 (41 patients). The median margin width was 5 mm and overall and disease-free 3-year survival rates were 87% and 51%, respectively. In our series of 21 cases, the mean margin width was 2.0 cm. Two-year overall and disease-free survival rates were 89% and 83%, respectively. Further studies are needed to clarify outcomes of laparoscopic resection in colorectal liver metastases.

Reproducibility In comparison with open hepatectomy series, the number of published papers about laparoscopic liver surgery is

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extremely low and only few centers have reported their experience. As of March 2008, about 20 groups had reported more than 15 laparoscopic hepatectomies, but only nine of these reported 50 or more cases [3–10, 56] (see Table 18.1). Laparoscopic liver resections are long and difficult operations. They require considerable expertise in both hepatic and laparoscopic surgery, dedication, specific training, and the availability of appropriate technology. Some skilled surgeons have developed a special expertise in the laparoscopic approach, regardless of the organ and pathology being treated, a paradox at a time when there is a trend towards organ subspecialization, particularly in colorectal, pancreatic, and hepatic surgery. However, it seems unreasonable that even an experienced laparoscopist should perform laparoscopic liver resection outside of a regular practice of open liver surgery. Conversely, mastering simple laparoscopic procedures is insufficient training for an experienced liver surgeon to embark on laparoscopic liver resection. A few surgeons may acquire all the requisite skills but, in most cases, the collaboration of two surgeons, one expert in each field, seems desirable when initiating a laparoscopic liver resection program.

Conclusion For laparoscopic liver resection to be effective, specific training and access to adequate technology are required. Patient selection must be accurate, and the availability of laparoscopy should not change the indications for resection. The rules of oncologic surgery must be followed for minimally invasive operations, just as in their open counterparts. At present, good candidates for laparoscopic liver resection are patients with peripheral lesions requiring limited hepatectomy or left lateral sectionectomy. Further prospective evaluation is required to assess the results of laparoscopy in major liver resections and to define its long-term outcomes in cancer patients.

CHAPTER 18

Self-assessment questions 1 Currently, in which percentage of liver resections can the laparoscopic approach be planned? A 50% 2 In which percentage can the laparoscopic approach for left lateral sectionectomy be proposed? A 80% 3 Which of the following statements about laparoscopic liver surgery are true? (more than one answer is possible) A The use of two monitors is recommended B 0 °-laparoscopes are preferred by most authors C Different patient positions are recommended according to the lesion site D The specimen should be extracted in a plastic bag E Hand assistance is useful in left-sided resections 4 Which one of the following statements about the pneumoperitoneum is false? A Pneumoperitoneum should be maintained at less than 14 mmHg B Carbon dioxide pneumoperitoneum gas embolism is more severe than air embolism C Gas embolism occurrence is increased by argon beam coagulation D Gasless laparoscopy is no longer practiced 5 Is pedicle clamping feasible during laparoscopic liver surgery? A Yes, it should be systematically performed B No, it should be avoided C To date, no study has clarified its feasibility D Yes, it can be performed whenever necessary 6 Which of the following lesions can be scheduled for laparoscopic resection? (more than one answer is possible) A Peripheral lesion of segment 2 B Deep lesion of the right liver with a diameter of 3 cm far from portal pedicles C Peripheral lesion of segment 8 D Right liver lesion adjacent to the hepatocaval junction E Left liver tumor of 15 cm in diameter

Laparoscopic Liver Resection

7 Which of the following are not “laparoscopic segments”? (more than one answer is possible) A Segment 2 B Segment 5 C Segment 1 D Segment 6 E Segment 7 8 Laparoscopic liver resection for hepatocellular carcinoma is recommended because it reduces morbidity and facilitates subsequent reoperations A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 9 Which one of the following describes the reported advantages of laparoscopic resection? A Lower intraoperative blood loss B Shorter hospital stay C Earlier period of first oral intake D Reduced need for postoperative analgesia E All previous advantages 10 Which one of the following statements concerning laparoscopic liver resection for hepatocellular carcinoma on cirrhosis is false? A Overall and disease-free survival rates are similar to open series B It is preferred for small deep-located tumors C Reduced postoperative morbidity has been reported D It can offer advantages if subsequent liver transplantation is required E It preserves collateral veins of abdominal veins 11 Which of the following statements concerning laparoscopic major hepatectomies are true? (more than one answer is possible) A Laparoscopic left hepatectomy does not represent a difficult procedure B The majority of reported procedures are right hepatectomies C For laparoscopic right hepatectomy, a pure laparoscopic approach is recommended D For laparoscopic right hepatectomy, hand assistance can be useful E To date laparoscopic major hepatectomy can be considered a standardized procedure

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Resection, Ablation or Transplantation

References 1 2

3

4

5 6

7 8

9 10

11

12

13

14 15

16

17

18

19

Gagner M, Rheault M, Dubuc J. Laparoscopic partial hepatectomy for liver tumor. Surg Endosc 1993;6:99. Cherqui D, Husson E, Hammoud R, et al. Laparoscopic liver resections: a feasibility study in 30 patients. Ann Surg 2000;232:753–62. Koffron AJ, Auffenberg G, Kung R, Abecassis M. Evaluation of 300 minimally invasive liver resections at a single institution: less is more. Ann Surg 2007;246:385–92. Dagher I, Proske JM, Carloni A, Richa H, Tranchart H, Franco D. Laparoscopic liver resection: results for 70 patients. Surg Endosc 2007;21:619–24. Vibert E, Perniceni T, Levard H, Denet C, Shahri NK, Gayet B. Laparoscopic liver resection. Br J Surg 2006;93:67–72. Mala T, Edwin B, Rosseland AR, Gladhaug I, Fosse E, Mathisen O. Laparoscopic liver resection: experience of 53 procedures at a single center. J Hepatobiliary Pancreat Surg 2005;12:298–303. Kaneko H. Laparoscopic hepatectomy: indications and outcomes. J Hepatobiliary Pancreat Surg 2005;12:438–43. Chen HY, Juan CC, Ker CG. Laparoscopic liver surgery for patients with hepatocellular carcinoma. Ann Surg Oncol 2008;15:800–6. Descottes B, Glineur D, Lachachi F, et al. Laparoscopic liver resection of benign liver tumors. Surg Endosc 2003;17;23–30. Cai XJ, Yu H, Liang X, et al. Laparoscopic hepatectomy by curettage and aspiration. Experiences of 62 cases. Surg Endosc 2006;20:1531–5. Schmandra TC, Mierdl S, Bauer H, Gutt C, Hanisch E. Transoesophageal echocardiography shows high risk of gas embolism during laparoscopic hepatic resection under carbon dioxide pneumoperitoneum. Br J Surg 2002;89:870–6. Watanabe Y, Sato M, Ueda S, et al. Laparoscopic hepatic resection: A new and safe procedure by abdominal wall lifting method. Hepatogastroenterology 1997;44:143–47. Farges O, Jagot P, Kirstetter P, Marty J, Belghiti J. Prospective assessment of the safety and benefit of laparoscopic liver resections. J Hepatobiliary Pancreat Surg 2002;9:242–8. Biertho L, Waage A, Gagner M. Laparoscopic hepatectomy. Ann Chir 2002;127:164–70. Tang CN, Tsui KK, Ha JP, Yang GP, Li MK. A single-centre experience of 40 laparoscopic liver resections. Hong Kong Med J 2006;12:419–25. Bazin JE, Gillart T, Rasson P, Conio N, Aigouy L, Schoeffler P. Haemodynamic conditions enhancing gas embolism after venous injury during laparoscopy: a study in pigs. Br J Anaesth 1997;78:570–5. Palmer M, Miller CW, van Way CW 3rd, Orton EC. Venous gas embolism associated with argon-enhanced coagulation of the liver. J Invest Surg 1993;6:391–9. Fong Y, Jarnagin W, Conlon KC, DeMatteo R, Dougherty E, Blumgart LH. Hand-assisted laparoscopic liver resection: lessons from an initial experience. Arch Surg 2000;135:854–9. Milsom JW, Jerby BL, Kessler H, Hale JC, Herts BR, O’Malley CM. Prospective, blinded comparison of laparoscopic ultrasonography vs. Contrast-enhanced computerized tomography for liver assessment in patients undergoing colorectal carcinoma surgery. Dis Colon Rectum 2000;43:44–9.

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20 Foroutani A, Garland AM, Berber E, et al. Laparoscopic ultrasound vs triphasic computed tomography for detecting liver tumors. Arch Surg 2000;135:933–8. 21 Callery MP, Strasberg SM, Doherty GM, Soper NJ, Newton JA. Staging laparoscopy with laparoscopic ultrasonography: optimizing resectability in hepatobiliary and pancreatic malignancy. J Am Coll Surg 1997;80:33–9. 22 Decailliot F, Cherqui D, Leroux B, et al. Effects of portal triad clamping on haemodynamic conditions during laparoscopic liver resection. Br J Anaesth 2001;87:493–6. 23 Decailliot F, Streich B, Heurtematte Y, Duvaldestin P, Cherqui D, Stéphan F. Hemodynamic effects of portal triad clamping with and without pneumoperitoneum: an echocardiographic study. Anesth Analg 2005;100:617–22. 24 Chang S, Laurent A, Tayar C, Karoui M, Cherqui D. Laparoscopy as a routine approach for left lateral sectionectomy. Br J Surg 2007;94:58–63. 25 Schemmer P, Friess H, Hinz U, et al. Stapler hepatectomy is a safe dissection technique: analysis of 300 patients. World J Surg 2006;30:419–30. 26 Ros A, Gustafsson L, Krook H, et al. Laparoscopic cholecystectomy versus mini-laparotomy cholecystectomy: a prospective, randomized, single-blind study. Ann Surg 2001;234: 741–9. 27 McMahon AJ, Russell IT, Baxter JN, et al. Laparoscopic versus minilaparotomy cholecystectomy: a randomised trial. Lancet 1994;343:135–8. 28 Fleshman J, Sargent DJ, Green E, et al. Laparoscopic colectomy for cancer is not inferior to open surgery based on 5-year data from the COST Study Group trial. Ann Surg 2007;246:655–62. 29 Belli G, Fantini C, D’Agostino A, et al. Laparoscopic versus open liver resection for hepatocellular carcinoma in patients with histologically proven cirrhosis: short- and middle-term results. Surg Endosc 2007;21:2004–11. 30 Huscher CG, Lirici MM, Chiodini S. Laparoscopic liver resections. Semin Laparosc Surg 1998;5:204–10. 31 Simillis C, Constantinides VA, Tekkis PP, et al. Laparoscopic versus open hepatic resections for benign and malignant neoplasms - a meta-analysis. Surgery 2007;141:203–11. 32 Dulucq JL, Wintringer P, Stabilini C, Berticelli J, Mahajna A. Laparoscopic liver resections: a single center experience. Surg Endosc 2005;19:886–91. 33 Rau HG, Buttler E, Meyer G, Schardey HM, Schildberg FW. Laparoscopic liver resection compared with conventional partial hepatectomy – a prospective analysis. Hepatogastroenterology 1998;45:2333–8. 34 Lesurtel M, Cherqui D, Laurent A, Tayar C, Fagniez PL. Laparoscopic versus open left lateral hepatic lobectomy: a case-control study. J Am Coll Surg 2003;196:236–42. 35 Laurent A, Cherqui D, Lesurtel M, Brunetti F, Tayar C, Fagniez PL. Laparoscopic liver resection for subcapsular hepatocellular carcinoma complicating chronic liver disease. Arch Surg 2003;138:763–9. 36 Morino M, Morra I, Rosso E, Miglietta C, Garrone C. Laparoscopic vs open hepatic resection: a comparative study. Surg Endosc 2003;17:1914–8. 37 Troisi R, Montalti R, Smeets P, et al. The value of laparoscopic liver surgery for solid benign hepatic tumors. Surg Endosc 2008;22:38–44.

CHAPTER 18

38 Shimada M, Hashizume M, Maehara S, et al. Laparoscopic hepatectomy for hepatocellular carcinoma. Surg Endosc 2001;15:541–4. 39 Mala T, Edwin B, Gladhaug I, et al. A comparative study of the short-term outcome following open and laparoscopic liver resection of colorectal metastases. Surg Endosc 2002;16:1059–63. 40 Buell JF, Thomas MJ, Doty TC, et al. An initial experience and evolution of laparoscopic hepatic resectional surgery. Surgery 2004;136:804–11. 41 Kaneko H, Takagi S, Otsuka Y, et al. Laparoscopic liver resection of hepatocellular carcinoma. Am J Surg 2005;189:190–4. 42 Soubrane O, Cherqui D, Scatton O, et al. Laparoscopic left lateral sectionectomy in living donors: safety and reproducibility of the technique in a single center. Ann Surg 2006;244:815–20. 43 Cai X, Wang Y, Yu H, Liang X, Peng S. Laparoscopic hepatectomy for hepatolithiasis: a feasibility and safety study in 29 patients. Surg Endosc 2007;21:1074–8. 44 Abdel-Atty MY, Farges O, Jagot P, Belghiti J. Laparoscopy extends the indications for liver resection in patients with cirrhosis. Br J Surg 1999;86:1397–400. 45 Teramoto K, Kawamura T, Takamatsu S, et al. Laparoscopic and thoracoscopic approaches for the treatment of hepatocellular carcinoma. Am J Surg 2005;189:474–8. 46 Huang MT, Lee WJ, Wang W, Wei PL, Chen RJ. Hand-assisted laparoscopic hepatectomy for solid tumor in the posterior portion of the right lobe: initial experience. Ann Surg 2003;238:674–9. 47 Gayet B, Cavaliere D, Vibert E, et al. Totally laparoscopic right hepatectomy. Am J Surg 2007;194:685–9. 48 O’Rourke N, Fielding G. Laparoscopic right hepatectomy: surgical technique. J Gastrointest Surg 2004;8:213–6. 49 Cherqui D, Soubrane O, Husson E, et al. Laparoscopic living donor hepatectomy for liver transplantation in children. Lancet 2002;359:392–6. 50 Fong Y, Brennan MF, Turnbull A, et al. Gallbladder cancer discovered during laparoscopic surgery–potential for iatrogenic dissemination. Arch Surg 1993;128:1054 –6. 51 Johnstone PA, Rohde DC, Swartz SE, Fetter JE, Wexner SD. Port site recurrences after laparoscopic and thoracoscopic procedures in malignancy. J Clin Oncol 1996;14:1950–6. 52 Cherqui D, Laurent A, Tayar C, et al. Laparoscopic liver resection for peripheral hepatocellular carcinoma in patients with chronic

53 54

55

56

57

58

59

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liver disease: midterm results and perspectives. Ann Surg 2006;243:499–506. Dagher I, Lainas P, Carloni A, et al. Laparoscopic liver resection for hepatocellular carcinoma. Surg Endosc 2008;22:372–8. Adam R, Azoulay D, Castaing D, et al. Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis: a reasonable strategy? Ann Surg 2003;238:508–18. Laurent A, Tayar C, Andreoletti M, Lauzet JY, Merle JC, Cherqui D. Laparoscopic liver resection facilitates salvage liver transplantation for hepatocellular carcinoma. J Hepatobiliary Pancreat Surg 2009;16:310–4. Ardito F, Tayar C, Laurent A, Karoui M, Loriau J, Cherqui D. Laparoscopic liver resection for benign disease. Arch Surg 2007;142:1188–93. Bryant R, Laurent A, Tayar C, Cherqui D. Laparoscopic liver resection – understanding its role in current practice: the Henri Mondor Hospital experience. Ann Surg 2009;250:103–11. Santambrogio R, Opoche E, Ceretti AP, et al. Impact of intraoperative ultrasonography in laparoscopic liver surgery. Surg Endosc 2007;21:181–8. O’Rourke N, Shaw I, Nathanson L, Martin I, Fielding G. Laparoscopic resection of hepatic colorectal metastases. HPB 2004;6:230–5.

Self-assessment answers 1 2 3 4 5 6 7 8 9 10 11

B C A, C, D B D A, B C, E E E B A, B, D

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19

Repeat Resection for Liver Tumors Mickael Lesurtel1 and Henrik Petrowsky2 1 Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland 2 The Dumont-UCLA Transplant Center, Ronald Reagan Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Introduction Over the past 30 years, hepatic resection has evolved into the treatment of choice for a wide array of primary and metastatic hepatic malignancies. Historically, the first large series of first liver resections for secondary tumors was reported in 1978 [1]. Improvements in surgical technique, perioperative patient care, and management of postoperative complications have greatly reduced the morbidity and mortality associated with liver resection, resulting in a broadening of its application [2]. Metastatic colorectal cancer and hepatocellular carcinoma (HCC) remain the most common indications for liver resection. Although surgery is the only potentially curative treatment for these diseases, recurrence is common. The inefficacy of alternative nonsurgical therapies, as well as the recent advances in perioperative management and hepatic resection, have led to an increasing number of repeat hepatic resections. Historically, one of the first reports of repeat liver resections was reported by Tomas-de la Vega et al in 1984 [3] and consisted of four patients. Since then, larger experiences have been reported from several centers. This growing literature shows that, while repeat resection is possible in only a minority of patients, it can be done safely and with good long-term results. This chapter will summarize the reported experience to date, define patient selection, and discuss technical surgical issues. In addition, a brief discussion of the role for other locoregional treatment modalities, such as hepatic artery embolization, alcohol injection, cryoablation, and radiofrequency ablation (RFA) will be undertaken.

Technical considerations Repeat hepatic resection poses technical difficulties not commonly encountered at initial resection. First, adhesions at


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the previous line of parenchymal transection can make reexposure of the liver difficult. Mobilizing the liver off the vena cava and re-exposing the porta hepatis and hepatic veins can be extremely hazardous if there has been previous dissection in these areas. Second, liver parenchyma after liver regeneration and/or chemotherapy is more friable [4]. Especially certain chemotherapeutical drugs such as irinotecan and oxaliplatin can cause the development of friable liver parenchyma by steatohepatitis and severe sinusoidal obstruction [5, 6]. This further adds to the difficulties of reexposure and predisposes to tearing of Glisson’s capsule. Third, regeneration alters the normal anatomic configuration of the portal structures. For example, after an extended right hepatectomy, the porta hepatis is rotated posteriorly and to the right due to liver regeneration. The normal relationship among the portal structures may also be altered, with the bile duct displaced posteriorly and the portal vein displaced anteriorly. Therefore, repeat hepatic resections are generally more difficult and challenging. The fact that repeat hepatectomy is more difficult and more demanding is reflected by the findings of a recently published meta-analysis of outcome after first and second liver resection for colorectal liver metastases [7]. This analysis revealed a significant lower intraoperative blood loss and faster operating time by 30 min for the first liver resection compared with repeat hepatectomy. A major limiting factor at repeat hepatectomy is the extent of resection that can be performed. This is especially true if the initial resection was extensive. In a single-institution series of 615 patients with metastatic colorectal cancer, Adam et al [8] reported that major resections (three or more segments) accounted for 62% of initial hepatectomies, 59% of second hepatectomies, and 24% of third hepatectomies. Additionally, a multiinstitutional series from the French Surgical Association revealed that a second major resection (two or more adjacent segments) was possible in only 34% of patients previously subjected to a major resection [9]. Deterioration of hepatic function may also limit the extent of resection that can be safely performed, particularly in patients with HCC and underlying cirrhosis [10, 11]. Normally, for resection of liver tumors, we avoid wedge excisions. Evidence suggests

CHAPTER 19

Repeat Resection for Liver Tumors

Table 19.1 Selected series of repeat hepatic resection for metastatic colorectal cancer with more than 50 patients. First Authors (year)

Country

Number of patients (initial resection)

Number of patients (second resection)

Time interval, H1 to H2 (months)

Morbidity (%)

Mortality (%)

3-Year survival (%)

5-Year survival (%)

Median Survival (months)

Nordlinger et al (1994) [9] Fernandez-Trigo et al (1995) [12] Adam (1997) et al [4] Yamamoto et al (1999) [26] Petrowsky et al (2002) [28] Adam et al (2003) [8] Shaw et al (2006) [24] Yan, et al (2006) [27] Ishiguro et al (2006) [22] Thelen et al (2007) [25] Nishio et al (2007) [23]

France Worldwide

1818 –

116 (6%) 170

17 12

25 28

1 0

33 –

– 28

30 30

France Japan USA, Germany France Great Britain Australia Japan Germany Great Britain

243 362 1488 615 718 382 – 811 540

64 (26%) 75 (21%) 126 (8%) 199 (32%) 66 (9%) 55 (14%) 111 94 (12%) 54 (10%)

16 11 14 16 14 – 16 – –

20 – 19 23 18 29 14 23 19

0 0 2 4 0 0 0 3 6

60 48 51 54 68 – 74 55 53

41 31 34 35 44 49 41 38 46

46 30 37 – 56 53 43 – 50

H1 to H2 refers to the time interval between the first and second hepatectomies.

that wedge resections are more often associated with greater blood loss and tumor-involved margins than are anatomic resections, and survival after a wedge resection may be adversely affected [12, 13]. However, during a repeat liver resection, a wedge resection may be dictated by anatomic considerations of the regenerated liver. An analysis of 14 studies demonstrated that there were significantly fewer wedge resections performed in patients undergoing first liver resection (39%) compared to those having repeat hepatectomy (46%) [7]. In that case cryoassisted wedge excision, in which the tumor and a predetermined margin of noncancerous liver tissue are frozen and then excised, is an alternative strategy for achieving complete tumor clearance. This may be a better approach when anatomic resection is not feasible [13]. This approach is limited to tumors that can be adequately frozen and is generally not applicable to large tumors or those adjacent to major vascular structures.

Repeat hepatic resection for metastatic colorectal cancer Scope of the problem Each year approximately 150 000 new cases of colorectal carcinoma are diagnosed in the United States. Half of these patients (70 000–80 000) will present with metastatic disease in the liver. If patients with extrahepatic disease, those with extensive bilobar hepatic disease, and those unfit for surgery are discounted, approximately 10 000 patients are candidates for potentially curative liver resection annually [14].

Recurrence can be expected in roughly two-thirds of those resected, and the remnant liver is frequently involved. However, only 30–50% of these cases are isolated hepatic recurrences, of which 25–30% are resectable [9, 15]. Thus, of those patients submitted for initial hepatic resection, only 6–32% are candidates for potentially curative repeat hepatectomy (Table 19.1). This amounts to 1000–2000 patients a year.

Safety and efficacy There is no doubt that liver resections represent safe and effective therapy for patients with first presentation of hepatic metastases. Surgery is associated with a 5-year survival rate of 20–40% [16, 17]. Most major centers consistently report an operative mortality of less than 5%, which has been linked to the volume of cases performed [16, 17]. Surgery therefore remains the treatment of choice for all medically fit patients, provided that there is no or limited resectable extrahepatic disease and that all hepatic disease can be safely removed. The indications for hepatic resection have thus been expanded, and the number of patients presenting with recurrence after initial hepatectomy will likely increase until effective adjuvant therapies are developed. Recurrence after initial hepatectomy can be expected in the majority of patients. Repeat hepatectomy has emerged as a safe and effective intervention. The first report of repeat liver resection goes back to 1984 [3] and until the early 1990s, studies involved small numbers of patients, had a relatively short follow-up, and were almost anecdotal in nature [18–20]. Other than documenting feasibility in selected patients, these studies provided little

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meaningful information. Some authors suggested increased bleeding and other complications after repeat hepatectomy, but most reported acceptable morbidity and mortality figures [21]. As hepatic resections are done more frequently, the proportion of repeat resections performed is also increasing. Therefore, larger series of repeat hepatectomy for colorectal liver metastases can be analyzed (Table 19.1). More recently, the meta-analysis of several larger series has confirmed that morbidity and mortality rates after repeat hepatectomy are similar to those reported for initial hepatectomy [7]. Moreover, extended survival was also demonstrated, and in some cases survival rate was equivalent to or even better than that observed after initial hepatectomy (Table 19.1). In the two largest multicenter series, the operative morbidity rates were 25% and 28% and mortality rates were 1% and 0% [9, 12]. Median survival in both studies was 30 months. In the largest single-center series, similarly low morbidity and mortality rates and a 5-year survival rate of 31–49% were reported [4, 22–27]. The findings of the large bi-institutional experience of 126 second liver resections from an American and a European Surgical Oncology Center confirm the data of the previous large multi- and single-center studies in regard to morbidity, mortality, and survival [28] (Table 19.1). In another report of 96 patients who survived for 5 years after hepatic resection for metastatic colorectal cancer, half of the patients had been subjected to repeat resections [29]. Thus, these studies demonstrate that repeat hepatic resection is not only feasible, but can result in long-term survival. These data are the basis for the view that liver resection is the treatment of choice for recurrent resectable liver metastases from colorectal cancer since neither chemotherapy nor other nonsurgical therapies has been shown to achieve such favorable results. Comparison of resection results with historic data on untreated patients strongly suggests that repeat resection prolongs survival. This is probably the reason why no prospective comparison of repeat hepatic resection with supportive care has ever been performed. Median survival of untreated recurrence after liver resection is approximately 4 months, and 5-year survivors are extremely uncommon [9, 30]. The results of repeat resection also appear to be better than those achievable with systemic chemotherapy [30]. In most series, the response rates for chemotherapy are less than 40%, and the median response duration is less than 8 months [31]. By the time most patients present for repeat hepatectomy, they have received one or more courses of chemotherapy. In fact, some authors routinely treat all patients with chemotherapy after initial hepatectomy, despite the paucity of data to support such a policy [4]. Although it seemed unlikely in the past that these agents would be any more effective in treating hepatic recurrences than they are in preventing them, a recent large multicentric

218

randomized controlled trial demonstrated that perioperative chemotherapy using the FOLFOX4 regimen was beneficial in terms of reducing recurrence after liver resection for colorectal liver metastases [32].

Patient selection Several authors have attempted to refine the indications for repeat hepatectomy by identifying risk factors associated with early treatment failure, a task made difficult by the small number of patients in each study. Early reports suggested that patients with more than one tumor and those with hepatic recurrence less than 1 year after initial hepatectomy were less likely to benefit from repeat hepatectomy [33]. Subsequent studies were unable to confirm these observations [12, 15, 34, 35]. The large series of the French Surgical Association study failed to identify any prognostic variables that would simplify patient selection [9]. This could be attributed to the heterogenous study population of this multicenter series since it is composed of 116 second liver resections from 85 centers. By contrast, the Repeat Hepatic Metastases Registry study found that, as with initial hepatic resection, extrahepatic disease and incomplete resection had a significant negative impact on survival [12]. However, this study did not demonstrate that these variables are independent predictors of outcome. More recently, larger series identified independent predictors of outcome (Table 19.2). In these studies, the curative nature of the resection [4, 23, 25, 26], size [23, 25, 28], and number [22, 26, 28] of hepatic lesions, bilobar involvement [25], time interval between first and second liver resections [4], regional lymph node metastases [26], extrahepatic disease [26], and elevated carcinoembryonic antigen (CEA) at time of repeat resection [23, 27] were independent outcome predictors in multivariate analysis. However, the curative nature of the resection, as well as the size and number of hepatic metastases, were the most frequently reported independent predictors associated with survival outcome after repeat hepatectomy (Table 19.2). Thus, in selecting patients for repeat resection, the ability to clear all disease (R0 resection) and a low tumor load (size and number of hepatic lesions) are the most important criteria for consideration. Although these prognostic variables provide rough indicators of prognosis, they should not be used as absolute contraindications to surgery. Long-term survival is possible despite the presence of poor prognostic variables [4], as is the case after initial hepatectomy [4]. Given the potential benefit of repeat hepatectomy, which is unavailable with other modalities, it is reasonable to use the same selection criteria as those applied for initial hepatectomy. Many centers have therefore adopted the policy of repeat resection in all medically fit patients with resectable hepatic disease [4, 26, 28, 36]. Complete resection must be possible, because the results of palliative repeat resection are poor [4, 23, 25, 26].

CHAPTER 19


Table 19.2 Independent predictors of outcome associated with repeat liver resection for recurrent colorectal liver metastases. Authors (year)

Period of H2

Curative

Time interval H1 to H2

Number

Size

Bilobar

Regional LN metastases

Extrahepatic disease

CEA at H2

Adam et al (1997) [4] Yamamoto et al (1999) [26] Petrowsky et al (2002) [28] Yan et al (2006) [27] Ishiguro et al (2006) [22] Thelen et al (2007) [25] Nishio et al (2007) [23]

– – – – – Y –

Y Y – – – Y Y

Y – – – – – –

– Y Y – Y – –

– – Y – – Y Y

– – – – – Y –

– Y – – – – –

– Y – – – – –

– – – Y – – Y

H1 to H2 refers to the time interval between the first and second hepatectomies; CEA, carcinoembryonic antigen; LN, lymph node.

The statement that the presence of extrahepatic disease generally precludes repeat hepatectomy, even if the extrahepatic disease is resectable, has been revised during the last decade. Especially, there is growing evidence that well-selected patients with hepatic and pulmonary metastases from colorectal cancer benefit from combined liver and lung surgery as long as the complete clearance of the disease can be achieved [37, 38]. Although Nordlinger et al [9] demonstrated that rapid recurrence occurred in those patients subjected to simultaneous removal of hepatic and extrahepatic metastases, limited and resectable extrahepatic disease is no longer an absolute contraindication for liver surgery. This fact is supported by Adam et al and Petrowsky et al [4, 28], who reported that the presence of extrahepatic disease was not an independent predictor of outcome after synchronous repeat hepatectomy and resection of resectable extrahepatic disease. Therefore, some authors have adopted a more aggressive posture with respect to such patients. They and others argue that resectable extrahepatic recurrence should not necessarily preclude repeat hepatectomy [4, 28, 39]. Close follow-up is mandatory after initial hepatectomy. Nordlinger et al [9] reported that resectability of hepatic recurrences after initial resection was closely related to tumor size, underscoring the need for early detection. CEA levels and abdominal/pelvic computed tomography (CT) scans should be performed every 4–6 months for the first 2 years after resection, within which time most recurrences are diagnosed [15, 34]. Some surgeons prefer abdominal ultrasound as a routine surveillance study [15]. During the past 5 years, positron emission tomography (PET)/CT has become a useful tool in preoperative staging and postoperative follow-up. There is also growing evidence that PET/CT is superior to conventional imaging modalities in terms of detecting extrahepatic disease [40]. Regular colonoscopic evaluation should also be practiced. Recurrences after 2 years are not uncommon, however. Continued surveillance is required, although the interval between investigations

may be extended to every 6 months [29]. Recurrent disease 5 years after initial hepatic resection is rare [29]. Some authors have recommended a brief period (4–8 weeks) of close observation before repeat hepatectomy [4, 15], but this is by no means a universally accepted recommendation. The rationale is to allow radiographically occult metastases to manifest themselves, thus allowing a change in the operative strategy or avoiding an unnecessary laparotomy. Although there is no proven benefit to this approach, it is not without some merit. A short interval between discovery of the disease and surgery is unlikely to affect the outcome.

Multiple repeat hepatic resections Recurrence after repeat hepatectomy has been reported in 60–80% of patients [34]. A select few have resectable disease limited to the liver and may be candidates for third or even fourth hepatic resections. Reports of large repeat hepatectomy series show that 9–30% of patients who underwent a second hepatectomy for colorectal liver metastases had a third resection [8, 9, 26, 28] and 4% a fourth liver resection [8, 26]. The safety of multiple repeat hepatic resections has been demonstrated in recent reports, and long-term survivors have been documented [8, 9, 26, 28]. Adam et al [8] published the largest series (n = 60) of third hepatectomies for recurrent colorectal liver metastases. Patients who underwent a third liver resection had zero mortality, and the morbidity rate (25%) and median hospital stay (14 days) were not significantly different from in those who had only one or two liver resections. In addition, patients with a third liver resection had a survival benefit of 32–38% at 5 years [8, 26]. Major hepatectomy is possible in the minority of these patients but patients likely to benefit represent a small and highly selected group [8, 9, 26].

Nonresectional approaches Cryoablation (Chapter 20), hepatic artery embolization, percutaneous ethanol injection (Chapter 22), and cryoablation

219

SECTION 4


and RFA (Chapter 21) are examples of nonresectional strategies that have shown some promise in the management of unresectable hepatic metastases. Most reports to date have included small numbers of patients with diverse tumors. Also, the majority of studies have focused on establishing safety and efficacy in patients who are not candidates for initial hepatic resection. Although these approaches are generally not considered curative, none has been compared directly with resection in a randomized trial. However, local ablation techniques, especially RFA, have been increasingly performed in patients with colorectal liver metastases during the last years, but the roles of these techniques in patients with recurrence after initial hepatic resection have to be defined. RFA has been used for the treatment of recurrent liver metastases from colorectal cancer following initial hepatectomy [41, 42]. Elias et al [41] demonstrated that percutaneous radiofrequency increases the number of patients with recurrent liver metastases amenable for curative treatment. Furthermore, the authors stated that repeat resection is only indicated when RFA is contraindicated. A more recently published series on colorectal hepatic recurrence after initial liver surgery suggested that RFA and repeat resection achieved similar results [42]. However, none of these studies compare the treatment groups in a randomized fashion and have therefore a lower level of evidence. This demonstrates the need for randomized studies to clarify the role of repeat resection and local ablation for recurrent colorectal liver metastases. Cryoablation involves placement of a specialized probe, designed for delivery of nitrogen or argon at its tip, directly into the tumor under ultrasound guidance. This has previously required laparotomy but is now adaptable to laparoscopy. Basically, cryoablation can be used as a therapeutic modality to treat unresectable liver tumors or to assist hepatic resection (edge or contralobe cryotherapy) [13, 43]. However, there are no reports that specifically address the use of cryoablation for treatment of hepatic recurrence after initial resection. Hepatic artery chemoembolization has shown some efficacy in treating HCC and its role is questionable in patients with metastatic colorectal cancer. Tellez et al reported a median survival of 8.6 months in patients with unresectable colorectal metastases treated with chemoembolization [44]. Percutaneous ethanol injection is limited to relatively soft tumors, such as HCC. Hard metastatic tumors such as metastatic colorectal cancer on the other hand, are not well ablated by this technique because the alcohol tends to diffuse into the relatively softer hepatic parenchyma rather than the dense tumor stroma [45]. Strategies aimed at preventing recurrence after first hepatic resection have been generally disappointing in the recent past. However, a recent randomized trial has shown that adjuvant chemotherapy with FOLFOX at the time of

220

initial liver resection can reduce the rate of tumor recurrence after hepatectomy [32]. No study has addressed the role of adjuvant regional chemotherapy after repeat hepatectomy. Immunotherapy may also find a role in preventing recurrent disease, although this approach remains largely experimental.

Repeat hepatic resection for hepatocellular carcinoma Scope of the problem HCC is among the fifth most common fatal malignancies in the world, responsible for approximately one million deaths annually [46]. There are dramatic geographic variations in the incidence of HCC. The United States has one of the lowest incidence rates in the world at 1 per 100 000. On the other hand, incidence rates of 60–100 per 100 000 are common in Asia and sub-Saharan Africa, making HCC one of the most common adult malignancies in these areas [46]. HCC commonly arises in the setting of hepatic cirrhosis, although not all forms of cirrhosis carry the same risk. Worldwide, 70–80% of all patients with HCC have some degree of underlying chronic liver disease. As a result, extensive hepatic resection, or indeed any resection at all, is often not possible. Although screening programs in high-risk populations and improvements in imaging have resulted in earlier diagnosis, resectability at initial presentation remains low, approximately 20–30% in some estimates. Similarly, repeat hepatic resection is possible in a minority of patients that recur, perhaps as low as 10–20% (Table 19.3). The extent of tumor within the liver and underlying cirrhosis are the most common factors that preclude resection, both at initial presentation and at the time of recurrence [47, 48]. Despite its limitations, resection offers, beside liver transplantation, the best chance for long-term survival. The 5-year survival rate after initial resection is approximately 40–50% in most large series [49–52]. Recurrence is common, however, and may be as high as 70–80%. Unlike metastatic colorectal cancer, where extrahepatic recurrence is common, the overwhelming majority of cases of HCC recur in the remnant liver [49, 50, 52]. The reason for the large number of recurrences after initial hepatectomy is the subject of debate [48, 53–56]. The majority of cases recur within 2 years of initial hepatectomy, but recurrences after 2 years are not uncommon. Thus, as is speculated for metastatic colorectal cancer, undetected microscopic disease at the initial resection may be the principal underlying cause. Patients with HCC are at risk for multicentric tumors as well as intrahepatic spread of tumor by portal vein invasion and embolization. Both mechanisms put the remnant liver at risk for recurrent or persistent disease. Multicentric disease has been estimated to account for 25% of recurrences, but more recent studies suggest that

CHAPTER 19


Table 19.3 Selected series of repeat hepatic resections for hepatocellular carcinoma (number of patients >20). Study

Number of patients (initial resection)

Number of patients (second resection) (%)

Time interval H1 to H2 (months)

Morbidity (%)

Mortality (%)

3-Year survival (%)

5-Year survival (%)

Median Survival (months)

Lee et al (1995) [66] Neelemann and Andersson (1996) [11] Hu et al 1996 [64] Nagasue et al (1996) [10] Shimada et al (1996) [48] Shuto et al (1996) [69] Shimada et al (1998) [68] Sugimachi et al (2001) [70] Minagawa et al (2003) [47] Itamoto et al (2007) [65] Liang et al (2008) [67]

196 –

25 (13) 128

26 19

24 13

0 2

45 56

– 40

27 40

– 290 312 341 312 474 334 483 853

60 50 22 31 41 78 67 84 44

23 21 – – – – – – –

15 16 – – – – – 23 68

3 8 – – – 0 0 0 0

44 64 70 71 65 83 70 67 44

– 38 70 52 42 47 56 50 28

30 – – – – – – – –

(17) (7) (9) (13) (16) (20) (17) (5)

H1 to H2 refers to the time interval between the first and second hepatectomies.

it may be closer to 15% [55, 56]. Moreover, patients with significant cirrhosis or chronic hepatitis infection remain at high risk for new primary tumors (i.e. metachronous tumor growth) in the liver remnant. After initial resection, patients with HCC face not only the probability of recurrence but also the added burden of progressive hepatic dysfunction. The extent of repeat resection that can be safely performed may thus be limited, or surgery may not be possible at all [57]. In contrast to repeat resection of colorectal metastases where major procedures are performed in approximately 30%, only small numbers of patients, probably less than 15%, are candidates for major repeat resections in HCC (Table 19.3). Moreover, progressive deterioration in hepatic function also represents a major source of morbidity and mortality, irrespective of cancer status. Death from complications of portal hypertension has been reported [52, 58] and portal hypertension is today considered a contraindication for liver resection [2].

Safety and efficacy Although the majority of HCC cases recur after initial hepatectomy, surgery remains the most effective therapy. Earlier diagnosis and improvements in surgical technique have significantly lowered operative mortality [2]. Other interventions, such as hepatic artery embolization, percutaneous ethanol injection, and RFA have emerged as effective alternatives, but none has proven superior to resection [59–61]. Liver transplantation is appropriate only in patients with limited disease, and the critical shortage of donor organs markedly limits its applicability [62]. Repeat resection for

HCC has been performed with increasing frequency, although it has only recently gained acceptance as a safe and effective treatment. Initial reports were few and involved small numbers of patients, making it difficult to ascertain the true role of repeat resection [53, 63]. More recent reports, with larger numbers of patients (Table 19.3), have shown that repeat hepatectomy can be performed with morbidity and mortality comparable to those of initial hepatectomy, and it offers the possibility of extended survival [10, 11, 47, 48, 64–69]. Nagasue et al found no difference between initial and repeat hepatectomy in operative blood loss or operating time [10]. Morbidity after repeat hepatectomy is acceptable, ranging from 10% to 35%, and most of the recent series have not reported any mortality [47, 65, 67, 70]. A 5-year survival rate ranging from 28% to 70% has been reported and these results are comparable to those of initial hepatectomy for HCC. As previously discussed, underlying hepatic dysfunction is a significant problem for patients with recurrent HCC. The need to preserve hepatic parenchyma is reflected by the number of second major resections performed for HCC, which is dramatically lower than for metastatic colorectal cancer, and may partially explain the relatively low operative morbidity. In one study, lobar resections accounted for 33% of initial resections but only 5% of second resections [11].

Patient selection Several authors have identified variables associated with poor prognosis at the time of recurrence, including portal

221

SECTION 4


Table 19.4 Series of repeat hepatic resection for hepatocellular carcinoma (HCC) that identified independent predictors of outcome by multivariate analysis. Study

Year

Number of second resections (%)

Predictors of reduced outcome

Shimada et al [68]

1998

41 (13)

Minagawa et al [47]

2003

67 (20)

Itamoto et al [65]

2007

84 (17)

Portal vein invasion at first resection Portal vein invasion at second resection Several HCC at primary Disease-free interval 35%) Partial thawing of the iceball to about 1 cm before refreezing Management Supportive management, including treatment of the DIC with fresh frozen plasma. Cryoprecipitate and platelets. Ventilatory support for those patients with acute respiratory distress syndrome, and dialysis for those with renal failure Prognosis Though cryoshock is uncommon, occurring in about 1% of those having cryotherapy, it accounted for 18% of the mortality following hepatic cryotherapy [28]

(see Chapter 26). Local ablative therapies have been used for the treatment of patients with unresectable liver tumors, poor liver reserve, and severe cirrhosis. There are limited reports on the use of cryoablation for the treatment of HCC, with many studies including a mixture of tumor types. Zhou et al reported on 235 patients with primary liver tumors treated with cryoablation for unresectable tumors [36]. They included 232 patients with HCC. The majority of patients had additional treatments such as hepatic artery ligation and/or perfusion or resection. There was no mortality and the only significant complication was an intra-abdominal abscess. The overall 1-, 3- and 5-year survival rates were 78.4%, 54.1%, and 39.8%, respectively [36]. The 5-year survival for patients with tumors of 5 cm or less was better than those with larger tumors.

234

Experience with cryotherapy for HCC from other centers is limited to smaller series. Wren et al reported on 12 patients with unresectable HCC, five of the patients having had preoperative intra-arterial chemoembolization [37]. There was no mortality and a mean survival of 19 months. Seven of nine patients treated with a curative intent developed recurrence of the HCC. Adam et al treated nine patients with unresectable HCC with cryotherapy either alone or in combination with resection. The cumulative survival rate at 2 years was 63% [38]. Xu et al treated 65 patients with unresectable HCC by percutaneous cryoablation followed by ethanol injection [39]. With a mean follow-up of 14 months, 50.8% of the patients were alive without recurrence and 33.8% were alive with recurrence. There were only three patients with recurrence at the cryosite. These studies support the use of cryotherapy for the treatment of unresectable HCC. The results of published series using cryotherapy for the treatment of HCC are shown in Table 20.3. Long-term follow-up of patients treated by cryoablation was reported by Kerkar et al [40]. They treated 98 patients by cryoablation. In the 14 patients who had HCC, the 1-, 3- and 5-year survival rates were 77%, 57%, and 48%, respectively, with a median survival of 40 months. The use of preoperative transarterial chemoembolization followed by cryosurgery was reported by Clavien et al in 15 patients with HCC and cirrhosis [41]. The aim of this was to decrease the complication rate from hemorrhage and decrease the local recurrence rate. They treated mainly solitary tumors but with a median diameter of 6.5 cm (range 3.5–12 cm). At a median follow-up of 2.5 years, 79% of the patients were alive. They reported a local recurrence rate at the cryosite of 20%. Tumor marker response in patients following cryotherapy gives a good indication of the effectiveness of the cryoablation. Xu et al reported that tumor markers were lowered to normal or near-normal levels in 91.3% of patients in the 3–6-month postablative period [39]. Adam et al reported reduction in the tumor markers in 60% of patients with preoperatively elevated serum tumor marker [38].

Neuroendocrine metastases Malignant neuroendocrine tumors are a heterogeneous group of tumors which are generally slow growing with a potential for long-term survival albeit with disabling symptoms. In this group of patients, significant palliation from symptoms and improved survival can be achieved with tumor debulking (see Chapter 37). Resection of neuroendocrine liver metastases has been shown to offer symptomatic response in 90% of patients at a mean duration of 19.3 months [42]. Cryotherapy has been evaluated in unresectable tumors and as an alternative to liver resection. The

Table 20.2 Morbidity and mortality associated with cryoablation of liver tumors. Patients (n)

Mortality n (%)

Morbidity n (%)

Pleural effusion n (%)

Cracking of iceball n (%)

Biliary fistula bile leak n (%)

Myoglobinuria renal failure/ ATN n (%)

Hepatic/ abdominal abscess n (%)

Chest infection n (%)

Coagulopathy n (%)

Intraabdominal hemorrhage n (%)

Others n (%)

Weaver et al [31] Zhou et al [73] Morris et al [74] Shafir et al [62] Adam et al [38] Yeh et al [63] Wren et al [37] Korpan et al [44] Seifert et al [45]

1995

140

6 (4)

–

7 (5)

–

6 (4)

1 (1)

2 (1)

–

2 (1)

–

Cryoinjury colon 1

1995

145

0

–

–

–

0

–

0

–

–

0

–

1996

110

2 (2)

–

4 (4)

10 (9)

9(9)

1 (1)

2 (2)

28 (25)

–

10 (9)

–

1996

39

0

9%

–

–

0

1 (3)

0

0

1 (3)

1 (3)

1997

34

1 (3)

8%

–

–

1 (3)

0

0

0

–

–

Cryoinjury – lung 1, skin 1 Abdominal collection 1 (3)

1997

24

2 (8)

–

2 (8)

3 (13)

1 (4)

–

–

–

–

0

Cardiac 3, CVA 1, line sepsis 1

1997

12

0

1 (8)

–

–

1 (8)

–

0

1 (8)

–

–

–

1997

63

0

6 (10)

–

–

0

–

0

3 (5)

–

0

Wound infection 1

1998

116

1 (1)

28%

4 (3)

–

4 (3)

5 (4)

5 (4)

8 (7)

–

4 (4)

Haddad et al [64] Rivoire et al [65] Rehrig et al [46] Ruers et al [66] Bilchik et al [13] Bageacu et al [11]

1998

31

2 (6)

19 (59)

–

–

4 (13)

3 (10)

–

–

20 (63)

1 (3)

Liver failure 1, DIC 1, PE 1, wound infection 2, cardiac compl 2, UTI 1 Encephalopathy 1

2000

19

0

21%

1 (5)

5 (26)

1 (5)

–

–

–

–

–

Liver failure 2

2001

24

0

25%

–

–

–

–

–

–

4 (17)

1 (4)

–

2001

30

1 (3)

–

–

2 (7)

–

–

4 (13)

3 (10)

–

–

–

2000

159

5/159 (3)

–

80%

–

7/159 (4)

–

11/159 (7)

–

–

–

2007

53

2/53 (3.8)

66%

20/53 (37.7)

2/53 (3.8)

2/53 (3.8)

2/53 (3.8)

2/53 (3.8)

4/53 (7.5)

–

4/53 (7.5)

Colitis 1, cholecystitis 1, enterocutaneous fistula 1

235

PE, pulmonary embolus; ATN, acute tubular necrosis; cardiac, cardiac complications; UTI, urinary tract infection; DIC, disseminated intravascular coagulation; CVA, cerebrovascular accident; −, no data available.

Cryoablation of Liver Tumors

Year

CHAPTER 20

Study

SECTION 4


Table 20.3 Cryoablation of hepatocellular carcinoma (HCC). Study

Zhou et al [36]

Patient number

235

Adam et al [38]

9

Wren et al [37]

12

Xu et al [39] Zhao et al [75]

65 12

Kerker et al [40]

98

Pathology

HCC 232 Cholan 1 Mixed 2 HCC HCC with cirrhosis HCC HCC CRC 56 N-CRC 28 HCC 14

Median age (range)

Follow-up median months (range)

Median survival (months)

Survival (%) 1

2

3

4

47 (26–72)

–

–

78.4

–

54.1

58.1* (44–66) 62.1* (43–74) 51* 64 (35–75) 60*

16* (2–27) –

–

77

63

19*

–

14 (5–21) 13

– 21

40

5

Marker response n (%)

Liver recurrence n (%)

Recurrence at cryosite n (%)

–

39.8

–

–

–

–

–

–

3/5 (60)

3(33)

0

–

–

–

–

8/8 (100)

7/9 (78)

–

– –

– –

– –

– –

– –

91.30% 5/7 (71)

24/65 (37) 4/12 (33)

3/65 (4.6) 1/12 (8)

77

67

57

–

48

–

–

–

54

*, mean value. Cholan, cholangiocarcinoma.

Table 20.4 Published trials on neuroendocrine liver metastases treated by cryotherapy. Study

Year

Number (n)

Median follow-up months (range)

Symptomatic response n (%)

Marker response reduction n (%)

Operative mortality

Survival

Cozzi et al [43] Johnson et al [67] Bilchik et al [68] Shapiro et al [76] Seifert et al [69]* Sheen et al [70]

1995 1996 1997 1998 1998 2002

6 1 19 5 13 7

24 (6–72) 6# 17 (3–49) 30 13.5 30

7/7 (100) 1/1 (100) 19/19 (100) 5/5 (100) 5.0/7 (71) 7/7 (100)

3/3 (100) 100% 17/18 (94) 4/4 (100) 3/3 (100) –

0% 0% 0% 0% 0% 0%

100% 100% 72% 20% 92% 100%

*Includes six patients previously reported. #Last follow-up.

initial report by Cozzi et al showed symptomatic response in all six patients with hepatic metastases from neuroendocrine tumors by cryotherapy with a median follow-up of 24 months [43]. Similar results were achieved with cryoablation of neuroendocrine liver metastases in other reports. The published reports on the treatment of neuroendocrine liver metastases (Table 20.4) show good palliation of symptoms with good marker response.

Colorectal liver metastases The published reports of cryotherapy for the treatment of hepatic metastases from colorectal cancer, either as the sole therapy or in combination with liver resection or hepatic artery chemotherapy, are shown in Tables 20.5 and 20.6.

236

There is only one report of a prospective randomized control study comparing cryotherapy with liver resection [44]. In this paper, 123 patients were randomized to cryotherapy or liver resection, with 5- and 10-year survival rates of 44% and 19%, respectively, for the cryotherapy group, and 36% and 8%, respectively, for liver resection. Seifert et al reported on the long-term outcome of 116 patients with unresectable liver metastases from colorectal cancer. The median survival was 26 months with a 5-year survival of 13.5% [45]. Rehrig et al reported on 24 patients, 16 of whom had colorectal liver metastases. The survival estimate was 48.5% for the patients with colorectal metastases at a median follow-up of 33.7 months. The lesion size in these patients, however, was 2.24 ± 0.29 cm [46].

Table 20.5 Cryoablation of colorectal liver metastases. Study

Year

n

Etiology and number

Median age

CRC 119 NE 6 HCC 1 Other 14 CRC

1995

140

Weaver et al [71] Shafir et al [62]

1995

47

1996

39

Adam et al 1997 [38] Morris 1996 et al [74] Yeh et al 1997 [63] Seifert et al 1998 [45] Ruers et al 2001 [66] Rehrig 2001 et al [46]

25

CRC 25 HCC 4 NE 7 Other 3 CRC

92

CRC

24

CRC

116

CRC

30

CRC

24

CRC 16 HCC 6 NE 2 CRC 41 Other 22

1997

63+

Joosten et al [16] Bageacu et al [11]

2005

60++ 30

CRC

2007

53

CRC

Median survival months (range) n (%)

Patients alive n (%)

Patients dead n (%)

Alive disease free n (%)

Liver recurr n (%)

Cryosite n (%)

62 (14–79)

3 (1–15)

27 (7–80)

22 (4–80)

65/140 (46)

75/140 (54)

–

–

63 (31–75) –

3 (1–12) 4.8 (1–30)

26 (24–57) 14 (1–34)

26 (5–57) –

–

–

–

31/39 (79)

–

58.2* (38–73) –

1.5* (1–4) –

16* (2–27) –

–

15/25 (60)

25

63* (34–84) 60 (31–85)

–

19

3.9* (1–12) –

Extra hepatic n (%)

Survival (%) 1

2

3

–

–

–

–

–

–

–

–

–

–

62

–

–

20/39 (51)

–

–

–

–

–

–

–

5 (20)

15/25 (60)

11/25 (44)

10/25 (40)

77

52

–

–

53 (58)

10/25 (40) 39 (42)

18 (20)

–

–

–

–

–

–

–

32.7

20 (83)

4 (17)

4/21 (19)

1/21 (5)

8/21 (38)

–

–

–

–

26

43(37)

73 (63)

–

–

–

82.4

56

32.3

13

32

16/30 (53)

18/25 (72)

6/25 (24)

14/25 (56)

76

61

–

–

–

46%

14/30 (47) –

7%#

3.8*

20.5 (0–64) 26 (9–73) 33.7

9/20 (45) –

–

–

–

–

–

71

–

–

42 ± 11.2*

–

6–120

–

–

–

–

54 (85)

–

–

60

44

40.6 ± 13* 62*

– 3 (1–10)

5–120 26

– –

– 16/30

– 14/30

–

57 (95)

–

–

51

36

61.8 * (42–77)

2.6* (1–6)

24.8

–

–

–

–

30.20%

–

62* (45–79) 53.8 ± 3.2*

*, mean. #, percentage alive at 2 years. CRC, colorectal cancer; HCC, hepatocellular carcinoma; NE, neuroendocrine liver metastases; +, cryosurgery group; ++, liver resection group; −, no data available.

86.1

33.8

4

27

5

–

237


Korpan et al [44]

Follow-up months (range)

CHAPTER 20

Weaver et al [31]

No of lesions median (range)

238 Table 20.6 Cryoablation combined with liver resection (results of these patients treated by the contained method). Study

Hewitt et al [4] Wallace et al [58] Cha et al [72]

Year

Pt n

Resection + Pathology cryotherapy n (%)

Median age No of (range) lesions median (range)

Size median (range)

Follow-up Median median survival (range) (months)

Patients alive n (%)

Patients dead n (%)

Alive disease free n (%)

Liver recurr n (%)

CRC

65 (43–78)

3 (2–8)

–

15 (6–53)

32

14 (70)

6 (30)

7 (35)

11 (55) –

88

60

–

1999 137 52 (49)

CRC

65.2 (36–85)

–

–

14

20

–

–

–

–

–

80

38

2001

CRC 13 HCC 1 Other 4 CRC 14

61 ± 12*

2

6.5* (1–13)

28 (18–51) –

11 (66)

7 (38)

6 (33)

11%

2/18 (11)

83

52 (24–73)

7.4 (5–25)

3 (1–13.5)

28 (5–60)

26

3/19 (16) 16/19 (84)

3/19 (16) 11(57)

2 (10)

Others 5 CRC

61 (30–80)

2 (1–7)

–

20

33

–

–

–

–

CRC 24 HCC 2 Others 5 CRC

61 ± 15*

3 (1–13)

– 1–8.0

18*

–

–

–

–

–

61 ± 10*

4.1 ± 3.5* 3.9 ± 3.6*

–

–

–

1998

20 20 (100)

38 18 (47)

Rivoire 2000 19 13 (68) et al [65] Finlay 2000 107 75(70) et al [5] Haddad 1998 31 17 (54) et al [64] Niu et al [6]

2007 415 124

+, mean value. CRC, colorectal cancer; HCC, hepatocellular carcinoma; −, no data available.

25 (1–124) 29 (1–117)

Cryosite Survival recurr 1 2 3 n (%)

Compl

Mortality

8 (40)

0

24 –

–

–

71

–

22

1(6)

89

–

31 16

21

0

–

–

–

–

–

–

–

59

33

22 –

59

2(6)

71 (60) –

84

61

43 24

–

5 (4)

5

–

–

CHAPTER 20


The serum tumor marker was a significant prognostic factor that indicated tumor response and outcome. The pattern of fall in the serum CEA level after cryotherapy was different from the fall following liver resection of isolated hepatic metastases. The fall was more gradual, occurring over a period of 6 weeks to 3 months [50]. A failure of complete tumor marker response following cryotherapy for hepatic metastases from colorectal cancer was associated with shorter liver-free and overall disease-free intervals, and may be either due to incomplete cryoablation or that the hepatic or extrahepatic disease was not detected before operation [48].

Noncolorectal liver metastases Figure 20.7 Inadequately treated hepatocellular carcinoma adjacent to the area of cryoablation shown here taking up lipiodal 131I.

We reported our long-term results in 224 patients with unresectable colorectal liver metastases treated with cryotherapy and regional chemotherapy with or without resection [47]. The mortality in this group was 0.4% with a morbidity of 21%. At a median follow-up of 26 months the overall median survival was 31 months, and the median survival in 200 patients with complete tumor eradication was 36 months. There was no significant difference in survival in patients with more than five metastases and bilobar disease compared to those with less extensive disease. Recurrence of the tumor after cryoablation has been reported either locally at the cryoablation site, at other sites in the liver or at extrahepatic sites. The local recurrence at the cryosite is particularly important as this indicates tumors that were inadequately treated (Figure 20.7). The recurrence at the cryosite varies between 5% and 44% (Tables 20.5 and 20.6). In the 224 patients who underwent cryotherapy and regional chemotherapy with or without liver resection, the cryosite recurrence was 39% [47]. In a retrospective review of 85 patients, recurrence at the cryosite was reported in 33% of patients after a median follow-up of 22 months. Multivariate analysis indicated that the size of the cryotreated metastases was the only independent factor associated with local recurrence [48]. A failure of complete postoperative CEA response was also associated with shorter disease-free interval and probably indicates a failure to detect other hepatic and extrahepatic disease before the operation [48]. PET scan may be useful to better stage these patients [17]. The recurrence of tumor at other sites in the liver has been reported in the majority of patients following cryotherapy (Tables 20.5 and 20.6). The use of adjuvant hepatic artery chemotherapy was associated with a significant increase in the survival of patients [49].

Local ablative therapy has been used for the treatment of unresectable liver metastases from noncolorectal liver metastases. Goering et al treated 23 patients with cryoablation with or without liver resection and 25 patients with liver resection only for noncolorectal liver metastases [51]. The tumors included metastases from neuroendocrine, genitourinary, soft tissue, gastrointestinal, and head and neck tumors. With a median follow-up of 48 months, the overall 1-, 3-, and 5-year survival rates were 82%, 55%, and 39%, respectively, and the median survival 45 months. The 1-, 3- and 5-year survival rates in the resection group were 79%, 49%, and 40%, respectively, and in the cryoablation with or without liver resection group, 86%, 62%, and 37%, respectively. There was no significant difference between these groups [51]. Kerkar et al reported the long-term results of 98 patients of whom 28 had noncolorectal liver metastases treated by cryoablation [40]. These included five patients with liver metastases from neuroendocrine tumors. The overall median follow-up was 54 months. The 1-, 3-, and 5-year survival rates for those patients with noncolorectal liver metastases were 70%, 44%, and 28%, respectively. The median survival in this subgroup was 24 months [40].

Prognostic factors after cryotherapy The prognostic factors have now been worked out for those patients treated with cryotherapy for liver metastases from colorectal cancer. The preoperative CEA level was prognostic in those patients with low or medium volume disease, but in those with high volume disease the preoperative CEA level had no impact on survival and in these patients the prognosis was poor [52]. Low preoperative and low postoperative CEA levels were associated with a favorable prognosis in multivariate analysis [53]. Postoperative CEA values reflect the completeness of cryoablation. The number of lesions and the total estimated area of cryoablation did not significantly affect overall and hepatic recurrence-free survival [40]. However, Yan et al found that

239

SECTION 4


cryoablation and resection compared to cryoablation alone, cryoablation of seven or fewer tumors, and a tumor diameter of 3 cm or less were associated with improved cryosite disease-free survival [53]. The other favorable prognostic factors were the small (10 kHz) could pass through living tissue without causing neuromuscular excitation. Shortly thereafter, Von Zeynek proved that the same


244

frequencies could be used to heat living tissue [6]. These discoveries led to the development of medical diathermy and electrocautery. In 1943, a report by King et al, which described the occurrence of hepatic damage with wholebody hyperthermia, began efforts to develop a clinically useful mechanism for harnessing RF to produce focal hepatic thermal injury [7]. However, it was not until 1990 that available technology was adapted to allow minimally invasive treatment of malignant hepatic tumors. In the same year, both Rossi et al and McGahan et al published papers on ultrasound-guided RFA of hepatic tissue [8, 9]. Both groups suggested that RF could be used to create focal coagulative necrosis of hepatic tumors while sparing normal liver tissue.

Basics of radiofrequency ablation: how radiofrequency current destroys tumors Temperature and cell death RF current destroys tumors and surrounding tissue by the generation of heat. Cells have a limited capacity to survive temperatures above 43 °C. At this temperature, cells die after 30 min. As temperature is raised, the time to death decreases. At 50 °C, death occurs at 30 s; at 55 °C it occurs at 1 s, and above 60 °C cell death is instantaneous. Higher temperatures have other important biologic effects. At 100 °C intracellular and extracellular water will start to boil. If the temperature rises over 200 °C, hydrocarbons will begin to break down, leaving a deposit of carbon in the tissues.

How alternating current causes tissue heating Heating of tissues due to passage of RF current is the result of two processes. These are ionic friction and the dissipation of the heat from the site of friction. Ionic friction is caused by the to and fro movement of ions induced by an alternating current circuit. Such circuits, as opposed to direct current circuits, cause electrons to flow back and forth. The friction generates heat. In fact, in such a circuit all the electrical energy is dissipated as heat. This type of heating is called electrical or resistive heating. The rate at which current switches back and forth, i.e. the number of cycles per second, is the “frequency” of the circuit

CHAPTER 21

Thermal Ablation of Liver Tumors by Radiofrequency, Microwave, and Laser Therapy

and is expressed in Hertz (Hz = cycles per second). In classic experiments it was determined that high frequency alternating current circuits were safe for passage through animals, i.e. would not cause muscle stimulation or potentially lifethreatening arrhythmias. The frequency range for medical RF is about 200 KHz–20 MHz. These frequencies overlap AM radiofrequencies and are just below the frequencies of FM radio, i.e. they are in the RF part of the electromagnetic spectrum.

Radiofrequency generators and electrodes To pass RF electrical current through animal tissues, an RF generator and two electrodes are required. The electrodes are connected to the patient and to the generator to create an electrical circuit. The generator uses oscillators to convert commercially supplied alternating electrical current (60 Hz) to a current of the appropriate RF. The generator also uses transformers to increase the voltage from the 100 V at which it is supplied. Generators may be set to produce alternating current of different voltages and waveforms, and these settings produce different tissue effects due to the type of heating that occurs (e.g. the cutting versus coagulation effects used by surgeons on standard cautery machines). Coagulating current, the type used for RFA, provides bursts of current. The interval between bursts allows time for conduction of heat into tissues so that the energy is dispersed. In this way small blood vessels are thrombosed and bleeding is arrested.

Effect of electrical resistance on the effectiveness of tissue heating In RFA, the active electrode(s) are placed within tissues. Such electrodes are referred to as interstitial electrodes as opposed to surface electrodes. To cause electrical heating, it is desirable to pass high levels of current through the active electrode, since it is the density of the current and the duration of application that determines the magnitude of the frictional movement and consequent heating (current density = current/area of electrode). As heating progresses, tissue changes occur, some of which are desirable and others that are not. The latter may undermine the effectiveness of the ablation. RF generators are constructed to maintain a fairly uniform current over a range of resistances by increasing voltage as resistance rises. However, when voltages approach dangerous levels, further increases are forbidden and increases in resistance past this point are accompanied by reductions in current. Stated otherwise, if electrical resistance at the active electrode goes too high, current will stop flowing and electrical heating will cease. Resistance in an alternating current circuit is given the special name “impedance” because, in addition to pure resistance, there are other factors that such as the capacitance of the tissues that determine the resistance to current in an alternating circuit.

As heating occurs and the temperature of instantaneous cell death is reached, i.e. 65 °C, coagulative necrosis occurs. At temperatures over 100 °C, boiling of tissue water begins, leading to drying or desiccation of the tissues. The more the temperature exceeds 100 °C, the faster the boiling and desiccation occurs. Once desiccation occurs there is a large and dramatic increase in impedance. Charring does not happen until temperatures reach about 200 °C. The impedance of desiccated tissue is so high that only a thin rim of tissue around the active electrode is needed to greatly reduce the flow of current and consequent heating of tissue. These issues are of critical practical importance.

Conductive heating Electrical heating is confined to the zone immediately adjacent to the active electrode where the current density and ionic agitation are high. In fact, electrical heating decreases as the fourth power of the distance from the electrode. In other words, heating due to pure electrical factors will be 625 times less at 5 mm from the electrode than at 1 mm from the electrode, and at 1 cm from the electrode that number rises to 10 000. However, heat is conducted through tissue by contact of hot, more energetic molecules with cooler, less energetic molecules. The effect is such that conductive heating spreads the heat generated by ionic agitation through the adjacent tissues. Heat conduction may be thought of as occurring in a series of rings around the electrode. As the distance from the electrode increases, the size of the rings increases and the volume of tissue in each successive ring that must be brought up to temperature rises sharply. For instance, to extend the distance of ablation from a single electrode from 4 to 5 mm from a single RF electrode requires that only half the volume of tissue be heated compared with that required when attempting to extend the ablation from 9 to 10 mm from the electrode. The effect is that there is a rapid drop-off of energy dispersal by conduction into tissue as the distance from the electrode increases. Practically this means that a single interstitial RF electrode will produce a zone of coagulative necrosis of about 1 cm in diameter [11]. The shape of the lesion will depend on the electrode length. An electrode of 1 cm in length will produce a spherical lesion, but as the electrode is lengthened the shape becomes more elongated.

Convective heating (convective heat loss) Convective heating or heating through movement of heated matter also occurs in tissues as a result of blood flow. However, since the blood moves rapidly out of the area, the heating of blood actually has a negative influence on the effectiveness of ablation. Hence the commonly observed phenomenon of a zone of spared tumor adjacent to a large blood vessel. This “heat sink” effect of blood flow actually protects large blood vessels and explains why bile ducts are much more susceptible to injury than blood vessels. The

245

SECTION 4


heat sink effect also applies to smaller blood vessels, but as flow in these vessels is less, the wall of the vessel becomes heated and thrombosis ensues. To avoid the effect of convection, inflow occlusion may be used. In an animal model, inflow occlusion increased the volume of necrosis and resulted in more nearly spherical lesions [10, 11].

Application of electrical and thermal principles to the creation of a spherical zone of radiofrequency ablation Most hepatic tumors are spheroids. Those that might be targets of RFA range in size from a few millimeters to many centimeters. Ideally, the technology should allow production of spherical ablations ranging from 1 to 10 cm or more in a single ablation. A single RF electrode of 1 cm in length will produce a spherical lesion of 1 cm in diameter. Multiple strategies have been applied to getting uniform heating of a large sphere of tissue to temperatures that will result in instantaneous cell death. To create a sphere, multiple active electrodes are used. These are deployed either as a single electrode with multiple deployable arms or tines, or as three-needle electrodes in a triangular pattern [12]. Probes spaced 1.5 cm or less apart act synergistically, producing a total volume tissue destruction that is greater than when the individual probes are operated sequentially. To be successful, the heating program must create a temperature immediately around the active electrode that does not result in charring and interruption of heating before the tissues between the electrodes have been heated to at least 65 °C. To some extent the heating program is empirical and therefore differs with type of generator and electrode, but all have this same goal – to heat all the tissues in the sphere of interest to at least 65 C. One approach used to retard development of high resistance at the active electrode has been to cool the electrode by flowing cold water through the interior during RFA [13]. This prevents boiling of tissue water immediately adjacent to the electrode and thereby prevents desiccation and charring. This has two beneficial effects. It allows continued electrical heating and provides time for heat to be conducted away from the area of electrical heating by conduction before tissue impedance rises to levels at which current flow stops. Another strategy is to enlarge the surface area of the active electrode. Since electrical heating occurs only immediately around the electrode and heating is dependent on current density, making the active electrode somewhat larger can increase the volume of tissue that has the maximum effective current density [12]. Enlarging the electrode beyond a certain point, however, would have negative effects on current density at the electrode at permitted powers. Infusion of saline at the active electrode also results in a greater zone of ablation [14]. This is probably due to effectively increasing the electrode area since saline is a conductor of

246

electricity. Other effects of saline may be to maintain good contact between tissue and electrode. Recently, electrodes have been produced that are cooled internally and also emit saline [15]. Another strategy is to effectively have a moving electrode, opening the electrode array in stages or to redeploy the electrode in a new area. Sending current in pulses gives time for conduction of heat away from the active electrode, preventing heat build-up, desiccation, and unacceptable rises in impedance.

Commercially available radiofrequency generators for treatment of hepatic tumors There are currently three commercially available RF generator/electrode systems. Two use single electrodes with deployable tines (RITA, Radiotherapeutics) and the third (Radionics/ Valleylab) uses a triangular array. For each generator a program has been developed based on empirical experimental observations in animals. This is necessary to convert the theoretical considerations discussed above to a working system that will produce spherical ablations. The RITA generator/electrode system has both nonperfused and saline perfusion electrodes. For ablations of 5 cm or less, the standard (nonperfused) electrodes are used. These electrode can project nine tines, one of which is central and the other eight peripheral. The projection tends to be further forward from the shaft than the comparable electrode made by Radiotherapeutics, which is more like an umbrella with the tines turning to face 180 ° to the shaft. Several of the tines have temperature thermistors. The RITA equipment functions on a combined electrode/generator program. The “burn” is performed at various degrees of electrode deployment (moving electrode). The generator endpoints are tissue temperature and time. At each level of deployment, a mean temperature, e.g. 105 °C, is reached before beginning the countdown or deploying the tines further. At the fully deployed state, the countdown starts when the desired temperature is reached and is continued for a fixed time. This is followed by a 30 s “cool-down” period at which time the temperature at the ends of the tines is displayed. Temperatures above 65 °C are taken as evidence of a satisfactory ablation. The saline-perfused electrode injects hypertonic saline using a pump. This electrode permits 7-cm spherical ablations, the largest to date. This electrode has passive tines that measure tissue temperature between active tines. The RITA electrodes, because of their spatial deployment, tend to produce truly spherical lesions. The Radiotherapeutics system also uses a single electrode with deployable tines. Its tines are somewhat more closely spaced and curve more during deployment. As a result this system, in the authors’ experience, tends to produce a more cylindrical spheroid or compressed sphere or cylinder. The endpoint of this system is high impedance. Power is applied

CHAPTER 21


and impedance is measured. Impedance stays low throughout the program as power is increased and heating occurs. The end of the program is signaled by a sudden increase in impedance (“rolloff”). Temperature is not measured. The largest diameter of ablation is about 4 cm. The Radionics/Valleylab system uses both a single electrode and a cluster electrode in a triangular array. Each electrode is internally perfused with cold saline, maintaining the temperature immediately adjacent to the electrode below 100 °C. This prevents desiccation and its deleterious effects. The individual electrodes are thicker than the tines of the other products and up to three electrodes can be used simultaneously to ablate a larger lesion or used separately to ablate up to three smaller lesions in one ablation cycle. There are now four lengths and four tip exposures for custom ablation lesions between 4.5 cm and 6.5 cm (cool tip, Valley Lab). The heating program is timed and is based on laboratory data that have varied time, power, electrode length, and diameter, and other variables. When this system senses a rise in impedance, power is automatically reduced and then increased again as impedance rises. Real-time feedback includes impedance, current, power, and temperature. After the 12–25-min cycle (the ablation time is dependent on the lesion size) is complete, the true tissue temperature is displayed on the generator. This system tends to produce an elongated spheroid. The largest diameter of ablation is now 6.5 cm. The maximum power of this generator is 200 W. There are two European companies also producing electrodes. One is a bipolar electrode that creates lesions of 5–6 cm in diameter (Celon, Germany), and the other monopolar electrode is saline perfused, reducing tissue impedance and allowing larger ablation lesions (Berchtold, Germany).

Technique Method of delivery RFA can be accomplished by an open, laparoscopic, or percutaneous approach. Each has advantages and disadvantages. Open surgery optimizes the chances of detection of unknown intrahepatic and extrahepatic tumors. Tumors in most areas of the liver can be treated, particularly peripheral lesions that otherwise risk injury to adjacent organs, including those touching the diaphragm. Accurate placement of electrodes is facilitated by open surgery and inflow occlusion, to prevent dissipation of heat, is easily applied. Also, it is easier to treat multiple tumors. Open surgery also permits the surgeon to combine resection with RFA, although now many resections may also be accomplished laparoscopically. However, open surgery requires a general anesthetic and an upper abdominal incision. Both open and laparoscopic surgery allow complete inspection of the abdomen to rule out extrahepatic disease as well as performance of intraoperative ultrasound, which has greater sensitivity for detection of hepatic lesions. With percutaneous techniques, the

advantages of open surgery are lost but the advantages of minimal invasiveness are gained. Open surgery is still the gold standard for treatment of hepatic tumors, however circumstances that contraindicate open surgery or even a general anesthetic may exist. Under these conditions laparoscopic or percutaneous methods are often tolerated and are the procedures of choice. For example, an otherwise healthy patient with multiple colorectal metastasis, some of which may be touching the diaphragm, is probably best served by open surgery. In contrast, a less invasive technique would be favored in a patient with end-stage liver disease and a hepatocellular carcinoma (HCC). A multivariate analysis of data comparing open, laparoscopic, and percutaneous techniques, that included all tumor types, suggests that an open or laparoscopic approach may be associated with less local recurrence (3.6% recurrence) than percutaneous ablation (16% recurrence) [16]. However, increased morbidity and mortality can be associated with an open approach [17]. Complete ablation of all viable tumor cells is the goal of RFA and so imaging the tumor for appropriate needle placement is of paramount importance. Ultrasound (either intraoperative or transcutaneous) remains the standard imaging modality [18], but it has some shortcomings. Unlike with cryoablation in which the formation of the “iceball” can be visualized ultrasonographically in real time, no reliable visible signs of the ablation zone with respect to the tumor are readily apparent at the time of tissue heating. Preablation positioning of the array must be precise and measured in three dimensions in order to optimize margins of ablation. Figure 21.1 shows an example of intraoperative images and placement and deployment of the RFA probe. Percutaneous RF can also be guided by magnetic resonance imaging (MRI). Several small studies demonstrate the feasibility of this technique and confirm its safety and efficacy [19–22]. However, the studies are small and no randomized comparisons to computerized tomography (CT) or ultrasound are available to prove its superiority, and also this technique is obviously limited by access and cost as many facilities do not have the capacity or experience to use intraprocedural MRI. There are several potential advantages of MRI guidance, such as accurate electrode placement, particularly when overlapping ablations are required, real-time monitoring of necrosis, and accurate thermal monitoring, so ablative temperatures can be reached and surrounding structures are protected from unintentional damage [23]. MRI guidance can also be used for MW and laser ablation [23]. Patient positioning is dependent on the number and position of tumors to be ablated, as well as the approach (i.e. laparoscopic or open). Grounding pad positioning is critical as severe skin burns have been reported in patients with malpositioned pads [24]. Two grounding pads should be used on the lower extremities with the long axis of the pad

247

SECTION 4


(b)

(a)

(c) Figure 21.1 (a) Longitudinal and (b) transverse ultrasound views of deployment of tines of a “Starburst” electrode through a tumor prior to ablation. Note that the tines encompass the tumor. (c) “Outgassing” is visible around tines after commencement of ablation.

facing the liver to allow for optimal heat dispersion. Previous reports suggesting that the grounding pad be placed on the patient’s back are incorrect and increase the risk of serious pad burns. Deployment of the RFA probe differs according to the type of probe used. The needle electrodes with retractable curved prongs (e.g. RITA, Radiotherapeutics) are positioned so that the epicenter of the sphere of ablation matches the epicenter of the tumor. After checking the position in two dimensions at full deployment, sequential ablations are performed, sometimes (RITA) with stepwise prong advancement (starting at 2 cm) to full extension (usually 5 cm). Real-time temperature monitoring and/or impedance monitoring is used to assure spherical ablation. Inflow occlusion can be used especially if focal target temperatures are not being reached due to a heat sink effect from surrounding blood vessels [25]. At laparotomy or laparoscopy, a Pringle maneuver can be employed, but it is associated with a 0.2–0.4% incidence of portal vein thrombosis so it must be used with caution

248

[26]. However, optimal technique in this regard needs to be defined as more studies correlate local recurrence with technical factors of deployment, ablation, and tumor size. On completion of the ablation, needle tracts can be cauterized to avoid bleeding and potentially prevent tumor cell implantation in the needle tract. Currently, the largest spherical diameter that can be ablated with a single deployment is 7 cm (as stated above). The ideal ablative margin is controversial and depends on the size and pathology of the tumor. For example, to obtain a 1-cm margin of ablation, the diameter of the ablation sphere must be 2 cm greater than the tumor sphere; therefore, if a 3-cm tumor exists, a 5-cm ablation should be performed. If a system is to be used that produces 5-cm ablations, for larger lesions multiple ablations are then usually needed. Mathematical models show that the number of overlapping deployments rises dramatically as lesion size increases (Table 21.1). This is critical to achieve a marginnegative ablation. However, as the number of needed

CHAPTER 21


Table 21.1 Number of overlapping ablations required assuming a 5-cm deployment. Size of spherical ablation (cm) Number of overlapping ablations required

5 1

6 6

8 12

9.5 30

ablations/lesions rises, so does the possibility of placement error. The difficulty of multiple accurate deployments is evidenced by the higher local recurrence rate in tumors larger than 5 cm. There are no studies currently comparing efficacy of different electrodes, and while technology is constantly changing we await a less complex method of ablation of larger lesions.

Clinical results RFA has become the most widely used modality for the thermal ablation of liver tumors, but the indications for its use remain controversial. For primary and certain secondary liver tumors, complete resection, when feasible, remains the only proven potentially curative treatment. However, many patients are not candidates for surgical resection of their hepatic neoplasm(s) and for this reason, there is increasing interest in ablative approaches. In addition, re-resection is not possible in many patients who recur after hepatic resection, and an ablative approach has much appeal. Improved equipment that allows larger spherical thermal ablation of tumors (and therefore higher likelihood of complete tumor destruction) has further kindled interest in this treatment modality. Clinical studies are ongoing and it is evident that liver lesions can be successfully ablated with low morbidity. The critical question that needs to be answered is whether RFA in unresectable patients impacts patient overall survival and/ or quality of life. The majority of patients treated to date have had HCC, metastatic colorectal cancer, or metastatic neuroendocrine tumors. Because many studies have heterogeneity of tumor origin, size, mode of delivery of ablation, and resectability, as well as a variety of definitions of resectability, interpretation of the data can be challenging. The principle of hepatic resection for colorectal metastasis are an important guide when considering patients for ablation. There are almost no 5-year survivors of untreated single or multiple hepatic metastasis, whereas approximately 30–60% of completely resected patients survive for 5 years [27] and this may be higher in patient screened by positron emission tomography (PET) [28]. Furthermore, no resected patients with positive microscopic margins survives 5 years, suggesting that survival benefit depends on a macroscopically and microscopically complete resection. This emphasizes the point that only with microscopically complete ablation are we likely to impact survival of metastatic liver

disease. Certainly, patient selection is critical, as those with extrahepatic disease or subclinical hepatic metastasis are unlikely to benefit from local ablative treatments. In our recent study, PET scans were more likely to be positive in patients with more advanced disease. Since patients with unresectable disease usually have more advanced disease, PET scanning prior to ablation to rule out extrahepatic disease should be advocated for every patient. There are three groups of patients who might be treated by RFA: those with unresectable lesions, those with resectable lesions who are ineligible for resection for reasons of general health, and those with resectable lesions who have no contraindication to open surgery. The appeal of a minimally invasive, ablative approach to liver tumors is obvious. Compared to resection, RFA is less morbid, spares more parenchyma, can be accomplished laparoscopically or percutaneously, and is less costly. However, resection remains the gold standard for primary and secondary liver tumors and until RFA is proven to be as effective in a randomized trial, resection should remain the standard therapy for eligible patients.

Colorectal metastases Efficacy of RFA can be measured in several ways and certain caveats are imperative in interpreting the available studies. Local recurrence rates are often emphasized, usually on a per lesion basis, but sometimes on a per patient basis (in patients who have multiple ablations). Emphasis on local recurrence is certainly warranted when attempting to identify technical or anatomic considerations that increase the risk of local failure. Nonetheless, overall survival and disease-free survival must be the true measure of the efficacy of RFA, just as they are for resection. Unfortunately, due to the short follow-up period of most published studies and the lack of trials comparing RFA to systemic or regional chemotherapy, no conclusions regarding improvement in survival or quality of life can be drawn. In addition, many published studies lump results for primary and secondary hepatic tumors together, or do not separately present results for colorectal metastasis and neuroendocrine tumors. This is an important distinction when considering local recurrence, because neuroendocrine tumors may be indolent. They may take many years to recur and long-term survivors are not uncommon even in untreated patients. As a result, lumping results of such patents with those of more aggressive tumors makes evaluation of efficacy problematic. There are some studies to date commenting on greater than 3-year survival after RFA for colorectal tumors (Table 21.2). None of the data is randomized and patients who received RFA were considered unresectable based on inability to tolerate surgery, refusal of surgery, or technical considerations. The largest clinical series of RFA of hepatic neoplasms are shown in Table 21.3. Based on the caveats outlined above,

249

SECTION 4


Table 21.2 Colorectal cancer liver metastases: survival studies after radiofrequency ablation. Survival (years) Author

Year

Patients

Size (cm)

1 (%)

2 (%)

3 (%)

4 (%)

Solbiati et al [29] Iannitti et al [30] Oshowo et al [31] White et al [32] Abdalla et al [27] Gillams et al [33] Joosten et al [33]

2001 2002 2003 2004 2004 2005 2005

117 52 25 30 57 167 28

3.2 5.2 3.0 3.0 2.5 3.9 2.0

93 87 – 75 – 99 93

69 77 – 45 – – 75

46 50 53

– – – – – 30 –

37 58 46

Table 21.3 Results from the largest clinical series of radiofrequency ablation of hepatic neoplasms. Authors (year)

Patient

Tumor

Histology

Technique

Complications

LR*

Median follow-up (months)

Rossi et al (1996) [37] Curley et al (1999) [38]

39 123

41 169

H H, CRM, NEM, Misc

P O, P

None 3/123 (2.4%)

22.6 15

Bilchik et al (1999) [39]

50

231

H, CRM, NEM, Misc

O, P, L

7/84 (8.0%)

Siperstein et al (2000) [35]

43

181

H, CRM, NEM, Misc

L

Not reported

De Baere et al (2000) [40] Machi et al (2001) [41]

68 60

121 204

CRM, NEM, Misc H, CRM, NEM, Misc

O, P O, P, L

7/68 (10%) 4/60 (6.7%)

CRM

P

3/117 (2%)

NEM CRM, HCC

L O, P, L

Minimal 36/153 (23.5%)

CRM

P

1/25

2/41 (4.9%) 3/169 (1.8%) 15/231 (6.4%) 22/181 (12.2%) 9/121 (7%) 18/204 (8.8%) 70/179 (39%) 6/227 (3%) 52/447 (12%) Not reported 13/227 (5.7%) 39 9 Not reported 6

Solbiati et al (2001) [29]

117

Berber et al (2002) [42] Bleicher et al (2003) [43]

34 153

222 447

Oshowo et al (2003) [31]

25

25

Elias et al (2004) [44]

88

227

CRM, NEM, Misc

O

None

30 57 167 28

30 57 167 28

CRM CRM CRM CRM

P O P O

Minimal Not reported 14/354 (4%) (11%)

White et al (2004) [32] Abdalla et al (2004) [27] Gillams et al (2005) [33] Joosten et al (2005) [34]

9 13.9 13.7 20.5 6–53 (range) 1.6 11 37 (median survival) 27.6 17 21 38 (median survival) 26

*LR reported on a per lesion, not a per patient, basis. LR, local recurrence; H, hepatocellular carcinoma; CRM, colorectal metastasis; NEM, neuroendocrine metastasis; Misc, miscellaneous metastases (breast, gastric, ovarian, adrenal carcinoma, melanoma, leiomyosarcoma; O, open; P, percutaneous; L, laparoscopic.

the data deserve some scrutiny. For example, in the study published by Siperstein et al [35], local recurrence is reported at 12%. However, when the analysis is performed on a per patient (rather than a per lesion) basis, the recurrence rate goes up to 28%. Furthermore, if the analysis is restricted to patients with metastatic adenocarcinoma (the group most

250

likely to recur rapidly), 12 of 18 (66%) had definite or suspected local recurrence even with a relatively short median follow-up. Based on these recurrence rates, a benefit in disease-free or overall survival is unlikely. As expected, studies with longer follow-up have higher local recurrence rates [36].

CHAPTER 21


Table 21.4 Comparison of partial hepatectomy and radiofrequency ablation for resectable hepatocellular carcinoma Authors

Patient no Abl vs Rx

Tumor size (mm) Abl vs Rx

Median follow-up (months)

Median DFS (months) Abl vs Rx

5-year survival Abl vs Rx

5-year DFS

Ueno et al (2009) [49] Guglielmi et al (2008) [50] Lupo et al (2007) [51] Chen et al (2006) [52] Lu et al (2006) [53]

110 vs 123 109 vs 91 60 vs 42 71 vs 90 51 vs 54

27 vs 20 10 mm, cholelithiasis, “porcelain” gallbladder

References 1 www.pubmed.gov (accessed March 2008). 2 www.tripdatabase.com (accessed March 2008). 3 National Cancer Comprehensive Network: NCCN Clinical Practice Guideline in Oncology Hepatobiliary Cancers V.2 2008. www.nccn.org (accessed March 2008). 4 Kondo S, Takada T, Miyazaki M, et al. Guidelines for the management of biliary tract and ampullary carcinomas: surgical treatment. J Hepatobiliary Pancreat Surg 2008;15:41– 54. 5 Garden OJ, Rees M, Poston GJ, et al. Guidelines for resection of colorectal cancer liver metastases. Gut 2006;55 (Suppl III): iii1–iii8 6 Sheth S, Bedford A, Chopra S. Primary gallbladder cancer: recognition of risk factors and the role of prophylactic cholecystectomy. Am J Gastroenterol 2000;95:1402–10. 7 Larsson SC, Wolk A. Obesity and the risk of gallbladder cancer: a meta-analysis. Br J Cancer 2007;96:1457–61. 8 Ishiguro S, Inoue M, Kurahashi N, Iwasaki M, Sasazuki S, Tsugane S. Risk factors of biliary tract cancer in a large –scale population-based cohort study in Japan (JPHC study); with special focus on cholelithiasis, body mass index and their effect modification. Cancer Causes Control 2008;19:33–41. 9 Roa I, Araya JC, Villaseca M, et al. Preneoplastic lesions and gallbladder cancer: an estimate of the period required for progression. Gastroenterology 1996;111:232–6. 10 Ransohoff DF, Gracie WA. Treatment of gallstones. Ann Intern Med 1993;119: 606–19. 11 Stephen AE, Berger DL. Carcinoma in the porcelain gallbladder: a relationship revisited. Surgery 2001;129:699–703. 12 Kokudo N, Makuuchi M, Natori T, Sakamoto Y, Yamamoto J, et al. Strategies for surgical treatment of gallbladder carcinoma base on information available before resection. Arch Surg 2003;138:741–50. 13 Miller G, Schwartz LH, D’Angelica M. The use of imaging in the diagnosis and staging of hepatobiliary malignancies. Surg Oncol Clin N Am 2007;16:343–68. 14 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. 15 Petrowsky H, Wildbrett P, Husarik DB, et al. Impact of integrated positron emission tomography and computed tomography on staging and management of gallbladder cancer and cholangiocarcinoma. J Hepatol 2006;45:43–50. 16 Kim SJ, Lee JM, Lee JY, et al. Accuracy of preoperative T-staging of gallbladder carcinoma using MDCT. AJR Am J Roentgenol 2008;190:74–80.

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17 Sarli L, Contini S, Sansebastiano G, Gobbi S, Costi R, Roncoroni L. Does laparoscopic cholecystectomy worsen the prognosis of unsuspected gallbladder cancer? Arch Surg 2000;135:1340–4. 18 Whalen GF, Bird I, Tanski W, Russell JC, Clive J. Laparoscopic cholecystectomy does not demonstrably decrease survival of patients with serendipitously treated gallbladder cancer. J Am Coll Surg 2001;192:189–95. 19 De Aretxabala X, Roa I, Mora J, et al. Laparoscopic cholecystectomy: its effect on the prognosis of patients with gallbladder cancer. World J Surg 2004;28:544–7. 20 Wakai T, Shirai Y, Yokoyamma N, Nagakura S, Watanabe H, Hatakeyama K. Early gallbladder carcinoma does not warrant radical resection. Br J Surg 2001;88:675–8. 21 Shirai Y, Yoshida K, Tsukada K, Muto T. Inapparent carcinoma of the gallbladder: an appraisal of a radical second operation after simple cholecystectomy. Ann Surg 1992;215:326–31. 22 Roa I, de Aretxabala X, Araya JC, Villaseca M, Roa J, Guzmán P. Incipient gallbladder carcinoma. Clinical and pathological study and prognosis in 196 cases. Rev Med Chil 2001;129: 1113–20. 23 De Aretxabala X, Roa I, Mora J, et al. Management of gallbladder cancer with invasion of the muscular layer. Rev Med Chil 2004;132:183–8. 24 Wakai T, Shirai Y, Yokoyama N, et al. Depth of subserosal invasion predicts long term survival after resection in patients with T2 gallbladder carcinoma. Ann Surg Oncol 2003;10:447–54. 25 De Aretxabala X, Roa I, Burgos L, et al. Gallbladder cancer: an analysis of a series of 139 patients with invasion restricted to the subserosal layer. J Gastrointest Surg 2006;10:186–92. 26 Chan SY, Poon RT, Lo CM, Ng KK, Fan ST. Management of carcinoma of the gallbladder: a single-institution experience in 16 years. J Surg Oncol 2008;97:156–64. 27 Goetze TO, Paolucci V. Benefits of reoperation of T2 and more advanced incidental gallbladder carcinoma: analysis of the German registry. Ann Surg 2008;247:104–8. 28 Kayahara M, Nagakawa T. Recent trends of gallbladder cancer in Japan: an analysis of 4,770 patients. Cancer 2007;110: 572–80. 29 De Aretxabala X, Roa I, Burgos L, et al. Gallbladder cancer in Chile. A report on 54 potentially resectable tumors. Cancer 1992;69:60–5. 30 Gallardo J, Rubio B, Villanueva L, Barajas O. Gallbladder cancer, a different disease that needs individual trials. J Clin Oncol 2005;23:7753–4. 31 De Aretxabala X, Roa I, Berrios M, et al. Chemoradiotherapy in gallbladder cancer. J Surg Oncol 2006;93:699–704. 32 Dingle BH, Rumble RB, Brouwers MC. The role of gemcitabine in the treatment of cholangiocarcinoma and gallbladder cancer: a systematic review. Can J Gastroenterol 2005;19:711–6. 33 De Aretxabala X, Losada H, Mora J, et al. Neoadjuvant chemoradiotherapy in gallbladder cancer. Rev Med Chil 2004;132: 51–7.

Gallbladder Cancer

34 Goere D, Wagholikar GD, Pessaux P, et al. Utility of staging laparoscopy in subsets of biliary cancers : laparoscopy is a powerful diagnostic tool in patients with intrahepatic and gallbladder carcinoma. Surg Endosc 2006;20:721–5. 35 Shih SP, Schulick RD, Cameron JL, et al. Gallbladder cancer: the role of laparoscopy and radical resection. Ann Surg 2007;245:893–901. 36 Scheingraber S, Justinger C, Stremovskaia T, Weinrich M, Igna D, Schilling MK. The standardized surgical approach improves outcome of gallbladder cancer. World J Surg Oncol 2007;5: 55–62. 37 Fong Y, Wagman L, Gonen M, et al. Evidence-based gallbladder cancer staging: changing cancer staging by analysis of data from the National Cancer Database. Ann Surg 2006;243:767–71. 38 Ott R, Hauss J. Need and extension of lymph node dissection in gallbladder carcinoma. Zentralbl Chir 2006;131:474–7. 39 Kondo S, Nimura Y, Hayakava N, Kamiya J, Nagino M, Uesaka K. Regional and para aortic lymphadenectomy in radical surgery for advanced gallbladder carcinoma. Br J Surg 2000;87:418–22. 40 Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual, 6th edn. New York: Springer, 2002: 140. 41 Henson DE, Albores-Saavedra J, Compton CC. Protocol for the examination of specimens from patients with carcinomas of the gallbladder, including those showing focal endocrine differentiation: a basis for checklists. Cancer Committee of the College of American Pathologists. Arch Pathol Lab Med 2000;124:37–40. 42 Agarwal AK, Mandal S, Singh S, Bhojwani R, Sakhuja P, Uppal R. Biliary obstruction in gall bladder cancer is not sine qua non of inoperability. Ann Surg Oncol 2007;14:2831–7. 43 Reddy SK, Marroquin CE, Kuo PC, Pappas TN, Clary BM. Extended hepatic resection for gallbladder cancer. Am J Surg 2007;194:355–61. 44 Dixon E, Vollmer CM Jr, Sahajpal A, et al. An aggressive surgical approach leads to improved survival in patients with gallbladder cancer: a 12-year study at a North American Center. Ann Surg 2005;241:385–94. Shimizu H, Kimura F, Yoshidome H, et al. Aggressive surgical approach for stage IV gallbladder carcinoma based on Japanese Society of Biliary Surgery classification. J Hepatobiliary Pancreat Surg 2007;14:358–65.


A D E A D

341

29

Colorectal Liver Metastases Phuong L. Doan1, Jean-Nicolas Vauthey2, Martin Palavecino2, and Michael A. Morse1 1 2

Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC, USA Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

Initial evaluation and diagnosis Approximately 15% of patients with colorectal cancer will have liver metastases at diagnosis, and more than half will develop liver metastases during the course of their disease. The initial evaluation of a patient with colorectal cancer with liver metastases should include carcinoembryonic antigen (CEA) testing, colonoscopy, computed tomography (CT) of abdomen and pelvis, and fluorodeoxyglucose-positron emission tomography (FDG-PET; Figure 29.1) [1, 2]. More than 75% of colorectal cancers express CEA, and levels normalize after curative resection of colorectal primary. Secondary elevation indicates recurrent disease and should be further evaluated. In patients who did not previously undergo colectomy, colonoscopy is performed to exclude local recurrence as part of the evaluation for resection of liver metastases. FDG-PET is performed in some centers to rule out unexpected sites of extrahepatic disease. The addition of PET to identify patients who are candidates for resection of liver metastases was associated with better disease-free survival and overall survival in those with clinical risk score (Fong Score) greater than 2, but not those with a score of 2 or less [2].

Treatment (Figure 29.1) Resection of liver metastases and extrahepatic disease Hepatic resection is the gold standard treatment for colorectal liver metastases and provides a 5-year survival of 58% [3]. Another treatment option, such as radiofrequency ablation, provides only a slightly better survival than chemotherapy alone [4]. Simultaneous resection of the primary colorectal cancer and minor hepatic resection can be safely


342

performed [5, 6], but simultaneous major resections and colorectal resection are associated with an increased risk of severe complications. In the latter cases, patients should undergo staged primary and liver resections using the traditional approach (primary first) or the reverse approach (liver first) [7]. In addition, a two-stage hepatectomy can be offered if a single resection would not achieve complete treatment. In one study, 35 of 51 patients (69%) were able to undergo a two-stage hepatectomy with a 2-month mortality of 11% [5]. The mean interval between procedures was 4.3 months. Overall 3- and 5-year survival rates were 57% and 39%, respectively. The resection of liver metastases can be done simultaneously with the resection of extrahepatic disease. Seventyfive patients who underwent simultaneous R0 resection of colorectal liver metastases and extrahepatic disease had a 5-year survival rate of 28%. This cohort included 10 patients (13%) with lung metastases and 10 patients (13%) with hilar lymph node involvement. In patients with lung metastases, hepatectomy was performed first, followed by resection of lung metastases 2 months later, provided that there had been no interval disease progression and patients were still resectable at that time. This survival rate was not statistically different from 219 patients in the same study who did not have extrahepatic disease at the time of study enrolment. In addition to simultaneous resection of pulmonary metastases, simultaneous resection of regional lymph node metastases can improve overall survival [6]. In comparison to patients with colorectal liver metastases only, the involvement of a regional lymph node (RLN) with metastases is a poor prognostic factor [8]. Forty-seven patients with intraoperatively confirmed RLN metastases who underwent hepatectomy with simultaneous lymphadenectomy were compared with 710 patients without RLN metastases who underwent hepatectomy alone. Both groups had received preoperative systemic chemotherapy. Five-year overall survival for patients with and without RLN metastases was 18% and 53%, respectively. While there are no randomized studies comparing resection with no resection, natural history studies suggest 100% mortality at 5 years without resection of liver metastases.

CHAPTER 29

D I A G N O S I S

Preoperative consideration and work-up • Hx & PE • CEA[1] • Colonoscopy[2] • CT abd/pelvis + CXR or chest CT • FDG-PET scan[3]

Unresectable Colorectal liver metastasis

Resectable Systemic therapy

Follow resectable pathway

Colon resection if imminent risk of obstruction, bleeding

Resectable T R E A T M E N T

Colorectal Liver Metastases

Resectable

Simultaneous vs staged liver resection[4] ± colectomy ± lung resection of metastases[5–9]

FOLFIRI[10], FolFOX[11–14], or CapeOX[14] ± bevacizumab[15–17]

Unresectable

Second-line chemotherapy for advanced disease Unresectable

Selective internal radiation therapy[22]

Liver resection ± colectomy[4,5,18 ] A D J U V A N T T H E R A P Y S U R V E I L L A N C E

FolFIRI, FolFOX, or CapeOX ± bevacizumab for 6 months ±

Additional chemo to total 6 months if patient received neoadjuvant therapy

Evaluate for repeat hepatectomy

± Evaluate for repeat hepatectomy

Systemic chemo as for advanced disease

FUDR by intrahepatic arterial pump for 6 months[19–21]

If no evidence of disease, then: • CEA every 3 month x 2 year, then 6 month x 3–5 year • CT chest/abd/pelvis every 3–6 month x 2 year, then every 6–12 month to total of 5 year • Colonoscopy in 1 year or in 3–6 month if no preoperative colonoscopy done

Recurrence

Figure 29.1 Algorithm for the management of a patient with colorectal cancer with liver metastases. Hx & PE, history and physical examination; CEA, carcinoembryonic antigen; CT, computed tomography; CXR, chest X-ray; FDG-PET, fluorodeoxyglucose-positron emission tomography; FUDR, floxuridine.

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Guidelines for Liver Tumor Treatment

The 2006 American Hepato-Pancreato-Biliary Association (AHPBA) sponsored Consensus Conference on Colorectal Liver Metastases defined resectability as: (1) the ability to preserve two contiguous hepatic segments; (2) the preservation of adequate vascular inflow and outflow as well as biliary drainage; and (3) the ability to preserve adequate future liver remnant (>20% in a healthy liver). Unfortunately, 90% of patients are deemed unresectable at initial evaluation, with metastatic liver disease being the major cause of death in these patients [9]. Therefore, resection of liver metastases should be offered to all patients who are suitable candidates and neoadjuvant chemotherapy should be considered in patients who are deemed unresectable at initial evaluation (see also Chapter 17).

Neoadjuvant chemotherapy Neoadjuvant chemotherapy offers earlier treatment of micrometastases, predicts chemotherapy sensitivity to plan adjuvant therapy, and allows for systemic treatment of early progressive disease [10]. The most important goal of neoadjuvant chemotherapy is to downsize colorectal liver metastases such that unresectable disease becomes resectable. Neoadjuvant chemotherapy can convert unresectable liver metastases to resectable metastases in up to 38% of patients [11]. In this section, we will discuss selected references to support the use of irinotecan, oxaliplatin, 5-fluorouracil (5FU), and bevacizumab as neoadjuvant chemotherapy. Forty patients received neoadjuvant irinotecan 180 mg/m2 and infusional 5-FU with folinic acid for colorectal cancer with initially unresectable hepatic metastases. Objective responses were obtained in 19 patients (47.5%) with two complete responses. Thirteen patients (32.5%) were able to undergo potentially curative liver resection of metastases. Median time to progression was 14.3 months. All patients were alive at median follow-up of 19 months. Grade 3/4 hematologic and gastrointestinal toxicities were 35% and 12.5%, respectively [12]. In a study with oxaliplatin, 364 patients with colorectal cancer and up to four liver metastases were randomized to receive six cycles of FOLFOX preand post-operatively versus surgery alone. Neoadjuvant chemotherapy with FOLFOX was shown to increase progression-free survival by 7.3% at 3 years (from 28.1% to 35.4%). Overall survival is still being monitored [13]. In another study, 56 patients with high risk of early recurrence (using Fong score) were selected for a single center, nonrandomized phase II trial. Chemotherapy consisted of six cycles (biweekly) of bevacizumab plus capecitabine and oxaliplatin. The median time between last dose of bevacizumab and surgery was 5 weeks. The last cycle did not include bevacizumab. The authors observed no increased surgical or wound healing complications. Bevacizumab did not impair liver function and regeneration [14]. Thirty-two patients received bevacizumab prior to or after liver resection for colorectal metastasis and were compared to a matched

344

control group. Morbidity between the two groups was statistically similar (41% versus 38%, respectively; p = 1) [15]. Taken together, these studies demonstrate that neoadjuvant chemotherapy improves progression-free survival and possibly overall survival in patients with colorectal liver metastases. The prolonged progression-free survival with neoadjuvant chemotherapy comes with chemotherapy-induced hepatotoxicity. Surgery should be performed as soon as resectability is determined so that hepatotoxicity from chemotherapy is limited. Chemotherapy can induce regimen-specific histopathologic changes. In a systematic review, 248 patients had histopathologic changes after neoadjuvant chemotherapy. Preoperative irinotecan was associated with increased steatohepatitis rate. The 90-day mortality in patients with steatohepatitis was higher (14.7% versus 1.6% in patients without steatohepatitis; p = 0.001). The risk was increased in patients with a body mass index (BMI) of 25 or more [16]. The study included 66 metastases with complete response. To compensate for severe chemotherapy-induced hepatotoxicity and reduce morbidity, portal vein embolization should be considered in patients who have received extensive chemotherapy (six or more cycles) with a future liver remnant of 30% or less of the total estimated liver volume [17]. Despite downsizing of lesions due to neoadjuvant therapy, all sites of original disease should be resected. Sixty-six metastases with apparent complete response were resected and 53 (83%) of these metastases contained residual disease [18]. Duration of neoadjuvant therapy is usually less than 3–4 months (see also Chapter 10).

Adjuvant chemotherapy Adjuvant chemotherapy is recommended to eliminate residual microscopic disease [19]. A hepatic arterial port or implantable pump can be placed during surgical resection of liver metastases to allow for infusion of cytotoxic agents through the hepatic artery to better target liver metastases. One hundred fifty-six patients with colorectal liver metastases were randomized at the time of resection to receive six cycles of hepatic arterial infusion (HAI) with floxuridine and dexamethasone plus intravenous 5-FU with or without leucovorin versus six cycles of systemic therapy alone. At 2 years, the overall survival for the combined therapy group was 86% compared to 72% in the group that received systemic chemotherapy. Median survival was 72.2 months in the combined therapy group compared with 59.3 months in the systemic chemotherapy group [20, 21]. Early studies suggest infusion of fluorodeoxyuridine by the hepatic artery with systemic chemotherapy prolongs overall survival and time to hepatic progression compared to chemotherapy alone. Until these results are validated, HAI should not be offered routinely outside the setting of a clinical trial. Future studies are investigating the use of HAI in combination with capecitabine and oxaliplatin. In total, the duration of

CHAPTER 29

adjuvant therapy is 6 months. Patients who received neoadjuvant therapy may be considered for an abbreviated course of adjuvant therapy (see also Chapter 10).

Salvage therapy for refractory disease or disease recurrence Patients who do not respond to first-line systemic chemotherapy therapy and are unresectable should receive salvage chemotherapy. If these patients have colorectal metastases limited to the liver only, they may benefit from selective internal radiation therapy. In a study of 30 patients with unresectable colorectal liver metastases previously treated with 5-FU-based chemotherapy, 33% of patients had response with selective internal radiation therapy compared to 21% response with standard chemotherapy. Selective internal radiation therapy should be reserved for patients with intrahepatic disease only. Additional studies are required [22].

Surveillance After initial therapies with resection of colorectal liver metastases and adjuvant chemotherapy, patients should have ongoing close surveillance for disease recurrence. If there is evidence of disease recurrence, then patients should have re-evaluation for repeat hepatectomy (see also Chapter 19) or systemic chemotherapy if lesions are not resectable (Figure 29.1).

Self-assessment questions 1 How did the 2006 AHPBA-sponsored Consensus Conference on Colorectal Liver Metastases define respectability? A The ability to preserve two contiguous hepatic segments B Preservation of adequate vascular inflow and outflow as well as biliary drainage C The ability to preserve adequate future liver remnant (>20% in a healthy liver) D All of the above 2 Which one of the following statements regarding neoadjuvant chemotherapy for initially unresectable hepatic metastases is false? A Neoadjuvant chemotherapy can convert unresectable liver metastases to resectable metastases in up to 38% of patients B Neoadjuvant chemotherapy including bevacizumb did not result in a higher rate of surgical or wound healing complications C Neoadjuvant chemotherapy including bevacizumab did not impair liver function and regeneration

Colorectal Liver Metastases

D As much chemotherapy as possible should be administered before attempting hepatic metastasis resection 3 Which one of the following statements regarding chemotherapy for patients undergoing hepatic metastasis resections is false? A Preoperative irinotecan was associated with an increased steatohepatitis rate B The 90-day mortality in patients with steatohepatitis is higher than in patients without steatohepatitis C Only sites of residual disease should be resected D Portal vein embolization should be considered in patients who have received extensive chemotherapy (≥6 cycles) with a future liver remnant of 30% or less of the total estimated liver volume 4 Which one of the following statements is incorrect regarding the evaluation of hepatic metastases of colorectal cancer? A Approximately 50% of patients with colorectal cancer will have liver metastases at diagnosis, and more than 80% will develop liver metastases during the course of their disease B In patients who did not previously undergo colectomy, colonoscopy is performed to exclude local recurrence as part of the evaluation for resection of liver metastases C More than 75% of colorectal cancers express CEA, and levels normalize after curative resection of colorectal primary D The addition of PET to identify patients who are candidates for resection of liver metastases was associated with better disease-free survival and overall survival in those with a clinical risk score (Fong score) > 2, but not those ≤2 5 Which one of the following statements about resections is false? A Resection of the primary colorectal cancer and hepatic resection should never be performed simultaneously B The resection of liver metastases can be done simultaneously with the resection of extrahepatic disease C In comparison to patients with colorectal liver metastases only, the involvement of regional lymph node with metastases is a poor prognostic factor

References 1 Goldstein MJ, Mitchell EP. Carcinoembryonic antigen in the staging and follow-up of patients with colorectal cancer. Cancer Invest 2005;23:338–51.

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2 Fernandez FG, Drebin JA, Linehan DC, et al. Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron tomography with F-18 fluorodeoxyglucose (FDG-PET). Ann Surg 2004;240:438–50. 3 Abdalla EK, Vauthey J-N, Ellis LM, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 2004;239:818–27. 4 Abdalla EK, Adam R, Bilchi AJ, et al. Improving respectability of hepatic colorectal metastases: Expert Consensus Statement. Ann Surg Oncol 2006;13:1261–8. 5 Reddy SK, Pawlik TM, Zorzi D, et al. Simultaneous resections of colorectal cancer and synchronous liver metastases: a multiinstitutional analysis. Ann Surg Oncol 2007;14:3481–91. 6 Mentha G, Majno PE, Andres A, et al. Neoadjuvant chemotherapy and resection of advanced synchronous liver metastases before treatment of the colorectal primary. Br J Surg 2006;93:872–8. 7 Adam R, Wicherts D, Miller R, et al. Two-stage hepatectomy for irresectable colorectal cancer liver metastases: A 14-year experience. ASCO 2008 Gastrointestinal Cancers Symposium 2008: a283. 8 Adam R, de Haas RJ, Wicherts DA, et al. Is hepatic resection justified after chemotherapy in patients with colorectal liver metastases and lymph node involvement? J Clin Oncol 2008;26:3672–80. 9 Charnsangavej C, Clary B, Fong Y, et al. Selection of patients for resection of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol 2006;13:1261–8. 10 Leonard GD, Brenner B, and Kemeny NE. Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol 2005; 23:2038–48. 11 Giachetti S, Itzhaki M, Gruia G, et al. Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin, and surgery. Ann Oncol 1999;10:663–9. 12 Pozzo C, Basso B, Cassano A, et al. Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol 2004;15:933–9. 13 Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomized controlled trial. Lancet 2008;371:1007–16.

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14 Gruenberger B, Tamandl D, Schueller J, et al. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol 2008;26:1830–5. 15 D’Angelica M, Kornprat P, Gonen M, et al. Lack of evidence for increased operative mortality after hepatectomy with perioperative use of bevacizumab: a matched case-control study. Ann Surg Oncol 2007;14:759–65. 16 Vauthey JN, Pawlik TM, Rivero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006;24: 2065–72. 17 Zorzi D, Laurent A, Pawlik TM, et al. Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br J Surg 2007;94:274–86. 18 Benoist S, Brouquet A, Penna C, et al. Complete response of colorectal liver metastases after chemotherapy: does it mean cure? J Clin Oncol 2006;24:3939–45. 19 Bartlett DL, Berlin J, Lauwers GY, et al. Chemotherapy and regional therapy of hepatic colorectal metastases: Expert Consensus Statement. Ann Surg Oncol 2006;13:1284–92. 20 Kemeny N, Huang Y, Cohen A, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999;341:2039–48. 21 Kemeny MM, Adak S, Gray B, et al. Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy- an intergroup study. J Clin Oncol 2002;20:1499–505. 22 Lim L, Gibbs P, Yip D, et al. A prospective evaluation of treatment with selective internal radiation therapy (SIR-spheres) in patients with unresectable liver metastases from colorectal cancer previously treated with 5-FU based chemotherapy. BMC Cancer 2005;5:132–7.


D D C A A

6

Emerging Therapies

Introduction Michael A. Morse1 and Josep M. Llovet2 1

Medical Oncology, Duke University Medical Center, Durham, NC, USA Mount Sinai Liver Cancer Program, Division of Liver Diseases, Mount Sinai School of Medicine, New York, USA and BCLC Group, IDIBAPS, Liver Unit, CIBEREHD, Hospital Clínic, Barcelona, Spain 2

The poor prognosis for unresectable or metastatic liver tumors, and the need to prevent progression or relapse following surgical or local therapies, remain the major drivers for developing new therapies. Previously, the negative results for a series of chemotherapeutic agents had deterred pharmaceutical interest, but an emerging understanding of the important pathways in liver tumor development and progression [1], coupled with the first supportive evidence of survival improvement from systemic treatment of a targeted agent, such as sorafenib, for hepatocellular carcinoma (HCC) [2, 3], have now spurred considerable development in the field. There is a blossom of studies testing novel molecular targeted therapies in experimental models and clinical trials in HCC [3]. Although HCCs and their host milieu are heterogeneous, a number of key pathways appear to be relevant to many HCCs, such as vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), Ras/extracellular signal-regulated kinase (ERK), phosphoinositid-3-kinase (PI3K)/mammalian target of rapamycin (mTOR), hepatocyte growth factor (HGF)/MET, Wnt, Hedgehog, and apoptotic signaling. Clearly, HCCs are vascular tumors with increased VEGF factor A (VEGF-A) levels and microvessel density [4]. High-level amplifications of VEGF-A have been described in 5–7% of HCCs [5]. Sorafenib, which includes among its roles inhibition of the kinase functions of the VEGF and platelet-derived growth factor (PDGF) receptors, inhibited tumor angiogenesis in an HCC model, PLC/PRF/5 [6]. In addition to sorafenib, a number of other drugs with antiangiogenic activity (bevacizumab, sunitinib, brivanib, AZD2171, and others) have entered the developmental path for HCC. In fact, in 2009 phase III studies testing sunitinib, brivanib, and bevacizumab are being conducted. Understanding the actual mechanism by which antiangiogenic therapy inhibits HCC clinically, and determining how resistance occurs, will now be major research directions.


In principle, it is established that after antiangiogenic therapy, there is an increase in systemic VEGF-A levels. However, in a recently published study of bevacizumab [7], VEGF levels were noted to decrease from baseline in all patients after 8 weeks of bevacizumab therapy, but at the time of disease progression, VEGF increased from the 8-week values to near-baseline levels. Whether this increase in VEGF is the cause of progression, and could be addressed by higher doses of bevacizumab or the addition of a VEGF receptor (VEGFR) tyrosine kinase inhibitor (TKI), or whether it is associated with other causes of progressive disease, which would not be addressed by anti-VEGF therapy, is unclear. Also, targeting other molecules relevant for angiogenesis, such as fibroblast growth factor receptor (FGFR), may be necessary. Drugs such as TSU-68, an oral multikinase inhibitor (VEGFR, PDGFR, FGFR), and brivanib (VEGFR and FGFR inhibitor) are under development currently in HCC. The EGFR pathway has also been implicated in hepatocarcinogenesis. The expression of EGFR and its ligands (EGF, transforming growth factor-alpha [TGF-α], and heparinbinding EGF) have been reported in HCC [8]. Mutations or amplification of EGFR have been described as marginal aberrations. Sorafenib, in addition to VEGFR, also inhibits Raf kinase, a molecule in the EGFR cascade. In the phase II experience with sorafenib, the time to progression was longer in patients whose pretreatment tumor demonstrated activation of the EGFR pathway. Nonetheless, the activity of EGFR-targeting agents remains unclear and clinical trials thus far have raised more unanswered questions. For example, although the EGFR TKI erlotinib (EGFR and Her2 TKI) have been reported to achieve modest response rates in HCC as single agents [9], cetuximab and lapatinib alone have not [10]. Furthermore, drugs or combinations of agents that target both the VEGF and EGFR pathways, such as sorafenib or bevacizumab plus erlotinib, have shown possibly enhanced activity. Several other signaling cascades have been implicated in the pathogenesis of HCC. A number of genomic analyses have been performed to identify genes or pathways important for HCC development in general [11], solitary or

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multinodular development [12], metastasis, and tumor recurrence after surgical resection [11–13]. In general, the main observations thus far are that there is significant heterogeneity of HCC, but multiple potential pathways for targeting it have been suggested by this work [14]. There is no common agreement on the molecular classification of HCC Nonetheless, the main whole-genome studies suggest two common subclasses: Wnt-β-catenin and proliferation subclass [5]. Other molecular classes, such as those defined by activation of TGF-β or polysomy of chromosome 7, need to be confirmed. Also, distinct expression profiles have been observed in HCC caused by chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection [15]. Among the newer pathways now being viewed as potential targets for HCC therapies is the c-MET/hepatocyte growth factor pathway. Overexpression of hepatocyte growth factor and c-MET is an adverse prognostic factor for patients with liver cancer. Another pathway signaling through insulin-like growth factor receptor-1 (IGFR-1) is also prominent within HCC. IGFR-1-mediated signaling promotes survival, oncogenic transformation, and tumor growth and spread. Hopfner et al [16] demonstrated that the IGFR-1 TKI NVP-AEW541 inhibited growth and caused apoptosis and cell cycle arrest in HCC cell lines. The PI3K/Akt/mTOR pathway plays an important role in liver carcinogenesis and its blockade with rapamycin or everolimus inhibits growth in HCC cell lines and in experimental models. Finally, dysregulation of the Wnt pathway was also found to be a frequent event. Activation of the Wnt cascade has been shown in one-third of HCCs, as a consequence of mutations in ßcatenin, aberrant methylation of the tumor suppressors adenomatosis polyposis coli (APC) and E-cadherin, or increase of autocrine/paracrine secretion of Wnt ligands. New drugs targeting this pathway are in early clinical development. Challenges for new drug development in HCC include the lack of a dominant, single pathway to target, the lack of completely predictive animal models or cell lines, and the need to contend with underlying comorbidity related to cirrhosis at the same time as the tumor. Experimental models that recapitulate human HCC subclasses are urgently needed. Only the double transgenic TGF-α/Myc is considered to mimic genomic aberrations common in the proliferation subclass [17]. Also, it will be important for the research community to develop appropriate systems for determining clinical activity. It is clear from the randomized studies with sorafenib that stable disease may occur without therapy in some patients. It is also clear from studies of targeted therapies that tumors may appear to have stable disease according to the tumor dimensions, but the majority of the tumor tissue will be necrotic, suggesting a response to therapy. Other measures of activity, such as changes in tumor perfusion, may be more relevant to the development of some drugs. Guidelines for clinical trials in HCC are important and

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have recently been promulgated. According to these guidelines, randomized phase II trials with a time-to-event primary endpoint, such as time to progression, are pivotal in clinical research on HCC. Survival remains the main endpoint to measure effectiveness in phase III studies, whereas time to recurrence is proposed as an appropriate endpoint in the adjuvant setting. It was recommended that new drugs should be tested in patients with well-preserved liver function (Child–Pugh class A). Biomarkers and molecular imaging should be part of the trials, in order to optimize the enrichment of study populations and identify drug responders. Thus, we are facing a new era in HCC management, where mechanical treatments will be progressively supplemented by combinations of molecular therapies in a more personalized medicine. Guidelines for clinical trials in HCC are important and have recently been promulgated [18].

References 1 Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 2006;6:674–87. 2 Llovet JM, Ricci S, Mazzaferro V, et al. SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–90. 3 Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology 2008;48:1312–27. 4 Pang R, Poon RT. Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma. Cancer Lett 2006;242:151–67. 5 Chiang DY, Villanueva A, Hoshida Y, et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res 2008;68:6779–88. 6 Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 2006;66:11851–8. 7 Siegel AB, Cohen EI, Ocean A, et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 2008;26:2992–8. 8 Kiss A, Wang NJ, Xie JP, Thorgeirsson SS. Analysis of transforming growth factor (TGF)-alpha/epidermal growth factor receptor, hepatocyte growth factor/c-met,TGF-beta receptor type II, and p53 expression in human hepatocellular carcinomas. Clin Cancer Res 1997;3:1059–1066. 9 Ramanathan RK, Belani CP, Singh DA, et al. Phase II study of lapatinib, a dual inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase 1 and 2 (Her2/Neu) in patients (pts) with advanced biliary tree cancer (BTC) or hepatocellular cancer (HCC). A California Consortium (CCC-P) Trial. J Clin Oncol 2006;24 (Suppl 18):a4010. 10 Zhu AX, Stuart K, Blaszkowsky LS, et al. Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma. Cancer 2007;110:581–9. 11 Nam SW, Lee JH, Noh JH, et al. Comparative analysis of expression profiling of early-stage carcinogenesis using nodule-innodule-type hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2006;18:239–47.

Introduction 12 Okamoto M, Utsunomiya T, Wakiyama S, et al. Specific geneexpression profiles of noncancerous liver tissue predict the risk for multicentric occurrence of hepatocellular carcinoma in hepatitis C virus-positive patients. Ann Surg Oncol 2006;13:947–54. 13 Budhu AS, Zipser B, Forgues M, et al. The molecular signature of metastases of human hepatocellular carcinoma. Oncology 2005;69 (Suppl 1):23–7. 14 Lee JS, Thorgeirsson SS. Genome-scale profiling of gene expression in hepatocellular carcinoma: classification, survival prediction, and identification of therapeutic targets. Gastroenterology 2004;127:S51–S55 15 Iizuka N, Oka M, Yamada-Okabe H, et al. Comparison of gene expression profiles between hepatitis B virus- and hepatitis C

virus-infected hepatocellular carcinoma by oligonucleotide microarray data on the basis of a supervised learning method. Cancer Res 2002;62:3939–44. 16 Höpfner M, Huether A, Sutter AP, et al. Blockade of IGF-1 receptor tyrosine kinase has antineoplastic effects in hepatocellular carcinoma cells. Biochem Pharmacol 2006;71:1435–48. 17 Lee JS, Chu IS, Mikaelyan A, et al. Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nat Genet 2004;36:1306–11. 18 Llovet JM, Di Bisceglie A, Bruix J, Kramer B, Lencioni R, Zhu A, Sherman M, Schwartz M, Lotze M, Talwalkar J, and Gores GJ on behalf of Panel of Experts in HCC. Design and end-points of clinical trials in HCC. J Natl Cancer Inst 2008;100:698–711.

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Viral-Based Therapies for Primary and Secondary Liver Cancer Menghua Dai, Lorena Gonzalez, and Yuman Fong Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Introduction Viral-based gene therapy represents a promising field with many novel strategies directed at malignancies. Evidence has been presented in the literature from as early as 1912 linking viruses to regression of cancer [1]. Several laboratories have now accumulated evidence of antitumor activity of various viruses against a myriad of cancers [2–4] and such therapies have reached human clinical testing. This chapter focuses on the use of viral vectors against liver tumors of primary and metastatic origin. We will describe major vector systems, anticancer strategies, and preclinical data supporting their use. We will also summarize the clinical investigations to date.

History of viral therapy The initial observation of the beneficial effect that viruses could have on cancer came in 1912, when DePace noted the regression of cervical carcinoma in patients who had received viral treatment (Pasteur’s treatment) for rabies [2]. By the 1950s, several viruses were being studied for their therapeutic effects, including adenovirus and Newcastle disease virus. In the middle of that decade, a National Cancer Institute (NCI) study examined treatment of 30 patients with locally advanced cervical cancer by intra-arterial or intratumoral injection of wild-type adenovirus [5]. As the immune reaction to adenovirus was thought to be a major obstacle to success of such therapy, patients were given a serotype of adenovirus for which they did not have antibodies. Furthermore, half of the study group received concomitant corticosteroid therapy for immunosuppression [5]. The study found “marked-to-moderate” response in two-thirds of all patients, including those receiving steroid therapy [5]. Also encouraging was the lack of major side effects, though a

subset of patients experienced a flu-like syndrome [5]. Virus was clearly the effector of treatment as there was no response when patients received heat-inactivated virus or supernatant of virally infected cells [5]. However, virotherapy was not attractive at the time due to several factors: (1) the effects were variable in vivo and unpredictable; (2) there was no way to direct the activity of the virus to tumor cells while sparing normal host cells; (3) it was difficult to make high titers of pure virus, and equally difficult to assay its biologic activity; and (4) there was the inherent and unpredictable danger of high-dose viral systemic therapy. The combination of these factors led to the abandonment of oncolytic viral therapy by 1960. Advancements in technology and our understanding of viral and tumor biology have led to renewed interest in viral-based therapies. It is now feasible to make high titers of purified viruses. The herpesvirus and adenovirus can be made in titers up to 109 and 1012 plaque-forming units (pfu)/ mL, respectively. Furthermore, the elucidation of viral genomes and specific gene functions combined with the advance of recombinant DNA technology has given researchers the ability to delete nonessential viral genes, at the same time allowing for insertion of potential therapeutic genes of interest.

Strategies for viral therapy There have been many approaches to the utilization of viral vectors for treatment of malignancy. The four main strategies under active investigation that have shown the most promise are: suicide gene prodrug therapy; tumor suppressor gene replacement; immunomodulation; and oncolytic therapy. The characteristics of these strategies are enumerated in Table 30.1.

Suicide gene prodrug therapy Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

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In this therapy, a gene encoding for a metabolically active enzyme is transduced into a cancer cell [6]. The enzyme converts a benign prodrug into its active, toxic metabolite,

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Viral-Based Therapies for Primary and Secondary Liver Cancer

Table 30.1 Viral-based strategies targeting primary and metastatic liver cancer. Strategy

Gene delivered

Effect

Virus

Suicide gene prodrug therapy

Thymidine kinase, cytosine deaminase

Tumor suppressor gene replacement

Wild-type p53

Immunomodulation

GM-CSF, IL-2, IL-4, IL-12, IL-18, IL-24, IFN, TNF, TRAIL

Conversion of benign prodrug to active metabolite, leading to interruption of DNA and RNA pathways and to apoptosis Apoptosis, normalization of cell-cycle regulation Immune system upregulation, local cytokine induction, antiangiogenesis, creation of immune memory

Retrovirus Vaccinia Adenovirus Herpesvirus Retrovirus Adenovirus Retrovirus Vaccinia Newcastle disease virus Adenovirus Herpesvirus Retrovirus Reovirus Newcastle disease virus Adenovirus Herpesvirus

Oncolytic therapy

Lysis of tumor and propagation of virus

GM-CSF, granulocyte macrophage colony-stimulating factor; IL, interleukin; IFN, interferon; TNF, tumor necrosis factor; TRAIL, TNF-related apoptosisinducing ligand.

causing death in the cells that have been transduced [7]. Often, the process also induces killing of nontransduced cells via a bystander effect [7–9]. Many hypotheses have been proposed to explain the physiology behind the bystander effect, which seems to be mediated by a cell–cell interaction through gap junctions. The attractiveness of the prodrug approach is that benign compounds can be delivered systemically to a patient and have good effect locally, without the systemic effects that would otherwise occur with general administration of the toxic metabolite. The two genes most often exploited encode for herpes simplex virus (HSV) thymidine kinase (tk) or cytosine deaminase (CD). Thymidine kinase allows a cell to phosphorylate ganciclovir (GCV) to the monophosphorylated state, which is then converted further by native cellular kinases into genotoxic triphosphates, which cause DNA chain termination and apoptosis [10]. Cytosine deaminase causes conversion of the inactive prodrug 5-fluorocytosine (5-FC) into the toxic metabolite 5-fluorouracil (5-FU), the chemotherapeutic agent with the longest record in treating colorectal cancer (CRC) metastases [7]. 5-FU is a pyrimidine analog and inhibits thymidylate synthase, in turn halting DNA synthesis and preventing replication.

Tumor suppressor gene replacement The most common tumor suppressor gene targeted by gene therapy to date is p53. Fifty to 70% of colorectal liver metastases and up to 60% of hepatocellular carcinomas (HCCs) have p53 mutations [11]. This gene normally serves several

functions: maintenance of genomic stability, prevention of tumor development and growth by entry into apoptosis, and surveillance for DNA damage. With loss of p53, cells with DNA damage do not enter cell cycle arrest or undergo apoptosis, which can then lead to oncogenesis in these defective cells [12]. Overexpression of mutated p53 may also result in oncogenesis. Replacement with a functioning p53 gene can suppress tumor growth and induce apoptosis [12].

Immunomodulation Immunotherapy involves stimulation of the host immune system to recognize normally nonimmunogenic tumors, thereby enhancing tumor cell killing. This is accomplished by provoking both specific and nonspecific immune responses. The most commonly studied strategy involves delivery of an immunostimulatory molecule, such as a chemokine, cytokine or costimulatory molecule, to enhance local immunomodulation at the tumor site.

Oncolytic therapy Viral oncolysis evolved due to observations of the ability of viruses to lyse tumors [5, 13]. Several effects are at work: the ability of viruses to lyse cells directly and, perhaps more importantly, the ability of viruses to infect, replicate within, and produce progeny virions. These daughter virus particles are then able to infect and kill other tumor cells. There are many benefits to using replication-competent viral vectors. The amount of virus required to achieve an effect is theoretically smaller compared with what is needed when delivering

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Table 30.2 Characteristics of viruses used for gene therapy of liver cancer. Characteristic

Retrovirus

Vaccinia virus

Newcastle disease virus

Adenovirus

Herpes simplex virus type 1

RNA/DNA Viral integration Efficiency of infection Viral titer production Transgene insert size Duration of transgene expression Level of transgene expression Target cells

RNA Genomic Low–moderate Moderate (105–108) ∼ 8 kb Long-term

DNA Episomal High High (107–109) ∼ 25 kb Transient

RNA Episomal Moderate High (109) N/A N/A

DNA Episomal High High (109–1012) ∼ 7.5 kb Transient

DNA Episomal High Moderate (107–109) ∼ 30–50 kb Transient

Moderate

High

N/A

High

High

Dividing

Dividing

Dividing/quiescent

Replication competence Risks

Incompetent

Competent or incompetent Immune response, fast effect

Dividing/some quiescent Replication competent Immune response

Dividing/some quiescent Competent or incompetent Systemic infection

Insertional mutagenesis, lymphoma with chronic administration

Replication competent Systemic infection, immune response

NA, not applicable.

a replication-incompetent vector. The effect will be of longer duration, theoretically continuing until there are no more tumor cells left to infect and lyse. Further, replicationcompetent viruses that can accommodate transgenes will be able to exert a more durable effect as well, upregulating the host immune system to join in antitumor activity. Of course, introducing any vector with the capability of latent infection demands that it be thoroughly tested for safety. Overall, the potential for replication-competent oncolytic viruses is very promising and exciting.

Viruses A number of viral vectors are under development for use in man as cancer therapy. The major classes of vectors are summarized in Table 30.2 and are discussed below.

Retroviruses Retroviruses are distinct from other viruses due to the presence of reverse transcriptase, which allows the viral RNA to form DNA, which is then incorporated into the host genome. This provides the benefit of long-lasting gene expression, though this is limited to proliferating cells only [14]. Genes of interest are inserted in place of the packaging genes gag, pol, and env, and these recombinant vectors are unable to replicate unless a packaging cell line is introduced to provide the missing genes [14]. The insert size is limited to 7–8 kilobases (kb) and historically these viruses have been produced

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in low titers of 105–107 pfu/mL. More recently, changes in production technique have produced titers up to 108 pfu/mL [15]. Importantly, retroviruses do not cause significant host immune response [16]. These replication-deficient retroviral vectors have been used in a variety of clinical trials evaluating treatment for malignant tumors [17, 18].

Suicide gene prodrug therapy A retroviral vector containing HSV-tk under control of an albumin promoter and given in combination with GCV has shown efficacy in treating murine HCC [19]. One study showed complete regression of HCC flank tumors with multiple injections of HSV-tk retrovirus, as well as production of tumor immunity up to 60 days after rechallenge [19]. The low immunogenicity of retroviral vectors facilitates repeat administration without decreasing efficacy, which is important given the relatively low transduction efficacy, with only up to 16% of HCC or CRC tumor cells expressing tk postinjection [15, 16]. A phase I trial in which 16 patients with various tumors received serial intratumoral injections of retroviral vectors with HSV-tk followed by GCV revealed minimal side effects due to the treatment [17].

Tumor suppressor gene replacement A retrovirus has also been used to transduce p53 using an alpha-fetoprotein (AFP) promoter, causing apoptosis and slower growth in vitro of AFP-producing HCC cells, as well as increased sensitivity to chemotherapy [20]. AFP is usually expressed in the fetus and does not persist after birth.

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However, most HCCs express the protein, which is rarely found in normal or cirrhotic liver tissue. Given this overexpression of AFP, the promoters associated with it have been targeted for therapeutic aims. Several viruses have been designed which utilize AFP transcriptional regulatory elements in order to make an HCC-specific oncolytic virus.

[2, 24, 25]. Reovirus is attractive as a potential vector because it appears to replicate in tumor cells while sparing normal tissue, without any modification [25].

Oncolytic therapy

Immunomodulation has also been successful in a retrovirus with an albumin promoter and AFP enhancer targeting and increasing expression of a fused interleukin (IL)-2/interferon (IFN)-2b gene in HCC cells producing AFP [21]. Nude mice with AFP-producing HCC tumors showed increased cytokine production proportional to the amount of AFP expressed in the cell, along with significantly increased tumor cell kill [21]. Another recent experiment has shown the in vivo efficacy of combined gene therapy of HCC with two different Moloney murine leukemia virus (MoMLV)derived retroviral vectors containing HSV-tk and human IL (hIL)-2, where treatment with GCV led not only to complete regression of hepatic tumors composed of transduced cells but also resulted in regression of distant nontransduced tumors [22].

Reovirus replication in untransformed NIH3T3 cells is restricted by its own early viral transcripts activating the double-stranded protein kinase (PKR) [25]. The PKR in turn inhibits translation of the viral transcripts. Reovirus is allowed to replicate by the activated Ras signal pathway, which alters PKR, allowing viral protein synthesis to proceed [25, 26]. The Ras mutations occur in about 30% of all tumors, particularly in pancreatic, colorectal, and lung carcinomas [27]. An in vivo study in mice using a tumor cell line with activated Ras showed tumor regression in 80% of immunocompetent mice with a multiple dosing regimen [27]. Moreover, no recurrence was noted for the follow-up period of 6 months. Prior immunity did not seem to have an effect on tumor kill, though an immune response was noted. Human phase I/II trials are planned, including a trial for colon cancer [24]. These will address some of the questions about reovirus, including dose-related effects and the effect of route of administration.

Oncolytic therapy

Vaccinia

A recent development is the creation of a retrovirus vector which is replication competent and has demonstrated efficacious and stable gene transfer to murine tumors [23]. Within 9 days, at least 75% of flank tumors were transduced with a marker green fluorescent protein (GFP) gene, with little transduction of normal cells [23]. While this is promising, chronic retroviral infection has been previously shown to lead to aggressive lymphoma in primates, though this was not an issue in this study [14, 23]. Another safety issue which has not been completely addressed is the possibility of insertional mutagenesis. Finally, there is no treatment available for disseminated retroviral infections, and this is an even more pressing concern if the use of replicationcompetent vectors becomes a reality.

Vaccinia is a linear, double-stranded DNA virus, best known for its use as a smallpox vaccine [2]. The genome is approximately 200 kb, and can tolerate gene inserts of 25 kb in length without compromising tumor lysis [28]. Studies have shown efficacy of treatment with recombinant vaccinia viral oncolysate injection and there is evidence of upregulation of the immune system by vaccinia [28].

Immunomodulation

Thus, retroviral vectors have yielded some success in in vivo animal models using several approaches to tumor cell killing. A phase I trial has shown a limited toxicity due to virus, though there was little to no effect on tumor growth (Table 30.3) [17]. Retroviral vectors provide durable gene transfer and if safety issues are addressed, the potential of replication-competent vectors will be promising.

Reovirus Reovirus is a double-stranded, nonenveloped RNA virus. Infections in humans affect the respiratory and enteral tracts, and are generally mild [24, 25]. In fact, reovirus is ubiquitous in the environment and studies have shown that at least 50% of adults in the third decade are seropositive

Suicide gene prodrug therapy A tk-negative strain of vaccinia was developed with a CD gene insertion [29]. Administration of this vector to mice with CRC metastases showed uptake of the virus preferentially in tumor, and increased survival in animals treated with the vector followed by 5-FC [29]. Though the therapy showed benefit, the mechanism of infection has not yet been worked out [29]. More recently, the genome of the modified vaccinia virus Ankara (MVA), a highly attenuated vaccinia virus which has been previously used safely in humans as a smallpox vaccine, has been customized to include FCU1 [30]. This suicide gene encodes a bifunctional chimeric protein that combines the enzymatic activities of FCY1 and FUR1, genes found in fungi which catalyze the direct conversion of 5-FC into the toxic metabolite 5-FU. Though the virus itself is nonreplicating in mammalian cells, rapid replication of the viral DNA does occur after infection with MVA, resulting in large amounts of FCU1. This provides a solution for generating therapeutic concentrations of 5-FU locally, while avoiding excessive toxicity in normal tissues [30]. This resulted in significant tumor growth delay when

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given to animals with various types of subcutaneously injected human tumors.

Immunomodulation From past experience with its use as a smallpox vaccine, vaccinia is known to induce long-term immunity [2]. A phase I trial using recombinant vaccinia with a carcinoembryonic antigen (CEA) promoter (rV-CEA) as a vaccine to treat patients with CRC with liver metastases established that administration of the vector caused minimal toxicity (Table 30.3) [31]. Furthermore, animal models have shown regression of tumor. However, dosing for humans remains to be worked out. Other recent work with vaccinia has used the virus as a vector for the transduction of genes encoding cytokines (granulocyte macrophage colony-stimulating factor [GMCSF]) and tumor antigens (CEA, AFP, 5T4 [TroVax], etc) into tumor cells. Expression of these immunomodulators activated host immune activity, resulting in oncolytic and immunologic therapy for primary and secondary liver cancer [31–33]. An MVA virus carrying the gene for the tumor antigen 5T4 (TroVax) has also been used as a vaccine in a phase I clinical trial and has been evaluated in an open-label phase II study of patients with CRC metastases to the liver. Ten of 12 patients evaluated mounted 5T4-specific antibody responses, and six of eight presenting with elevated CEA levels showed a greater than 50% reduction after chemotherapy treatment combined with the vaccine. Six of the 19 treated patients had complete or partial responses, one had a complete response, and five showed stable disease. Therefore, not only were 5T4-specific immune responses detected, but these also correlated with clinical benefit (Table 30.3) [31, 33].

tion with the tumor cells and is then delivered to the patient [36]. Studies using this therapy have been completed for patients with melanoma, primary and metastatic breast cancer, and CRC metastases, with some success. NDV greatly enhances the body’s immune response against tumor cells via upregulation of macrophages, T lymphocytes, and a variety of cytokines, including tumor necrosis factor (TNF), IL-1, and IL-6 [2, 37]. Using the Ulster strain of NDV and the patients’ own tumor cells, a phase II trial of autologous vaccine for treatment of micrometastatic CRC of the liver showed a significant increase in recurrence-free interval, though there was no significant increase in survival at 18 months [38].

Oncolytic therapy Two strains of NDV have been used for the study of oncolysis: 73T and MTH68. However, little was known of the mechanisms by which oncolysis occurs until recent in vitro work determined that NDV acts as an oncolytic agent by both intrinsic and extrinsic caspase-dependent apoptotic pathways [39]. The 73T strain has shown efficacy in treating fibrosarcoma and neuroblastoma xenografts with a single injection [37]. More recently, murine in vivo models of colon cancer have shown regression of tumor with 73T [40]. The MTH68 strain, available commercially as a poultry vaccine, was administered in a phase III trial to a cohort of patients with various terminal cancers [34, 41]. Eighteen of the 33 patients responded to treatment with tumor regression or stabilization [41]. In particular, seven of the eight patients in the treatment group who had CRC metastatic to the liver survived to 1 year, compared with one of five control patients [41].

Adenovirus Newcastle disease virus Newcastle disease virus (NDV) is an avian paramyxovirus first isolated in chickens in 1927 [2, 34]. It is an enveloped RNA virus with a genome of approximately 16 kb, encoding for six proteins [34]. Though potentially lethal in poultry, this virus causes little harm to humans, e.g. mild conjunctivitis or laryngitis [2]. Recognition of the oncolytic potential of NDV came from a case report detailing a farmer with a gastric tumor who went into remission during an outbreak of NDV within his poultry stocks [35]. There are several strains of NDV, differing by point mutations in the viral genome. The strain with the greatest oncolytic function has been 73-T. The Ulster strain is efficacious in induction of host-organism immunity against NDV antigens expressed by infected tumor cells [35].

Immunomodulation NDV vaccine is created in vitro by incubating NDV with tumor cells, whether from a cell line or the patient’s own tumor cells. The oncolysate is harvested after 1 h of incuba-

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Adenovirus is a double-stranded DNA virus prevalent in humans, with 55–80% of individuals carrying antibodies to it. Its ability to replicate in mammalian cells is exploited for clinical use. Furthermore, the virus is known to have low pathogenicity in humans, usually causing only the common cold [2]. Its genome is approximately 38-kb long [2], so genes up to 7.5 kb can be inserted into the genome. Replication is achieved by promoting entry of infected cells into the S phase. The hepatotropic nature of adenovirus renders it especially suited for treating liver cancer [42].

Suicide gene prodrug therapy Adenoviral vectors with HSV-tk have produced significant tumor cell kill when administered along with GCV, partly due to the bystander effect previously discussed [8]. However, significant hepatotoxicity has been observed from the adenovirus (Ad)-tk/GCV combination. Administration of intratumoral Ad-HSV-tk to humans followed by intravenous GCV resulted in transient elevation of serum

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aminotransferase levels, fevers, thrombocytopenia, and leukopenia, and in one study, a single death reportedly not due to viral administration [43]. In an effort to minimize toxicity, Ad-tk vectors have been engineered with AFP promoters. Though the vector can still infect a variety of human hepatoma cells, GCV only causes lysis in AFP-positive cell lines, producing excellent in vitro and in vivo lysis of tumor. Adenoviral vectors with CD have also produced promising results. A murine model of CRC liver metastases treated with Ad-cytomegalovirus (CMV)-CD showed transduction of the CD gene to normal hepatocytes with subsequent tumor growth suppression after systemic administration of 5-FC [44], and minimal hepatotoxicity and mortality. Direct intratumoral injections of CRC metastases to the liver have also been studied in a phase I human trial.

Selectivity for malignant tumor cells was preserved by employing the AFP promoter [52].

Tumor suppressor gene replacement Intravenous infusion of Ad-p53 vectors in animal models has failed due to greater than 80% animal death before reaching titers necessary to transduce tumor cells [45]. However, local infusion via the hepatic artery has produced suppression of tumor growth and induction of apoptosis in tumor cells [46]. Subsequently, a phase I/II trial of hepatic artery infusion of Ad-CMV-p53 for CRC metastases performed in 2001 showed that the virus was well tolerated when administered directly intratumorally, intra-arterially or intravenously.

Immunomodulation Adenovirus has been successful in delivering IL-2 to HCC, and CRC metastases and lung metastases to the liver, with lasting immunity and tumor burden reduction [47]. IL-2 recruits CD4 and CD8 cells to tumors, upregulates natural killer cell activity in the liver, and induces CD8-dependent cytotoxic response to tumor [48]. An adenoviral vector with an AFP promoter for the IL-2 gene has achieved significantly lower toxicity without loss of efficacy [49]. Many other immunomodulators and human cytokines, such as IL-18, IL-24 and the TNF-related apoptosis-inducing ligand (TRAIL), have been investigated in conjunction with adenovirus as vector. IL-18 augments the cytotoxicity of T and natural killer (NK) cells and the proliferation of T cells, and stimulates T helper (Th) cells to produce IL-12 and IFN-γ, suggesting that it has potential for the treatment of cancer by inducing tumor-specific cellular immunity as well as activating NK cells in the host [50]. A recombinant adenovirus expressing human (h)IL-18 exhibited a significant antitumor effect in a Huh-7 human hepatoma-bearing mouse tumor model with a defect in T-cell function [51]. Lastly, TRAIL, a member of the TNF cytokine family, has also been shown to induce apoptosis. Conditionally replicative adenovirus (CRAd) bearing the TRAIL gene increases the oncolytic activity of HCC in vitro and in vivo via apoptosis.

Oncolytic therapy Three general approaches are used to engineer tumor-selective adenoviral replication [53]. One approach involves the E1A gene. The adenoviral genome contains genes in the E1A region which bind and inhibit the retinoblastoma tumor suppressor protein (Rb) as well as other transcription factors [53]. As a result, the transcription factor E2F is released, with entry into S phase and upregulation of DNA synthesis for both host and virus. Another strategy to achieve tumor specificity is the use of tumor- or tissuespecific promoters, such as AFP, human telomerase reverse transcriptase promoter (hTERT), and hypoxia response promoter, to drive adenoviral genes that are essential for replication. CNHK500 is a dual-regulated oncolytic adenovirus modified with dual promoters: hTERT drives expression of the E1A gene and the hypoxia response promoter controls expression of the E1B gene. Preclinical experimental results with this virus showed efficient tumor cell specificity with significant regression of HCC xenografts as well as prolonged survival [54]. A third way to induce tumor specificity is to delete genes that are required for replication of the virus in normal cells but not in tumor cells [20]. To provide tumor specificity, Barker and Berk genetically engineered dl1520, also known as Onyx-015 or CI-1042, an adenovirus with a deletion of the E1B-55K-encoding gene [55]. This gene is theorized to inhibit apoptosis by binding the cellular p53 tumor suppressor protein [20]. With this deletion, the virus would replicate only in cells that had defective p53 protein, or in tumor cells. Normal cells with normal p53, and therefore normal apoptotic pathways, would not support viral replication. Direct oncolysis is achieved by several mechanisms. Expression of the E1A early protein causes cell sensitization to TNF-mediated killing. There is also direct cytotoxicity from the late viral proteins, E311.6 adenovirus death protein and E4ORF4. Finally, there is cytolysis from infection of tumor cells with subsequent replication and lysis. This replication and lysis also cause upregulation of cell-mediated immunity [54]. A number of clinical trials have been conducted to evaluate the antitumor effect and safety of adenovirus dl1520, both as a single therapeutic agent and in combination with systemic chemotherapy (5-FU, leucovorin) [4, 56, 57]. The maximally tolerated dose or dose-limiting toxicities were not identified following intratumoral or hepatic artery infusion in these studies. With intratumoral treatments, the most common side effects were limited to flu-like symptoms. Transient elevation in transaminases resolved spontaneously after 2 days and the reported mortality rate attributable to treatment with virus was zero. A trial looking at intra-arterial administration of dl1520 in combination with

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358 Table 30.3 Clinical trials with viral-based therapies for liver cancer. Mutant virus

Trial

Tumor type

Dosing regimen

Route of administration

Toxicity (due to viral treatment)

Results

Source

Retrovirus

HSV-tk insert

Phase I n = 16

Various

2 × 106–1 × 107 pfu × 5 daily doses

Intratumoral

Injection site pain, swelling/ cellulitis

No regression of tumor

Singh et al (2001) [17]

Vaccinia virus

rV-CEA

Phase I n = 17

CRCM

2 × 105–1 × 107 pfu, 3 doses at 4-week intervals

Intradermal

No regression of tumor

McAneny et al (1996) [31]

MVA

Phase II n = 17

Encoding the tumor antigen 5T4 (TroVax)

5 × 108 pfu for first 2 weeks and weeks 11 and 17, 5-FU, folinic acid, oxaliplatin for first 2 weeks/4 weeks

Intramuscular

Pruritus, erythema (injection site), adenopathy, fevers/ sweats/chills, flu-like symptoms, pain, nausea/ vomiting Rigors/chills, myalgia, fever/ sweating, dizziness, disorientation, hallucinations, headache

6/11 CR or PR

Harrop et al (2007) [33]

(Ulster)

Phase I/II n = 16

HCC, CRCM

Autologous vaccine 1 dose

Intradermal

Transient temperature elevation

Schlag et al (1992) [38]

(MTH68)

Phase III n = 33

Various

4000 U twice weekly

Inhalation

Transient fever

Increase in recurrence-free interval without survival benefit Increased survival in CRCM patients

dl1520 (ONYX015)

Phase I n = 16

GILM

108–1011 pfu, multiple dosing

Intratumoral

dl1520 (ONYX015)

Phase I/II n = 16

HCC, CRCM

3 × 109–3 × 1011 pfu, 3 escalating daily doses; 3 daily doses of 3 × 1011 pfu, in combination with 5-FU

Intravenous, intrahepatic, arterial, intratumoral

Flu-like symptoms, coagulopathy, lymphopenia, LFT elevation, transient hypotension Mild fever, injection site pain, shivers, LFTs normal.

Newcastle disease virus

Adenovirus

Csatary et al (1993) [41]

Bergsland et al (1998) [91]

3/6 with 50% reduction in CEA; 6/7 with SD by CT; 1/7 with PD

Habib et al (2001) [92]

Emerging Therapies

Virus family

Virus family

Tumor type

Dosing regimen

Route of administration

Toxicity (due to viral treatment)

Results

Source

dl1520 (ONYX-015)

Phase II n = 27

GILM

3 × 1010 pfu on days 1 and 8, combined with 5-FU and leucovorin at day 22

Intrahepatic arterial

3/27 PR; 4/27 MR; 9/27 SD; 11/27 PD

Reid et al (2002) [57]

dl1520 (ONYX-015) dl1520 (ONYX-015)

Phase I n = 10 Phase II n = 19

HCC

3 × 1010 pfu

Intratumoral

Fever , chills, alkaline phosphate increase, AST, ALT increase, lymphopenia, bilirubinemia, hypochronic anemia, granulocytosis, asthenia Pain, fever, rigors

PR 1/5; PD 4/5

HCC

6 × 109–3 × 1010 pfu

Intratumoral

8/16 Reductions in tumor marker by >50% 1/16 PR; 12/16 SD

dl1520 (ONYX-015)

Phase I and II n = 34

2 × 1012 pfu

Intrahepatic arterial

CTL102

Phase I n = 17

Cholangiocarcinoma, gallbladder carcinoma HCC and CRCM CRCM

Hypotension, leukopenia, anemia, thrombocytopenia, fever, hepatic cytotoxity, hypotension, hypertension, atrial fibrillation Transient liver function abnormalities

Habib et al (2002) [56] Makower et al (2003) [93]

1 × 108–5 × 1011 pfu

Intratumoral

Local pain, pyrexia

Adv-RSV-tk

Phase I n = 16

CRCM

1 × 1010–1 × 1013 pfu

Intratumoral

Minimal transient increase of aminotransferase, transient fever, thrombocytopenia, leukopenia

Sung et al (2001) [43]

NV1020

Phase I n = 12

CRCM

3 × 106– 1 × 108 pfu

Hepatic artery

Transient rise in serum γ-glutamyltransferase diarrhea, leukocytosis

Kemeny et al (2006) [88]

7/17 SD

Au et al (2007) [94]

Dose-related increase of nitroreductase antibody in tumor tissue

Palmer et al (2004) [59]

HCC, hepatocellular carcinoma, CRCM, colorectal carcinoma liver metastases; GILM, gastrointestinal tumors with liver metastases; PR, partial response; MR, moderate response; SD, stable disease; PD, progressive disease; CEA, carcinoembryonic antigen; 5-FU, 5-fluorouracil; LFT, liver function test; HSV-tk, herpes simplex virus thymidine kinase.

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Trial

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Herpesvirus

Mutant virus

SECTION 6

Emerging Therapies

chemotherapy reported reversible yet significant grade 3/4 hyperbilirubinemia in two patients and grade 4 dyspnea in one patient [23]. Response to single agent therapy with dl1520 was poor in patients with HCC or CRC metastasis, but significantly better if combined with chemotherapy, suggesting that adenoviruses are better suited for use in combination with chemotherapy (see Table 30.2). Although the side effects are mild to moderate in all clinical trials, safety remains an important issue when considering adenoviridae as potential vectors for gene therapy. This is secondary to an isolated yet infamous case at the University of Pennsylvania in 1999 where, within hours of hepatic arterial infusion with a replication-incompetent adenovirus, a patient developed thrombocytopenia, a severe coagulopathy, pyrexia, and jaundice. He expired within 3 days, succumbing to multiple organ failure and acute respiratory distress syndrome [3]. To date there is no consensus as to what caused the events that led to the patient’s death. In general, adenoviral vectors have been associated with relatively mild and self-limiting side effects, including transient flu-like symptoms, pain at injection site, mild left ventricular function changes, and a subclinical disseminated intravascular coagulation (DIC)-like state [3]. The DIC-like state is associated with Ad-p53 vectors and is manifested by small elevations in fibrin split products and the partial thromboplastin time, as well as by thrombocytopenia [3]. Reid et al determined that some side effects are associated and likely secondary to elevations of specific cytokines, specifically IL-6 and IL-10, which may lead to an acute inflammatory response [57]. Furthermore, other in vitro studies found that activation of complement may occur even at low doses of adenovirus (5 × 107 pfu) in clinical samples of subjects who had adenovirus antibodies present, independent of the transgene carried by the virus [24, 58]. A clinical trial of intratumoral injections of either primary or secondary (colorectal) hepatic tumors with the adenovirus vector CTL102 prior to undergoing surgical resection examined the safety and tolerability of the vector. This trial of 18 patients was not able to establish a dose-limiting toxicity (up to and including the maximum dose of 5 × 1011 virus particles), suggesting that direct intratumoral inoculation of CTL102 to patients with liver cancer is well tolerated [59]. The safety profile of adenoviral vectors continues to be elucidated.

Herpes simplex type 1 virus The herpes simplex type 1 virus (HSV-1) is a DNA virus which, like adenovirus, remains episomal post infection [2]. The genome is approximately 152-kb long, and of 84 characterized genes, only 45 are required for viral replication in cultured cells [60, 61]. In fact, 30–50 kb of genetic material can be inserted without compromising replication. The wildtype virus usually only causes cold sores. However, it can also produce keratoconjunctivitis and encephalitis [61]. HSV

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can remain latent for years, residing in nerve ganglia. It is this neurotropism that initially drew researchers to the use of mutated HSV vectors for the treatment of central nervous system (CNS) tumors [13, 62]. There are several ways in which the HSV-1 virus has been used as a vector for gene therapy of hepatic tumors. For example, amplicons of HSV have been constructed to package and deliver transgenes [63]. In this case, the DNA is derived from HSV but is itself replication deficient. Amplicons can be delivered with or without “helper” virus; however, a packaging cell line is required [63]. Another subset of HSV vectors, called defective infection single-cycle HSVs (DISCs), are replication competent for one cycle of replication only, and can be used for short-term amplification of transgenes without long-term viral production [64]. Finally, mutated HSV can be used as an oncolytic vector, not only to kill tumor cells, but also to infect, replicate within, and subsequently produce progeny to infect and kill other surrounding tumor cells not infected initially. After successful initial work with CNS tumors [13], oncolytic HSV vectors have been used to treat experimental models of tumors of the stomach [65], pancreas [66], head and neck [67], gallbladder, and liver [68], etc. Notably, a significant amount of work has been done with HCC and CRC metastatic to the liver [64, 69].

Immunomodulation HSV amplicons Amplicons are replication-defective viral vectors, which are utilized as gene transfer vectors. Genes of interest are cloned into these bacteria-based plasmids, which have an origin of replication and cleavage/packing signals from HSV [63]. For HSV amplicons to be converted into infectious particles, they require a packaging cell line and “helper” viruses to produce the other viral elements, as previously mentioned. An HSV IL-2 amplicon has been used as a vaccine to confer antitumor immunity when transduced into irradiated tumor cells and injected into animal models [70, 71]. Not only can single amplicons have a good effect, but multiple amplicons can be used in the same site to deliver several genes with synergistic effect, as has been shown in a murine HCC model [72]. Delivery of an IL-12 amplicon and an IL-2 amplicon together produced stronger immunization than did either amplicon alone [72]. Use of an HSV IL-12 amplicon as neoadjuvant therapy for HCC in a murine model produced a significant reduction in postoperative recurrence [69]. Oncolytic herpesviruses have also been used as helper viruses for packaging amplicon vectors showing efficacy in experimental tumor models [71]. Furthermore, when combining multiple transgenes for infection with the use of an HSV amplicon, the effect is significantly increased. A preclinical experiment transferring the multiagents GM-CSF (cytokine), B7-1 (adhesion/costimulatory molecule), and RANTES (chemokine) with HSV amplicon into tumor cells produced a

CHAPTER 30


Table 30.4 HSV-1 mutants investigated for oncolysis in primary and secondary liver cancers. Virus

tk

RR

ICP34.5

Dlsptk hrR3 rRp450

− + +

+ − −

+/+ +/+

R3616 G207 R7020 (NV1020) NV1023 NV1034

+ + + + +

+ − + + +

−/− −/− +/− +/− +/−

NV1042 NV1066

+ −

+ +

+/− +/+

Transgene

E. coli lacZ Rat P450 2B1 (CYP2B1)

E. coli lacZ HSV-2 Murine GM-CSF Murine IL-12 GFP

Reference Martuza et al (1991) [13] Goldstein et al (1988) [77] Pawlik et al (2000, 2002) [95, 96] Zhao et al (2001) [81] Chou et al (1990) [97] Mineta et al (1995) [82] Meignier et al (1989) [87] Wong et al (2001) [90] Wong et al (2001) [90] Malhotra et al (2007) [98] Wong et al (2001) [90] Adusumilli et al (2006) [99]

GM-CSF, granulocyte macrophage colony-stimulating factor; tk, thymidine kinase; HSV, herpes simplex virus; RR, ribonucleotide reductase; GFP, green fluorescent protein; IL, interleukin.

significantly stronger host immune response to tumor cells compared with single-agent therapy [73]. DISC is a herpes simplex type 2 virus (HSV-2) vector originally designed as a vaccine for genital herpes. DISCHSV lacks the essential glycoprotein H, thus limiting viral infection. DISC-HSV grown in a cell line that expresses glycoprotein H produces viral progeny that infect cells but are unable to initiate further infection. These viruses have also been used to deliver transgenes to upregulate tumor cell expression of various immunostimulatory molecules, thereby enhancing tumor immunogenicity and tumor cell kill [64]. DISC-HSV containing murine GM-CSF caused tumor regression in murine CRC flank tumors and yielded tumor immunity when rechallenged [64]. Human tumor cells harvested from patients have also been successfully transduced with the vector, with resultant secretion of GM-CSF by the host tumor cells [64]. This new gene therapy can be used to target tumor angiogenesis in hepatic malignancies. An HSV amplicon-mediated delivery of a hypoxiainducible soluble vascular endothelial growth factor (VEGF) receptor was found to substantially reduce new vessel formation and tumor growth in hepatoma flank tumor models in mice [74].

Oncolytic therapy HSV-1 is well suited for use as an oncolytic agent. The virus is able to infect a wide variety of tumor types and its life cycle is well described [75, 76]. Furthermore, the viral genome has been mapped out and the majority of the genes have been correlated to function [60]. With the development of recombinant gene technology, the genome can be manipulated to create selective deletions or alterations that

make safe and efficacious vectors (Table 30.4). As previously mentioned, there is room for up to 50 kb of genetic material to be placed within the HSV viral genome without compromising the ability of the virus to infect and replicate within tumor cells [60]. The major safety advantage of HSV compared with any of the other replication-competent viruses in use is the existence of antiviral drugs which can halt replication of HSV.

First-generation oncolytic herpesviruses Dlsptk The first generation of HSV mutants each contained a single gene deletion or mutation. The first virus used, dlsptk, contains a deletion of the gene encoding tk [13]. Thymidine kinase is required for viral replication; deletion of this enzyme results in viral dependence on host replication machinery [13, 60]. This virus can only replicate when the host cell tk gene is upregulated during its own replication. Thus, the virus replicates best in rapidly proliferating cells, such as tumor cells. This virus demonstrated excellent in vitro glioblastoma cell infection and oncolysis [13]. Yet with deletion of the tk locus, there was no safety mechanism to halt further replication of the virus if the infection became uncontrollable. Due to this and the toxicity associated with administration of this virus, there was little further study. hrR3 Derived from the HSV wild-type KOS strain, hrR3 targets another enzyme critical to viral replication. Ribonucleotide reductase (RR) is an enzyme required for DNA synthesis and replication of HSV [60, 77]. This enzyme is found in

361

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abundance in dividing cells, allowing an HSV mutant deficient in RR to replicate in this subpopulation. To render the gene inactive, an insertional mutation of Escherichia coli lacZ gene was placed into the UL39 region, which encodes for ICP6, the large subunit of RR [77]. lacZ is a marker gene encoding for β-galactosidase, a histochemically identifiable protein. Importantly, this HSV vector retained tk, allowing for antiviral therapy if needed [77]. A biodistribution study with radiolabeled virus injected into nontumorbearing rats showed viral uptake predominantly in the liver and spleen, with moderate uptake in the kidneys and minimal uptake at 12 h in the brain, lung, pancreas, and blood [78]. hrR3 preferentially infects colon carcinoma tumor cells and replicates well within them, while replicating poorly in normal hepatocytes, as expected since RR levels are much higher in the tumor cells. Intraportal delivery of hrR3 resulted in 95% infection of liver nodules in a murine model, with minimal infection of normal parenchyma [79]. However, when mice received a 75% hepatectomy, the regenerating liver cells were also infected with virus, raising the clinical question of timing of virus administration in relation to resection [80].

phamide [81]. Thus, the rRp450 virus can not only produce tumor cell kill by direct oncolysis, but can also activate alkylating metabolites. Ideally, the drug and its actions would only have an effect intratumorally. In vitro and rat model in vivo studies showed that the rRp450 virus in combination with cyclophosphamide enhanced tumor cell kill [81]. Further, the presence of cyclophosphamide did not inhibit viral replication [81].

Second-generation oncolytic herpesviruses The second-generation viruses are multimutated, making the possibility of reversion back to wild-type extraordinarily rare. Among the nonessential viral genes are two regions encoding for neurovirulence, and many of the second-generation viruses are deleted for one or both of the copies [60, 61]. This adds an important safety feature in this virus that otherwise normally has selective tropism for the CNS. Other genes which are variably deleted or altered are RR and tk. Like the first-generation oncolytic viruses, these vectors are replication conditional and are engineered to replicate in rapidly proliferating cells. The result of this is minimal toxicity to normal host tissue.

G207 G207 is an attenuated, multimutated virus derived from R3616. This virus was originally constructed for treatment of malignant CNS neoplasms, and was therefore designed to be non-neurovirulent [82]. Both copies of γ134.5 are deleted, and as with hrR3, an insertional mutation of E. coli lacZ gene has been inserted into the UL39 region, which encodes for ICP6 [82]. The tk is retained, rendering the virus sensitive to GCV and acyclovir, for control of overwhelming infection [82]. Further, the virus was shown to be temperature sensitive, with poor replication at temperatures of 39.5 °C or higher [82]. Thus, a patient with fever or encephalitis would not support further replication of G207. The combination of these mutations provides the final safety factor for G207; it would be highly unlikely for all of the mutations to revert to wild-type at one time. G207 is active against human CRC metastases as well, both in vitro and in animal models. The distribution of virus in in vivo models of hepatic CRC metastases showed virus to be only in the liver in the metastatic model, and scarcely present in the normal liver parenchyma. Furthermore, by 24 h, no virus was detectable by polymerase chain reaction (PCR) in any organ but the liver [82]. Therefore, multimutated oncolytic virus G207 preferentially infects, replicates within, and lyses human CRC cells in an in vivo model [82]. Replication, and thereby amplification of tumor lysis, are dependent on cell cycle and doubling time. The animal models also showed that intratumoral or intravenous injection of virus is safe and effective [82]. In addition, when AFP-regulated RR is driven by an AFP-alb enhancer–promoter complex or a CEA enhancer–promoter (CEA E-P), the cytotoxicity and specificity of G207 in AFP-producing HCC cells and CRC is improved [83].

rRp450 This virus is derived from the hrR3 virus, and contains two mutations. The large subunit of RR is again rendered dysfunctional, but in this virus, a significant portion of the ICP6 coding region is deleted instead of simply disrupted with lacZ [81]. It was felt that this conferred an extra measure of safety by further decreasing the possibility of reversion to wild-type. The second mutation is an insertion into the viral genome of rat P450 2B1 (CYP2B1) transgene, which encodes an enzyme that activates prodrugs, particularly cyclophos-

Oncolysis with immunomodulation. G207 shows greater efficacy when combined with other vectors and chemotherapy or radiotherapy. The combined, intrasplenic injection of G207 and the HSV-IL-2 amplicon into mice with HCC or CRC metastases was more efficacious than either therapy alone, and the effect was T-cell mediated [84]. With this combination therapy, smaller doses of each may be used clinically, maintaining the overall beneficial effect while decreasing the potential for toxicity from either vector. G207 synergizes with floxuridine (FUDR), which upregulates RR in tumor

Though the single mutation viruses showed some efficacy in treating liver cancers, they were quickly abandoned for fear that the single-site mutations could revert back to wildtype in one step. This was admittedly a rare possibility, but a possibility nonetheless.

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cells, providing a complement for the lack of viral RR. A similar synergy was observed between G207 and radiation [85], possibly due to an increase in RR levels following external beam radiation. Given the neurotropism of the wild-type herpesvirus, safety has always been a primary concern in the use of oncolytic mutant herpesviruses. Initial studies established safety of intracerebral inoculations [86]. However, a maximum tolerated dose was not reached due to the inability to concentrate higher titers of virus in small enough volumes for intracerebral inoculation. The same study established safety of intrahepatic injections of 3 × 107 pfu in mice, which survived over 10 weeks compared with no survivors among those receiving injections of 1 × 106 pfu of HSV wild-type strain KOS. Multiple studies have examined organs by PCR and found little to no virus outside peritumoral areas. G207 is currently being tested in phase I and II clinical trials for neurologic malignancies. No clinical trials of G207 to treat hepatic malignancies have been performed to date. NV1020 NV1020, also known as R7020, was originally constructed with the intent of creating a vaccine to HSV-1 and -2 [87]. The virus is constructed on the backbone of HSV-1 with an HSV-2 insert, containing several glycoproteins and a copy of tk. NV1020 has shown efficacy in both in vitro and in vivo models against HCC and CRC metastases. A phase I, openlabel, dose-escalating study was performed to prove that NV1020, a genetically engineered but replication-competent HSV-1 oncolytic virus, can be safely administered into the hepatic artery without significant effects on normal liver function [88]. Oncolysis with immunomodulation. NV1034 and NV1042 each contain cytokine gene inserts and the viruses generate their effects by a combination of oncolysis and immune modulation. NV1034 contains the gene for murine GM-CSF and NV1042 contains the gene encoding murine IL-12 [89]. In this way, not only is there tumor lysis, but there can potentially also be systemic and specific tumor immunity. NV1034 has shown equivalent or better oncolytic properties against head and neck cancers [90]. Similar results have been achieved for CRC and HCC. NV1042 therapy combined with local immune stimulation with IL-12 offers effective control of parent hepatic tumors and also protects against microscopic residual disease after resection. Results of this preclinical study support potential clinical relevance for the virus, both as a primary treatment for patients with unresectable tumors and as a neoadjuvant strategy for reducing recurrence after resection [1]. These viral vectors take the next step of modulating the immune system while providing tumor lysis.


Conclusion The large number of patients whose tumors are unresectable or who are failing conventional therapies for liver cancers continues to grow. Gene therapy presents alternatives to treating these tumors; the data become stronger with every study. Replication-competent oncolytic viruses hold particular promise for achieving tumor kill with small initial doses of virus which can then propagate to an amount necessary to further lyse tumor cells. These replication-competent viruses can also provide prolonged immune upregulation with transgene delivery, such as the insertion of GM-CSF into the herpes vector. Though certain safety issues and regulatory obstacles remain, the efficacy of viral vectors in treating liver cancers is clear in animal models and continues to be elucidated in preclinical and clinical trials. Furthermore, there is a growing body of evidence that viral vectors may be synergistic with conventional chemotherapy or radiotherapy. Future directions of research will involve elucidating the mechanisms of interaction between viruses and these modalities, and working out the proper dose, route, and timing of administration.

Self-assessment questions 1 When was the notion that viruses possess oncolytic properties first established? A In 1912 when DePace noted the regression of cervical carcinoma in patients who had received viral treatment for rabies B In 1950 when farmers had regression of squamous cell carcinoma after a Newcastle disease virus outbreak in their poultry stocks C In 1981 when Bluming and Ziegler reported remissions of Burkitt and Hodgkin lymphomas following natural infections with measles virus D In 1940 when the National Cancer Institute performed a clinical study employing wild-type virus 2 Which one of the following is not a strategy employed in viral therapy of cancer? A Transgene expression B Oncolytic therapy C Immunomodulation D Methylation of viral genome E Suicide gene prodrug therapy 3 With which one of the following viruses have clinical trials not been conducted? A Myxoma virus B Vaccinia virus

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C D E F G H

Emerging Therapies

Herpes virus Newcastle disease virus Reovirus Adenovirus A and F A and E

4 Regarding Newcastle disease virus (NDV), which one of the following statements is true? A NDV upregulates natural killer cells, macrophages, and both B and T lymphocytes in humans B NDV causes a mild conjunctivitis and laryngitis in humans while being lethal to poultry C While all poultry in the United States are vaccinated against NDV, there is no treatment for the virus in humans D A, B and C E B and C 5 Regarding oncolytic herpesviruses, which one of the following statements is true? A First-generation viruses easily revert back to the wild-type strain B First-generation viruses contain a single gene deletion or mutation while second-generation viruses are multimutated C The oncolytic herpes viral genome has regions encoding for neurovirulence, which are essential for viral proliferation D B and C

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Signaling Pathways and Rationale for Molecular Therapies in Hepatocellular Carcinoma Augusto Villanueva1, Clara Alsinet1, and Josep M. Llovet2 1 HCC Translational Research Lab, Barcelona-Clinic Liver Cancer (BCLC) Group, IDIBAPS, CIBEREHD, Liver Unit, Hospital Clínic, Barcelona, Spain 2 Liver Cancer Program (Division of Liver Diseases), Mount Sinai School of Medicine, New York, NY, USA, and HCC Translational Research Lab, Barcelona-Clinic Liver Cancer (BCLC) Group, IDIBAPS, CIBEREHD, Liver Unit, Hospital Clínic, Barcelona, Spain

Introduction Hepatocellular carcinoma (HCC) is a global health problem and it is the leading cause of death among cirrhotic patients [1], being the sixth most common cancer worldwide with 626 000 new cases every year. In some Western countries, its incidence has doubled in the past four decades, increasing the attention it receives in the medical and scientific communities. The most relevant factor involved in the increase in the HCC incidence is associated with hepatitis C viral (HCV) infection [2]. HCC is considered a neoplasm with a dismal prognosis, and only 40% of patients are eligible for potential curative treatment at the time of presentation [3]. However, with the advent of surveillance programs, a switch in the type of tumors has been detected, as well as the medical interventions potentially effective for them. In the future, most newly diagnosed HCC probably will be in early stages [4] (Figure 31.1) that are suitable for effective treatment with potentially curative therapies (i.e. resection, transplantation, and percutaneous ablation) [3, 5]. Since genetic aberrations tend to accumulate during tumor progression, it seems reasonable that early tumors will be less genetically polymorphic and hence, easier to target with molecular therapies. Nevertheless, and due to the current high prevalence of advanced tumors, new therapeutic approaches are urgently needed. Systemic therapies, such as traditional chemotherapy, have been extensively evaluated in HCC [6]. No robust single phase III randomized clinical trial (RCT) has shown any of the traditional agents studied (e.g. tamoxifen, immu-


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notherapy, systemic chemotherapy, etc [6]) to increase survival. Indeed, some therapeutic regimens have shown unacceptable rates of toxicity. Recently, a phase III trial with a combination chemotherapeutic regimen (cisplatin, interferon-α2b, doxorubicin, and fluorouracil; PIAF regimen) versus doxorubicin has shown rates of treatment-related death close to 10%. As will be discussed below, HCC is very heterogenic from a molecular perspective [7]. Unlike most other human malignancies, HCC usually develops in the context of inflammation and organ injury. This high molecular variability, added to the number of different etiologies responsible for liver damage (e.g. viral hepatitis, alcohol, etc), precludes any simplistic approach to understand the molecular pathogenesis of this disease. In order to move towards so-called personalized medicine, identification of the activation of specific pathways on an individual basis is required. It is hoped that by clarifying the genomics and signaling pathways implicated in human hepatocarcinogenesis, new therapeutic targets will be uncovered in order to tackle this devastating disease [7].

Molecular pathogenesis of hepatocellular carcinoma During the preneoplastic stage of human hepatocarcinogenesis, there is an upregulation of mitogenic pathways, leading to the selection of certain clones of dysplastic cells. These clones, organized as dysplastic nodules and surrounded by fibrous septa of connective tissue, may acquire a malignant phenotype after undergoing different genomic alterations [8]. Multiple genetic alterations that activate oncogenes or disrupt tumor suppressor genes are thought to accompany the observed histologic changes, yet the precise molecular mechanisms involved in this process are not fully understood (Table 31.1). Notably, different combinations of

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Signaling Pathways and Rationale for Molecular Therapies in Hepatocellular Carcinoma

HCC

Stage 0 PST 0, Child–Pugh class A

Very early stage (O) Single < 2 cm Carcinoma in situ

Stage A–C Okuda 1–2, PST 0–2, Child–Pugh class A and B

Early stage (A) Single or 3 nodules < 3 cm, PS 0

Intermediate stage (B) Multinodular, PS 0

Stage D Okuda 3, PST > 2, Child–Pugh class C

Advanced stage (C) Portal invasion, N1, M1, PS 1–2

Terminal stage (D)

1980–1990 Early HCC Curative treatments: 5–10% 1990–2010 Early HCC Curative treatments: 30–40%

2010–2015 Early HCC Curative treatments: 50–60% Figure 31.1 Changes in the clinical spectrum of hepatocellular carcinoma (HCC). In the last three decades, and due to the establishment of surveillance programs, the number of patients diagnosed with early HCC has increased significantly. Predictions suggest that this trend will continue during the next 20 years. Since genetic aberrations tend to accumulate during tumor progression, it can be assumed that early tumors will be less polymorphic in terms of molecular pathogenesis and hence, easier to target with molecular therapies. The top part of the panel shows the different HCC stages according to the BCLC (Barcelona Clinic Liver Cancer) classification. (Adapted from Llovet & Bruix et al [51], with permission.)

genetic alterations are often observed among different individuals, and sometimes even within different nodules arising in the same individual [9]. Thus, an important goal is to classify HCC into subgroups based on the observed spectrum of genetic alterations, and to determine the treatment modalities that are most effective for each subgroup. Probably, dysregulation of certain pathways is specific for each tumor and accounts for cell proliferation and survival (i.e. Wnt-ß-catenin, IGF/Akt/mTOR, etc). Identification of these pathways is pivotal to allowing the classification of patients based on molecular data. In addition, there may be other genomic disturbances common to different tumors, such as cell-cycle checkpoint inactivation, limitless replicative potential, angiogenesis, and metastasis (Figure 31.2).

Genetic alterations: DNA copy number changes and point mutations In HCC, genetic alterations can range from point mutations in individual genes to the gain or loss of entire chromosomal arms. Several candidate genes in hepatocarcinogenesis emerged from surveys of genetic alterations, including c-Myc (8q), cyclin A2 (4q), cyclin D1 (11q), Rb1 (13q), AXIN1 (16p), p53 (17p), IGFR-II/M6PR (6q), p16 (9p), E-cadherin (16q),

SOCS (16p), and PTEN (10q) [7]. The most frequently mutated genes in HCC include p53, PIK3CA, and ß-catenin, although mutation prevalence varies depending on etiology. Dozens of studies have investigated chromosomal alterations in HCC using comparative genomic hybridization (CGH), as reviewed by Moinzadeh et al [10]. Genes in regions of chromosomal gain with increased expression levels are more likely to represent oncogenes, while genes in regions of chromosome loss with decreased expression probably represent tumor suppressor genes. The most frequently affected chromosome arm is 1q, with rates of amplification ranging between 58% and 78% in HCC. Other chromosome arms commonly altered with amplifications include 6p, 8q, 17q, and 20q, and with deletions include 4q, 8p, 13q, 16q, and 17p. The majority of the reports include patients with hepatitis B virus (HBV)-related liver disease, but associations between chromosomal alterations and etiology of the underlying liver disease have been inconsistent [11]. The application of more sophisticated technologies (e.g. bacterial artificial chromosome [BAC] array comparative genomic hybridization [CGH] studies, single nucleotide polymorphism [SNP] array, etc) to assess copy number

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Table 31.1 Genomic alterations in hepatocellular carcinoma (HCC). (Adapted from Llovet & Bruix [50].) Function

Gene

Genomic alteration

Growth factors and receptors

IGF-2 IGF-2R (M6PR) EGF EGFR TGF-α k-Ras RASSF1 PIK3CA PTEN Akt mTOR HGF/c-MET

Overexpression LOH, decrease in copy number Overexpression Overexpression, infrequently mutated Overexpression Mutated in 11% of HCC (associated with vinyl chloride exposure) Downregulation, aberrant methylation Variable mutation rate (0–35%) Mutations (< 10%), downregulation, aberrant methylation Activated by phosphorylation (Ser 473) Overexpression Overexpression

Cell differentiation

ß-Catenin E-cadherin Sonic Hedgehog Gli

Variables mutation rate (0–44%), frequent nuclear translocation Downregulation, aberrant methylation Overexpression Overexpression

Angiogenesis

VEGFA VEGF-2R Angiopoietin-2

Overexpression, high gain amplifications Overexpression Overexpression

Metastasis

MMP-9 Topoisomerase 2A Osteopontin

Overexpression Overexpression Overexpression

Cell cycle

Rb Cyclin D1 p53 p16 p27kip Survivin Gankyrin

High level amplification, overexpression Variable mutation rate (0–67%) Downregulation, aberrant methylation Downregulation Overexpression Overexpression

LOH, loss of heterozygosity; IGF, insulin-like growth factor; IGFR, insulin-like growth factor receptor; TGF-α, transforming growth factor-α; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; HGF, hepatocyte growth factor; VEGFA, vascular endothelial growth factor A; VEGFR, vascular endothelial growth factor receptor; MMP-9, matrix metalloproteinase 9.

changes in HCC specimens confirm the initial findings obtained with CGH. Recurrent high-level amplification at 11q13 was reported in three studies at a combined frequency of 5% [12]. This evolutionarily conserved locus contains several genes in the Wnt-ß-catenin and mitogenactivated protein kinase (MAPK) pathways. Several other high-level amplifications have been reported in individual tumors, yet none of them has been replicated in multiple studies. The potential predictive power of genetic alterations regarding other clinical parameters like prognosis, recurrence after surgery, and tumor stage remains unclear. In a meta-analysis including 785 patients [10], there was a significant correlation between several high-frequency genomic imbalances and tumor grade (loss of 4q and 13q), as well as

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HBV infection (loss of 4q, 8p, 13q, and 16q). Similarly, additional studies reported significant associations with stage (gain of 1q, 3q, and 7q), tumor size (loss of 8p and gain of 8q), and vascular invasion (gain of 1q, 6q, and 17q, and loss of 11q). However, two recently published studies failed to show any correlation between CGH data and clinicopathologic features [13, 14]. This discrepancy may arise from the multifactorial and heterogeneous contributions of genetic alterations to clinicopathologic variables. The genes that have been most comprehensively studied for mutations in HCC are p53 and ß-catenin. In HCC, the rate of p53 mutations is variable and ranges from 0% to 67% [7]. Indeed, there are remarkable differences in the mutation rate depending on the geographic area: higher rates have been documented in West Africa and South-East Asia and

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Molecular alterations specific to each subclass

Signaling Pathways and Rationale for Molecular Therapies in Hepatocellular Carcinoma

Wnt-b-catenin (proliferation and differentiation)

Tyrosine kinase receptor (proliferation)

IFN response (immunomodulation)

Others (gains in Chr7, TGF-β, etc)

Inactivation of checkpoints (p53, RB, CCND) Molecular alterations common to different tumors

Replicative potential (TERT)

Angiogenesis (VEGF, angiopoietin, PDGFR)

Metastasis (osteopontin, MMPs)

Figure 31.2 Implication of genomic alterations in the molecular pathogenesis of hepatocellular carcinoma (HCC). Activation analysis of specific signaling pathways allows HCC classification into different molecular subgroups. In addition, there are common alterations in almost all tumors that have limitless replicative potential resulting from activation of telomerase reverse transcriptase (TERT), neoangiogenesis, insensitivity to antigrowth signals, and checkpoint disruption, and metastasis. TGF-β, transforming growth factor-β; MMP, matrix metalloproteinase; VEGF, vascular endothelial growth factor; PDGFR, platelet-derived growth factor receptor. (Adapted from Llovet & Bruix [50], with permission.)

lower rates in Western countries. This difference is tightly correlated to aflatoxin B exposure. The p53 G-to-T mutation at the third position of codon 249 is the target for this carcinogen. In Western countries where aflatoxin B exposure is not endemic, high mutation rates of p53 are seen only in patients with hemochromatosis-related HCC. In addition, findings from a European cohort of 42 patients showed significant differences in median survival after surgery when patients were clustered according to p53 mutations. On the other hand, the mutation rate of CTNNB1 in HCC ranges from 0% to 44%, and these mutations are mostly located in exon 3 of the CTNNB1 gene, the phosphorylation site for glycogen synthase kinase 3 beta (GSK3B). Mutations of genes transcribing other components of the Wnt pathway also have been described, including AXIN1 and AXIN2, and several extracellular inhibitors of Wnt signaling [7].

Gene expression dysregulation Gene expression profiles obtained from studies using highthroughput technologies (e.g. oligonucleotide gene expression microarray) have revolutionized the approach to human malignancies, including HCC. These technologies allow the simultaneous analysis of thousands of transcripts that cover the entire genome. The application of clustering algorithms to the dysregulated genes permits the classification of samples on the basis of expression profiles. These

clusters (i.e. gene signatures) can be used for diagnostic purposes, as well as to assess response to treatment and to predict survival in several types of tumors [15]. Several clinical staging systems have been proposed to predict HCC prognosis but only the Barcelona Clinic Liver Cancer (BCLC) staging system has gained wide recognition among scientific communities [16, 17]. It, however, does not incorporate biologic information from the tumor. Considerable efforts have been made to obtain a molecular classification of HCC, most of them based on gene expression microarrays. Initial studies compared gene expression between HCC and nontumoral tissue, and were later improved by gene expression analysis of the whole hepatocarcinogenic process (including cirrhotic tissue and preneoplastic lesions [4]). Ye et al studied 67 primary and metastatic HCC by an unsupervised hierarchical clustering algorithm interrogating 9180 genes [18]. They found that primary metastasis-free HCC had a gene expression profile markedly different from that of primary HCC with metastatic lesions, as well as differences in patient survival. The 153-gene model provided a robust signature that correctly classified 100% of the training samples during cross-validation. All these data implied that genes favoring metastasis progression are initiated in the primary tumors, and the authors argued that primary HCC with metastatic potential may be evolutionarily distinct from metastasis-free primary HCC.

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Emerging Therapies

Furthermore, stringent analysis of expression data unleashed osteopontin as a relevant mediator in metastatic HCC. Similarly, another study using high-density oligonucleotide microarray reported a 12-gene signature able to predict early intrahepatic HCC recurrence with an accuracy of 93% [19]. Subsequently, and using a different technology (adaptor-tagged competitive polymerase chain reaction [PCR]), Kurokawa et al studied gene expression in 60 HCC patients [20]. The authors selected a 20-gene signature out of 92 candidate genes able to predict early recurrence (90% E 100% 3 Currently the preferred nuclear imaging modality for both carcinoid and islet cell tumors is 111In-octreotide scintigraphy, because it has greater than 95% sensitivity and specificity for both tumor types. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 4 Liver metastases ultimately occur in what percentage of patients with carcinoid tumors? A 10% B 25% C 50% D 75% E 90%

6 Biotherapy with somatostatin analogs is useful in treating carcinoid symptoms but offers palliative benefits only, with no chance of tumor stabilization or shrinkage. A True B False 7 Which of the following laboratory results are often elevated in patients with endocrine tumors? (more than one answer is possible) A 5-HIAA B Chromogranin-A C α-Fetoprotein D Neuron-specific enolase E Transferrin 8 Which one of the following therapeutic radiolabeled somatostatin analogs represents the most recent addition to the class? A 90Y-somatostatin B 111In-octreotide C 177Lu-octreotate D 131I-MIBG E 91Y-somatostatin 9 Which of the following are common symptoms of carcinoid syndrome? (more than one answer is possible) A Flushing B Constipation C Diarrhea D Wheezing E Paraesthesias 10 The literature clearly demonstrates that hepatic artery embolization is superior to chemoembolization. A True B False

References 5 Whenever a complete resection of liver metastasis from endocrine tumor is possible, the operation should be performed, because randomized controlled trials have demonstrated a survival benefit in patients undergoing resection. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct

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CHAPTER 36

6 Modlin IM, Lye KD, Kidd M. A 50-year analysis of 562 gastric carcinoids: small tumor or larger problem? Am J Gastroenterol 2004;99:23–32. 7 Thompson GB, Heerden JA, Martin JK, et al. Carcinoid tumors of the gastrointestinal tract: presentation, management, and prognosis. Surgery 1985;98:1054–63. 8 Norton JA. Neuroendocrine tumors of the pancreas and duodenum. Curr Probl Surg 1994;31:77–82. 9 Steinmueller T, Kianmanesh R, Falconi M, et al. Consensus guidelines for the management of patients with liver metastases from digestive (neuro)endocrine tumors: foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 2008;87: 47–62. 10 Bilimoria KY, Tomlinson JS, Merkow RP, et al. Clinicopathologic features and treatment trends of pancreatic neuroendocrine tumors: analysis of 9,821 patients. J Gastrointest Surg 2007;11: 1460–7. 11 Vinik AI, Strodel WE, Eckhauser FE, et al. Somatostatinomas, PPomas, neurotensinomas. Semin Oncol 1987;14:263–81. 12 Wolfe MM, Jensen RT. Zollinger-Ellison syndrome. Current concepts in diagnosis and management. N Engl J Med 1987; 317:1200–09. 13 Wiseman GA, Kvols LK. Therapy of neuroendocrine tumors with radiolabeled MIBG and somatostatin analogues. Semin Nucl Med 1995;25:272–8. 14 Martin, WH, Delbeke D. Oncologic imaging. In: Habibian MR, Delbeke D., Martin WH, Sandler MP, eds. Nuclear Medicine Imaging: A Teaching File. Baltimore: Williams & Wilkins, 1999:619–722. 15 Gabriel M, Decristoforo C, Kendler D, et al. 68Ga-DOTA-Tyr3octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT. J Nucl Med 2007;48: 508–18. 16 Imam H, Eriksson B, Lukinius A, et al. Induction of apoptosis in neuroendocrine tumors of the digestive system during treatment with somatostatin analogs. Acta Oncol 1997;36: 607–14. 17 Jacobsen MB, Hanssen LE. Clinical effects of octreotide compared to placebo in patients with gastrointestinal neuroendocrine tumours. Report on a double-blind, randomized trial. J Int Med Res 1995;237:269–75. 18 Arnold R, Trautmann ME, Creutzfeldt W, et al. Somatostatin analogue octreotide and inhibition of tumour growth in metastatic endocrine gastroenteropancreatic tumours. Gut 1996;38: 430–8. 19 Chung MH, Pisegna S, Spirt M, et al. Hepatic cytoreduction followed by a novel long-acting somatostatin analog: a paradigm for intractable neuroendocrine tumors metastatic to the liver. Surgery 2001;130:954–62. 20 Yao KA, Talamonti MS, Nemcek A, et al. Indications and results of liver resection and hepatic chemoembolization for metastatic gastrointestinal neuroendocrine tumors. Surgery 2001;130: 677–85. 21 Andersson T, Wilander E, Eriksson B, et al. Effects of interferon on tumor tissue content in liver metastases of carcinoid tumors. Cancer Res 1990;50:3413–15. 22 Oberg K. Neuroendocrine gastrointestinal tumours. Ann Oncol 1996;7:453–463.

Liver Metastases from Endocrine Tumors

23 McEntee GP, Nagorney DM, Kvols LK, et al. Cytoreductive hepatic surgery for neuroendocrine tumors. Surgery 1990;108: 1091–6. 24 Foster J, Lundy J. Pathology of liver metastases. Curr Probl Surg 1981;18:157–63. 25 Clary B. Treatment of isolated neuroendocrine liver metastases. J Gastrointest Surg 2006;10:332–4. 26 Osborne DA, Zervos EE, Strosberg J, et al. Improved outcome with cytoreduction versus embolization for symptomatic hepatic metastases of carcinoid and neuroendocrine tumors. Ann Surg Oncol 2006;13:572–81. 27 Knox CD, Feurer ID, Wise PE, et al. Survival and functional quality of life after resection for hepatic carcinoid metastasis. J Gastrointest Surg 2004;8:653–9. 28 Touzios JG, Kiely JM, Pitt SC, et al. Neuroendocrine hepatic metastases: does aggressive management improve survival? Ann Surg 2005;241:776–83. 29 Musunuru S, Chen H, Rajpal S, et al. Metastatic neuroendocrine hepatic tumors: resection improves survival. Arch Surg 2006; 141:1000–4. 30 Grazi GL, Cescon M, Pierangeli F, et al. Highly aggressive policy of hepatic resections for neuroendocrine liver metastases. Hepatogastroenterology 2000;47:481–6. 31 Sarmiento JM, Heywood G, Rubin J, et al. Surgical treatment of neuroendocrine metastases to the liver: a plea for resection to increase survival. J Am Coll Surg 2003;197:29–37. 32 Chamberlain RS, Canes D, Brown KT, et al. Hepatic neuroendocrine metastases: Does intervention alter outcomes? J Am Coll Surg 2000;190:432–45. 33 Coppa J, Pulvirenti A, Schiavo M, et al. Resection versus transplantation for liver metastases from neuroendocrine tumors. Transplant Proc 2001;33:1537–9. 34 Jaeck D, Oussoultzoglou E, Bachellier P, et al. Hepatic metastases of gastroenteropancreatic neuroendocrine tumors: safe hepatic surgery. World J Surg 2001;25:689–92. 35 Cozzi PJ, Englund R, Morris DL. Cryotherapy treatment of patients with hepatic metastases from neuroendocrine tumors. Cancer 1995;76:501–9. 36 Seifert JK, Cozzi PJ, Morris DL. Cryotherapy for neuroendocrine liver metastases. Semin Surg Oncol 1998;14:175–83. 37 Mazzaglia PJ, Berber E, Milas M, et al. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases: a 10-year experience evaluating predictors of survival. Surgery 2007;142: 10–19. 38 Lencioni RA, Allgaier HP, Cioni D, et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radiofrequency thermal ablation versus percutaneous ethanol injection. Radiology 2003;228:235–40. 39 Lehnert T. Liver transplantation for metastatic neuroendocrine carcinoma: an analysis of 103 patients. Transplantation 1998;66: 1307–12. 40 LeTreut YP, Gregoire E, Belghiti J, et al. Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: An 85-case French multicentric report. Am J Transplant 2008;8:1205–13. 41 Marín C, Robles R, Fernández JA, et al. Role of liver transplantation in the management of unresectable neuroendocrine liver metastases. Transplant Proc 2007;39:2302–3.

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Special Tumors, Population, and Special Considerations

42 Olausson M, Friman S, Herlenius G, et al. Orthotopic liver or multivisceral transplantation as treatment of metastatic neuroendocrine tumors. Liver Transpl 2007;13:327–33. 43 Florman S, Toure B, Kim L, et al. Liver transplantation for neuroendocrine tumors. J Gastrointest Surg 2004;8:208–12. 44 Frilling A, Rogiers X, Malago M, et al. Treatment of liver metastases in patients with neuroendocrine tumors. Langenbeck’s Arch Surg 1998;383:62–70. 45 Ringe B, Lorf T, Dopkens K, Canelo R. Treatment of hepatic metastases from gastroenteropancreatic neuroendocrine tumors: role of liver transplantation. World J Surg 2001;25:697–99. 46 Moertel CG, Lefkopoulo M, Lipistz S, et al. Streptozotocin-doxorubicin, streptozotocin-fluorouracil, or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 1992; 326:519. 47 Moertel CG, Kvols LK, O’Connell MJ, Rubin J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 1991;68:227–32. 48 Anthony LB, Woltering EA, Espanan GD, et al. Indium-111pentetreotide prolongs survival in gastroenteropancreatic malignancies. Seminars Nucl Med 2002;32:123–32. 49 Waldherr C, Schumacher T, Maecke HR, et al. Does tumor response depend on the number of treatment sessions at constant injected dose using 90Yttrium-DOTATOC in neuroendocrine tumors? Eur J Nucl Med Mol Imaging 2002;29 (Suppl 1): S100. 50 Paganelli G, Bodei L, Junak D, et al. 90Y-DOTA-D-Phe1-Tyr3octreotide in therapy of neuroendocrine malignancies. Biopolymers 2002;66:393–8. 51 Bushnell D. Therapy with radiolabeled somatostatin peptide analogs for metastatic neuroendocrine tumors. J Gastrointest Surg 2006;10:335–6. 52 Kwekkeboom DJ, Teunissen JJ, Bakker WH, et al. Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors. J Clin Oncol 2005;23:2754–62. 53 Aune S, Schistad G. Carcinoid liver metastases treated with hepatic dearterialization. Am J Surg 1972;123:715–17.

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54 Carrasco CH, Charnsangavej C, Ajani J, et al. The carcinoid syndrome: palliation by hepatic artery embolization. AJR Am J Roentgenol 1986;147:149–154. 55 Ho AS, Picus J, Darcy MD, et al. Long-term outcome after chemoembolization and embolization of hepatic metastatic lesions from neuroendocrine tumors. AJR Am J Roentgenol 2007;188: 1201–7. 56 Gupta S, Johnson MM, Murthy R, et al. Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors: variables affecting response rates and survival. Cancer 2005;104:1590–602. 57 Perry LJ, Stuart K, Stokes KR, Clouse ME. Hepatic arterial chemoembolization for metastatic neuroendocrine tumors. Surgery 1994;116:1111–17. 58 Kamat PP, Gupta S, Ensor JE, et al. Hepatic arterial embolization and chemoembolization in the management of patients with large-volume liver metastases. Cardiovasc Intervent Radiol 2008;31: 299–307. 59 Ruutiainen AT, Soulen MC, Tuite CM, et al. Chemoembolization and bland embolization of neuroendocrine tumor metastases to the liver. J Vasc Interv Radiol 2007;18:847–55. 60 Que FG, Nagorney DM, Batts KP, et al. Hepatic resection for meteastatic neuroendocrine carcinomas. Am J Surg 1995; 169:36–43.


C D B D B B A, B, D C A, C, D B

37

Uncommon Primary and Metastatic Liver Tumors Stefan Breitenstein, Ashraf Mohammad El-Badry, and Pierre-Alain Clavien Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland

While a large amount of data is available on hepatocellular carcinoma, cholangiocellular carcinoma, and liver metastases from colorectal cancer, only a few studies have presented other liver tumors. Treatment and outcome of these uncommon tumors remain largely controversial, and therapeutic strategies for them have not been clearly defined [1]. This chapter will review the data available on (1) rare primary hepatic tumors, including sarcomas (angiosarcomas, undifferentiated sarcomas, schwannomas, epithelioid hemangioendotheliomas) and primary liver lymphomas; (2) liver metastases from breast cancer, melanoma, and gastric cancer; and finally (3) liver tumors of unknown origin. The topic of neuroendocrine tumors metastatic to the liver is covered in Chapter 36.

Uncommon primary tumors of the liver Sarcomas Sarcomas of the liver are rare, representing less than 1% of all hepatic malignancies in adults, with only exceptional reports in the pediatric population. The most common histologic types are angiosarcoma, undifferentiated sarcoma, epithelioid hemangiosarcoma, and schwannoma.

Angiosarcoma Angiosarcoma is the most common type of liver sarcoma in adults with a peak incidence in the sixth and seventh decades. The annual incidence in the general population is 1.4 per 100 million [2] with a tendency toward elderly males [3]. Several etiologic factors have been identified, including exposure to vinyl chloride, thorotrast, and arsenic [4]. A link has been suggested between the development of angiosarcoma and the long-term use of oral contraceptives [5]. The clinical presentation is nonspecific, with abdominal pain, fatigue, jaundice, and loss of weight [6]. More dra-


matic presentations include intra-abdominal bleeding [7] and high output heart failure [2]. Most of these tumors are very large at the time of diagnosis [2] with massive hepatomegaly and ascites [6, 8]. Hepatic angiosarcoma may appear as scattered multiple small nodules, a solitary large mass with multiple small lesions or a diffusely infiltrating tumor [9]. The contrast computed tomography (CT) scan often shows patchy enhancement of the tumor. Angiosarcomas can be distinguished from benign hemangiomas by the absence of peripheral enhancement completely encircling the low-density areas, together with the heterogeneous enhancement. At angiography, angiosarcoma appears as a focal hepatic mass with peripheral contrast staining, puddling of contrast, and central areas of hypovascularity. Due to the risk of bleeding, the diagnosis is usually made by open or laparoscopic biopsy. Percutaneous biopsies have been associated with a 5% mortality rate [2]. The prognosis of angiosarcoma is very poor, with a rapid progressive clinical course in most cases. Overall, the mean survival of patients with hepatic angiosarcoma is 6 months, with a 2-year survival rate of only 3%. Distant metastases develop in about 60% of patients with angiosarcoma. Hemorrhage and thrombocytopenia are frequent clinical features in advanced stages of the disease. The number of reported cases of hepatic angiosarcoma remains low. The results of different therapeutic modalities are summarized in Table 37.1. In early stages when the tumor is still localized, resection in combination with chemotherapy has been used with limited success. For instance, of three adult patients treated with liver resection and adjuvant doxorubicin hydrochloride (adriamycin), none survived beyond 2 years [10]. A 4-yearold child survived 44 months after hemihepatectomy and adjuvant chemotherapy containing ifosfamide, etoposide, cisplatinum, and adriamycin [11]. Arima-Iwasa et al [12] reported a patient with hepatic angiosarcoma who was alive without evidence of recurrence 16 months after resection. Ozden et al [13] reported the case of a 54-year-old female patient with a solitary large angiosarcoma treated by right hemihepatectomy and postoperative chemoembolization of the remnant liver. The patient was alive for more than 5

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Table 37.1 Outcome of primary angiosarcoma of the liver treated by various modalities. Authors (year)

Number of patients

Treatment

Death (months)

Locker et al (1979) [2] Das Gupta et al (1982) [10] Penn (1991) [15] Peiper et al (1994) [79] Awan et al (1996) [19]

4 3 14 1 1 1 2 1 1 1 1

Chemotherapy Resection + chemotherapy Transplantation Segmentectomy (R1) + chemotherapy Hemihepatectomy Transplantation Chemotherapy + chemotherapy Resection + chemotherapy Resection Resection (trisegmentectomy) Resection (hemihepatectomy), prophylactic chemoembolization (lipiodol + adriamycin + mitomycin) of the remnant liver Vascular ablation + chemotherapy and liver transplantation Transplantation Resection

12, 12, 7, 5 30–45 days

Proceed to the operating room with aspirin

Drug-eluting stent

< 30–45 days < 365 days

> 365 days

Delay elective or nonurgent surgery

Proceed to the operating room with aspirin

Figure 38.2 Proposed approach to the management of patients with previous percutaneous coronary intervention (PCI), based on expert opinion. (Adapted from the ACC/AHA 2007 perioperative guideline, Fleisher et al [54].)

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Acute MI, high-risk ACS, or high-risk cardiac anatomy

Bleeding risk of surgery

Low

Stent and continue dual-antiplatelet therapy

Not low

14–29 days

Balloon angioplasty

30–365 days

Bare-metal stent

> 365 days

Timing of surgery

Drug-eluting stent

Figure 38.3 Treatment for patients requiring percutaneous coronary intervention who need subsequent surgery. MI, myocardial infarction. (Adapted from the ACC/AHA 2007 perioperative guideline, Fleisher et al [54].)

in the ACC/AHA 2007 perioperative guidelines (Figure 38.3) [54]. If the hepatobiliary surgery is imminent (within 2–6 weeks) and the risk of bleeding is high, angioplasty and provisional bare-metal stenting plus continued aspirin antiplatelet monotherapy can be considered with restenosis being dealt with by repeat PCI if necessary [54].

Hepatic resection in elderly patients In recent years, the number of elderly patients who have undergone hepatic resection has increased because of advances in surgical technique, postsurgical management, and a prolongation in life-expectancy. Certain issues have been raised in elderly patients regarding the appropriateness and extent of surgical resection due to a presumed impaired ability of the remaining hepatic mass to regenerate after resection. During aging, the liver undergoes physiologic changes, such as decreased size and blood flow [70]. These factors may reduce the functional reserve of the organ. Unexpected liver failure can occur post resection in some patients who were expected preoperatively to have sufficient hepatic functional reserve for postoperative recovery. Liver regeneration after hepatectomy has been clinically studied with evidence of impaired regeneration in older patients [71, 72]. Based on computed tomography (CT) scan estimates of hepatic volume, older patients have been found to have a smaller regenerative volume increase than agematched controls following similar hepatic resections [71]. On the other hand, other studies have shown that the volu-

460

metric recovery is similar despite age, but hepatocyte synthetic function is impaired in elderly patients post resection. In a review of 56 patients with HCC who had undergone a right hemihepatectomy, Yamamoto et al found that there was a marked decline in postoperative protein synthesis in the older group over 70 years of age. Although specific correlations between degree of synthetic dysfunction and hepatic failure could not be proven, postoperative hepatic failure occurred more frequently in patients over 65 years of age. Of note, this group of patients was the only group in the review with concomitant diseases such as diabetes, hypertension, and ischemic heart and pulmonary disease [72]. Conversely, other studies have shown that age is not a significant independent variable for prediction of survival despite the concerns about regeneration [73]. There also studies that have shown that livers with cirrhosis or chronic hepatitis regenerate less effectively than normal liver parenchyma after similar resections, independent of the age of the patient. The ethical issues of decisions regarding palliative versus curative therapy must be approached with care and individualized for each patient. To date, sufficient evidence exists that hepatic resection can be safely performed in selected aged patients [74–76], although old age (70 years or older) used to be recognized as an adverse factor for hepatic resection [77, 78]. Hanazaki et al reported on 87 liver resections for HCC in patients over 70 years of age, comparing them with 237 liver resections in patients younger than 70 years. There were no significant differences in postoperative complications, operative mortality, and overall hospital death rate between the two groups.

CHAPTER 38

Liver Tumors in Special Populations

Table 38.5 Results of hepatic resection for colorectal liver metastasis in elderly patients. Authors

Year

Number. of patients

Age

Mortality (%)

Preoperative morbidity (%)

Complications (%)

1-Year survival (%)

3-Year survival (%)

5-Year survival (%)

p value*

Fong et al [79] Brand et al [185] Zacharias et al [80] Nagano et al [76]

1995 2000 2004 2005

128 41 56 62

≥70 ≥70 ≥70 ≥71

4 7 0 0

55 NA NA 34.50

42 39 41 19.70

85 NA 86 79.40

NA 29 44 46.50

35% 16% 21% 34.10%

NS NS NA p < 0.01

*p value compares elderly patients with younger patient in their study. NA, not available, NS, not significant.

Overall 3- and 5-year survival rates for the older and younger groups were similar: 51.0% versus 55.2%, and 42.2% versus 40.0%, respectively (p = 0.95) [79]. They concluded that selected elderly patients with HCC benefited from resection as much as younger patients, and age by itself may not be a contraindication to surgery. Similar results have been reported in hepatic resections for colorectal metastases [76, 80]. Table 38.5 lists recent studies involving hepatic resections for colorectal liver metastases in advanced age. All the reports conclude that advanced chronologic age is not a contraindication for hepatic resection for colorectal liver metastases. Furthermore, the most recent reports from Zacharias et al [81] and Nagano et al [76] showed 0% mortality, although the latter study showed significantly lower survival rates in older patients, possibly due to a higher rate of nontreatment for hepatic recurrence. The majority of reports that address the outcome of liver resection in the elderly relate to HCC, which behaves very differently from colorectal liver metastasis. Hepatic resection for HCC involves the additional risk factors of hepatitis and cirrhosis, whereas most colorectal liver metastases occur on a noncirrhotic liver background. Questions also arise about the feasibility of major hepatectomies in elderly patients. Cescon et al studied the outcome of 23 right hepatectomies in patients older than 70 years [82]. They showed excellent 1- and 3-year survival rates of 84.4% and 64.2%, respectively, and there were no differences compared to the group younger than 70 years of age. They concluded that advanced age should not be a contraindication for major hepatectomies, but a careful preoperative evaluation to exclude liver cirrhosis and severe comorbid medical conditions is necessary. There are scarce data about hepatic resection for cholangiocarcinoma in elderly patients. One report from Yeh et al studied 33 hepatic resections for peripheral cholangiocarcinoma in patients older than 70 years of age, comparing them to 185 patients younger than 70 years [83]. Excluding

patients who died within the first postoperative month, the 1-, 2-, 3-, and 5-year actuarial survival rates were 59.6%, 34.8%, 0%, and 0%, respectively, which were not significantly different from those for patients younger than 70 years (52.6%, 31.6%, 22.7%, and 13.9%, respectively; p = 0.827). A low carcinoembryonic antigen (CEA) was an independent factor for favorable survival. They concluded that hepatic resection for peripheral cholangiocarcinoma is feasible for selected elderly patients. Most reports conclude that advanced age is not a contraindication for hepatic resection. However, the data should be reviewed carefully as many of the studies suffer from significant patient selection bias, and the excellent results reported are the culmination of careful patient selection as well as specialized surgical expertise and anesthetic care. It is clear that not all elderly patients with malignant disease of the liver are candidates for aggressive and extensive liver resections. However, the data also suggest that denying patients access to surgical therapy based upon chronologic age alone is unwarranted.

Hepatic tumors in immunosuppressed patients In this section two groups of patients are discussed: patients infected with human immunodeficiency virus (HIV) and solid organ transplant recipients. Both these groups share a common underlying characteristic: a profound decrease in cell-mediated immunity. Improvements in drug therapy and better monitoring techniques for response to therapy have resulted in an increase in life-expectancy in both these groups. However, a deficiency in cell-mediated immunity still places the patients in these groups at a higher risk for the development of malignancies. This section will focus on the development of hepatic malignancies in these two specific immune-deficient populations.

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Human immunodeficiency virus infectionassociated liver tumors According to the joint United Nations program on HIV/ AIDS in the 2007 AIDS epidemic update, the worldwide prevalence of HIV/acquired immunodeficiency syndrome (AIDS) is 33.2 million with 2.5 million new cases occurring in 2007, as well as 2.1 million AIDS-related deaths. The advent of highly active antiretroviral therapy (HAART) has resulted in an immunologic response (defined as sustained elevations in CD4 lymphocyte counts) after 6 months of HAART, indicating a favorable clinical outcome in HIV-infected patients regardless of the virologic response (defined as near complete suppression of the HIV viral load) [84]. However, despite significant advances in treatment, complete eradication of HIV has not been achieved due to the persistence of the virus in the lymphatic tissue. The use of HAART is associated with a decreased risk of non-Hodgkin lymphoma, whereas uncontrolled HIV RNA load may be associated with an increased risk [85]. The rates of the most common opportunistic infections are markedly reduced after the initiation of antiretroviral therapy, but a similar reduction has not been observed in the incidence of other infections and lymphomas, suggesting that the T-cell repertoire is not completely restored and that long treatment periods are needed. Liver tumors in an HIV/AIDS patient can be considered under two categories: HIV/AIDS- and non-HIV/AIDS-defining malignancies. HIV/AIDS-defining malignancies include Kaposi sarcoma and non-Hodgkin lymphoma. These are systemic diseases in which the role of surgery is limited to the occasional diagnostic biopsy. Non-HIV/AIDS-defining malignancies, which are on the rise in this patient population, include HCC. In such cases, surgical treatment may improve survival and palliate symptoms.

Kaposi sarcoma At one point in the AIDS epidemic, Kaposi sarcoma was the most common gastrointestinal tumor diagnosed. Although the proportion of AIDS patients developing this neoplasm during the course of their disease is declining due to HAART therapy [86], the actual number of Kaposi sarcoma cases is increasing due to the overall rise in the total number of patient suffering from AIDS. A strong association has been described between human herpes virus 8 infection and Kaposi sarcoma, with a 95% occurrence of the virus in the tumors in one study [87]. The patient population consisted of a combination of AIDS-associated, classic Kaposi sarcoma, and Kaposi sarcoma occurring in HIV-seronegative homosexual men. Kaposi sarcoma is predominantly a cutaneous disease and the prognosis is based upon the AIDS Clinical Trials Group (ACTG) staging classification, which includes the tumor stage (T), the state of the immune system (I),

462

Table 38.6 AIDS Clinical Trials Group staging classification for Kaposi sarcoma. Good risk

Poor risk

Tumor (T)

T0: Localized to skin and/or lymph nodes

Immune status (I) Systemic disease (S)

I0: CD4 count > 150/μL

T1: Tumor-related local complications (edema or ulceration) Oral or visceral involvement I1: CD4 count < 150/μL

S0: No AIDS-related opportunistic infections No constitutional symptoms Karnofsky performance scale > 70

S1: AIDS-related opportunistic infections Constitutional symptoms: fevers, night sweats, chronic diarrhea Karnofsky performance scale < 70 Other HIV/AIDS-related illnesses

and the presence of concurrent systemic illnesses [88] (Table 38.6). There are cases where Kaposi sarcoma may present as a widespread, aggressive tumor with visceral involvement. The liver is usually involved in these cases. It is very rare to have a symptomatic liver lesion without any other manifestation of the tumor [89], Isolated Kaposi sarcoma of the liver has not been described in the medical literature to this date. Kaposi sarcoma lesions are nests of endothelial cells forming channels intercalated with red blood cells that are responsible for their characteristic red and purple gross appearance. The diagnosis of hepatic Kaposi sarcoma is usually made clinically and in the majority of cases can be confirmed by a skin biopsy. Visceral involvement can be confirmed by direct visualization, i.e. endoscopy or laparoscopy. The radiologic diagnosis is characterized by visualization of low attenuation lesions on a CT scan. Percutaneous liver biopsy has a low yield in terms of obtaining tissue for a diagnosis of hepatic Kaposi sarcoma due to the fibrous and stromal nature of the tumor [90]. The utility of liver biopsies is also questionable due to the obvious presence of extrahepatic disease and the low accuracy of the biopsy result. Additionally, it has been reported that liver biopsies in patients with AIDS is associated with an increased risk of postbiopsy hemorrhage despite normal clotting studies. If a tissue diagnosis of hepatic Kaposi sarcoma is mandatory for proposed treatment, the biopsy can be performed in the operating room under direct laparoscopic visualization. If bleeding occurs, cautery or application of hemostatic agents can be implemented on the biopsy site for control of hemorrhage.

CHAPTER 38

Treatment of the HIV/AIDS-related Kaposi sarcoma is dependent upon the factors outlined in the ACTG staging system (see Table 38.6). The mainstay of treatment is highly active antiretroviral therapy, which has been shown to decrease the incidence of Kaposi sarcoma due to the immune restoration [91]. There is evidence to suggest that protease inhibitor-based and reverse transcriptase-based antiretroviral treatments may lead to an undetectable Kaposi sarcomaassociated herpes virus (KSHV) load and regression of the lesions [90]. In widespread Kaposi sarcoma with visceral involvement, chemotherapy is effective in inducing tumor regression, reduction of edema, and control of symptoms. The mainstay of therapy consists of a combination of pegylated-liposomal doxorubicin, liposomal daunorubicin, and paclitaxel [92, 93]. Moderate response rates (up to half of the treated patients) are described; although the side effects and toxicities, especially bone marrow suppression, may limit their use. It is recommended that chemotherapy be used in conjunction with antiretroviral therapy, prophylaxis for opportunistic infections, and hematopoietic growth factors [94]. Interferon-alpha in combination with antiretroviral therapy has been shown to cause complete or partial tumor regression in approximately 31–55% of patients studied, and both response and toxicities are dose dependent [95]. Matrix metalloproteinase inhibitors (COL-3) have a response rate of 41%, with major side effects being rash and photosensitivity [96]. Surgery has no current role in the management of Kaposi sarcoma. Before undertaking treatment of advanced disease with visceral involvement, clear goals of therapy should be identified. Patient involvement at each step of the way is necessary to maximize improvement in the quality of life as there is no cure for the disease.

Hepatic non-Hodgkin lymphoma Non-Hodgkin lymphoma (NHL) is the second most common malignancy in patients with AIDS/HIV, and hepatic involvement in NHL is usually a sign of disseminated disease. Survival amongst HIV/AIDS patients with generalized lymphoma is poor. There have been sporadic reports of isolated hepatic NHL in the literature [97]. It seems to be a rare occurrence. The majority of these lymphomas originate from B cells. Epstein-Barr virus (EBV) has been detected in 80% of B-cell NHLs associated with HIV when polymerase chain reaction (PCR)-based techniques were used [98]. There seems to be no direct role of HIV in the development of NHL. HIVinduced immune depression and EBV infection present in these cases can favor the expansion of B-cell clones, which in turn may increase the probability of occurrence of lymphoma carrying activated c-Myc rearrangements, thus leading to malignant transformation [99]. Mean age at presentation in the 15 cases of hepatic NHL reported in the literature was 40 years. Clinical symptoms


included fever, weight loss, right upper quadrant pain, and hepatomegaly. All patients had abnormal liver enzymes, including a markedly elevated lactate dehydrogenase, but normal routine tumor markers, such as CEA and alphafetoprotein (AFP). Unlike in patients with primary hepatic lymphoma but no HIV infection, the majority of these patients had multiple lesions detected on abdominal CT scan or abdominal ultrasound. On needle biopsy, the lymphomas were most commonly high-grade, B-cell type. Diffuse hepatic infiltration by a NHL has also been reported in patients with AIDS, leading to jaundice and biliary obstruction [100]. The clinical presentation of HIV/AIDS-related NHL has not changed since the introduction of HAART. There have been some reports of improvement in survival in these patients when chemotherapy and HAART are combined [101]. The chemotherapeutic regimen used in one report consisted of cyclophosphamide, doxorubicin, vincristine, and prednisolone. This approach has led to a more aggressive treatment of these lymphomas. Local therapy of lesions in isolated involvement of liver has not been studied. There are only a few case reports of surgical resection in such cases [102, 103]. Due to the lack of data, surgical resection of isolated NHL of the liver in HIV/AIDS patient cannot be recommended except within a study protocol.

Hepatocellular carcinoma in HIV/AIDS patients Due to advances in the treatment of HIV, patients are living longer and often have concomitant complications of liver disease due to coinfection with HBV and HCV. HIV coinfection has been shown to increase the progression of fibrosis in the liver [104, 105]. In the study performed by the HIV HCC Cooperative Italian–Spanish Group, an association between HIV and HCV infections along with infiltrating tumors and/or extra nodal metastasis at presentation was identified. They also found an independent association between HIV infection and a shorter survival period [106]. A study of HCC patients with HIV infection in six United States and Canadian centers found HIV-infected patients to be younger and more likely to have symptomatic lesions, although there was no significant difference in tumor staging and survival when compared to non-infected patients with HCC [107]. Upon diagnosis of cirrhosis in HIV patients coinfected with HCV or HBV, early initiation and more frequent screening for HCC is recommended. This is due to an observed early occurrence of HCC with a more aggressive course in this patient population. We recommend screening with an AFP level in combination with helical triphasic CT scan every 6 months. Treatment options are similar to those for patients suffering from HCC in the presence of viral hepatitis without HIV coinfection. The modality of treatment depends upon the extent of underlying liver disease, stage of the tumor, associated comorbidities, and immune status of the patient. These factors determine the suitability for curative resection versus

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liver transplantation. A detailed discussion of these modalities can be found elsewhere in Section 4. In our opinion, curative resection should be considered in HIV-infected patients suffering from early HCC in the absence of comorbidities and without significant synthetic dysfunction of the liver and portal hypertension, particularly since the results may be similar to those for patients not infected with HIV undergoing liver resection [107]. Patients who are not candidates for resection due to underlying cirrhosis and portal hypertension should be referred to a transplant center with experience in transplantation in HIV-infected patients who are early in their course. There have been multiple reports of successful orthotopic liver transplantation (OLT) in carefully selected patients, with survival data approaching those of cirrhotic patients without HIV coinfection [106, 108]. In HIV patients, the selection criteria are similar to those for non-HIV patients, and the Milan criteria for OLT in HCC (one HCC < 5 cm or three HCCs, each less than 3 cm) should be strictly adhered to. Liver transplant candidates with an HIV infection should have immune reconstitution with CD4 counts greater than 100/mL and an undetectable viral load that has been previously responsive to a HAART regimen. Patients who are not candidates for curative therapies should be considered for radiofrequency ablation (RFA) or transarterial chemoembolization (TACE). The goals of therapy for advanced disease should be directed by full participation of the patient and through a multidisciplinary approach.

Hepatobiliary tumors in solid organ transplant recipients Over the past three decades there has been a significant increase in solid organ transplantation with associated immune deficiencies induced by immunosuppressive regimens, which appear to place transplant recipients at a higher risk of developing malignancies. In the Cincinnati Transplant Tumor Registry (CTTR, initiated by Israel Penn), of the 10 151 organ allograft recipients who developed 10 813 de novo malignancies after transplantation, 755 involved the hepato-biliarypancreatico-duodenal (HBPD) area, forming approximately 10% of this population. Many of the tumors encountered were uncommon in the general population [109]. The largest group of neoplasms consisted of 474 lymphomas, which comprised 63% of the total. Other major malignancies were HCCs (15%), pancreatic carcinomas (11%), cholangiocarcinomas (3%), Kaposi sarcomas (3%), and other sarcomas (1%).

Post-transplant lymphomas In contrast to the general population where lymphomas form only 3–4% of all neoplasms, in post-transplant patients, lymphomas and lymphoproliferations comprise 22% of all

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tumors. There is a strong association between EBV and posttransplant lymphoproliferative disorders (PTLD). The majority of these disorders originate from B cells. There are reports of T-cell-origin lymphomas but these are not a common occurrence [110]. They are characterized by a heterogeneous spectrum, starting from acute infectious mononucleosis that results in a benign polyclonal B-cell hyperplasia with normal cytogenetics and no evidence of immunoglobulin gene rearrangements. This accounts for approximately 50% of cases. If unresolved, these cases may progress to a polyclonal B-cell proliferation with evidence of early malignant transformation, including clonal cytogenetic abnormalities and immunoglobulin gene rearrangements. One-third of the patients may present with this disorder, which may then turn into a monoclonal B-cell proliferation. These can involve extranodal sites and represent up to 15% of cases. These findings are similar to those found in AIDSrelated lymphomas described in the previous section [111, 112].The main risk factors for the development of PTLD include increased intensity of induction and maintenance immunosuppression, recipient EBV seronegativity, and a younger age group [113, 114]. Exceptions are intestinal transplant recipients, where the incidence of EBV disease has been observed to be equal in both pretransplant seronegative and seropositive EBV intestinal allograft recipients [115]. The EBV-negative lymphomas occur later in the posttransplant course. These can be considered to be an entity distinct from early EBV-positive lymphomas. They are similar to lymphomas found in immunocompetent patients with a monoclonal nature and frequent m-Myc rearrangement. They have a poor prognosis as compared to EBVpositive lymphomas [116]. The presentation usually involves an insidious onset. A low threshold of suspicion is needed for early diagnosis and treatment. The usual presentation includes constitutional symptoms such as fever, lethargy, and malaise, associated with weight loss and diarrhea that can be positive for occult blood. Clinical signs may include palpable enlarged lymph nodes, ulceration, and an increased size of the oropharyngeal tonsils, as well as a palpably enlarged spleen and/or liver. The gastrointestinal system is the most commonly affected extranodal site, with involvement of the liver in up to threequarters of patients with multiorgan disease. Involvement of the liver but no other organ is less frequent, but not uncommon, as it can occur in up to 16% of nonhepatic transplant recipients. Isolated involvement of the allograft can be present in 21% of liver transplant recipients [117, 118]. In such cases, examination may reveal only mildly elevated liver function tests or, at the extreme of the spectrum, there may be diffuse infiltration of the allograft resulting in acute liver failure. Sometimes an incidental lesion can be discovered on ultrasound or CT scan of the abdomen. Such lesions usually appear hypodense on

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contrast enhancement. The diagnosis can be confirmed by excisional biopsy of the associated enlarged lymph nodes. In cases where isolated hepatic involvement is encountered, percutaneous ultrasound or CT-guided biopsy can be performed. Rapid processing of the biopsy, including viral stains, is the key, as the lymphomatous infiltrates seen can sometimes be confused with acute rejection, which may result in an increased intensity of immunosuppression with worsening of the underlying PTLD [119]. In cases where the lesions are not accessible to percutaneous biopsy due to a difficult location or a previously failed attempt, laparoscopic or open biopsy may be required to confirm the diagnosis. The majority of the post-transplant lymphomas are of host (recipient) origin. There are, however, multiple reports of donor-origin PTLD [120–122]. One report found that two of three isolated PTLD were of donor origin, and the author also noted, upon review of reported cases, that a high proportion were of donor lymphocyte origin [119]. The mainstay of treatment in PTLD is a reduction in immunosuppression. This allows cell-mediated immunity to stop proliferation of EBV-infected cells. The response to a reduction in immunosuppression is dependent on the number of poor prognostic indicators (older age, elevated lactate dehydrogenase [LDH], organ dysfunction, multiorgan involvement with PTLD, and the presence of constitutional symptoms). An 89% response rate has been reported in patients without a negative prognostic indicator, while patients with at least one such indicator showed only a 60% response rate [123]. There was no response in patients who had two or more poor prognostic indicators. Median time to response was less than 4 weeks. Ganciclovir and intravenous immunoglobulin has not been effective in randomized control trials [124]. In monoclonal lymphomas and other PTLD nonresponsive to a reduction in immunosuppression, rituximab has been used. There are retrospective data evaluating rituximab and/or chemotherapy in patients with PTLD who failed to respond to a reduction in immunosuppression. Patients treated with rituximab had an overall response rate of 68% with an overall survival of 31 months, compared to 74% and 42 months, respectively, for those who underwent chemotherapy. Treatment-related deaths were 0% in the rituximab group and 26% in the chemotherapy group [125]. The efficacy and safety of rituximab has been studied in a prospective manner and an overall response rate and patient survival of 68% and 56%, respectively, have been reported at 1 year [126]. It is a reasonable approach to use rituximab early in patients unresponsive to a reduction or discontinuation of immunosuppression. In patients unresponsive to a reduction in immunosuppression and rituximab, chemotherapy is usually recommended. There are no controlled randomized trials comparing these modalities. Due to treatment-related mortality and the significant side effect profile of current chemo-


therapeutic regimens, it may be prudent to treat these patients with rituximab first. The standard chemotherapy for NHL is cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP), with reported complete remission rates of 70% [127]. Another option is dose-adjusted doxorubicin, cyclophosphamide, vincristine, bleomycin, and prednisolone (ACVBP), which has been reported to result in a survival of 60% at 5 years [128]. Local therapy is reserved for either a solitary hepatic lesion without systemic involvement, or small residual or symptomatic lesions not responsive to systemic therapy. The options available are radiation, surgical resection, and RFA. The need for local treatment should be weighed against the potential risks of these procedures [129]. The treatment plan in such cases is best served by a multidisciplinary approach.

Nonlymphoma post-transplant hepatobiliary tumors The most common nonlymphoma hepatobiliary malignancy in recipients of a previous solid organ transplant is HCC. This can be categorized as either recurrent HCC or a de novo lesion in recipients of hepatic allografts. Liver transplant recipients have the highest risk of developing HCC post transplant. Among recipients who received an organ other than liver, renal transplants are at a substantial risk of developing HCC due to a higher prevalence of hepatitis in dialysis patients. In patients receiving chronic dialysis, reports suggest that hepatitis C is present in up to 10% in the United States, up to 15% in Italy, 42% in France, and 49% in Syria [130–133]. Also, the incidence of hepatitis B surface antigen positivity was 1% in the United States, 13% in Italy, 1.6% in Japan, 10% in Hong Kong, 12% in Brazil, and 16.8% Taiwan [130, 134–138]. In the presence of immunosuppression and cirrhosis, this group of patients should undergo aggressive screening with ultrasound, triphasic CT scan of the abdomen, and AFP monitoring every 6 months. The surveillance data in transplant recipients have not been reported in large cohorts and there are no studies on the cost-effectiveness of such an approach in these patients. This is a recommendation based on our experience and surveillance studies in HIV/AIDS patients with HBV and HCV coinfection showing the aggressive nature of the tumor. The initial results of liver transplantation for HCC were very poor with unacceptable recurrence rates and mortality post transplantation in the early reported data. After the Milan criteria for transplantation in cirrhotics with HCC were adopted (one lesion less than 5 cm or three lesions each less than 3 cm in the absence of extrahepatic spread), there was a better patient selection, which resulted in a reduction of HCC recurrence to ∼ 8% [46]. Post-transplantation surveillance in these patients has not been studied. The majority of recurrences post liver transplantation are extrahepatic and not amenable to local therapy [46, 139]. The majority

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of these tumors recurred within the first 2 years after liver transplantation [139]. De novo occurrence of HCC in patients who have undergone liver transplantation has been reported. These are usually associated with recurrent hepatitis B and C with cirrhosis of the liver allograft [140]. The treatment of HCC arising in a transplant recipient of an organ other than liver is dictated by the stage of the tumor, the underlying liver disease, and the presence of comorbidities. Patients who have a resectable tumor and are good operative candidates should undergo liver resection with curative intent. In a series of 18 patients with previous kidney transplantation who developed HCC, liver resection resulted in an actuarial 5-year survival of 59%. Two patients in that series lost the kidney allograft 3 and 8 years after resection, and treatment-related mortality was 5% [141]. In patients with underlying cirrhosis with tumors within the Milan criteria, liver transplantation can be an option, although no reports pertaining to this are available in the literature. HCC in transplant recipients who are not candidates for a potentially curative therapy due to advanced underlying liver disease or comorbidities can be managed with RFA, and there are some reports of a short-term increase in survival of patients with advanced HCC [142]. If TACE is being considered in advanced HCC in renal transplant recipients, special attention should be paid to the fact that this can result in kidney allograft failure and a return to dialysis. Such a complication can in turn negatively impact on the patient’s quality of life with only a short-term gain in survival. In liver transplant recipients who have recurrent HCC, only 1–2% will be localized in the absence of significant underlying liver disease and comorbidities and warrant potential cure by liver resection [46, 139, 143]. Retransplantation in a patient has been reported [144]. It is unlikely that studies in this population will result in any definitive guidelines due to the small numbers involved. Every case has to be individually evaluated for possible curative therapy in a multidisciplinary fashion. Advanced disease is treated to palliate symptoms as prognosis for these patients is very poor [46, 139, 143]. De novo HCC in the setting of a previous liver transplant is usually associated with significant underlying liver disease, preventing curative resection. Bridge therapy with RFA and retransplantation has been reported [140]. Other malignant tumors reported in the CTTR registry in solid organ transplant recipients include sarcomas and cholangiocarcinomas. Kaposi sarcoma was dominant with 24 cases reported, only one of which was localized to the liver, while the remaining 23 patients had multiorgan involvement. The incidence of Kaposi sarcoma in the transplant population is reported to range between 2% and 3.5%. The other sarcomas in the CTTR registry were five leiomy-

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osarcomas, one angiosarcoma, one fibrosarcoma, one mesothelioma, and one spindle cell sarcoma. Leiomyosarcoma was predominantly present in pediatric solid organ transplant recipients [145]. Human herpes simplex virus 8 (HHSV 8) has been detected in virtually all patients with Kaposi sarcoma. The presence of viral DNA as well as serum antibodies to HHSV 8 seems to be predictive for the future development of Kaposi sarcoma, especially in immunocompromised patients [146, 147]. Treatment of Kaposi sarcoma in the transplant recipient consists of a reduction in immunosuppression, when it can be done safely, and early lesions may show a favorable response to this approach [148]. Close surveillance of the transplanted organ for rejection should be performed. There are reports of regression of Kaposi sarcoma when sirolimus was used, replacing other immunosuppressive agents [149– 151]. The outcome of advanced and disseminated disease is poor, and surgery has no role. Cholangiocarcinoma in transplantation can recur in patients who have undergone liver transplantation for primary sclerosing cholangitis (PSC). The recurrence rate for cholangiocarcinoma is documented as 51% in the CTTR, with most of the recurrences occurring within 2 years of transplantation. Survival after recurrence was rarely more than a year. Half of the recurrent tumors were in liver allografts and one-third in the lungs. It was concluded that due to the high rate of recurrence and the lack of positive prognostic factors, liver transplantation should seldom be used as a treatment for cholangiocarcinoma [152]. This is corroborated by the Canadian experience which concluded that early survival appears to be good for incidental cholangiocarcinoma but intermediate and longterms result are poor in liver transplantation for known cholangiocarcinoma [153]. The Mayo Clinic group, on the other hand, found improved 5-year survival and fewer recurrences using neoadjuvant therapy and liver transplantation (82% and 13%, respectively) when compared to bile duct resection with lymphadenectomy and liver resection (21% and 27%, respectively). The patients were highly selected in this study and the protocol used consisted of external beam radiotherapy (4500 cGy in 30 fractions) with concurrent, intravenous 5-fluorouracil (5-FU) given at 500 mg/m2 as a daily bolus for the first 3 days of radiation. Two to 3 weeks after the completion of external beam radiotherapy, a transluminal boost of radiation was delivered using a transcatheter iridium-192 brachytherapy wire, with a target dose of 2000–3000 cGy. Following brachytherapy, patients initially continued to receive 5-FU at the same dose through an ambulatory infusion pump. During the last 4 years, patients have been treated with oral capecitabine (2000 mg/m2 per day in two divided doses, 2 in every 3 weeks) as tolerated until transplantation [154].

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De novo cholangiocarcinoma in a patient with liver transplant and recurrent PSC has been described. This was treated with retransplantation of the liver [155]. De novo cholangiocarcinoma has also been reported in one patient 10 years after receiving a kidney transplant [156]. In general, recurrence of cholangiocarcinoma after liver transplantation carries a poor prognosis and surgical resection is seldom indicated. We do not recommend liver transplantation for known cholangiocarcinoma outside a study protocol.

Liver tumors during pregnancy Liver tumors during pregnancy are rare [157] and the diagnosis, management, and treatment of such tumors during pregnancy is challenging. Maternal and fetal wellbeing must be continuously assessed at all stages of the disease course. Hepatic adenoma, focal nodular hyperplasia (FNH), and hemangioma appear to be the more common tumors during pregnancy, but the actual incidence of each in this particular population of patients is unknown [158]. The clinical presentation of a liver mass during pregnancy is similar to that in a nonpregnant patient; however, the diagnosis may be delayed because symptoms may initially be attributed to the pregnancy.

Hemangioma Hemangiomas are the most common benign tumors of the liver. Their incidence is estimated to be 0.4–7.3% in autopsy studies and has been reported to reach 2% with imaging studies [159–161]. The majority of hemangiomas in nonpregnant patients are asymptomatic, but they can present with pain, distention, or vague symptoms related to pressure on neighboring viscera [160]. The presentation of hemangiomas in pregnancy includes vomiting, epigastric pain radiating to the back, difficulty eating, and an awareness of an intra-abdominal mass. Tumors may be mistaken for cholecystitis, twin pregnancy, and an ovarian tumor [158]. Presentation can also include a consumptive coagulopathy and thrombocytopenia (Kasabach–Merritt phenomenon). There are several case reports of hemangiomas that have ruptured or shown a rapid increase in size during pregnancy [162, 163]. Estrogen has been suggested to play a role in the development of hemangiomas [164], but there are no reports to support the presence of estrogen receptors in hepatic hemangiomas. The concern relating to hepatic hemangiomas is the remote risk of possible spontaneous hemorrhage. In nonpregnant patients, complications from lesions of less than 10 cm in diameter are generally rare, and only 5% of symptomatic lesions are at risk for rupture [165]. The risk of rupture during pregnancy does not appear to differ between pregnant and nonpregnant women [166]. If a hemangioma ruptures during pregnancy, bleeding may be controlled by


arterial embolization [161, 162]. In general, hemangiomas during pregnancy are conservatively managed with serial monitoring using ultrasound, unless there is evidence of rapid growth.

Focal nodular hyperplasia FNH of the liver is the second most common benign lesion that can occur in the liver [167]. FNH is considered to be a local hyperplastic response of hepatocytes to a vascular abnormality. Most FNH lesions are asymptomatic and are discovered incidentally during liver ultrasound examination. Cobey et al reviewed 41 pregnancies associated with FNH [158]. The majority of the FNH lesions were asymptomatic in this study, but five cases had complaints of upper abdominal pain and six had a sensation of a mass. There was no occurrence of FNH rupture in association with pregnancy, although one case showed an increase in size of the lesion [158]. A 9-year study involving 216 women with FNH also suggested that pregnancy was not associated with FNH changes or complications [168]. It is therefore recommended that FNH in pregnancy be closely observed and monitored, unless there is rapid growth, in which case surgical resection should be considered [158].

Hepatocellular adenoma Hepatocellular adenoma was a rare tumor before oral contraceptives were introduced. The relationship between hepatic adenomas and oral contraceptives was reported in 1973 [169], and they have been described to regress with discontinuation of oral contraceptives [170]. The risk of development of an adenoma increases with the duration and the estrogen content of the oral contraceptive used [171]. A review of a series of hepatic adenomas has shown that the risk of spontaneous bleeding is 20–40% [172]. This risk is increased in women taking oral contraceptives, during pregnancy, and when adenomas are greater than 5 cm in diameter [173, 174]. The rupture of a hepatic adenoma is associated with a high maternal and fetal mortality of 44–59% and 38–63%, respectively [158]. Unlike hemangiomas and FNH, the presentation of a hepatic adenoma is frequently catastrophic in pregnancy, as it has been known to grow and rupture in that setting. A recent review of adenomas during pregnancy has shown that 16 of 26 cases presented with rupture [158]. In nonpregnant patients, it is recommended that adenomas greater than 5 cm should be resected, whereas those less than 5 cm should be closely followed up [173, 175]. This approach can also be applied for pregnant patients as there are no reports of rupture with adenomas less than 6.5 cm in diameter. However, because hepatic adenoma rupture is associated with a high maternal and fetal mortality [158], liver adenomas in pregnancy that are greater than 5 cm show rapid growth or become symptomatic should be resected [158].

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Hepatocellular carcinoma HCC is rare in pregnancy. In general, HCC is less common in women than in men, and, with the exception of Africans, it is rare in females of reproductive age [176]. Liver cirrhosis is also associated with infertility, particularly at an advanced stage [177]. HCC in pregnancy has been associated with poor maternal and fetal outcome. Lau et al. analyzed 28 patient with HCC in pregnancy: only two patients survived up to 1 year from diagnosis and live infants were delivered in only half of the cases [177]. Pregnancy appears to have an adverse effect on prognosis with HCC [158] because it is an aggressive tumor that has been reported to have a median survival of only 8 weeks in inoperable cases [178]. Lau et al showed a much shorter survival when pregnant patients were compared to nonpregnant women with inoperable HCC [177]. It has been suggested that estrogen may accelerate the evolution of HCC in gestation [179]. Additionally, AFP and placental steroids have been implicated as being responsible for the suppression of the immune response during pregnancy [177], and gestational immune suppression may be an enabling factor in tumor progression. However, the actual mechanism of the effect of pregnancy on HCC remains unclear. In the majority of reported cases, the pregnancy was terminated once the HCC was diagnosed [180]. Considering the frequent rapid tumor growth during pregnancy and the near universal poor outcome, early termination of pregnancy should be offered, followed by tumor resection when possible [158, 180].

Hepatobiliary surgery during pregnancy If surgery during pregnancy is chosen as the method of definitive treatment, it is crucial to consider a reduction of the risks to both mother and fetus. The timing of surgery in pregnant patients is also a controversial issue. It has been shown that surgery performed in the second trimester has a significantly lower abortion and preterm birth rate than surgery in the first or third trimesters [181]. A review of reports of cholecystectomy performed during pregnancy showed a miscarriage rate of only 5.6% in the second trimester compared to 12% in the first trimester. The rate of preterm labor was also low for surgery performed during the second trimester, but 40% for surgery in the third trimester [182]. Other advantages of surgery in the second trimester relate to the fact that the potential risk of teratogenesis is very small and the uterus is of an adequate size, but it does not obliterate the operative field, as it may during the third trimester. Therefore, the second trimester is the safest period to schedule surgery if possible [182, 183]. Intraoperative precautions should be undertaken to promote safety of the mother and fetus. The patient should be placed slightly to her left side in order to reduce compression of the vena cava. Intraoperative fetal monitoring is indicated as the supine position increases the risk of hypotension and ultimate uter-

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oplacental insufficiency [183]. Obstetricians should be consulted before the surgery, and preoperative, intraoperative, and postoperative fetal monitoring should be performed based on their recommendation. Epidural anesthesia can be used in higher risk patients in order to minimize fetal drug exposure and decrease the overall risk of general anesthesia. Postoperative antiembolic precautions are also important as the risk of thromboembolic complications is increased during pregnancy. In summary, a successful maternal and fetal outcome is dependent on multidisciplinary expertise and collaboration (the surgeons, anesthesiologists, and obstetricians) for optimal perioperative management.

Self-assessment questions 1 The prevalence of hepatocellular cancer is highest in cirrhosis due to which one of the following? A Nonalcoholic steatohepatitis B Hepatitis C C Alcohol-related liver cirrhosis D Primary biliary cirrhosis 2 Beta-blockers should be perioperatively discontinued in patients already being treated, because beta-blockade appears to increase the risk for complications in low-risk patients. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 3 Advanced age is not a contraindication for hepatic resection, because older patients appear to have the same regenerative volume and protein synthesis after liver resection as in younger patients. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 4 With regard to hepatic malignancies in HIV/AIDS patients, which one of the following statements is false? A Decreased incidence of non-Hodgkin lymphoma in HAART era is because of partial or near complete restoration of immune response B Kaposi sarcoma regression is associated with decreasing loads of human herpes simplex virus 8

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C HIV infection is an absolute contraindication to liver transplantation because of the need for immunosuppression D Hepatocellular carcinoma tends to occur earlier due to hepatitis C coinfection E Poor risk for Kaposi sarcoma is associated with high HIV PCR 5 The recommended treatment strategies for posttransplant lymphoproliferative disorder include which of the following? (more than one answer is possible) A Surgical debulking of the tumor mass B Reduction in immunosuppression C Administration of intravenous immunoglobulins D Anti CD-20 monoclonal antibody (rituximab) E Doxorubicin-based chemotherapy 6 Regarding nonlymphoma hepatobiliary tumors in solid organ transplant recipients, which one of the following statements is true? A Recurrence risk is highest for hepatocellular carcinoma in liver transplant recipients within 2 years B Kidney transplant recipients who develop hepatocellular carcinoma are not candidates for surgical resection C Most common site of recurrence of hepatocellular carcinoma is the lung D Primary treatment modality of Kaposi sarcoma in solid organ transplant recipients is pegylated daunorubicin E Incidental cholangiocarcinoma at the time of liver transplantation has no adverse effects on outcome 7 Which one of the following liver tumors mostly grows and ruptures in pregnancy? A Focal nodular hyperplasia B Hepatocellular carcinoma C Cyst D Adenoma E Hemangioma

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137 Chan TM, Lok AS, Cheng IK. Hepatitis C infection among dialysis patients: a comparison between patients on maintenance haemodialysis and continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant 1991;6:944–7. 138 Chen KS, Lo SK, Lee N, Leu ML, Huang CC, Fang KM. Superinfection with hepatitis C virus in hemodialysis patients with hepatitis B surface antigenemia: its prevalence and clinical significance in Taiwan. Nephron 1996;73:158–64. 139 Roayaie S, Schwartz JD, Sung MW, et al. Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis. Liver Transpl 2004;10:534–40. 140 Croitoru A, Schiano TD, Schwartz M, et al. De novo hepatocellular carcinoma occurring in a transplanted liver: case report and review of the literature. Dig Dis Sci 2006;51: 1780–2. 141 Cheng SB, Yeh DC, Shu KH, et al. Liver resection for hepatocellular carcinoma in patients who have undergone prior renal transplantation. J Surg Oncol 2006;93:273–8. 142 Chok KS, Lam CM, Li FK, et al. Management of hepatocellular carcinoma in renal transplant recipients. J Surg Oncol 2004;87:139–42. 143 Schlitt HJ, Neipp M, Weimann A, et al. Recurrence patterns of hepatocellular and fibrolamellar carcinoma after liver transplantation. J Clin Oncol 1999;17:324–31. 144 Kita Y, Klintmalm G, Kobayashi S, Yanaga K. Retransplantation for de novo hepatocellular carcinoma in a liver allograft with recurrent hepatitis B cirrhosis 14 years after primary liver transplantation. Dig Dis Sci 2007;52:3392–3. 145 Aseni P, Vertemati M, Minola E, et al. Kaposi’s sarcoma in liver transplant recipients: morphological and clinical description. Liver Transpl 2001;7:816–23. 146 Cattani P, Capuano M, Graffeo R, et al. Kaposi’s sarcoma associated with previous human herpesvirus 8 infection in kidney transplant recipients. J Clin Microbiol 2001;39:506–8. 147 Chang Y, Moore PS. Kaposi’s Sarcoma (KS)-associated herpesvirus and its role in KS. Infect Agents Dis 1996;5:215–22. 148 Moosa MR. Kaposi’s sarcoma in kidney transplant recipients: a 23-year experience. Q J Med 2005;98:205–14. 149 Gheith O, Bakr A, Wafa E, et al. Sirolimus for visceral and cutaneous Kaposi’s sarcoma in a renal-transplant recipient. Clin Exp Nephrol 2007;11:251–4. 150 Iaria G, Anselmo A, De Luca L, et al. Conversion to rapamycin immunosuppression for malignancy after kidney transplantation: case reports. Transplant Proc 2007;39:2036–7. 151 Di Paolo S, Teutonico A, Ranieri E, Gesualdo L, Schena PF. Monitoring antitumor efficacy of rapamycin in Kaposi sarcoma. Am J Kidney Dis 2007;49:462–70. 152 Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation 2000;69: 1633–7. 153 Ghali P, Marotta PJ, Yoshida EM, et al. Liver transplantation for incidental cholangiocarcinoma: analysis of the Canadian experience. Liver Transpl 2005;11:1412–16. 154 Rea DJ, Heimbach JK, Rosen CB, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 2005;242:451–8; discussion 8–61. 155 Heneghan MA, Tuttle-Newhall JE, Suhocki PV, et al. De-novo cholangiocarcinoma in the setting of recurrent primary

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157 158

159 160 161 162

163

164

165

166

167

168

169

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173 Terkivatan T, de Wilt JH, de Man RA, Ijzermans JN. Management of hepatocellular adenoma during pregnancy. Liver 2000;20:186–7. 174 Terkivatan T, de Wilt JH, de Man RA, van Rijn RR, Tilanus HW, IJzermans JN. Treatment of ruptured hepatocellular adenoma. Br J Surg 2001;88:207–9. 175 Ault GT, Wren SM, Ralls PW, Reynolds TB, Stain SC. Selective management of hepatic adenomas. Am Surgeon 1996;62: 825–9. 176 El-Serag HB. Hepatocellular carcinoma: an epidemiologic view. J Clin Gastroenterol 2002;35 (5 Suppl 2):S72–8. 177 Lau WY, Leung WT, Ho S, et al. Hepatocellular carcinoma during pregnancy and its comparison with other pregnancyassociated malignancies. Cancer 1995;75:2669–76. 178 Shiu W, Dewar G, Leung N, et al. Hepatocellular carcinoma in Hong Kong: clinical study on 340 cases. Oncology 1990;47: 241–5. 179 Erfling W. Effect of estrogens on the liver. Case presentation. Gastroenterology 1978;75:512. 180 Alvarez de la Rosa M, Nicolas-Perez D, Muniz-Montes JR, Trujillo-Carrillo JL. Evolution and management of a hepatocellular carcinoma during pregnancy. J Obstet Gynaecol Res 2006; 32:437–9. 181 Goodman S. Anesthesia for nonobstetric surgery in the pregnant patient. Semin Perinatol 2002;26:136–45. 182 Fatum M, Rojansky N. Laparoscopic surgery during pregnancy. Obstet Gynecol Surv 2001;56:50–9. 183 Jabbour N, Brenner M, Gagandeep S, et al. Major hepatobiliary surgery during pregnancy: safety and timing. Am Surgeon 2005;71:354–8. 184 Campeau L. Letter: Grading of angina pectoris. Circulation 1976;54:522–3. 185 Brand MI, Saclarides TJ, Dobson HD, Millikan KW. Liver resection for colorectal cancer: liver metastases in the aged. Am Surg 2000;66:412–15.

Self-assessment answers 1 2 3 4 5 6 7

B C B C B, D, E A D

39

Malignant Liver Tumors in Children Xavier Rogiers1 and Ruth De Bruyne2 1 Department of General and Hepatobiliary Surgery, Transplantation Center, University Medical Center Ghent, Ghent, Belgium 2 Department of Pediatrics, Section of Pediatric Gastroenterology, University Medical Center Ghent, Ghent, Belgium

Malignant tumors of the liver or bile ducts during childhood are rare, with an incidence of 1.6–2 per million children [1–3] or 1–2% of childhood cancer. There is some suggestion of a higher incidence in the literature, but this may relate to greater diagnostic accuracy. Hepatoblastoma and hepatocellular carcinoma (HCC) are the most important malignant liver tumors in children, with hepatoblastoma accounting for more than half of the cases. Other, very rare tumors can also develop in children. There has been significant progress in the treatment of hepatic tumors in children in the past decades. The tools to diagnose and evaluate these tumors have improved dramatically, and are largely the same as for adult patients. The development of specialized liver surgery generally, and for children in particular, and the possibility of liver transplantation in children have contributed to higher resectability rates and a more radical treatment of these diseases. Furthermore, prospective multicenter interdisciplinary protocol designed strategies, seeking to optimally combine chemotherapy and surgery, have led to significant improvements in results, especially for hepatoblastoma. Staging of pediatric liver tumors can either be based on the pretreatment extent of the disease or on the surgical resectability [4] (Table 39.1). In North America, a staging system similar to that for other solid tumors, based on surgical resectability and presence of metastases, is used. The European staging system, called PRETEXT (PRETreatment EXTent of disease scoring system) only considers the pretreatment extent of disease (Figure 39.1). Liver surgery in children essentially follows the same rules as in adult patients. Children are mainly otherwise healthy, and the remaining liver usually has a normal aspect; they therefore tend to tolerate more extensive resections than adult patients. Intraoperative ultrasound plays a vital role in making the final intraoperative decision of resectability. In cases of nonresectability, total hepatectomy and orthotopic liver transplantation may be a valuable option [5].


In this chapter, we review the most common pediatric malignant tumors and their treatment.

Hepatoblastoma Epidemiology Hepatoblastomas represent 80% of all malignant hepatic tumors [6]. Hepatoblastoma is an embryonal tumor occurring predominantly in early childhood. According to a report from the Automated Childhood Cancer Information System (ACCIS) project, 42% of cases occurred in the first year of life, and 91% by the age of 5 years [7]. A male predominance for hepatoblastoma is reported in several epidemiologic studies [1, 6]. Data from the Surveillance, Epidemiology and End Result (SEER) program in the United States showed an important increase in hepatoblastoma incidence between the periods 1973–1977 and 1993–1997 from 0.6 to 1.2 per million [4]. However, no significant increase in incidence was seen in the European ACCIS study from 1978 to 1997 [7]. Most cases of hepatoblastoma are sporadic and the etiology of hepatoblastoma is not well understood. Nevertheless, hepatoblastoma is associated with several congenital or genetic syndromes. Beckwith–Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by macrosomia, macroglossia, abdominal wall defects, ear anomalies, and neonatal hypoglycemia. BWS is caused by genetic abnormalities in chromosome 11p15 and children with BWS are at an increased risk of developing intra-abdominal embryonal tumors, particularly hepatoblastoma and Wilms tumor. The relative risk for hepatoblastoma is as high as 2280 [8]. Tumor surveillance by serial abdominal ultrasound and serum alpha-fetoprotein (AFP) measurements is therefore recommended in these patients [9, 10]. Children with isolated hemihypertrophy and other overgrowth syndromes are also at a higher risk of developing hepatoblastoma [11, 12]. Additionally, the risk of hepatoblastoma is approximately 800-fold higher in children with a family history of familial adenomatous polyposis (FAP) [13, 14]. FAP is an autosomal dominant condition causing

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Stage 1: Three adjoining sectors free Right lobe of liver

Right lobe of liver

Left lobe of liver

Left lobe of liver

colonic polyp growth and ultimately colon cancer, and is due to a genetic mutation in the adenomatous polyposis coli (APC) gene. When 50 cases of apparently sporadic hepatoblastoma were examined for APC germline mutations, 10% was found to be positive. These findings raise the issue of screening children of FAP patients for hepatoblastoma, as well as routine APC mutation screening in patients diagnosed with sporadic hepatoblastoma. De novo FAP in a spo-

Stage 2: Two adjoining sectors free Right lobe of liver

Left lobe of liver

Right lobe of liver

Left lobe of liver

Table 39.1 Staging systems for pediatric liver tumors. (Modified from Litten & Tomlinson [4].)

Stage 1

Right lobe of liver

Left lobe of liver Stage 2

European staging SIOPEL/PRETEXT (presurgical staging)

North American staging (postsurgical staging)

Tumor involves only one quadrant; three adjoining quadrants are free of tumor Tumor involves two adjoining quadrants; two adjoining quadrants are free of tumor

No metastases; tumor completely resected

Stage 3: One sector free Right lobe of liver

Left lobe of liver

Right lobe of liver

Left lobe of liver

Stage 3

Stage 4

Right lobe of liver

Left lobe of liver

Right lobe of liver

Left lobe of liver

Tumor involves three adjoining quadrants or two nonadjoining quadrants; one quadrant or two nonadjoining quadrants are free of tumor Tumor involves all four quadrants; there is no quadrant free of tumor

No metastases; tumor grossly resected with microscopic residual diseases (i.e. positive margins, tumor rupture, or tumor spill at the time of surgery) No distant metastases; tumor unresectable or resected with gross residual tumor, or positive nodes

Distant regardless of the extent of liver involvement

PRETEXT, PRETreatment EXTent of disease scoring system; SIOPEL, Childhood Liver Tumor Strategy Group of the Société Internationale d’Oncologie Pédiatrique.

Stage 4: No free sector Right lobe of liver

476

Left lobe of liver

Right lobe of liver

Left lobe of liver

Figure 39.1 PRETEXT scoring system [4]. The PRETreatment EXTent of disease scoring system involves classification of liver tumors by dividing the liver on imaging into four sectors and determining how many sectors are involved by tumors. Extension of the tumor is also included in the staging as follows: V indicates extension into the vena cava and/or all three hepatic veins; P indicates extension into the main branch and/or both the left and right branches of the portal vein; E indicates extrahepatic disease, and unlike P and V is rare and must be biopsy proven; M indicates the presence of distant metastases. (Reproduced from Litten & Tomlinson [4], with permission.)

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radic hepatoblastoma patient should warrant colorectal surveillance [15]. Low birthweight (1500–2500 g) and particularly very low birthweight (VLBW; 15 mm short axis) in a child with no other criteria for high-risk hepatoblastoma.

478

All C1 patients are at least PRETEXT II Add suffix “a” if ascites is present, e.g. E0a

Add suffix or suffixes to indicate location (see text)

Add suffix “a” if intravascular tumor is present, e.g. P1a

Add suffix “a” if intravascular tumor is present, e.g. V3a

Venous involvement (portal vein, hepatic veins, inferior vena cava [IVC]) is defined as imaging evidence of obstruction, circumferential encasement or invasion of the vein. When the tumor only abuts or displaces the vein, this is not considered to be venous involvement as there may be shrinkage away from the vein following preoperative chemotherapy [30, 31]. Table 39.4 shows the criteria required for patients to be stratified as high risk [30, 31]. The staging system used by the United States Children’s Oncology Group (COG) is based on postoperative evaluation: stage I is defined as tumor completely resected at diagnosis; stage II as grossly resected tumor with microscopic residual disease; stage III as unresectable tumor, tumor resected with gross residual disease, involvement of local lymph nodes or tumor spill; and stage IV as tumor with distant metastases [32, 33]. The TNM system for liver tumors was mainly developed for use in adults with HCC and is not widely used for hepatoblastoma.

Histopathology Macroscopically, hepatoblastoma presents as a wellcircumscribed single mass which can be very large at diagnosis, up to 25 cm and weighing over 1 kg. The appearance

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Table 39.4 Risk stratification in hepatoblastoma for current SIOPEL studies. (Modified from Roebuck et al [30].) High risk

Standard risk

Patients with any of the following: Serum alpha-fetoprotein 100 μg/L PRETEXT IV Additional PRETEXT criteria: • E1, E1a, E2, E2a • H1 • M1 (any site) • N1, N2 • P2, P2a • V3, V3a

All other patients

varies according to the proportion of histologic components, i.e. brown to green, fibrous or calcified, and often showing areas of necrosis, cystic change, and hemorrhage. Vascularity is usually prominent, a thin capsule may be present, and the rest of the liver is normal [34]. Hepatoblastomas are probably derived from a stem cell precursor and most tumors contain many histologic patterns reflecting diverse stages of differentiation. The most recent all-embracing classification recognizes six main histologic patterns: epithelial (56%) (pure fetal, 31%; embryonal and fetal, 19%; macrotrabecular, 3%; small cell, 3%) and mixed epithelial/mesenchymal (44%) with (10%) or without (34%) teratoid features [35]. In completely resected hepatoblastoma, pure fetal histology has been associated with improved survival, while small cell undifferentiated histology is associated with a poor prognosis [36].

Treatment As only complete tumor resection can definitely cure a patient, surgery is the mainstay of treatment for hepatoblastoma. Modern treatment protocols combine surgery with chemotherapy as most hepatoblastomas respond to cytotoxic drugs. In a large number of cases the tumor is unresectable at diagnosis, requiring chemotherapy in order to reduce its size. The approach in the approximately 30– 50% of patients with a resectable tumor varies between the different study groups. The SIOPEL study group recommends no attempt at primary surgery and preoperative chemotherapy in all patients, while the United States COG has a primary surgical approach when possible, without induction chemotherapy. Following the protocol of the German Pediatric Oncology and Hematology (GPOH) group, primary resection with a wide margin in small localized tumors is done when this does not exceed hepatic lobectomy. More extensive surgery is discouraged. This approach results in 20% primary resections [37–39].

Malignant Liver Tumors in Children

Following the SIOPEL protocol, a diagnostic biopsy is necessary regardless of the size and the apparent resectability of the tumor. Traditionally an open biopsy was performed, but currently an image-guided needle biopsy is recommended. The COG and the GPOH group recommend laparotomy with a view to primary resection of tumor when this appears possible on the basis of preoperative imaging. Following the COG protocol, all other children have a diagnostic biopsy. The GPOH group regards biopsy as unnecessary in patients aged 6 months to 3 years with unequivocal clinical findings, imaging, and elevated AFP [40, 41]. An accurate preoperative assessment of resectability is crucial. This should be done by high-quality cross-sectional imaging with contrast-enhanced CT and/or MRI. Ultrasound with Doppler studies is also extremely informative (as discussed above); however, it requires the surgeon to be present during the examination. In selective cases, intraoperative ultrasound is useful for adequate planning of the surgical strategy, particularly in cases of segmental resection [40]. Conventional liver resections are recommended as atypical resections carry a much higher risk for incomplete tumor removal and postoperative complications. Hence, the most commonly performed surgical techniques are anatomic liver resections, such as left lateral sectionectomy, left and right hemihepatectomy, and extended left and right hemihepatectomy [40, 42]. The liver has extensive regenerative capacity and up to 75–85% of the parenchyma can safely be resected. Encasement or invasion of the retrohepatic IVC does not preclude radical excision, since the IVC can be resected en bloc and be replaced by either a prosthetic graft or a venous autograft. Special techniques of hepatic resection, such as tumor resection under hypothermia and extracorporal circulation, total vascular exclusion [43], and extended left atypical hepatectomy [44] are only indicated in very rare situations. These techniques have become controversial because of the excellent results with primary liver transplantation for hepatoblastoma [45]. Difficult liver resections with a high risk of residual tumor should therefore be avoided and liver transplantation performed instead [40]. It is of utmost importance that complete tumor resection is achieved. Frozen sections of the resection margin should be taken to confirm R0 resection [40]. Intra- and postoperative complications are mainly caused by severe bleeding. Other complications are postoperative bile leak or bleeding, air embolism, abdominal abscess, and bowel obstruction due to adhesions [40]. Liver transplantation is a valid treatment option and should be considered in every child presenting with unresectable hepatoblastoma. Analysis of the results for liver transplantation in the SIOPEL 1 study (12 patients) and a review of the world experience (147 patients) showed a good prognosis, with a 10-year survival of 85% for primary transplantation but only 40% for rescue transplantation in

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the SIOPEL group, and a 6-year survival of 82% and 30%, respectively, in the world experience review [45]. The following criteria are used by SIOPEL to select potential candidates for liver transplantation [46]: • Multifocal PRETEXT IV tumors • Unifocal PRETEXT IV tumors. These are relatively rare, but unless downstaging to PRETEXT III is obtained after preoperative chemotherapy, liver transplantation should be considered • PRETEXT III with proximity to major vessels, which makes adequate tumor clearance doubtful • Tumor extension into the vena cava and/or all three hepatic veins • Invasion of the main and/or both left and right branches of the portal vein • Intrahepatic recurrent or residual tumor after previous resection (“rescue” transplantation). Extension into the major vessels is not a contraindication for liver transplantation as long as all of the tumor can be excised at the time of hepatectomy. The persistence of viable extrahepatic metastases after chemotherapy not amenable to surgical resection is an absolute contraindication. Liver transplantation is an option in children presenting with lung metastases if complete clearance can be achieved by chemotherapy with or without surgical excision. Chemotherapy must be given prior to liver transplantation. The tumor should show at least a partial response to chemotherapy; stable or progressive disease is a relative contraindication to liver transplantation. The value of postoperative chemotherapy is still unclear. Optimal timing of liver transplantation is essential and it should not be delayed for more than 4 weeks after the last course of chemotherapy to avoid tumor progression. If this cannot be achieved on a cadaveric waiting list, the possibility of living related donor transplantation should be considered [45]. Careful pretransplant evaluation of the liver transplantation candidate is important, not only of the tumor but also of the fitness for transplantation. Doxorubicin is cardiotoxic, and cisplatin is nephro- and oto-toxic. A detailed echocardiography and assessment of renal function are essential prior to transplant [46]. There is some controversy as to whether the retrohepatic vena cava should always be removed en bloc with the liver during the transplant. Some authors advise doing so and reconstruct the cava with either donor iliac vein (cadaveric donor) or donor jugular vein (living related donor). Others preserve the native retrohepatic vena cava in selected patients, provided there is no evidence of direct tumor involvement [47]. In cases of incomplete tumor resection of intrahepatic recurrences after primary liver tumors, rescue liver transplantation can be done. However, the results in these patients are rather disappointing and in times of organ shortage the indication is controversial.

480

Thus, liver transplantation has become an effective treatment option for hepatoblastoma. Still, several issues remain to be elucidated, such as the prognostic significance of vascular invasion, optimal timing of liver transplantation, optimal amount and timing of pre- and post-operative chemotherapy, amount of immunosuppression needed, etc. An international electronic registry, PLUTO (Pediatric Liver Unresectable Tumor Observatory), for online registration of children undergoing liver transplantation for malignant liver tumors has therefore been created by the SIOPEL study group in collaboration with COG and GPOH [40, 45]. One of the most important advances in the management of hepatoblastoma was made in the 1980s thanks to the development of effective cisplatin-based chemotherapy protocols [48, 49]. Complete surgical tumor removal is still the goal of treatment because this provides the best chance for long-term survival. However, more than 50% of tumors are considered unresectable at diagnosis [50]. About half of these cases become resectable by preoperative chemotherapy [32, 51–53]. Another reason for preoperative chemotherapy is the fact that metastases are only detectable by imaging in about 20% of patients [54, 55]. Finally, tumor recurrence occurs in most children after surgery only [24, 56]. Radiotherapy only plays a very limited role in the treatment of hepatoblastoma due to its low efficacy and a high risk of complications. It has only been used in combination with chemotherapy in selected inoperable children and in a few cases of small residual tumors after resection [57]. However, transarterial catheter chemoembolization has been used successfully in the treatment of hepatoblastoma and should be considered as an alternative for patients with unresectable liver tumors not responding to primary systemic chemotherapy [58]. Other treatment modalities, such as AFP antibody-mediated therapy, antiangiogenic treatment or molecular therapies, are still experimental and might play a role in the development of future therapies for hepatoblastoma [59–64].

Prognosis The prognosis of hepatoblastoma has improved dramatically thanks to the availability of effective chemotherapy, better surgical techniques, safer anesthesia, improved postoperative care, and liver transplantation [65]. Standard-risk hepatoblastoma is associated with a cure rate nearing 90%, but results in extended and metastatic high-risk hepatoblastoma are still poor [37]. Complete tumor resection is essential to cure hepatoblastoma, and prognosis mainly depends on disease extension at the time of diagnosis. Extrahepatic tumor extension, multifocality, and vascular invasion are poor prognostic factors and PRETEXT correlates well with overall and event-free survival [66, 67].

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In cases of complete remission, AFP should normalize. However, this process takes up to 2 months because AFP levels can be very high and the half-life of AFP is about 6 days. A minimal rise of AFP post surgery can be a sign of liver regeneration [40], while a rapid decline in AFP during chemotherapy is correlated positively with prognosis [68]. Patients with a very low (1 000 000 ng/mL) AFP at diagnosis are at an increased risk [24]. Pure fetal histology is associated with improved prognosis [66, 67]. DNA aneuploidy [69], as well as other genetic and molecular markers [70, 71], also have poor prognostic significance. Ongoing research focuses on these markers and their use as prognostic indicators and possible targets for therapy.

Hepatocellular carcinoma HCC is the most frequent primary liver tumor in older children. The incidence of HCC in children differs widely with geography, with higher incidence in regions which are endemic for hepatitis B or C viruses (HBV and HCV). In these countries, routine immunization with HBV vaccine has proven effective in reducing the incidence of childhood HCC (see below). Apart from viral origin, HCC can occur in children with metabolic liver disease (alpha-1-antitrypsin deficiency, tyrosinemia) or other liver disorders (biliary atresia, androgen therapy, aflatoxin exposure). In contrast to hepatoblastoma, HCC tends to affect children older than 4 years [72]. The fact that HCC (in contrast to hepatoblastoma) frequently occurs in diseased livers, as well as its high tendency to metastasize, not only intrahepatically, but also into the lymphatic system or to distant organs, are major limiting factors for its curative surgical treatment [72, 73]. In contrast, the fibrolamellar variant of HCC, occurring in adolescents or young adults, has a typical histologic aspect with lamellar fibrosis around the large eosinophilic tumor cells. As this variant occurs in noncirrhotic livers, it has a higher rate of respectability, but it has not been finally proven if this results in higher survival rates than for regular HCC [74–78]. Clinically, children with HCC usually have a similar presentation to those with hepatoblastoma, with abdominal pain or an abdominal mass being the most frequent symptoms. AFP levels are not always high in HCC patients. Most HCCs do not respond (well) to radiotherapy or chemotherapy. Therefore, complete surgical resection of the tumor should be the ultimate goal of therapy. Intraoperative ultrasound should be performed to detect intrahepatic metastases or multifocal disease. However, only 10–30% of the cases are amenable to curative resection at the time of diagnosis [79–


81]. Neoadjuvant chemotherapy schemes are therefore attempted with the goal of increasing resectability. The SIOPEL study, a prospective study of PLADO neoadjuvant chemotherapy for pediatric HCC, reported a partial response in 49% of patients and a successful tumor excision rate of 36% [82]. Tumor regression due to neoadjuvant chemotherapy improves the prognosis [83, 84]. Another way to achieve complete resection of otherwise unresectable HCC is liver transplantation. This also has the potential to cure eventual underlying disease. Even today, the experience with liver transplantation for HCC is rather limited [85–87]. It is not clear whether the Milan criteria, used for adult patients with HCC, should also be applied to children. Beaunoyer et al reported excellent results (recurrence-free survival at 5 years 88.9%) after liver transplantation for HCC in 10 children, of whom seven were beyond the Milan criteria. Two patients with macrovascular invasion of the intrahepatic portal vein were alive and well with a follow-up of 17 and 13 years, respectively [86]. In an analysis of 59 liver transplantations for HCC and 62 for hepatoblastoma in children [87] between 1987 and 2004, the 1-, 5-, and 10-year survival rates for HCC recipients were 86%, 63%, and 58%, respectively. The primary cause of death was metastatic or recurrent disease. It should be noted that transplantation may be an important measure for preventing the occurrence of HCC in diseases with premalignant potential (e.g. tyrosinemia with nodular changes in the liver). It should also be noted that the most effective preventive measure is vaccination for HBV in endemic areas. The nationwide vaccination program in Taiwan since 1984 has reduced the annual incidence from 0.70 to 0.36 per 100 000 children [88]. In conclusion, total surgical removal should be the ultimate goal of any strategy to treat HCC in children. The precise roles of chemotherapy and transplantation in unresectable cases are still under evaluation; evidence is difficult to gather because of the small number of cases.

Angiosarcoma Most vascular liver tumors in children are of a benign nature. Cavernous hemangiomas of the liver in children are usually asymptomatic and will be found as incidental findings during childhood or later in life. Infantile hemangioendothelioma is the most common benign tumor of the liver in children. Despite its benign nature (in contrast to hepatic hemangioendothelioma in adults, from which it should be differentiated), it deserves greater attention because of its potential complications and the difficulty of differential diagnosis with angiosarcoma. Hemangioendothelioma occurs most frequently in very

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young children (87% in the first 6 months of life) and extremely rarely in patients over 3 years of age. The main symptoms are an abdominal mass or distention. Other potential symptoms are failure to thrive, jaundice, and fever. Spontaneous tumor rupture has been described. They may also lead to the Kasabach–Merritt syndrome [89]. The treatment of hemangioendothelioma depends on the presenting symptoms and the extent of the lesions. Single lesions can be resected, even in the face of congestive heart failure [90]. In cases of multiple lesions, digitalis and diuretics are used to control heart failure. Some use steroids or interferon-alpha in the hope of speeding up regression of the tumor [91, 92]. Hepatic artery ligation or embolization can also be helpful [90, 93, 94]. Exceptionally, total hepatectomy and liver transplantation may be needed [95]. Pediatric hepatic angiosarcoma, in contrast to infantile hepatic hemangioendothelioma, is a very rare but highly malignant tumor. It usually presents with a rapidly growing hepatic mass. The precise diagnosis may be difficult, even on a biopsy specimen [96, 97]; open biopsy of the tumor is therefore advisable. Chemotherapy and radiotherapy are notably inefficient in achieving tumor control. Radical hepatic resection or even liver transplantation should therefore be attempted if possible. The prognosis remains very poor, with only three survivors in 41 cases reported up to 2004 [97].

Undifferentiated (embryonal) sarcoma Undifferentiated embryonal sarcomas are highly malignant tumors of the liver [98, 99]. They usually occur in children, with half of cases occurring in children between 6 and 10 years of age. This tumor is usually large, with abdominal distention or pain at presentation. These tumors are often cystic in nature or show central necrosis. Spontaneous rupture of the tumor has been described [99]. Complete surgical removal, if necessary after neoadjuvant chemotherapy, should be aimed for. Despite the use of a variety of treatments, disease-free survival at 2 years is below 10%.

Embryonal rhabdomyosarcoma Embryonal rhabdomyosarcomas are very rare, highly malignant tumors that can occur in children of all ages, but most frequently below the age of 5 years. This tumor usually finds its origin in the common bile duct and the major hepatic ducts. The dominating clinical picture is usually one of obstructive jaundice. Ultrasound and magnetic resonance cholangiopancreatography (MRCP) are the diagnostic tools of choice to demonstrate the level of obstruction. Complete resection of the tumor should be attempted if possible. The resectability rates vary between 20% and 40% [100, 101].

482

Other tumors Other liver tumors that have been reported in children are primary malignant germ cell tumors, rhabdoid tumors, malignant fibrous histiocytoma, fibrosarcoma, leiomyosarcoma, and lymphoma.

Metastatic lesions Several typical childhood tumors, like neuroblastoma or nephroblastoma, can present with liver metastasis, either present at first presentation or later in the development of the disease. Since most of these tumors are treated within cooperative trial protocols, the rules of these protocols should be followed.

Self-assessment questions 1 Which of the following are indications for transplantation in children? (more than one answer is possible) A Multifocal PRETEXT IV hepatoblastoma B Resectable hepatoblastoma C Hepatocellular carcinoma with extrahepatic metastases D Tumor invasion of major vessels 2 Which of the following statements regarding hepatoblastoma are true? (more than one answer is possible) A Represent a minority of malignant hepatic tumors B Smoking might be a risk factor C The vast majority of patients are younger than 5 years of age D Jaundice is the primary symptom 3 Which of the following statements regarding hepatocellular carcinoma are true? (more than one answer is possible) A Is the most frequent primary liver tumor in older children B The highest incidence is in regions with endemic hepatitis B or C virus C Transplantation is the only curative treatment D Respond well to radio- or chemo-therapy 4 Which of the following are poor prognostic factors for malignant liver tumors? (more than one answer is possible) A Multifocality B Vascular infiltration

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C R0 resection D Preoperative chemotherapy 5 Which one of the following statements regarding angiosarcoma is true? A Is the most common malignant liver tumor B Grows slowly C Chemotherapy is efficient D Radiotherapy is inefficient

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A, D B, C A, B A, B D

40

Liver Tumors in Asia Norihiro Kokudo1, Sumihito Tamura1, and Masatoshi Makuuchi2 1 2

Department of Surgery, Hepato-Biliary-Pancreatic Surgery Division, University of Tokyo, Tokyo, Japan Japan Red Cross Medical Center, Tokyo, Japan

Hepatocellular carcinoma (HCC) continues to be endemic in East and South-East Asia, where the three major etiologic factors – hepatitis B, hepatitis C, and aflatoxin exposure – are still prevalent. Living donor liver transplantation (LDLT) has evolved and has become an accepted component of a multimodal approach in some regions in the area. Cholangiocarcinoma, another major histologic type of primary liver cancer, is also common in some parts of Asia. Liver fluke infection is endemic in such areas. To overcome these important public health problems, a number of investigations on the prophylaxis, early detection, and treatment of liver tumors have been conducted in the region. In this chapter, we review some of the major contributions made by Asian researchers in this field.

Historical background One year before the 1952 report of Lortat-Jacob and Robert [1], who introduced the modern era of anatomic hepatic lobectomy, Honjo and Araki in Kyoto successfully performed total resection of the right lobe of the liver [2]. They performed a right trisegmentectomy, as described by Healey and Schroy [3], in a 22-year-old man with metastatic liver tumor from rectal cancer. The patient “enjoyed a useful life for more than a year before he died of recurrent carcinoma.” The first liver resection in Japan was carried out by Ohno (Osaka) in 1937 [4]. He performed a wedge resection of a quadrate lobe for a hen egg-sized HCC in a 58-year-old female, who lived for at least 7 months after the operation. Before the report of Honjo and Araki, there had been several anecdotal reports of successful resection of liver tumors in Japanese medical journals. In 1958, just after Couinaud opened the door to segmentectomy, Lin et al [5, 6] in Taiwan popularized the finger

fracture technique for hepatic parenchymal dissection. In this method, the thumb and index finger are inserted into the liver tissue, and then the surgeon “fractures and crushes the tissue between the fingers, and when resistant vessels or ducts are encountered they are tied and divided.” They modified their method and introduced “a crushing method,” which was more efficient for hepatic transection. In Hong Kong, liver resection was started in the early 1950s, and Ong and Lee published a series of 125 liver resections, including 70 cases of HCC [7]. In 1979, Makuuchi et al presented a new ultrasonographic probe and established the use of intraoperative ultrasonography to define hepatic lesions and to plan resection [8]. Making the most of intraoperative ultrasound, they established a technique for systematic subsegmentectomy [9, 10] and reported a superior outcome in patients with HCC [11]. To increase the safety of major hepatectomy and to extend the indications for hepatectomy, hemihepatic portal vein embolization (PVE) was developed by Makuuchi et al in 1982 [12]. PVE induces homolateral atrophy of the portion of the liver scheduled for resection and contralateral compensatory hypertrophy of the remnant liver, thus decreasing the risk of postoperative liver failure. Soon after the first cases were attempted in Brazil and Australia, pediatric LDLT was initiated in 1989 in Japan [13, 14]. In 1993, Makuuchi et al successfully performed the first LDLT for an adult recipient [15]. After a decade of application, experience, and refinement of surgical techniques, LDLT has become a standard treatment for Japanese patients with end-stage liver failure. Trials of LDLT for patients with HCC have been carried out in Japanese centers. Major contributions to liver surgery from Asia are listed in Table 40.1 (see also Chapter 1).

Hepatocellular carcinoma Epidemiology


HCC is the fifth most common cancer in the world [16] and is most endemic in East and South-East Asia, and subSaharan Africa (Figure 40.1) [17]. In southern Guangxi,

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< 4.0 < 5.8 < 8.7 < 17.7 < 93.4

Figure 40.1 Regional variation in the mortality rates of hepatocellular carcinoma categorized according to age-adjusted mortality rates. The rates are reported per 100 000 persons. (Reproduced from El-Serag & Rudolph [16], with permission from Elsevier.)

Table 40.1 Major contributions to liver surgery from Asia. Year

Authors

Contributions

1937 1955 1958 1979 1982 1987 1989

Ohno [4] Honjo & Araki [2] Lin et al [5, 6] Makuuchi et al [8] Makuuchi et al [12] Makuuchi et al [9,10] Nagasue et al [13], Makuuchi et al [14] Makuuchi et al [15]

First successful liver resection in Japan First anatomic right lobectomy Finger fracture technique Intraoperative ultrasound Preoperative portal vein embolization Systematic subsegmentectomy Living donor liver transplantation

1994

Living donor liver transplantation in adult

China, a very high-risk area, the age-standardized (world population) incidence is approximately 120 per 100 000 person-years in men and 30 per /100 000 person-years in women. HCC is the second most common cause of death from cancer in China, where the mortality rate was 18 per 100 000 person-years from 1990 to 1992. Generally, males tend to be more commonly affected, with a male-to-female ratio that varies between 4:1 and 8:1. Chronic hepatitis B virus (HBV) infection and the presence of androgen receptors in HCC cells have been suggested as reasons for this male preponderance [18]. The three major etiologic factors associated with HCC are infection by HBV or HCV, as well as exposure to aflatoxin.

488

The relative contributions of these factors to the prevalence of HCC varies between high- versus low-incidence areas for the disease. It is estimated that 80% of HCC worldwide is etiologically associated with HBV. South-East Asia is an endemic region for type B hepatitis, and HCC is thought to be closely related to this factor. In high-risk areas of China, where the population prevalence of HbsAg positivity in men can be as high as 20−25%, the incidence of HCC among HBV carriers is about 1% per year. Furthermore, Taiwanese males who acquire carrier status early in life are estimated to be at a lifetime relative risk of 100 for developing HCC [19]. Virtually all carriers acquire the infection from their carrier mothers during infancy or by horizontal passage from infectious siblings. Many high-rate Asian countries now vaccinate all newborns against HBV, and HCC incidence has begun to decline among Chinese populations in Hong Kong, Shanghai, and Singapore [16]. Chronic infection by HCV is believed to play a relatively minor role in the development of HCC in Asia, except in Japan, where approximately 70% of HCC cases are HCV related [20]. A moderately high prevalence of anti-HCV has been observed in Taiwan (9−23%) and Hong Kong (7%) [17]. There is strong epidemiologic evidence that the increase in the incidence of HCC in Japan until the mid 1990s was due to an increase in HCV-induced chronic liver disease [21]. HCV hepatitis is believed to have existed in Japan since the early 19th century. It became endemic after World War II, probably via procedures that involve penetration of the skin, such as small pox vaccination, acupuncture, tattooing,

CHAPTER 40

use of unsterilized needles, unnecessary operations, and blood transfusions. It takes more than 20 years, perhaps about 30 years, for HCC to develop in patients with chronic HCV infection from the time of acute post-transfusion hepatitis [21]. HCC develops at a rate of more than 6% per year in HCV-positive cirrhotic patients [22]. HCC incidence rates among Japanese males declined for the first time between 1993 and 1997, probably due to popularized acknowledgement of HCV transmission [16]. The relative roles of HBV and HCV infection in hepatocellular carcinogenesis vary considerably among populations. A synergistic effect on the risk for HCC has recently been reported in Southern African blacks in whom both HBV and HCV markers are present [23]. Dietary aflatoxin exposure, which is an important codeterminant of the risk of HCC in Africa, is also a risk factor in some parts of Asia. Aflatoxin is a food contaminant arising from the improper storage of grains susceptible to mold formation during spoilage. For example, a traditional Chinese vegetarian diet has been associated with an increased risk of HCC. A study from Taiwan has demonstrated a multivariate-adjusted odds ratio of developing HCC of 5.5 for patients with detectable serum levels of aflatoxin B1 [24]. Exposure to aflatoxin is known to increase the risk of HCC in men with chronic HBV hepatitis [25]. The incidence of HCC in East Asia, including Singapore and Shanghai, China, has declined over the past several decades. This decline is considered to be related to the decreasing exposure to dietary aflatoxin. Recent economic development in East Asia has greatly diminished the population exposure to mycotoxins. HCC is a highly prevalent malignancy in Taiwan, and is now the highest ranking cause of death from malignancy among men. About 5000 people die from HCC each year in Taiwan. Although this high prevalence of HCC in Taiwan is mainly thought to be related to HBV, more and more HCCs have been found to be related to HCV since the development of an assay to detect HCV infection. Seventy to 80% of patients with HCC have cirrhosis or chronic hepatitis. Hong Kong is also an endemic area for HBV infection and has a high incidence of HCC. Of these cases, 80.3% are HBV related and 7.3% are HCV related [26]. Korea has the world’s highest rate of liver cancer mortality. Both HBV and HCV are known to be the major risk factors for HCC. HCC is the most common cancer in Thailand. Sixty-five to 87% of the cases are HBV related and 8−17% are HCV related [27]. The prevalence of HCC in India is lower than that in most parts of the world. This contrasts with the widespread contamination of foods with aflatoxin and the moderately high prevalence of HBV- and HCV-related chronic liver disease in India. There has been no conclusive explanation for this discrepancy. The annual incidence of HCC in India is around 3−5 per 100 000 population [28]. In Saudi Arabia, where HBV is endemic, the

Liver Tumors in Asia

overall prevalence of antibody to HCV is low. However, the incidence of HCV is around 30% in patients with chronic liver disease, and this is considered to be related to the development of HCC. The close relationship between HCC and Budd−Chiari syndrome (obstruction of the hepatic portion of the inferior vena cava) was first pointed out by Japanese researchers. Budd−Chiari syndrome is an important etiologic factor for HCC in Japan and Nepal [29] (see also Chapter 5).

Prophylaxis and early detection The transmission of HBV from mother to infant at or soon after birth is associated with a high incidence of HCC in early life. Since the 1980s, Asian governments have conducted extensive vaccination programs for HBV. HBV vaccination was launched in Taiwan in 1984 for neonates of mothers carrying hepatitis B e antigen. This substantially reduced the prevalence of HBsAg from 10% to 1% within a 10-year period, resulting in a decreased incidence of HCC in children [18, 30]. In Singapore, short- and long-term measures for the prevention of HCC have been tried. These include the introduction of prophylactic HBV immunization, discouragement of alcohol and tobacco consumption, screening for aflatoxin in imported human food materials, and testing for HCV. Prophylactic, intermittent long-term administration of lymphoblastoid interferon-alpha has also been tried in high-risk patients with favorable results. In general, the prognosis for patients with HCC is still dismal because of the low chance of curative treatment. To increase the chance of intervention and, more importantly, to improve survival, the early detection of subclinical HCC by alpha-fetoprotein (AFP) and/or ultrasonography screening has been implemented in many countries. AFP monitoring alone is inadequate for the early diagnosis of HCC among patients with chronic HBV infection, since it can be difficult to differentiate between benign and malignant causes of AFP elevation. HCC found at the time of a sharp rise in AFP already measures 4−5 cm [31]. Reports on HCC screening in Asian populations have shown encouraging results; HCC can be detected at a surgically resectable stage in most HbsAb-positive carriers and HCV-positive patients [22, 32]. Japanese gastroenterologists have pioneered clinical programs for the early detection of HCC [33]. In countries like Japan, where medicine is highly socialized and every person is covered by health insurance, people frequently consult physicians who can perform extensive investigations with little concern about cost, and most diseases are found before an advanced stage. With various liver function tests and imaging modalities available, patients with cirrhosis are diagnosed early and closely followed. Takayama et al defined early HCC as a well-differentiated cancer containing Glisson’s triad and showed that it is a distinct clinical entity

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with a high chance of surgical cure [34]. The usefulness of ultrasonography for the early detection of HCC has also been reported from other Asian regions [35]. Figure 40.2 shows the currently recommended surveillance algorithm in Japan. It consists of: measurement of serum AFP, L3 fraction of AFP (Lens culinaris agglutinin A-reactive AFP) [36], and PIVKA-II (protein induced by vitamin K absence, or des-gamma-carboxyprothrombin) [37] levels and ultrasonography. When there is a continuous rise in AFP by 200 ng/mL or more, a rise in PIVKA-II by 40 mAU/mL or more, or a rise in the AFP-L3 fraction by 15% or more, dynamic computed tomography (CT) or magnetic resonance imaging (MRI) should be performed even if tumors cannot be detected by ultrasonography [38]. If dynamic CT or MRI does not show a typical HCC image and the patient tests negative for other malignant liver tumors, the patient should be followed up using a tumor diameter of 2 cm as a temporary index. The interval of examination is 3 months as an index. If there is a tendency for the diameter to grow significantly, the patient is eligible for treatment [38]. Yuen et al from Hong Kong also recommended a screening program for HCC by AFP and/or ultrasonography [39].

Diagnosis Recent progress in imaging techniques has facilitated the recognition of early HCC as a principal tumor in at-risk subjects who undergo regular medical check-ups for chronic viral hepatitis or cirrhosis [33]. Imaging modalities including multidetector row computed tomography (MDCT), thinsection MRI, color Doppler sonography, CT during hepatic arteriography (CTA) or arterial portography (CTAP), and CT after hepatic intra-arterial injection of iodized oil (lipiodolCT) are promising in vivo tools for the diagnosis of HCC at an early stage [28]. According to Japanese clinical practice guidelines for HCC [38], dynamic CT or dynamic MRI is recommended for the first-line diagnosis of HCC. The use of contrast medium is indispensable for diagnostic imaging (CT/MRI) of HCCs. The examination of contrast enhancement in the arterial phase and injection of contrast medium in the delayed phase of CT are considered useful. For patients with definite HCC scheduled for liver resection, lipiodol-CT is routinely performed in some Japanese centers to check for intrahepatic metastasis. Intraoperative ultrasonography (IOUS) is also highly sensitive and is routinely performed in Japan as final diagnostic imaging before resection. Despite the recent progress in the imaging modalities for HCC, IOUS is still the most sensitive. It is not uncommon to detect new hepatic nodules by IOUS during hepatic resection for HCC [40, 41]. Patients with new tumors are at high risk for recurrence so that regular check-up is important to prolong survival [41].

490

Treatment Resection has generally been considered as a first-line therapy for HCC, with transplantation being reserved for patients with tumors that are unresectable because of the location or severity of the underlying liver disease [42]. The 5-year disease-free survival rates after liver resection in Asian series have ranged from 12% to 28%. The Liver Cancer Study Group of Japan has been conducting a nationwide survey of HCC patients every 2 years since 1965 and has accumulated more than 40 000 cases [32, 43]. In their most recent analysis of 27 062 HCC resections that were performed between 1992 and 2003 [20], the overall 5-year survival rate was 53.4%. The reported significant prognostic factors were the AFP level, tumor size, number of tumors, accompanying cirrhosis, age, surgical curability, and portal involvement. The most recent operative death rate (2002–2003) has been reported to be as low as 0.8% [20]. Since cancer cells from HCC tend to spread through the portal venous system, anatomic resection is theoretically effective for the eradication of intrahepatic metastases of HCC. There have been several reports from Japanese [11, 12] and French [44] centers providing evidence that supports the superiority of anatomic resection (Figure 40.3). The natural history of untreated HCC with portal vein tumor thrombosis is extremely poor, with a median survival time of 2.7 months [45]. Chemotherapy or transarterial chemoembolization (TACE) have been tried, but with unsatisfactory results. The surgical resection of such advanced HCCs with portal vein tumor thrombosis has also been tried by Japanese surgeons. Minagawa and Makuuchi established selection criteria for performing hepatectomies in such patients and reported a 5-year survival rate of 42% after surgery [46]. Since the pioneering work by Lin, there have been several reports on surgical treatment for HCC in Taiwan. In the mid 1980s, Lee et al reported a series of 109 resected cases of HCC with an operative mortality rate of 3%. In contrast to the poor outcome of symptomatic HCC (5-year survival, 8%), asymptomatic HCC had a favorable outcome, with a 5-year survival rate of 44%. Although short-term outcomes have improved greatly with better surgical techniques, the high rate of postoperative recurrence is now an important issue. According to Chen et al, the postoperative intrahepatic remnant rate is 80% at 5 years after resection [47]. In Hong Kong, Fan et al reported a large series of 330 patients who underwent liver resection for HCC [48]. By reducing intraoperative blood loss, they achieved an inhospital mortality rate of zero in their 110 most recent consecutive patients. Since its introduction, radiation frequency ablation (RFA) has rapidly gained popularity, and is now considered as a potentially curative treatment for small HCCs. RFA achieves

CHAPTER 40

1

Very high-risk group:


Ultrasonography at intervals of 3 or 4 months Measurement of AFP/PIVKA-II/AFP-L3 at intervals of 3 or 4 months *1, 2, 3 CT or MRI at intervals of 6–12 months (optional)

High-risk group:

Ultrasonography at intervals of 6 months Measurement of AFP/PIVKA-II/AFP-L3 at intervals of 6 months *1, 2, 3 *5

Detection of a nodular lesion by ultrasonography

Continuous rise in AFP, rise in AFP by 200 ng/mL or more, rise in PIVKA-II by 40 mAU/mL or more, or rise in the AFP-L3 fraction by 15% or more

Dynamic CT or dynamic MRI*4

2 Dynamic CT or dynamic MRI*4

Image of typical HCC*6

No lesion

Image of atypical HCC

3 Is tumor diameter 2 cm or larger?

No

No lesion

Not visualized

No growth in size and Ultrasonography at intervals of 3 disappearance months of tumor

Yes Optional examinations Angiography CT-angiography SPIO-MRI Contrast ultrasonography Tumor biopsy, etc

Image of typical HCC*6

Image of atypical HCC

1

Second ultrasonography

Growth in size/ rise in tumor marker level

Disappearance of tumor

CT/MRI at intervals of 3 months

1

Can be visualized 3

2

Growth in size/ appearance of hypervascular lesion

Definite diagnosis of HCC

Treatment

Figure 40.2 Algorithm for the surveillance of hepatocellular carcinoma (HCC) [38], cited with permission: *1, Current health insurance in Japan covers the measurement of only one tumor marker level per month; *2, alpha-fetoprotein (AFP)-lectin fraction (L3) can be measured only when the patient is diagnosed as having HCC; *3, When the AFP is 10 ng/mL or less, the AFP-L fraction cannot be measured; *4, if there is renal dysfunction or the patient is suspected of being allergic to iodinated contrast media, dynamic magnetic resonance imaging (MRI) is recommended; *5, computed tomography (CT)/MRI is performed at regular intervals; *6, a tumor that is visualized as a high signal intensity area in the arterial phase and as a relatively low signal intensity area in the venous phase; *7, if a patient is suspected of having other malignant tumors, such as cholangiocellular carcinoma or metastatic liver cancer, he/she proceeds to undergo a thorough examination for that disease. PIVKA, protein induced by vitamin K absence or antagonist; SPIO, super paramagnetic iron oxide. (Reproduced from Makuuchi et al [38]; with permission from John Wiley & Sons.)

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1 Anatomic resection

0.8

(n = 156) 0.6 0.4 Nonanatomic resection 0.2

(n = 54) P = 0.01

0 0

1

2

6 3 4 5 Overall survival (years)

7

8

Figure 40.3 Impact of type of surgical resection on long-term outcome in patients with hepatocellular carcinoma. Comparison of anatomic resection (subsegmentectomy, segmentectomy or lobectomy; n = 82) with nonanatomical resection (limited resection; n = 56); p = 0.012 (log-rank test). (Reproduced from Hasegawa et al [11], with permission from Wolters Kluwer Health.)

higher total necrosis rates with fewer treatment sessions than percutaneous ethanol injection (PEI), which had been a mainstay of percutaneous local therapy until 2000. The superiority of RFA over PEI in terms of patient survival has been demonstrated by a recent randomized controlled trial conducted in Asia [49]. The therapeutic effect of percutaneous local ablative therapy and surgical resection for small HCC has been compared in a randomized controlled study conducted in China. Chen et al [50] concluded that the therapeutic effects of the two treatment options are similar; however, this study suffered from an insufficient number of enrolled patients and a high drop-out rate because a considerable number of patients who had been assigned to the ablation treatment arm wished to undergo surgery. TACE involves the administration of a chemotherapeutic agent (usually doxorubicin, mitomycin C, or cisplatin) into the hepatic artery, followed by hepatic artery embolization (usually with a gelatin sponge). Since liver tumors preferentially receive their blood supply from the hepatic artery, the occlusion of this artery causes selective ischemia of the tumor and enhances the cytotoxicity of the chemotherapeutic agent. A Japanese radiologist was the first physician to use TACE for the treatment of patients with unresectable HCC [51]. TACE has also been used as an adjunctive therapy with liver resection or liver transplantation in an attempt to shrink the tumor or to control its growth before transplantation (see Chapter 13). Takayasu et al accumulated 8150 TACE-treated patients with unresectable HCC from the database of the Liver Cancer Study Group of Japan [52]. They concluded that TACE is a safe therapeutic modality with 0.5% treatment-related mortality and a 5-year overall

492

survival rate as high as 26%. The degree of liver damage, TNM stage, and AFP value were independent risk factors for patient survival. Chemotherapy is usually given to patients with metastatic disease or for persistent recurrent disease. No single drug or combination of drugs given systemically leads to a reproducible response rate of more than 25% or adds any survival benefit. Based on favorable preliminary data for sorafenib in Western countries, a prospective clinical trial for this promising new agent may be conducted in Asian countries. Total hepatectomy with transplantation was expected to be the solution to HCC in cirrhotic livers when hepatic resection was not feasible. Mazzafero developed these factors further into the rules known today as the Milan criteria [53]. Mazzaferro reported that the outcomes of deceased donor liver transplantation (DDLT) for patients with single (≤5 cm) or fewer than three (≤3 cm) HCC nodules are no different from those obtained for nonmalignant indications. The cumulative excellent results based on these criteria have led to their acceptance in many regions worldwide. Currently, liver transplantation remains the most attractive option for HCC complicated by liver cirrhosis (see Chapter 23). In the era of critical organ shortage, however, the bottleneck to applying liver transplantation for HCC is the limited supply of liver grafts in a timely manner, especially in the Far East. Due to the limited numbers of organs available from deceased donors in many Asian countries, LDLT has become accepted as the mainstream treatment for endstage liver disease and HCC [54−58]. In the management of HCC with LDLT, much has been applied from the lessons learned from the published experience of DDLT for HCC, including that gained from the application of the Milan criteria. However, although the current application of the Milan criteria to LDLT for HCC represents a reasonable starting point to gain public support, a more flexible approach may be considered in LDLT for two reasons. First, unlike in DDLT, the graft supply is not dependent on a nationwide organ-sharing network. Graft availability strongly depends on the donor’s altruistic decision for the benefit of a specific recipient based on their unique relationship, allowing an act of further oncologic risk taking. Second, liver transplantation for HCC can be performed in a scheduled and timelier manner, compared to DDLT, within a short waiting period from the time of the initial diagnosis. The combination of these two factors has led to a reconsideration of the rationale for imposing the current strict Milan criteria for LDLT (Table 40.2). The registry data on LDLT for HCC surveyed by the Japanese Study Group for Liver Transplantation, summarized by Todo et al [54], show that, by the end of 2003, 316 adult patients had undergone LDLT in Japan. The median followup period was 16 months. Interestingly, a strict adoption of the Milan criteria was recognized in only one-third of the

CHAPTER 40


Table 40.2 Outcomes in the Far East of living donor liver transplantation for hepatocellular carcinoma exceeding the Milan criteria. Center

Japan* [54] Seoul, Korea [57] Kyoto, Japan [56] Tokyo, Japan [60] Kyushu, Japan [58]

Number of patients

316 237 125 78 60

Number exceeding Milan criteria (%)

172 (54) 64 (27) 55 (44) 10 (13) 40 (67)

Overall survival (%)

Recurrence-free survival (%)

1 year

3 years

5 years

1 year

3 years

5 years

75 NA NA 90 NA

60 63 NA 90 NA

NA NA 64 NA NA

65 NA NA 70 83

53 NA NA 70 74

NA NA 66 NA NA

*Multicenter nationwide survey, involving 49 centers

Cumulative recurrence rate (%)

50 40 30 20 No Yes

10

p < 0.0001 0 1 2 Years post transplant

our LDLT program in 1996, a rule designated as the “5−5 rule” has been applied to patient selection. In other words, patients with up to five HCC nodules each less than 5 cm in diameter are regarded as candidates for LDLT. When stratified according to the 5−5 rule, the recurrence-free survival rate at 3 years for patients fulfilling the criteria and those exceeding the criteria was 94% and 50%, respectively [60]. Other centers in the Far East have adopted various criteria modestly expanding the Milan criteria, with cumulative data demonstrating that a mild expansion may still provide satisfactory results in LDLT for HCC (Table 40.3) (see also Chapters 16, 26).

3

Figure 40.4 Cumulative recurrence rate of hepatocellular carcinoma following living donor liver transplantation among patients selected using the Milan criteria. (Reproduced from Todo et al [54], with permission from Wolters Kluwer Health.)

LDLT centers in Japan. The overall patient survival rates at 1 and 3 years were 78% and 69%, respectively. The recurrence-free survival rates at 1 and 3 years were 73% and 65%, respectively. When stratified according to the Milan criteria, patient survival at 3 years was 79% in patients who met the criteria, and 60% in those who presented with further advanced tumors. The cumulative HCC recurrence rate in patients meeting or exceeding the Milan criteria was 3% and 20%, respectively, at 1 year, and 3% and 37%, respectively, at 3 years (Figure 40.4). From an oncologic point of view, however, these outcomes may be considered excellent. Some Asian regions [55, 57] have adopted the rules known as the University of California San Francisco (UCSF) criteria: solitary tumor less than 6.5 cm or fewer than three nodules with the largest lesion smaller than 4.5 cm and the total tumor diameter less than 8 cm, originally based on pathologic findings [59]. In Tokyo, since the beginning of

Evidence-based practice guidelines for hepatocellular carcinoma in Japan The “clinical practice guidelines for HCC,” the first evidencebased guidelines for the treatment of HCC in Japan, were compiled by an expert panel supported by the Japanese Ministry of Health, Labor, and Welfare in 2001. A systematic review of the English medical literature on HCC was performed, and a total of 7192 publications were extracted, mainly from Medline (1966–2002). There are 58 pairs of research questions and recommendations covering six research fields: prevention, diagnosis and surveillance, surgery, chemotherapy, TACE, and percutaneous local ablation therapy. For the users’ convenience, practical algorithms for the surveillance (see Figure 40.2) and treatment of HCC (Figure 40.5) were created based on evidence from the selected articles for the guidelines, and modified according to the current status of medical practice in Japan, where liver resection for HCC is regarded as safe with less than 1% mortality, and cadaveric donors for liver transplantation are extremely difficult to obtain. These guidelines have been acknowledged by most Japanese hepatologists and liver surgeons, and algorithms for the treatment of HCC (Figure 40.5) are now widely utilized in daily practice [61] (see also Chapter 26).

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Table 40.3 Various criteria applied in living donor liver transplantation for hepatocellular carcinoma in the Far East. Center

Seoul, Korea [57] Hong Kong, China [55] Kyoto, Japan [56] Kyushu, Japan [58] Tokyo, Japan [60]

Criteria other than Milan criteria

Number of tumors

UCSF No major vessel invasion UCSF DCP ≤400, tumor number ≤10, and size ≤5 cm Any tumor number and size ≤5 cm DCP ≤300 alone Tumor number ≤5 and size ≤5 cm

Overall survival (%)

Recurrence-free survival (%)

1 year

3 years

5 years

1 year

3 years

5 years

167 197 43 78

NA NA 97 NA

91 87 80 NA

NA NA 58 87

NA NA 93 NA

NA NA 71 NA

NA NA 71 95

53 46 72

NA NA 90

NA NA 88

NA NA NA

>77* 100 97

>77* 94 94

NA NA NA

*In the cited reference, the outcome data are stratified according to the size of the tumor into four groups; ≤2 cm, 2–3 cm, 3–5 cm and >5 cm. 1- and 3-year recurrence-free survival rates of groups ≤2 cm, 2–3 cm, and 3–5 cm were 95%, 100%, and 77%, and 95%, 83%, and 77%, respectively. UCSF, the University of California San Francisco criteria; DCP, des-gamma-carboxy prothrombin value in mAU/mL.

HCC*

Degree of liver damage (Child class)

Number of tumors

A, B

Treatment

2 or 3

Single

Tumor diameter

≤ 3 cm

Resection ablation†

C

Resection ablation

4 or more

> 3 cm

Resection embolization

1–3

4 or more

≤ 3 cm**

Embolization hepatic arterial infusion chemotherapy

Transplantation

Palliative care

Figure 40.5 Treatment algorithm for hepatocellular carcinoma [38]. *Presence of vascular invasion or extrahepatic metastasis to be indicated separately; Selected when the severity of liver damage is class B and the tumor diameter is ≤2 cm; **Tumor diameter ≤5 cm, when there is only one tumor. (From Makuuchi M et al. [38]; with permission from John Wiley & Sons.)

Cholangiocellular carcinoma Epidemiology According to the Classification of Primary Liver Cancer of the Liver Cancer Study Group of Japan [62], the term

494

“intrahepatic cholangiocarcinoma (ICC)” refers to malignant epithelial tumors that originate in the intrahepatic bile ducts. ICC is classified into three types based on the macroscopic appearance of the cut surface of the tumor: mass forming, periductal infiltrating, and intraductal growth.

CHAPTER 40


Table 40.4 Distribution of microscopically verified cases with liver tumor by histologic type.* Country (city)

Total number of cases

HCC (%)

ICC (%)

Hepatoblastoma (%)

Sarcoma (%)

Others (%)

Unspecified (%)

Hong Kong India (Bombay) Japan (Osaka) Korea (Kangwha) Kuwait Philippines (Manila) Singapore (Chinese) Thailand (Chiang Mai) Thailand (Khon Kaen) Vietnam (Hanoi)

3 200 732 16 350 114 57 1 775 1 281 962 3 046 633

64.1 74.8 75.1 38.5 85.7 74.7 78.8 45.9 6.8 68.8

26.3 13.0 5.4 7.7 9.5 11.2 10.9 43.7 87.3 10.9

0.5 6.6 0.4 0.0 0.0 2.2 1.6 0.3 0.8 0.0

0.3 0.3 0.2 0.0 0.0 0.5 0.6 0.6 0.0 0.7

0.6 1.6 0.6 3.8 4.8 0.5 0.9 0.0 0.4 1.4

8.8 5.3 18.9 53.8 4.8 11.4 8.1 9.5 5.1 19.6

HCC: hepatocellular carcinoma, ICC, intrahepatic cholangiocarcinoma.

ICC is another major histologic type of primary cancer of the liver, which occurs rather less frequently than HCC. In published studies, the frequency of ICC is almost always reported based on a clinical series, as a percentage of all liver cancer (on biopsy or at autopsy). The reported frequencies range from 5% to 30% of all liver cancers (Table 40.4) [17, 63]. According to a recent report on a nationwide survey in Japan [20], ICC is the second most frequent primary liver cancer in Japan, but it constitutes only 4.1% of all liver tumors (Table 40.5). Most international comparisons of the incidence of cancer usually do not distinguish between HCC and ICC. Therefore, it has been suggested that most available descriptive data only describe primary cancer as a whole. Liver flukes, including Opisthorchis viverrini and Clonorchis sinensis, are established etiologic agents of cholangiocarcinoma [63]. In an area in north-east Thailand where O. viverrini infection is endemic (70% of the population), 90% of primary liver cancers are cholangiocarcinoma. The mechanisms of carcinogenesis in O. viverrini infection have been a subject of considerable research; the presence of parasites induces DNA damage and mutations as a consequence of the formation of carcinogens/free radicals and the cellular proliferation of intrahepatic bile duct epithelium. Cholangiocarcinoma accounts for more than 20% of liver cancer around Pusan, Korea. C. sinensis in stools and heavy drinking are reported to be associated with the risk of cholangiocarcinoma. C. sinensis was endemic in Korea, Japan, China, and Vietnam. However, it is much less prevalent than it once was, and ICC from this cause appears to have been relatively infrequent in recent years [63]. Intrahepatic stones (hepatolithiasis) are another possible etiologic factor for ICC. Such stones are observed in a fairly large proportion of ICC cases, from 5.7% to 17.5% of cases in a Japanese series [64]. Bile duct epithelium in hepatolithi-

Table 40.5 Incidence of primary liver tumors in Japan.* Histologic type

Male

Female

Total (%)

Hepatocellular carcinoma Cholangiocarcinoma Combined HCC and ICC* Cystadenocarcinoma Hepatoblastoma Sarcoma Others Total

12 481 384 74 19 9 10 57 13 034

4185 243 19 13 9 3 28 4500

16 666 627 93 32 18 13 85 17 534

(95.05) (3.58) (0.53) (0.18) (0.10) (0.07) (0.48)

*Data taken from The Liver Cancer Study Group of Japan, 2000 [74] HCC: hepatocellular carcinoma, ICC, intrahepatic cholangiocarcinoma.

asis shows chronic proliferative cholangitis and epithelial hyperplasia. Most of the cases in an ICC series in Taiwan were associated with hepatolithiasis. According to Chen et al, 106 of 162 (65.4%) patients with ICC had associated hepatolithiasis [65] (see also Chapter 6).

Treatment As is the case in HCC, surgery is currently the only treatment modality that provides a chance of cure for ICC. ICC shows variable patterns of intrahepatic invasion, including dissemination through the portal vein or lymphatic vessels and direct expansion via sinusoidal spaces. Of these, the main route of intrahepatic spread of ICC is considered to be dissemination through the portal tree. From this oncologic perspective, anatomic resection seems to be the best approach for the treatment of ICC [66]. The long-term outcome of patients with ICC who undergo liver resection is slightly worse than that for patients with

495

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100 90 80 Survival rate (%)

70 60 50 40 30 20 10 0

0

1

2

3

4

5

6

7

8

Years post resection

HCC. According to a recent report on a nationwide survey in Japan [20], the 5-year survival rate of 1626 patients who underwent surgery for ICC was 32.7%. Patients with lymph node metastasis had an extremely poor prognosis. Inoue and Makuuchi reported an overall 5-year survival rate of 36% in 52 patients with so-called mass-forming type ICC. Of these, there were no long-term survivors among 21 patients with lymph node metastasis (Figure 40.6). Notably, among patients with mass-forming type ICC, almost all recurrence occurred within a year and most of the patients died within 2 years after hepatic resection [66]. Chu and Fan from Hong Kong reported a series of 48 resected cases of ICC with a 5-year survival rate of 22.0% [67]. Kim et al reported a series of 28 cases of ICC in Korea. Twelve of these cases (46.2%) had associated Clonorchis sinensis infection, and their overall 3-year survival rate was 22.1% [68]. In Thailand, Uttaravichien et al reported a large series of mass-forming type ICC [69]. The 3-year survival rate in 100 patients was 16%. According to a report from Taiwan that included 138 patients with ICC [65], the 5-year survival rate was 16.5% and 7.8% in those with and without hepatolithiasis, respectively (p > 0.05). Thus, hepatolithiasis per se did not influence long-term survival (see also Chapter 16).

Other primary liver tumors According to a recent report on a nationwide survey in Japan [20], HCC and ICC are the most frequent primary liver cancers in Japan and constitute 98.3% of all liver tumors. Other histologic types, including cystadenocarcinoma, combined type, hepatoblastoma, and sarcoma, are extremely rare (Table 40.5).

496

9

10

11

12

Figure 40.6 Impact of lymph node metastasis on the survival rate of patients with mass-forming type cholangiocarcinoma who underwent resection with curative intent. Thick line, patients without lymph node metastasis (n = 21); thin line, patients with lymph node metastasis (n = 31) (p = 0.0001). (Reproduced from Inoue et al [66], with permission from Elsevier.)

Hepatoblastoma and HCC are two frequent liver cancers in childhood (see also Chapter 39). Approximately twothirds of patients with hepatoblastoma have resectable tumors, and in those undergoing complete resections, surgery alone results in a long-term survival rate of around 60%. According to the cancer registry of Taiwan (1979−1992), 43 cases of hepatoblastoma were reported among 377 young patients (0−15 years of age) suffering from liver cancer [70]. Their outcome was not favorable; only 17 of these 43 patients underwent surgical resection and the 5-year survival rate of the resected cases was 47%.

Secondary liver tumors Since the report of Foster and Berman [71], liver resection has also been utilized in Asian centers for secondary liver tumors, mainly colorectal metastasis. There have been a number of reports in the English literature from Asian centers since the early 1990s [72, 73]. The reported operative mortality and 5-year survival rate after hepatectomy ranged from 0% to 3.7%, and 25.5% to 51.0%, respectively. According to the nationwide survey conducted by the Japanese Study Group of Colorectal Cancer, a total of 2779 cases of synchronous colorectal metastasis underwent liver resection between 1995 and 1998. The 5-year survival rates in patients with unilobar metastases, bilobar metastases with fewer than five lesions, and bilobar metastases with more than five lesions were approximately 40%, 35%, and 20%, respectively. Hepatic resection for secondary liver tumors from other primaries, including gastric cancer and breast cancer, has

CHAPTER 40

also been performed by Japanese surgeons. However, the survival benefit of liver surgery in such settings has yet to be determined.

Self-assessment questions 1 Which of the following are the three major etiologic factors associated with hepatocellular carcinoma in Asia? A Infection by HIV B Infection by hepatitis B virus C Infection by hepatitis C virus D Exposure to aflatoxin E Liver fluke infection 2 Which of the following are etiologic agents for cholangiocellular carcinoma? (more than one answer is possible) A Budd−Chiari syndrome B Exposure to aflatoxin C Liver fluke infection D Infection by hepatitis B virus E Hepatolithiasis 3 Surgical resection is the best treatment for HCC when sufficient hepatic function is preserved because it rarely recurs in the remnant liver. A First and second parts are wrong B First part is correct, second part is wrong C First part is wrong, second part is correct D First and second parts are correct, but “because” is incorrect E First and second parts are correct, and “because” is correct 4 In hepatocellular carcinoma (HCC), anatomic resection with complete removal of the tumor is the treatment of first choice, when feasible, because HCC tends to spread through the portal venous system. A First and second parts are wrong B First part is correct, second part is wrong C First part is wrong, second part is correct D First and second parts are correct, but “because” is incorrect E First and second parts are correct, and “because” is correct 5 The survival benefit from liver surgery has yet to be determined for which one of the following? A Hepatocellular carcinoma B Intrahepatic cholangiocarcinoma C Hepatoblastoma D Metastasis of colorectal cancer E Metastasis of breast cancer


References 1 Lortat-Jacob JL, Robert HG. Hepatectomie droite reglee. Presse Med 1952;60:549–51. 2 Honjo I, Araki C. Total resection of the right lobe of the liverreport of a successful case. J Int Coll Surg 1955;7:23–8. 3 Healey JE, Schroy PC. Anatomy of the biliary ducts within the human liver. Analysis of the prevailing pattern of branchings and the major variations of the biliary ducts. Arch Surg 1953;66: 599–616. 4 Ohno Y. Resection of liver cancer [in Japanese]. Tokyo Iji Shinpo Shi 1937;3014:8–11. 5 Lin T-Y, Tsu KY, Mien C, et al. Study on lobectomy of the liver. J Formosa Med Assoc 1958;57:742–59. 6 Lin T-Y, Chen KM, Lin T-K. Total right hepatic lobectomy for primary hepatoma. Surgery 1969;48:1048–60. 7 Ong GB, Lee NW. Hepatic resection. Br J Surg 1966;62:421– 30. 8 Makuuchi M, Hasegawa H, Yamazaki S, et al. Newly devised intraoperative probe. Image Technol Information Display Med 1979;11:1167. 9 Makuuchi M, Hasegawa H, Yamazaki S, et al. The use of operative ultrasound as an aid to liver resection in patients with hepatocellular carcinoma. World J Surg 1987;11:615–21. 10 Makuuchi M, Hasegawa H, Yamazaki S. Ultrasonically guided subsegmentectomy. Surg Gynecol Obstet 1985;161:346–50. 11 Hasegawa K, Kokudo N, Imamura H, et al. Prognostic impact of anatomic resection for hepatocellular carcinoma. Ann Surg 2005;242:252–9. 12 Makuuchi M, Thai BL, Takayasu K, et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery 1990;107: 521–7. 13 Nagasue N, Kohno H, Matsuo S, et al. Segmental (partial) liver transplantation from a living donor. Transplant Proc 1992;24: 1958–9. 14 Makuuchi M, Kawasaki S, Iwanaka T, et al. Living related liver transplantation. Surg Today 1992;22:297–300. 15 Hashikura Y, Makuuchi M, Kawasaki S, et al. Successful livingrelated partial liver transplantation to an adult patient. Lancet 1994;343:1233–4. 16 El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007;132:2557 –6. 17 Parkin DM, Whelan SL, Ferlay J, et al. Cancer Incidence in Five Continents, vol VII. IARC Science Publications No. 143. Lyons: IARC, 1997. 18 Ogunbiyi JO. Hepatocellular carcinoma in the developing world. Semin Oncol 2001;28:179–87. 19 Wogan GN. Aflatoxin as a human carcinogen. Hepatology 1999;30:573–5. 20 Ikai I, Arii S, Okazaki M, et al. Report of the 17th Nationwide Follow-up Survey of Primary Liver Cancer in Japan. Hepatol Res 2007;37:676–91. 21 Kiyosawa K, Sodeyama T, Tanaka E, et al. Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibody to hepatitis C virus. Hepatology 1990;12:671–5.

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22 Oka H, Kurioka N, Kim K, et al. Prospective study of early detection of hepatocellular carcinoma in patients with cirrhosis. Hepatology 1990;12:680–7. 23 Kew MC, Yu MC, Kedda M-A, et al. The relative roles of hepatitis B and C viruses in the etiology of hepatocellular carcinoma in Southern African blacks. Gastroenterology 1997;112:184–7. 24 Chen W, Wang LY, Lu SN, et al. Elevated aflatoxin exposure and increased risk of hepatocellular carcinoma. Hepatology 1994;24:38– 42. 25 Sun Z, Lu P, Gail MH, et al. Increased risk of hepatocellular carcinoma in male hepatitis B surface antigen carriers with chronic hepatitis who have detectable urinary aflatoxin metabolite M1. Hepatology 1999;30:379–83. 26 Leung NW, Tam JS, Lai JY, et al. Does hepatitis C virus infection contribute to hepatocellular carcinoma in Hong Kong? Cancer 1992;70:40–4. 27 Tangkijvanich P, Hirsch P, Theamboonlers A, et al. Association of hepatitis virus with hepatocellular carcinoma in Thailand. J Gastroenterol 1999;34:227–33. 28 Akriviadis EA, Llovet JM, Efremidis SC, et al. Hepatocellular carcinoma. Br J Surg 1998;85:1319–31. 29 Shresta S M, Okuda K, Uchida T, et al. Endemicity and clinical picture of liver disease due to obstruction of the hepatic portion of the inferior vena cava. J Gastroenterol Hepatol 1996;11:170– 9. 30 Chang MH, Shau WY, Chen CJ, et al. Hepatitis B vaccination and hepatocellular carcinoma rates in boys and girls. JAMA 2000;284:3040–2. 31 Kubo Y, Okuda K, Musha H, et al. Detection of hepatocellular carcinoma during a clinical follow-up of chronic liver disease. Observations in 31 patients. Gastroenterology 1978;74:578–82. 32 The Liver Cancer Study Group of Japan. Primary liver cancer in Japan. Clinicopathologic features and results of surgical treatment. Ann Surg 1990;211:277–87. 33 Okuda K. Early recognition of hepatocellular carcinoma. Hepatology 1986;6:729–38. 34 Takayama T, Makuuchi M, Hirohashi S, et al. Early hepatocellular carcinoma as an entity with a high rate of surgical cure. Hepatology 1998;28:1241–6. 35 Liaw Y-F, Tai D-R, Chu C-M, et al. Early detection of hepatocellular carcinoma in patients with chronic type B hepatitis. Gastroenterology 1986;90:263–7. 36 Sato Y, Nakata K, Kato Y, et al. Early recognition of hepatocellular carcinoma based on altered profiles of alpha-fetoprotein. N Engl J Med 1993;328:1802–6. 37 Liebman HA, Furie BC, Tong MJ, et al. Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma. N Engl J Med 1984;310:1427–31. 38 Makuuchi M, Kokudo N, Arii S, et al. Development of evidencebased clinical guidelines for the diagnosis and treatment of hepatocellular carcinoma in Japan. Hepatol Res 2008;38:37–51. 39 Yuan M-F, Cheng C-C, Lauder IJ, Lam S-K, Ooi G-CC, Lai C-L. Early detection of hepatocellular carcinoma increases the chance of treatment: Hong Kong experience. Hepatology 2000;31:330– 5. 40 Kokudo N, Bandai Y, Imanishi H, et al. Management of new hepatic nodules detected by intraoperative ultrasonography during hepatic resection for hepatocellular carcinoma. Sugery 1996;119:634–40.

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41 Zhang K, Kokudo N, Hasegawa K, et al. Detection of new tumors by intraoperative ultrasonography during repeated hepatic resections for hepatocellular carcinoma. Arch Surg 2007;142: 1170–5. 42 Sudan D, Sudan R, Schafer D, et al. Without victory there is no survival: transarterial lipiodol chemoembolization and hepatocellular carcinoma. Hepatology 1998;28:270–1. 43 Arii S, Yamaoka Y, Futagawa S, et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. Hepatology 2000;32:1224–9. 44 Belghiti J. Systematic hepatectomy for liver cancer. J Hepatobiliary Pancreat Surg 2005;12:362–4. 45 Llovet JM, Bustamante J, Castells A, et al. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology 1999;29:62–7. 46 Minagawa M, Makuuchi M, Takayama T, et al. Selection criteria for hepatectomy in patients with hepatocellular carcinoma and portal vein tumor thrombus. Ann Surg 2001;233:379–84. 47 Chen M-F, Hwang T-L, Jeng L-B, et al. Postoperative recurrence of hepatocellular carcinoma. Two hundred five consecutive patients who underwent hepatic resection in 15 years. Arch Surg 1994;129:738–42. 48 Fan S-T, Lo CM, Liu CL, et al. Hepatectomy for hepatocellular carcinoma: toward zero hospital deaths. Ann Surg 1999;229: 322–30. 49 Shiina S, Teratani T, Obi S, et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology 2005;129: 122–30. 50 Chen MS, Li JQ, Zheng Y, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg 2006;243: 321–8. 51 Yamada K, Sato M, Kawabata M, et al. Hepatic artery embolization in 120 patients with unresectable hepatoma. Radiology 1983;148:397–401. 52 Takayasu K, Arii S, Ikai I, et al. Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 patients. Gastroenterology 2006;131: 461–9. 53 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;334:693–9. 54 Todo S, Furukawa H; Japanese Study Group on Organ Transplantation. Living donor liver transplantation for adult patients with hepatocellular carcinoma. Experience in Japan. Ann Surg 2004;240:451–61 55 Lo CM, Fan ST, Liu CL, Chan SC, Ng IO, Wong J. Living donor versus deceased donor liver transplantation for early irresectable hepatocellular carcinoma. Br J Surg 2007;94:78–86. 56 Ito T, Takada Y, Ueda M, et al. Expansion of selection criteria for patients with hepatocellular carcinoma in living donor liver transplantation. Liver Transpl 2007;13:1637–44. 57 Hwang S, Lee SG, Joh JW, Suh KS, Kim DG. Liver transplantation for adult patients with hepatocellular carcinoma in Korea: comparison between cadaveric donor and living donor liver transplantations. Liver Transpl 2005;11:1265–72.

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58 Soejima Y, Taketomi A, Yoshizumi T, et al. Extended indication for living donor liver transplantation in patients with hepatocellular carcinoma. Transplantation 2007;83:893–9. 59 Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394–403. 60 Sugawara Y, Tamura S, Makuuchi M. Living donor liver transplantation for hepatocellular carcinoma: Tokyo University series. Dig Dis Sci 2007;25:310–12. 61 Kokudo N, Sasaki Y, Nakayama T, et al. Dissemination of evidence-based clinical practice guidelines for hepatocellular carcinoma among Japanese hepatologists, liver surgeons and primary care physicians. Gut 2007;56:1020–1. 62 Liver Cancer Study Group of Japan. Classification of Primary Liver Cancer. Tokyo: Kanehara & Co Ltd, 1997:21. 63 Parkin DM, Ohshima H, Srivatanakul P, et al. Cholangiocarcinoma: epidemiology, mechanisms of carcinogenesis and prevention. Cancer Epidemiol Biomarkers Prev 1993;2:537–44. 64 Sugihara S, Kojiro M. Pathology of cholangiocarcinoma. In: Okuda K, Ishak KG, eds. Neoplasms of the Liver. Tokyo: Springer Verlag, 1987. 65 Chen M-F, Jan Y-Y, Jeng L-B, et al. Intrahepatic cholangiocarcinoma in Taiwan. J Hepatobiliary Pancreat Surg 1999;6:136–41. 66 Inoue K, Makuuchi M, Takayama T, et al. Long-term survival and prognostic factors in the surgical treatment of mass-forming type cholangiocarcinoma. Surgery 2000;127:498–505. 67 Chu K-M, Fan S-T. Intrahepatic cholangiocarcinoma in Hong Kong. J Hepatobiliary Pancreat Surg 1999;6:149–53.


68 Kim H-J, Yun S-S, Jung K-H, et al. Intrahepatic cholangiocarcinoma in Korea. J Hepatobiliary Pancreat Surg 1999;6:142–8. 69 Uttaravichien T, Bhudhisawasdi V, Pairojkul C, et al. Intrahepatic cholangiocarcinoma in Thailand. J Hepatobiliary Pancreat Surg 1999;6:128–35. 70 Lee CL, Ko YC. Survival and distribution pattern of childhood liver cancer in Taiwan. Eur J Cancer 1998;34:2064–7. 71 Foster JH, Berman MM. Solid Liver Tumors. Major Problems in Clinical Surgery. Philadelphia: WB Saunders, 1977:1−342. 72 Kokudo N. Seki M, Ohta H, et al. Effects of systemic and regional chemotherapy after hepatic resection for colorectal metastases. Ann Surg Oncol 1988;5:706–12. 73 Minagawa M, Makuuchi M, Torzilli G, et al. Extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer. Ann Surg 2000;231:487–99. 74 The Liver Cancer Study Group of Japan. The 14th Report of the Nationwide Survey of Primary Liver Cancer in Japan (1996∼1997) [in Japanese]. Kyoto: The Liver Cancer Study Group of Japan, 2000.


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41

Liver Tumors in South America Lucas McCormack1 and Eduardo de Santibañes2 1 2

General Surgery Service, Hospital Aleman, Buenos Aires, Argentina Hepatobiliopancreatic and Liver Transplant Unit, Hospital Italiano, Buenos Aires, Argentina

Medicine in South America was nurtured by the influences of the European and North American schools. The endemic pathologies conditioned health professionals to develop techniques useful for local application, using the resources at their disposal. The same occurred with hepatic surgery, where the influence of immigration and ethnic mix stimulated the creativity of surgeons who, due to lack of means or from necessity, became pioneers in the development of certain techniques of our specialty. Thus, we find reports in the medical literature at the start of the last century that describe previously unpublished procedures to approach the liver [1]. The high prevalence of hydatid disease and of gallbladder cancer in many countries of South America conditioned the early development of hepatic and biliary surgery, training surgeons in liver mobilization and parenchymal fracture to treat patients with these disorders [2–4]. The high incidence of biliary lithiasis and its complications were a constant stimulus, and Pablo Mirizzi in 1931 described his experience with intraoperative cholangiography [5, 6]. In the 1970s and 80s, South American surgeons trained at centers of liver transplant in North America and Europe, returning to their native countries to set up more than 70 specialist units. However, the lack of adequate finance, education and organization has limited the development of liver surgery and transplantation in Latin America (Table 41.1). For an estimated population of 470 million, approximately 1100 liver transplantations were performed in 2002, which represents 2.3 liver transplantations per million people per year. Compared with Europe (15 per million) or the United States (25 per million), in South America the donation rate is much lower (5–12 per million). A recent study showed that the highest transplantation rates per million were in Argentina (5.4), Brazil (4.5) and Chile (4.1). In 2001, liver transplantations were not performed in two of the 10 South American countries and in five of six Central American countries. In most Latin American coun-


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tries performing this procedure, living donor liver transplantation has been used for pediatric patients to compensate for the organ shortage for them. However, by 2004, only three countries had used this procedure for adult liver transplantation [7]. In this chapter we will describe the development of hepatic surgery and liver transplant in the various regions of South America.

Development of hepatic surgery and liver transplantation The River Plate school (Argentina and Uruguay) Although in 1917 Lorenzo Mérola described the technique to approach the upper aspect of the liver by means of thoraco-frenolaparotomy in studies carried out in cadavers [1], it was not until August 1931 when the Uruguayan surgeon G. Caprio practiced an anatomic left lobectomy in a case of metastasis for the first time. This pioneering experience was published that same year [8] and H. Virad and J. Sgro, in their handbook Les Hepatectomies Majeures [9], as well as H. Bismuth in the Encyclopédie Medico-Chirurgicale [10] recognized this achievement, which was carried out 8 years before the same procedure was reported by Mayer May and Tung in 1939 [11]. In turn, it should be recalled that the first right hepatectomy was performed by Lortat-Jacob in 1951, i.e. 20 years later [12]. Concurrently in Argentina, the surgeon P. Mirizzi carried out the first intraoperative cholangiography in 1931, introducing a rationale approach to the treatment of biliary tree disease and leading to the popularity of a technique that today bears his name and is employed by all liver surgeons [5, 6]. In 1961, the Uruguayan surgeon R. Praderi described “transhepatic tumoral intubation,” and in the following years diverse modifications improved the technique, which was useful not only for the treatment of neoplasms but also for benign stenosis [2–4, 13].

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Liver Tumors in South America

Table 41.1 Liver transplantation (LT) in Latin America.

Argentina Brazil Chile Peru Uruguay Mexico Colombia Cuba Costa Rica Venezuela Bolivia Ecuador

Year

Donation rate (per million population)

Population (millions)

Number of LT centers

Number of LTs

LT rate (per million population)

Cost of cadaveric LT (US$)

2005 2005 2005 2002 2002 2005 2004 2002 2002 2002 2002 2002

10.5 6.3 8.6 2 17.1 4.0 4.3 NA NA NA NA NA

38.7 186.4 16.3 27.9 4.0 107 45.6 10 4 23 8 12

14 62 7 1 1 20 3 2 1 1 1 1

1969 5258 471 20 13 546 553 59 22 19 6 1

5.4 4.5 4.1 0.2 1.0 0.7 2.2 1.6 2.5 0.1 0.3 0

27 000 21 505 28 600 37 000 NA NA NA NA NA NA NA NA

NA, not available.

Encouraged by Claude Couinaud’s work, who in 1957 published his studies on hepatic anatomy in the Presse Medicale [14], the Argentine J. M. Mainetti carried out anatomic resections, mainly to treat gallbladder neoplasias. His disciple, J. R. Defelitto, jointly with J. Viaggio, wrote in later years about their experiences as the leaders in the development of Argentine hepatic surgery at that time [15]. In January 1988, E. de Santibañes at the Hospital Italiano of Buenos Aires carried out the first liver transplant in an adult patient in Argentina [16]. His pioneering team was also the first in Argentina to perform hepatic transplant in children using the range of reduction techniques, including the “Split” technique (1992), living related donor transplantation in children (1992) and adults (1998), and using an artificial biologic support with porcine liver in a case of fulminant hepatitis (1998) [17–19]. This team contributed to surgical education in the hepato-pancreato-biliary field, developing the first Fellowship program in the region and collaborating in training members of other transplant programs, not only in Argentina but also in neighboring countries, such as Uruguay, Chile, Brazil, Peru, Paraguay, and Bolivia. Up to November 2007, in Argentina a total of 1701 liver transplants had been carried out in 18 centers, nine of them located in Buenos Aires and the others in the hinterland. Although in 1999 a team led by E. Torterolo in Uruguay performed the first liver transplant at the Armed Forces Hospital, this program is currently closed and today there is no active liver transplant program in this country.

Brazil The first hepatic resection performed in Brazil is attributed to Edmundo Vasconcelos in São Paulo at the beginning of the 1950s (unpublished data). “Extended” anatomic right lobectomy was originally reported in 1956 in Revista do Colégio Brasileiro de Cirurgiões by Oliveira Jr in a patient with a gallbladder tumor. A report of “extended” right hepatic lobectomy involving segments I and IV was first published in the same journal in 1959 by Ari Fauzino, from the National Cancer Institute of Rio de Janeiro (INCA), who had been performing resections since the early 1950s. It should be highlighted that, in the mid-1950s, Célio Diniz, a disciple of Couinaud’s, from Belo Horizonte, studied hepatic segmentation and vascularization in his doctoral thesis (Mies S, personal communication). As pioneers of hepatic resection in Brazil, Raia et al described the use of temporary clamping of the inferior vena cava below and above the liver [20]. The first successful liver transplant in Brazil was performed at the Liver Unit of the São Paulo Medical School, São Paulo University on September 1, 1985 in a patient with a hepatoblastoma [21]. This unit also performed the first liver transplant from a living related donor in December 1988. The child recipient died on the sixth postoperative day during a hemodialysis session due to an incompatible blood transfusion. The second transplant of this type was performed by the same team on July 21, 1989, and its result was published as a brief communication in the Lancet [22]. The patient survived for almost 5 months after transplantation and died due to cytomegalovirus infection. More than 5000 liver transplantations have now been performed in

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Brazil, and Brazil has performed the seventh highest number of liver transplants in the Western world and the most in Latin America (see Table 41.1). Almost 1000 procedures were performed in 2004, 19% of them involving living donors [23].

Chile There is a high prevalence of hydatid disease and of gallbladder cancer in Chile and these are the leading indications of liver surgery in this country. It is estimated that 400 hepatic resections per year (26 cases per million) are carried out for hydatid disease and 1600 new interventions per year (110 cases per million population) for gallbladder cancer, which corresponds to a hepatic resection rate of 3–5% for patients with gallbladder cancers. In Chile, there are 25 centers where these procedures are practiced (J. Hepp, personal communication). The first liver transplant was performed in 1985 at the Military Hospital in Santiago de Chile. E. Buckel at the Las Condes Clinic in the same city carried out the first successful pediatric transplant using a living related donor in 1999. Currently, there are four active centers for hepatic transplant in Chile [24].

Peru The first left hepatic resection was carried out in Peru in 1955 by A. Sabogal at the Institute of Neoplasic Disorders. The following year, V. Baracco Gandolfo performed the first right hepatectomy at the Archbishop Loayza Hospital. Currently, surgery of greater complexity is performed at the following centers: the Edgardo Rebagliati Martins and Guillermo Beacon Irigoyen Social Security Hospitals, as well as the Institute of Neoplasic Disorders. As regards liver transplant, the first attempt was carried out in 1968 at experimental level by V. Baracco’s team [25], but it was only at the end of the 1990s that J. Chaman Ortiz set up the first transplant team in humans at the Guillermo Beacon Irigoyen Social Security Hospital in Lima, and carried out its first transplant in 2001 (E. Barboza, personal communication).

Colombia The first 11 hepatic transplants in Colombia were performed at the San Vicente de Paul Hospital in 1980 by A. Velásquez. In 1988 the Santa Fe Foundation of Bogotá restarted the program with a team trained by Paul McMaster. Fourteen transplants were performed over a 6-year period [25]. In 1996, L. A. Caicedo, at the Valle el Lili Foundation (Cali), began a program of liver transplants, and since then an average of 40 interventions per year have been carried out. Recently, A. Velásquez restarted his transplant program in Medellín, and this is the second active center at the present time (L. A. Caicedo, personal communication).

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Common hepatic tumors Worldwide surveys of the incidence, prevalence and mortality of cancer estimated that in the year 2000 mortality due to cancer in developing countries would be twice as high as in developed countries [26]. This scale of difference is also observed between South American countries, with Chile displaying the highest and Venezuela the lowest prevalence [26]. Also, the general mortality rate for cancer has been rising in Chile during the last decade [27]. The presentation of hepatic tumors in South America correlates with the demographic, social, economic, cultural, and geographic features of this region, where the mixing of races with the indigenous population, as well as widespread poverty, low educational level and peculiar feeding habits prevail. As already mentioned, certain pathologies, such as gallbladder cancer and hydatid hepatic cysts, have a high incidence in Chile. Within most South American countries, local changes in the incidence and prevalence of diverse cancer types are seen. For example, in Argentina, while the overall rate of mortality due to liver cancer is 5 per 100 000, it is 9 per 100 000 in the Southern province of Santa Cruz and 2.8 per 100 000 in the Northern province of Misiones [28]. Although the general features of hepatic tumors diagnosed in South America are similar to those reported in the international literature, there are certain marked differences and these are described below.

Gallbladder cancer The incidence of gallbladder cancer is very variable throughout South America: 5% in Colombia, 5.4% in Argentina, 5.2% in Bolivia, 3% in Brazil, 2.3% in Venezuela, 3% in Uruguay, and 1.4% in Ecuador [29–36] (Figure 41.1). In Chile, gallbladder cancer represents the leading cause of death due to cancer in women [37]. Its incidence varies according to the geographic area. Its prevalence rate of 11.5 cases per 100 000 in 1995 is among the highest in the world [38]. Presentation patterns are similar to those reported in the world literature: there is a female preponderance (3.6 : 1) and the diagnosis increases with age, being highest in the seventh decade of life [31, 39, 40]. An association with cholelithiasis is very frequent (85–95%) and cases are generally diagnosed intraoperatively at an advanced stage [41]. The predominance of gallbladder cancer in the female sex suggests the influence of estrogens in its development [42]. Moreover, multiple and early pregnancies are associated with the development of gallbladder cancer, probably due to the lithogenic effect secondary to hormonal changes [43].

Lithiasis Cholelithiasis is currently the major risk factor for gallbladder cancer. The frequency of gallbladder cancer increases in

CHAPTER 41

Venezuela (2.3%) Colombia (5%) Ecuador (1.4%) Brazil (3%) Bolivia (5.2%)


nitroreductase, and glucoronidase on biliary acids. Other bacteria present in the gallbladder bile, by the same mechanism, could also be related to tumor development [49]. However, in a study of 608 gallbladders obtained by cholecystectomies from patients in high-risk populations for gallbladder cancer, which were subjected to microbiologic bile analysis and pathologic evaluation of the surgical specimen, Salmonella spp in the bile was an infrequent finding in patients with or without gallbladder cancer, thus questioning the leading pathogenic role of this bacterium in the development of gallbladder cancer [49].

Early diagnosis Uruguay (3%)

direct proportion to the patient’s age and the duration of lithiasis. In turn, in more than 80% of cases, lesions are found in the mucosa adjacent to the cancerous tumor, as well as in hyperplasic foci, atypical hyperplasia, dysplasia, and carcinoma in situ [40, 43, 44]. There is a raised frequency of gallbladder cancer in certain population groups of South America, including females, lithiasis carriers, and those aged over 50 years. It is in these groups of patients where the performance of “prophylactic cholecystectomy” has been advanced in order to reduce the incidence of gallbladder cancer [40, 45–47]. During the last decade in Chile, there has been an increase in the rate of mortality from 7.84 to 9.6 per 100 000. While the most significant risk factor was cholelithiasis, during this period there was no increase in the prevalence of lithiasic disease; on the contrary, cholecystectomy indexes dropped markedly. It is estimated that by increasing the number of cholecystectomies to 12 500 per year in a specific area of high prevalence in Chile, mortality due to gallbladder cancer could be reduced in 2 years to roughly 1 per 100 000 [48].

Even today, most diagnoses are made intraoperatively or by the pathologist. Ultrasonography and computed tomography are useful for diagnosing gallbladder cancer in advanced stages. Their low sensitivity in detecting early stages is attributable to the presence of cholelithiasis and chronic inflammatory alterations, findings that considerably hinder careful observation of the gallbladder wall [50]. However, a Japanese study detected early gallbladder tumors in 30% of cases by means of ultrasonography. This procedure in Japan would be facilitated by the high percentage of these lesions associated with alithiasic gallbladder [50]. The use of tumor markers is a poor screening method to detect this pathology, since usually positive results are only observed in advanced disease. It has been reported in highrisk populations that the highest predictive capacity for gallbladder cancer is achieved with CA 19-9 levels above 37 U/ mL and carcinoembryonic antigen (CEA) values greater than 4 ng/mL [51]. That the diagnosis of gallbladder cancer is challenging is demonstrated by the 54% incidence of flat and occult lesions not recognized even by the pathologist during examination of the cholecystectomy specimen [51]. Given the high incidence of this neoplasm in South America, it is recommended that all extirpated gallbladders should be opened in the operation room to be examined in the first instance by the surgical team. In regions displaying an incidence of gallbladder cancer greater than 5%, it is useful to subject smears of the gallbladder mucosa on a microscope slide to cytologic analysis. This highly sensitive and specific study is valuable for intraoperative diagnosis of early gallbladder cancer, thus avoiding a second surgical intervention [52].

Other etiologic factors

Staging and treatment

Other factors associated with gallbladder cancer in South American populations include a family history of neoplasia, abnormalities of the biliopancreatic junction, porcelain gallbladder, gallstone size, choledochal cyst, increased intake of fats and particularly green and red peppers, constipation, and previous infection with Salmonella spp [37]. The association between this bacterium and gallbladder cancer could be explained by the action of the enzymes azoreductase,

As in the rest of the world, only a few gallbladder cancer patients are candidates for surgical treatment, given the usually advanced stage at the time of diagnosis [30]. Treatment algorithms in South America are very similar to those reported in the worldwide medical literature [39, 53]. Consequently, T1 tumors require no more than a simple cholecystectomy as definitive therapy. For T2/T3 tumors, which have an incidence of locoregional node involvement of

Argentina (5.4%) Chile (10%)

Figure 41.1 Gallbladder cancer rates in South America.

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around 46%, simple cholecystectomy without node resection is inadequate. In T4 tumors, prognosis is poor, regardless of the treatment carried out, so the morbidity due to resection would not be justified [53]. However, good results have been achieved when treating T4 N0 tumor cases by radical resections, achieving 27% 5-year survival [54]. Radical resection in T2 and T3 tumors should include hepatic segments IVb and V, complete node resection up to the level of the celiac axis, and resection of the extrahepatic biliary duct, especially in tumors located in the vesicular infundibulum. In locally advanced tumors, an hepatic lobectomy or trisegmentectomy could be required, particularly in T4 N0 tumors. Surgical treatment for gallbladder cancer should include the resection of the parietal surgical wound at initial surgery, when recurrence would not be a contraindication provided the lesion is surgically resectable. The finding of hepatic and/ or peritoneal metastatic spread at the time of exploration is a contraindication for surgical resection. De Aretxabala considers the degree of gallbladder wall invasion to be the single factor to bear in mind when determining a patient’s likelihood of cure [50]. He believes that the invasion of structures or of lymphatic nodes is almost invariably associated with a poor prognosis, and divides patients into five categories when deciding which treatment to carry out. Before radical resection he recommends intraoperative anatomopathologic assessment of para-aortic and retropancreatic nodes, as their involvement rules out any possibility of cure. Likewise, direct infiltration of hepatic pedicle structures, such as the biliary tree or the portal vein; indicates that the lesion is unresectable. According to this author, on occasion radical surgery is indicated for resection of the biliary tree to ensure resection of the infiltrating foci. However, its role is controversial due to the presence of extensive lymphatic and perineural networks surrounding the remaining components of the hepatic pedicle [50].

Complementary therapies Radiotherapy and chemotherapy have been widely used in the management of gallbladder cancer. Regrettably, most reported studies include only a small number of poorly staged patients, making it very difficult to draw definitive conclusions [55]. As adjuvant therapy to radical surgery, radiotherapy has been studied in cases of unresectable lesions, sometimes together with 5-fluorouracyl as prior sensitizer. Chemotherapy has been preferably given for palliation in such patients, since its use as adjuvant to radical surgery has proved even more debatable. Randomized prospective studies are still lacking to clarify the role of complementary treatments in gallbladder cancer.

Laparoscopic surgery As in the rest of the world, the widespread application of laparoscopic surgery in Latin America led to controversy and

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the appearance of diverse patterns of neoplasm dissemination. This approach is contraindicated in cases of suspected gallbladder cancer where there is curative intention, since tumor manipulation by means of specific surgical instruments may disseminate the neoplasm both locally and systemically. Studies of laparoscopic surgery in other abdominal tumors have shown there is a risk of implanting tumor cells in the suspension within the CO2-insufflated cavity at the site of surgical incision. The high concentration of this gas will also favor the growth of tumor cells [56].

Histopathologic prognostic factors Adenocarcinoma is the most common histologic type in South America (90–97.9%), particularly its differentiated forms (tubular, papillary, and mucinous) [30, 40, 46]. Prospective anatomopathologic analysis of 474 surgical specimens of gallbladder cancer, diagnosed over a 7-year period in region IX of Chile, demonstrated that unsuspected tumors (34%) displayed a lower degree of gallbladder wall infiltration and a greater index of differentiation [57]. The degree of gallbladder wall invasion indicates not only the type of resective treatment, but is also the major prognostic factor [58]. Greater gallbladder wall infiltration correlates with lesser cell differentiation, increased vascular invasion, and enhanced perineural and node infiltration, all proven factors of an unfavorable oncologic prognosis [57]. Survival rates in those with gallbladder cancer in South America are similar to those reported for the rest of the world [35, 36], with global 5-year figures around 7.5% and a better prognosis in patients operated on at early stages [46].

Hepatocellular carcinoma Epidemiology Worldwide, hepatocellular carcinoma (HCC) is the most frequent solid organ tumor, responsible for over a million deaths per year. An increased incidence has been observed during the last decade in European and American countries, due probably to higher rates of hepatitis B (HBV) and C virus (HCV) infection. The experience in Western countries differs from that reported in the Far East in several ways: the incidence of cirrhosis and HCC are much lower in the West and a significant number of HCC patients do not present with cirrhosis [59]. In order to discern the features of HCC in the Brazilian population, a national survey assembled information from 19 medical centers in eight states of Brazil. The number of HCC patients selected was 287 and HCC was more common in males (male-to-female ratio, 3.4 : 1) The incidence of HCC was very variable across the diverse geographic regions studied [60]. In 71.2% of cases, HCC was associated with hepatic cirrhosis. Interestingly, 42% of the patients studied had negative serology for HBV and HCV. A history of chronic

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alcoholism was found in 37%, indicating a possible role for other etiologic factors in the development of HCC. Given the favorable climatic conditions for fungal food contamination in most Brazilian regions, aflatoxin could be an etiologic factor [60]. A study carried out in Peru investigated the prevalence of hepatitis virus in 105 patients with a biopsy compatible with chronic liver disease, but did not find either HBV or HCV infection to be a major cause of chronic liver disease, also suggesting the possibility of other etiologic factors [61]. A Chilean study investigated the prevalence of HCV virus in three different populations: 21 000 blood donors, 133 patients with chronic nonalcoholic liver disease, and 50 cases of HCC. The prevalence of antibodies against HCV in these populations was 0.3%, 53%, and 48%, respectively. When HCC was associated with liver disease, the percentage climbed to 100%. In turn, the 1b genotype was found in 100% of HCC cases and in 86% of patients with chronic nonalcoholic liver disease. At odds with the above reports from Brazil and Peru, the authors concluded that infection with HCV is a major etiologic factor for the development of chronic liver disease in Chile where the 1b viral genotype prevails [62].

Diagnosis and treatment The algorithms for diagnosis and treatment do not differ from those used in the rest of the world [63]. At the time of diagnosis, tumors are generally at an advanced stages, which frequently means that only nonresective treatments or conservative clinical support can be implemented [64]. Recently liver transplantation has become a new therapeutic option for the treatment of HCC cases. This approach, however, is limited by the lack of cadaveric donors. In Argentina, the global procurement rate of solid cadaveric organs per million inhabitants in 2005 was 10.5 [65]. This low availability of organs is reflected in the estimated waiting list time of 17 months [65]. This has encouraged the development of new strategies, such as living donor transplant, in adult patients with HCC within and outside the accepted Milan criteria. In addition, in 2005 Argentina became the second country after the United States to implement the model for end-stage liver disease (MELD) scoring system for diseased donor liver allocation. Similar to the United States, in Argentina priority points (i.e. 22 points) are given to cirrhotic patients with T2 stage HCC to reduce mortality while on the waiting list. Preliminary results have shown a significant reduction in mortality rates in these patients compared with patients without HCC. This policy for the allocation of donor livers has so far not been adopted in other Latin America countries.

Liver metastasis Metastasis is the greatest cause of death due to cancer. Initially, the presence of hepatic metastasis was synonymous


with death. This encouraged novel strategies to modify the natural history of the disease. Currently, multimodal treatment of patients with liver metastasis can offer a cure in a considerable percentage of cases. As in the rest of the world, hepatic metastases originating in the colon and rectum are the most frequent in South America. This is due to the high incidence of colorectal carcinoma, with a third of such patients developing liver metastasis during the course of their illness. The prevalence of colorectal carcinoma in Argentina has been reported to be 13.7 per 100 000 population, and it is the second most common cancer in males after lung cancer [28]. The features of the primary tumor and of its metastases are similar to those reported in the European and American medical literature, as is the influence of adverse oncologic factors on patient survival, suggesting a consistent tumor biology in the West [66]. Prevailing lines of treatment for hepatic metastases at surgery centers in South America are based on the experience reported by world reference centers, with similar results [19, 67]. One of the current lines of investigation at the Italian Hospital of Buenos Aires, Argentina, is simultaneous treatment of the primary colorectal tumor and its secondary liver involvement [68]. We showed in patients undergoing simultaneous resection of the liver and colorectal tumor, similar surgical and oncologic results when compared with those obtained by resection in two stages. Hepatic resections of noncolorectal liver metastases are low throughout the world, including South America, which hinders the reliable analysis of results due to the limited number of cases. A recent multicenter study at five HPB Centers in Argentina collected 106 patients who underwent liver resection for noncolorectal non-neuroendocrine metastases in the period 1989 to 2006 [69]. Primary tumor sites included the urogenital tract (37.7%), sarcomas (21.7%), breast (17.9%), gastrointestinal tract (6.6%), melanoma (5.7%), and others (10.4%). Although 51 major hepatectomies and 55 minor resections were performed, R0 could be achieved in only 89.6%. Perioperative mortality was 1.8%. Overall, 1-, 3-, and 5-year survival rates were 67%, 34%, and 19%, respectively. Survival was significantly longer for metastases of urogenital (p = 0.0001) and breast (p = 0.003) origin. Curative resections (p = 0.04) and metachronous disease (p = 0.0001) were predictors of better survival.

Self-assessment questions 1 Which one of the following statements regarding liver transplantation in South America is false? A Up to November 2007, in Argentina a total of 1701 liver transplants had been carried out in 18 centers B The largest liver transplant programs are located in Uruguay and Bolivia

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C When compared with Europe (15 donors per million) or the United states (25 per million), in South America the donation rate is much lower (5–12 per million) D The first liver transplant from a living related donor was performed by the Liver Unit of the São Paulo Medical School, São Paulo University, in December 1988 E In Brazil, almost 1000 procedures were performed in 2004, 19% of which involved living donors 2 In which country is gallbladder cancer the most common cause of cancer death in women? A Argentina B Chile C Bolivia D Colombia E Peru

E Only a very limited number of cases of noncolorectal non-neuroendocrine metastases have undergone liver resection in South America

References 1 2 3 4 5 6

3 Which one of the following statements regarding gallbladder cancer is false? A It is more frequent in females B The diagnosis increases with age, and has highest frequency in the seventh decade of life C An association with cholelithiasis is very common D Prognosis is very good even in the presence of lymph node metastasis E Cases are generally diagnosed in advanced stages and intraoperatively

7

4 Which one of the following is not an etiologic factor associated with gallbladder cancer in South America? A Abnormalities of the biliopancreatic junction B Porcelain gallbladder C Family history of neoplasia D Gallstone size E Increased alcohol intake

13

5 Which one of the following statements with regard to malignant liver tumors in South America is false? A Similar to the United States, in Argentina priority MELD score points are given for cirrhotic patients with T2 stage hepatocellular carcinoma waiting for liver transplantation B As in the rest of the world, hepatic metastases originating in the colon and rectum are the most frequent in South America C PET/CT scan is not widely available for staging patients with malignant liver tumors in South America D Simultaneous resection of the liver metastasis and the primary colorectal tumor is not performed in South America for cultural and socioeconomic reasons

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8 9 10 11 12

14 15 16

17

18

19

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21 22

Mérola L. Manera de abordar la cara superior del hígado. Incisión toraco-abdominal. Ann Fac Med 1917;2:105. Praderi R. Twelve years experience with transhepatic intubation. Ann Surg 1974;179:937. Praderi L, Gomez Fossati C. Ictericia por compresión hidatídica de las vías biliares. Cir Urg 1973;43:506–9. Praderi R, Delgado B, Mazza M, et al. Drainage trans-hépatiques doubles. Lyon Chir 1974;70:294. Mirizzi P. Fisiopatología del hepato-colédoco. In: Colangiografía Operatoria. Buenos Aires: El Ateneo, 1939. Mirizzi P. La colangiografía operatoria. Ejemplos que fundamentan sus ventajas y justifican su practica sistemática. Bol Acad Arg Cir 1942;26:908–17. Hepp J, Innocenti FA. Liver transplantation in Latin America: current status. Transplant Proc 2004;36:1667–8. Caprio G. Un caso de extirpación del lóbulo izquierdo del hígado. Bol Soc Cir Montevideo 1931;2:159. Virad H, Sgro J. Les Hepatectomies Majeures. Paris: L’expansion, 1970. Bismuth H. Les hépatectomies. In: Encyclopedia Med-Chirugie. Paris: Techniques Chirurgicales, 2007. Meyer May J, Tung TT. Resection anatomique du lobe gauche pour cancer. Mem Acad Chir 1939;65:1208. Lortat-Jacob J, Robert H, Henry C. Un cas d′hepatectomie doitre reglée. Mem Acad Chir 1932;78:244. Praderi R, Estefan AET. Transhepatic intubation in the benign and malignant lesions of biliary duct. Curr Prob Surg 1985;22:1. Couinaud C. Le Foie. Etude Anatomique et Chirurgicale. Paris: La Presse Medicale, Masson, 1957. de Felitto J, Biaggio. Hepatectomías. Relato oficial. LIII Congreso Argentino de Cirugía. Rev Arg Cir, 1983. de Santibañes E, Sívori J, Ciardullo M, et al. Trasplante hepático: experiencia clínica en el Hospital Italiano de Buenos Aires. Rev Arg Cir 1990;62:60. de Santibañes E, Ciardullo M, Mattera J, Pekolj J, McCormack L. Doce anos de experiencia en transplante hepático con donante vivo relacionado en el Hospital Italiano de Buenos Aires: Evolución y resultados. Rev Argent Cirug 2006;90:132–41. Argibay P, Hyon S, Martinez G. Extracorporeal auxiliary xenoperfusion: animal model of support in fulminant liver failure. Transplant Proc 1996;28:749–50. de Santibañes E. Tumores del hígado y trasplante hepático. In: Amarillo H, Brahim A, Leon S, eds. Cirugía II. Aparato DigestivoHernias-Peritoneo. Tucumán: El Graduado, 1998:326. Raia S, Guijon P, Nogueira G, et al. Major hepatectomy with temporary clamping of the inferior vena cava below and above the liver. Rev Hosp Clin Fac Med São Paulo 1970;25:165–74. Mies S, Massarollo P, Baia C, et al. Liver transplantation in Brazil. Transplant Proc 1998;30:2880–2. Raia S, Nery J, Mies S. Liver transplantation from live donors. Lancet 1989;2:497.

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23 Mies S, Baia CE, Almeida MD, et al. Twenty years of liver transplantation in Brazil. Transplant Proc 2006;38:1909–10. 24 Buckel E, Uribe M, Brahm J, et al. Outcomes of orthotopic liver transplantation in Chile. Transplant Proc 2003;35:2509–10. 25 Delpín S, García D. The 11th report of the Latin American transplant registry: 62,000 transplants. Transplant Proc 2001; 33:1986–8. 26 Ferlay J, Bray F, Pisani P, Parkin D. Globalcan 2000: Cancer Incidence, Mortality and Prevalence Worldwide, version 1.0. IARC Cancer base no 5. Lyon: IARC Press, 2001. 27 Organization PAH. La Salud de las Américas, edición de 1998. Washington, DC: OPS, 1998-2v. (OPS. Publicación científica; 569):174. 28 Matos E, Vilensky M, García C. Atlas de mortalidad por cáncer. Argentina 1989–1992. Comité Argentino de Coordinación. Programa Latinoamérica Contra el Cáncer. Buenos Aires: Edigraf SA, 1997:16. 29 Smith S, Bermudez G. Premalignant lesions of the gallbladder. Acta Med Colomb 1982;7:115–20. 30 Gutierrez V, Gallardo H, Mateu M. Lesions associated with gallbladder carcinoma. Rev Argent Cir 1985;48:274–6. 31 Ford M, Contreras M, Buguña S. Cancer of the gallbladder, San Juan de Dios Hospital (1956–1985). Bol Hosp San Juan de Dios 1988;35:57–62. 32 Monteiro M, Freitas L, Leite A. Carcinoma of the gallbladder. Rev Col Bras Cir 1993;20:109–12. 33 Travieso C, Correa J. Gallbladder neoplasms. Rev Venez Cir 1994;47:168–72. 34 Vivas C, Ferreira C, Czarnevicz D, et al. Gallbladder cancer. Cir Urug 1995;65:121–4. 35 Acosta M, Pazmino P, Gonzalez H. Gallbladder cancer. Enrique Garces Hospital, Quito. Rev Cienc 1995;5:35–40. 36 Sívori J. Cáncer de vesícula. In: Ferraina P, Oría A, eds. Cirugía de Michans, 5th edn. Buenos Aires: El Ateneo, 2000:632–5. 37 De Aretxabala X, Riedemann P, Burgos L. Gallbladder cancer: a case control study. Rev Med Chile 1995;123:581–5. 38 Serra I, Calvo A, Maturana M, Sharp A. Biliary-tract cancer in Chile. Int J Cancer 1990;46:965–71. 39 Chijiiwa K, Noshiro H, Nakano E. Role of surgery for gallbladder carcinoma with special reference to lymph node metastasis and stage using western and Japanese classification systems. World J Surg 2000;24:1271–6. 40 Rodriguez J, Monti J, Celorio G. Clinicopathological aspects of cancer of the gallbladder. Rev Argent Cir 1988;54:42–8. 41 Roa I, Araya J, Villaseca M. Gallbladder cancer in a high risk area: morphological features and spread patterns. Hepatogastroenterology 1999;46:1540–6. 42 Roa I, Araya J, Villaseca M. Cancer of gallbladder: immunohistochemical expression of estrogen receptor related protein (p29) and estrogen induced protein (pS2). Rev Med Chile 1995;123: 1333–40. 43 Roa I, Araya J, Villaseca M. Cancer of gallbladder: study of cases and controls in Chile. Rev Chil Cir 1996;48:139–47. 44 Martinez G, de la Rosa J. Neoplasm and dysplasia of the gallbladder and their relation with lithiasis. A case-control clinicalpathological study. Rev Gastroenterol Mex 1998;63:82–8. 45 Astete G, Lynch O, Madariaga J. Upper injuries of the gallbladder. Rev Chil Cir 1999;51:159–63.


46 Cubillos L, Duarte I, Quappe G. Gallbladder cancer: anatomoclinical study of 1000 cases. Rev Chil Cir 1987;39:201–7. 47 De Aretxabala X, Burgos L, Roa I. Early gallbladder cancer. Rev Chil Cir 1997;49:646–9. 48 Chianale J, Valdivia G, del Pino G. Gallbladder carcinoma mortality rates and their relation with cholecystectomy rates. Rev Med Chile 1990;118:1284–8. 49 Roa I, Ibacache G, Carvallo J. Microbiological study of gallbladder bile in a high risk zone for gallbladder cancer. Rev Med Chile 1999;127:1049–55. 50 De Aretxabala X. Cáncer de vesícula biliar. In: Barboza E, ed. Principios y Terapéutica Quirúrgica. Lima: Didi de Arteta SA, 1999:368–73. 51 De Aretxabala X, Riedemann J, Roa I. CA 19-9 and carcinoembryonic antigen in gallbladder cancer. Rev Med Chile 1996;124:11–20. 52 Carneiro P, Sales R, Oliveira D. Histopathological aspects in pregnancy of the gallbladder: a study of 40 cases. Folha Med 1993;106:157–63. 53 Reid KM. Ramos-De la Medina A, Donohue JH. Diagnosis and surgical management of gallbladder cancer: a review. J Gastrointest Surg 2007;11:671–81. 54 Todoroki T. Chemotherapy for gallbladder carcinoma: a surgeon’s perspective. Hepatogastroenterology 2000;47:948–55. 55 Todoroki T, Kawamoto T, Otsuka M. IORT combined with resection for stage IV gallbladder carcinoma. Front Radiat Ther Oncol 1997;31:165–72. 56 Pekolj J, Aldet A, Sendin R, et al. Cáncer de vesícula y colecistectomía laparoscópica. Rev Argent Cirug 1997;73:97–106. 57 Roa I, Araya J, Wistuba I. Gallbladder cancer in the IX region of Chile: Importance of anatomopathological study in 474 cases. Rev Med Chile 1994;122:1248–56. 58 Garrido L, Aretxabala X, Roa I. Prognostic factor analysis in gallblader cancer with subserosal infiltration. Rev Chil Cir 1996;48:483–9. 59 Fong Y, Sun RL, Jarnagin W, Blumgart LH. An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg 1999;229:790–9; discussion 799–800. 60 Goncalves C, Pereira F, Gayotto L. Hepatocellular carcinoma in Brazil: report of a national survey (Florianopolis, SC, 1995). Rev Inst Med Trop São Paulo 1997;39:165–70. 61 Barham WB, Figueroa R, Phillips IA, Hyams KC. Chronic liver disease in Peru: role of viral hepatitis. J Med Virol 1994;42: 129–32. 62 Muñoz G, Velasco M, Thiers V, et al. Prevalence and genotypes of hepatitis C virus in blood donors and in patients with chronic liver disease and hepatocarcinoma in a Chilean population. Rev Med Chile 1998;126:1035–42. 63 McCormack L, Petrowsky H, Clavien PA. Surgical therapy of hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2005;17: 497–503. 64 de Santibanes E, McCormack L, Pekolj J, et al. Multimodal treatment of hepatocellular carcinoma. Acta Gastroenterol Latinoam 2001;31:367–75. 65 INCUCAI. www.incucai.gov.ar (accessed 30th November 2007). 66 de Santibañes E, Argibay P, Campi O, et al. Results of resective surgery of liver metastases from colorectal cancer. Rev Arg Cir 1991;60:1–7.

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67 de Santibañes E. Tratamento das metástases hepáticas. In: Pereira-Lima L, ed. Conductas em Cirugia Hepatobiliopancreática. Rio de Janeiro: Medsi, 1995:71–108. 68 de Santibanes E, Lassalle FB, McCormack L, et al. Simultaneous colorectal and hepatic resections for colorectal cancer: postoperative and longterm outcomes. J Am Coll Surg 2002;195: 196–202. 69 Lendoire J, Moro M, Andriani O, et al. Liver resection for noncolorectal, non-neuroendocrine metastases: analysis of a multicenter study from Argentina. HPB (Oxford) 2007;9:435–9.

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Liver Tumors in Africa Michael C. Kew Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, and Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa

Introduction Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver, constituting 85–90% of these tumors. A number of important differences exist between HCC as it occurs in sub-Saharan Africa and as it is seen in other parts of the world. The exception is HCC in ethnic Chinese patients, which varies little from that occurring in black Africans. No obvious differences have been noted in the other primary malignant tumors of the liver or in hepatic metastases, as they occur in sub-Saharan Africa and the rest of the world. The differences between HCC in black Africans and that in other populations are reviewed in this chapter.

tration or the findings on hepatic imaging, without obtaining histologic confirmation. Underdiagnosis is compounded by underreporting. In addition, very few African countries have reliable cancer registries. The highest recorded incidence of HCC in Africa is in Mozambique, where the age-adjusted annual frequency among men is 113 per 100 000 and among women 30.8 per 100 000, and the cancer is responsible for 65% of all malignant diseases in men and 31% of those in women [3]. Annual age-adjusted frequencies of 64.6 per 100 000 in men and 25.8 per 100 000 in women have been documented in Zimbabwe [4]. In contrast, HCC occurs in less than 5, and usually less than 3, per 100 000 men per annum in most other parts of the world [1, 2, 5].

Gender and age distribution

Epidemiology Incidence HCC occurs appreciably more often in the indigenous peoples of sub-Saharan Africa than in all other regions of the world, with the exception of East and South-East Asia and some of the Western Pacific islands [1, 2]. Approximately 46 000 new cases of the tumor are diagnosed in Africa annually [1]. This figure, however, grossly underestimates the true incidence of HCC in sub-Saharan Africa because many, perhaps even most, cases are either not definitively diagnosed or are not recorded. The reasons for underdiagnosis of the cancer include inadequate medical and diagnostic facilities in rural areas, where the majority of cases occur, and a nihilistic attitude toward definitive diagnosis conditioned by the absence of effective treatment and the grave prognosis of symptomatic HCC in black Africans. Even in urban areas, the tumor is frequently diagnosed on the basis of a raised serum alpha-fetoprotein (AFP) concen-


Male predominance in the occurrence of HCC is more obvious in black African and ethnic Chinese populations than in other populations. The global male-to-female ratio for the occurrence of the tumor is 2.1 : 1 [1], whereas the ratio in different parts of sub-Saharan Africa ranges from 5.7 : 1 to 2.1 : 1, with an average of 3.4 : 1 [1, 2, 5]. Male predominance is even more evident in young black African patients (in one study the ratio was 8.1 : 1 in patients under 30 years of age compared with 4.2 : 1 in those over 50 years of age) [6], whereas in populations at low risk for HCC it is more obvious in older patients. In the lowrisk populations, the sex ratio may be close to parity or parity in younger patients. This difference may be partly explained by the occurrence in industrialized Western countries of the fibrolamellar variant of HCC, which affects mainly young people and has an equal sex distribution, and possibly by the greater use of oral contraceptive steroids, a minor risk factor for HCC, in these countries. In most populations HCC occurs principally in the sixth, seventh and eighth decades, with the mean age at presentation ranging from the late 50s to the early 70s. Few patients under the age of 40 years are seen [1, 2, 7, 8]. In contrast, in black Africans and in the native population of parts of the People’s Republic of China, the age distribution curves of

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patients with HCC show a distinct shift towards younger ages [9–12]. This difference is most striking in Mozambique, where 50% of the patients are younger than 30 years of age and the mean age is 33 years [3]. With the very high incidence of HCC in Mozambican men and the difference in age distribution between these patients and those in industrialized Western countries with a low incidence of the tumor, it has been estimated that the risk of a Mozambican male aged between 25 and 34 years developing this cancer is 500 times that of a Caucasian man living in North America or the United Kingdom. The difference is only 15-fold in those older than 65 years. In other Southern African blacks the mean age of the patients is 40 years and 22.5% are younger than 30 years of age [9]. The peak incidence of HCC in Uganda is between 35 and 45 years [10] and that in Kenya 30–40 years, with more than 50% of the patients being younger than 40 years of age [11]. In Qidong County and the Guanxi Autonomous Region in the People’s Republic of China, the mean age of the patients is around 40 years [4, 5], and in Taiwan most patients are aged between 41 and 50 years [12]. HCC is rarely seen in children in industrialized countries, and when it is these children generally suffer from one of the rare inherited diseases known to be complicated by this tumor (and usually cirrhosis), such as alpha-1-antitrypsin deficiency, hereditary tyrosinemia, glycogen storage disease (type 1), or ataxia telangiectasia. HCC is seen in black African (and ethnic Chinese) children, although manifestly not as often as in adults [11–13]. These children are almost invariably chronically infected with hepatitis B virus (HBV) [13]. Patients with HBV-induced HCC are generally younger than those with hepatitis C virus (HCV)-induced cancers: in sub-Saharan Africa the difference is as much as 20 years, whereas in industrialized countries it is 10 years or less [14].

Clinical presentation Symptomatic HCC is often diagnosed only when the tumor has reached an advanced stage. This applies in all geographic regions, but especially so in black African patients [9–11]. Before this late stage is reached, clinical recognition is frequently difficult. There are a number of reasons for this. HCC runs a silent course in its early stages; it produces no pathognomonic symptoms or signs; the liver is relatively inaccessible to the examining hand and its large size dictates that the tumor must reach a substantial size before it can be felt or before it invades adjacent structures; the considerable functional reserves of the liver ensure that jaundice and other evidence of hepatic failure do not appear until a large part of the organ has been replaced by the tumor; and spread of HCC to distant sites usually occurs late in the course of

510

the disease. Ease of clinical recognition of HCC also differs between populations at high or intermediate risk and those at low risk. In countries in which HCC is common, including those in sub-Saharan Africa, clinicians are especially mindful of the cancer and its many and diverse presentations. Accordingly, they recognize HCC with greater facility than do clinicians practicing in countries in which this tumor is rarely seen. Moreover, HCC commonly coexists with cirrhosis, and the effect of this associated disease on the diagnosis of HCC differs between populations with a high and a low or an intermediate incidence of the tumor [15]. In the latter countries (but also in Japan, which has a high incidence) HCC often develops as a complication of longstanding symptomatic cirrhosis and the patient has few, if any, symptoms attributable to the tumor [16, 17]. If, in addition, the cancer is small, as it often is in the presence of advanced cirrhosis, it may not be evident on physical examination. A sudden unexpected change or deterioration in the condition of these patients may alert the clinician to the possibility that HCC has supervened in the cirrhotic liver [7]. These changes include the onset of abdominal pain or weight loss, ascites may appear or become blood stained, the liver may suddenly enlarge, a hepatic arterial bruit may be heard, or hepatic failure may supervene. In contrast, in black African and ethnic Chinese populations at high risk of HCC the symptoms of the coexisting cirrhosis are usually overshadowed by those of the cancer, and its presence is then uncovered only during the diagnostic work-up for the tumor or at necropsy. Thus, in these populations the tumor usually develops in individuals who were otherwise apparently healthy [9–12, 18–20]. HCCs are commonly considerably larger in these populations [9–12,18–20]. Consequently, the symptoms and physical signs are more florid and this too facilitates diagnosis. Despite the extent of the tumor burden when black Africans with HCC are first seen, the duration of symptoms is often surprisingly short [9–11]. In an analysis of rural Southern African blacks, 30% of the patients admitted to symptoms of less than 2 weeks’ duration and 60% to less than 4 weeks’ duration [9]. The duration of symptoms is generally similar in ethnic Chinese patients with HCC, but is appreciably longer in patients in industrialized countries, where symptoms have usually been present for about 6 months [7].

Symptoms Upper abdominal pain, which is the most common symptom as well as the most frequent presenting complaint in patients with HCC, is almost invariable in black African patients [9–11, 18, 19]; 90% or more have this symptom, compared with 70% or less in industrialized countries with a low or an intermediate incidence of the tumor [20]. Surprisingly, abdominal pain is less frequent in ethnic Chinese than in

CHAPTER 42

Liver Tumors in Africa

Southern African blacks 40

30

20

10

0

black African patients [12, 20]. Not only is abdominal pain more common in black African patients, it is also more severe and more likely to become progressively worse. The severity and frequency of the pain reflect the generally far larger HCCs characteristic of black African patients (Figures 42.1 and 42.2). The average weight of the cancerous liver at necropsy in black Africans in different studies is 3914 g (ranging up to 8780 g) [21], 3387 g [22], and 3045 g [23] and in ethnic Chinese 3046 g (12), compared with 2036 g in Japanese [17], 2615 g in North Americans [24], and 2477 g in South African Caucasians [22]. The cancerous liver is especially large when HCC arises in a noncirrhotic liver: in Ugandan patients without and with cirrhosis, the cancerous liver weighed 4314 and 2786 g, respectively [23], and in Southern African blacks, it weighed 3981 and 3085 g, respectively [21] (Figure 42.2). The large tumor burden at the time of diagnosis contributes in no small measure to the limited therapeutic options and grave prognosis in black African and ethnic Chinese patients [9–12, 18–20]. Due to the often large size of the cancerous liver in black Africans and ethnic Chinese with HCC, these patients are more likely to be aware of an abdominal lump than are patients in industrialized countries [9–12, 18–20]. In contrast, abdominal swelling resulting from ascites is less likely to be present in the former patients because coexisting cirrhosis complicated by portal hypertension is less common and less advanced in these patients. Other symptoms of HCC in black African patients do not differ obviously in frequency or severity from those in other populations. However, spontaneous rupture of the tumor – or of attenuated liver tissue overlying the tumor – causing an acute and life-threatening hemoperitoneum, occurs significantly more often in black African and ethnic Chinese patients than it does in patients in industrialized countries.

Patients (%)

Figure 42.1 Example of a black African patient with massive hepatomegaly resulting from the presence of a large hepatocellular carcinoma.

1000 2000 3000 4000 5000 6000 7000 8000 Liver weight (g) 1000 2000 3000 4000 5000 6000 7000 8000 0

10

20

30

40 Japanese Figure 42.2 Comparison of the weights of the tumorous liver at necropsy in black African and Japanese patients with hepatocellular carcinoma (the data on the black African patients is obtained from [25] and from the author’s patients, and that from the Japanese patients from [17]).

This complication is occasionally the reason for admission to hospital. Far more often it occurs in patients known to have HCC, when it is commonly the terminal event. For example, tumor rupture is the terminal event in 26% of blacks in Uganda [23], 18.6% of rural blacks in Southern Africa [25], 20% of Taiwanese [12], 12% of Thais [24], and 17% of Hong Kong Chinese [20] with HCC. In an occasional patient the tumor ruptures as a result of blunt abdominal trauma [26]. Surprisingly, in these patients the prognosis may be less grave than it is with spontaneous rupture: in two of three black Africans in whom HCC ruptured as a result of abdominal trauma, the HCC found at the resulting laparotomy could be resected [26].

Physical signs An enlarged liver is the most frequent physical finding in patients with HCC in all geographic regions. Hepatomegaly

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is, however, more frequent and commonly of greater degree (Figures 42.1 and 42.2) in black African and ethnic Chinese patients (91–100%) [9–12, 18–20] than in patients in industrialized countries, such as North America (56–74%) [8, 16] and Japan [17], although 93% of patients in a series from the United Kingdom had an enlarged liver [7]. Because of the often large size of the cancer in black Africans, the enlarged liver is more likely to be tender and is not infrequently extremely tender. In general, in industrialized countries hepatic metastases cause a greater degree of hepatic enlargement than does HCC, whereas the converse is true in black African and ethnic Chinese populations. Physical evidence of chronic hepatic parenchymal disease is rarely evident in black Africans and ethnic Chinese with HCC [9–12, 18–20], but is present in 50% or more of patients in industrialized countries [7, 16, 17]. Fever appears to be more common (38%) in black African [9] and ethnic Chinese [54%] patients [12, 20] than in those from other countries (24% in the United Kingdom) [8], although it was reported to be present in only 11% of Ugandan patients [10]. If substantiated, the higher frequency of fever in these populations may reflect the greater likelihood of tumor necrosis with release of pyrogenic substances in the larger HCCs. The clinical presentation of HCC in a young black African male with a short history of right hypochondrial pain, an enlarged very tender liver, and high fever may result in the tumor being mistakenly diagnosed as an amoebic liver abscess, another common disease in parts of Africa. A large number and a wide variety of unusual clinical presentations, including paraneoplastic phenomena, have been described in black Africans with HCC [25, 27, 28], but in most of these there is no proof that they occur more often than in other populations. One exception is Pityriasis rotunda (circumscripta). This rash is seen in 10–15% of black Africans with HCC, especially in older patients [29, 30]. The only other patients in whom Pityriasis rotunda has been described were in Japan, and no indication of its frequency was given [31]. The lesions occur on the trunk, buttocks, and thighs, and are round or oval, hyperpigmented, and scaly. They vary in size from 0.5 to 25 cm, and may be single or multiple (Figure 42.3). Another exception may be the propensity for the tumor to invade and propagate along the hepatic veins. Invasion of the hepatic veins alone is responsible for a clinical presentation with the Budd–Chiari syndrome [25]. With propagation of the tumor into the lumen of the inferior vena cava (IVC) the patients develop, in addition, severe pitting edema of the lower limbs extending up to the groins. Growth of the cancer up the lumen of the IVC into the right atrium (and sometimes the right ventricle) usually causes circulatory collapse and sudden death [25]. Invasion into the hepatic veins is seen at necropsy in 14% of black Africans

512

Figure 42.3 Example of Pityriasis rotunda (circumscripta) on the anterior abdominal wall in a black African with hepatocellular carcinoma.

with HCC, propagation of the tumor into the IVC in 9%, and growth into the right atrium in 2% [25]. This complication is seldom reported in patients at low risk of HCC, but when mentioned is described as being rare.

Natural history, prognosis, and causes of death The usual course of HCC in black Africans is one of rapid progression, characterized by increasingly severe muscle wasting, increasing size of the liver and depth of jaundice, and worsening pain [9–11, 18, 19]. In all parts of the world, the prognosis of patients with symptomatic untreated HCC is poor, with survival times of 6 months or less being the rule [32]. The duration of survival is, however, typically even shorter in black African and ethnic Chinese patients [9–12, 18–20]. For example, the mean survival time in untreated rural Southern African blacks is 11 weeks from the time of onset of symptoms and 6 weeks from the time of diagnosis [9]. The often fulminant course of HCC in black Africans is related, at least in part, to the rate of growth of the tumor. Tumor doubling times in most populations range from about 30 days to as much as 180 days. In black Africans, based on AFP doubling times, it has been estimated that HCC may double in size in as few as 11 days [33]. In patients in industrialized countries the presence of advanced cirrhosis has a definite influence on the prognosis as well as the nature of the terminal event in patients with HCC, with liver failure and bleeding from esophageal varices being prominent. The presence of coexisting cirrhosis has little influence on prognosis in black African patients and its complications are seldom the cause of death [34]. The most common cause of death in black Africans with HCC is

CHAPTER 42


advanced malignant disease, although rupture of the tumor or hepatic failure may be responsible.

cally raised serum values [38]. Data on the diagnostic usefulness of the marker in black African patients with small asymptomatic tumors are not available.

Diagnosis

Hepatic imaging

Biochemical tests Biochemical tests of liver function are of little use in the diagnosis of HCC in all populations, including black Africans. Although these tests are almost always slightly deranged, the changes are not specific and it is difficult to determine which of the changes are attributable to the tumor and which to the coexisting cirrhosis. As raised serum cholesterol levels are rare in the general black population and because hypercholesterolemia is a not uncommon paraneoplastic phenomenon in this population (occurring in 16% of patients in one study [35]), the finding of a raised serum cholesterol level in a black African patient suspected to have HCC provides a strong clue to the diagnosis of the cancer. This may also be true in Taiwanese patients with HCC, because a raised serum cholesterol level is found in 24% of these patients [12]. A large number and variety of putative serum markers for HCC have been reported. However, with the exception of AFP, none has been found to be more useful in black African patients than in patients from other countries.

Alpha-fetoprotein Serum AFP levels are more often raised and to appreciably higher levels in black African and ethnic Chinese patients with HCC than in patients in industrialized countries. Approximately 90% of black African patients have a raised serum level (>20 ng/mL), and in about 75% the concentration is above 500 ng/mL, the value generally considered to be diagnostic of this tumor [36]. The mean concentration of the raised levels is around 70 000 ng/mL, and values as high as several million nanograms per milliliter are seen. This contrasts with a prevalence of less than 70% of patients with HCC in industrialized countries having a raised level and less than 50% a diagnostic level [36, 37]. The mean concentration of raised AFP in these populations is around 8000 ng/ mL. In black Africans production of the tumor marker by HCC is age related. This is shown in data from Southern Africa, where 96.4% of patients under the age of 30 years have raised values compared with 83.1% of those over 50 years of age, and 89.3% of the younger patients have a diagnostic level compared with 59.7% of the older patients [6]. The mean of the raised concentrations is 87 366 ng/mL in the younger patients and 43 827 ng/mL in the older patients [6]. Serum AFP concentrations are of limited use in screening for small asymptomatic HCCs in Oriental and Mediterranean patients, less than 50% of such tumors producing diagnosti-

The images obtained with ultrasonography, computerized tomography, and magnetic resonance imaging do not show features unique to HCC in black Africans or in any other population. The fact that the tumors are frequently very large in black Africans and ethnic Chinese patients is, however, confirmed. For the same reason, a raised right hemidiaphragm on plain chest X-ray is more frequently seen in black African (30%) [39] and ethnic Chinese patients (40%) [20]. Radiologically-evident pulmonary metastases are also more common in these patients: 20% [39], compared with 7% in the United Kingdom [7].

Pathology Growth patterns of HCC may be influenced both by the etiology of the tumor and by the presence and nature of coexisting liver disease. Nevertheless, the pathologic characteristics of HCC in black Africans are, in the main, similar to those in other population groups. One exception has already been mentioned, namely, the often large size of this cancer in black Africans. Another difference concerns the nature of the growth pattern. Expanding HCCs are common in Japanese (38%) and black African patients (36%), but are less common in North American patients (17%) [40]. There are, however, two differences between Japanese and black African patients in this regard: only 23% of expanding HCCs in the former compared with 54% in the latter arise in a normal liver, and expanding HCCs with a well-defined capsule are common in Japanese patients but rare in black African (and in North American) patients [40]. Moreover, encapsulated expanding tumors in Japanese patients arise almost exclusively in cirrhotic or precirrhotic livers [40]. In most black African populations, HCC coexists with cirrhosis less often than in other populations, including ethnic Chinese patients. In these other populations, cirrhosis is present in about 80% of patients with HCC [12, 20], whereas in black Africans this figure may be as low as 35% [15, 34, 41]. When the fibrolamellar variant of HCC occurs it almost always does so in patients living in the industrialized Western world: it either does not occur or is extremely rare in black African, ethnic Chinese, and Japanese patients. Patients with fibrolamellar HCC are typically young adults, have an equal sex distribution, do not have coexisting cirrhosis, have a normal serum AFP, and are not infected with either HBV or HCV. They generally have a better prognosis than do other forms of HCC.

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Treatment The treatment of HCC in black Africans is very unrewarding. Symptomatic HCC is rarely resectable in these patients. For example, only 8% of Ugandan [42] and only 1% of Southern African blacks with HCC [43] have resectable tumors, compared with resectability rates of up to 37% in some industrialized countries with a low incidence of the cancer [44] and up to 20% in Japanese patients [45]. Ethnic Chinese patients too have low resectability rates, e.g. 3% in Hong Kong Chinese [20]. The other surgical option in patients with HCC is liver transplantation. Because of the nature of this operation, more patients with HCC would be considered to be suitable for liver transplantation than would be amenable to hepatic resection. Even so, with the often advanced stage of the disease and the poor general condition of black African patients when they seek medical attention, as well as the frequency of spread beyond the liver, few would be suitable candidates for liver transplantation. In addition, facilities for liver transplantation are extremely limited in sub-Saharan Africa and very few, if any, such operations are being performed. Accordingly, there is no information on the results of liver transplantation for HCC in sub-Saharan Africa. No stratified randomized trials have shown that radiotherapy is of value in the treatment of HCC in black Africans, or indeed in any population [32]. A large number of anticancer agents, given alone or in combination and by intravenous and intra-arterial routes, have been administered to black Africans with HCC in adequate clinical trials without achieving a significant response rate, and this is also true of biologic response modifiers [32]. These results are worse than those in other populations. The reasons for the poorer results are the lateness of presentation with very large tumor burdens and perhaps a higher incidence of multiple drug resistance genes in black Africans. The use of new targeted chemotherapeutic drugs, such as the multikinase inhibitors, that are proving useful in treating patients in industrialized countries, have yet to be tried in black African patients.

Etiology and pathogenesis The spectrum of causal associations of HCC differs in different geographic regions. In sub-Saharan Africa the important environmental risk factors are chronic HBV infection, repeated dietary exposure to the fungal toxin, aflatoxin B1, dietary iron overload, and chronic HCV infection. Membranous obstruction of the IVC is also a risk factor, and alcoholic cirrhosis may play a lesser etiologic role in older urbanized black Africans. Minor environmental risk factors implicated in other populations, namely, cigarette smoking, oral con-

514

traceptive steroids, and anabolic androgenic steroids, have not been incriminated in black Africans, although the reason for this may be the difficulty in proving statistically a role for marginal risk factors in the presence of one or more major risk factors. Chronic HBV infection is also the main causal association of HCC in ethnic Chinese populations, and exposure to aflatoxin B1 contributes to the etiology of the tumor in the People’s Republic of China, Taiwan, Thailand, and perhaps other countries in the Far East. In Japan and most other industrialized countries, chronic HCV infection is the predominant causal association of HCC, often in association with alcoholic cirrhosis. Chronic HBV infection plays a secondary role in these countries.

Hepatitis B virus Chronic HBV infection is the predominant risk factor for HCC in sub-Saharan Africa. As many as 98% of black Africans (average figure 75%) are infected with this virus during their lifetime, and about 10% become chronically infected [46]. Based on case-control studies, the relative risk for a black African who is a chronic carrier of HBV developing HCC is as high as 23.3 [46–48]. The infection is largely acquired in early childhood, mainly as a result of horizontal transmission of the virus from recently infected and hence highly infectious young (under 5 years of age) siblings or playmates, with perinatal infection by HBV e antigenpositive carrier mothers playing a far lesser role [49, 50]. Fifty to 90% of children infected at this age become chronic carriers of the virus, and it is these early-onset carriers that are at very high risk for HCC development. The majority of black Africans suffering from HCC are actively infected with HBV at the time the tumor becomes clinically evident, and most of the remainder show serologic evidence of past infection with the virus [46, 47, 49]. The association between the virus and the tumor may be even closer than serologic data indicate. Studies using monoclonal rather than polyclonal antibodies to detect viral antigens have shown HBV surface antigen (HBsAg) to be present in the serum of patients testing negative for markers of current HBV infection with conventional assays [51]. Moreover, Southern hybridization and the polymerase chain reaction assays have detected HBV DNA in liver and tumor tissue of such patients [52]. Occult HBV infection has been demonstrated both in apparently healthy black African carriers of HBV [53] and in the majority of black African patients with HCC who are HBsAg-negative but positive for anti-HBc and/ or anti-HBs [54]. Individuals with occult HBV infection may progress to HCC formation [55]. The pathogenesis of HBV-induced HCC remains uncertain [56]. There is no evidence to suggest that the mechanisms involved are substantially different in black Africans from those in other populations. One possible difference is the role of specific mutations in the RNA encapsidation signal (ε) of HBV, which have been described in about 30% of

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HCCs in black Africans [57]. but not, thus far, in other populations. Mutations at nucleotide 1862 in the bulge of ε, frequently accompanied by a mutation at codon 1888 in the upper stem, may be responsible for an e antigen-negative phenotype as a result of its effect on signal peptide cleavage of the precore–core protein. The e antigen negativity favors persistence of the virus and might thus increase the likelihood of integration of HBV DNA into cellular DNA and set in motion the complex stepwise pathogenesis of HCC.

Aflatoxin B1 A hepatocarcinogenic role for aflatoxin B1, a toxin derived from the molds Aspergillus flavus and A. parasiticus, is confined to sub-Saharan Africa and parts of East and South-East Asia [58]. These fungi are ubiquitous in developing countries, particularly those with warm and humid climates, and may contaminate staple crops, either in the ground or as a result of improper storage. Aflatoxin B1 is metabolized to a highly reactive epoxide. Heavy exposure to the toxin has been shown in parts of sub-Saharan Africa and China to correlate with a specific inactivating mutation of the third base of codon 249 of the p53 tumor suppressor gene, suggesting one way in which the toxin may contribute to hepatocarcinogenesis [59–61]. Heavy exposure to aflatoxin B1 occurs in the same geographic regions as are endemic for HBV infection and a strong positive interaction between the two carcinogens has been demonstrated [62].

Hepatitis C virus With the exception of Somalia, where HBV and HCV appear to play equal causal roles in HCC [63], chronic HCV infection is implicated in the etiology of a minority only of these tumors in sub-Saharan Africa, ranging from 6.2% in Mozambique to 23.1% in Niger [14, 64, 65]. Black Africans with HCV-induced HCC are on average two decades older than those with HBV-induced tumors [14, 64, 65]. This age differential is more striking than that in industrialized countries, where the difference in average age is one decade or less [14]. Male predominance is less obvious in black Africans with HCV-related than in those with HBV-related HCC, although this difference just fails to reach statistical significance [65]. Black patients with HCV-related HCC are more likely to be urban dwellers and less likely to be rural dwellers than those with HBV-associated tumors [65]. Genotype 5a of HCV occurs almost exclusively in Southern Africa and accounts for approximately 50% of the isolates [66]. Its oncogenic potential appears to be no more or less than that of the other genotypes [66].


cally of the macronodular variety with thin fibrous septa between the nodules and very little inflammatory reaction. It is usually the result of chronic HBV infection. However, in older urban or urbanized blacks with the tumor, a small proportion of patients have coexisting cirrhosis that shows the typical features of prolonged alcohol abuse [41, 67]. These patients do not have evidence of chronic HBV or HCV infection, and alcoholic cirrhosis may be the main reason for neoplastic transformation. In contrast, in industrialized countries with a low incidence of HCC, alcoholic cirrhosis is a dominant risk factor, often together chronic HCV infection.

Iron-loading diseases The inherited iron-loading disease, hereditary hemochromatosis, which is well known to carry a high risk for HCC development, does not occur in black Africans. However, another iron-loading disease, dietary iron overload (previously called Bantu visceral siderosis), is unique to black Africans living in sub-Saharan Africa, and it too carries an increased risk for neoplastic transformation (relative risk 10.6) [68]. In some parts of sub-Saharan Africa as many as 15% of the men are iron overloaded. Generation of reactive oxygen species with resulting oxidative damage appears to play a central role in the pathogenesis of this form of HCC.

Membranous obstruction of the inferior vena cava This is a rare vascular abnormality that is either a developmental anomaly or the late result of early IVC thrombosis. In South Africa and Japan, and very occasionally elsewhere, it is often complicated by HCC development: the tumor occurs in 46% of black Africans [69, 70] with this anomaly. Malignant transformation is thought to be the result of continuous hepatocyte necrosis and regeneration secondary to the chronic hepatic venous hypertension.

Self-assessment questions 1 What are the reasons for the underdiagnosis of hepatocellular carcinoma in sub-Saharan black Africans? 2 What change in a patient’s condition may alert the clinician to the possibility that hepatocellular carcinoma has supervened in a cirrhotic liver?

Cirrhosis

3 Is a raised serum alpha-fetoprotein level a more useful test for the presence of hepatocellular carcinoma in Black African patients or in European Causcasian patients?

HCC coexists with cirrhosis in 80–90% of patients in most geographic regions. The exception is in black Africans, in whom the association is generally appreciably less common [15]. The cirrhosis found in black Africans with HCC is typi-

4 What are the two major environmental risk factors for hepatocellular carcinoma in sub-Saharan Black Africans?

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5 Which environmental risk factor for hepatocellular carcinoma causes a specific inactivating mutation of the p53 tumour suppressor gene?

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21 Davies JNP. Cancer of the Liver in Trans-Saharan Africa. UICC Monograph No. 1. Berlin: Springer-Verlag, 1961. 22 Steiner PE. Cancer of the liver and cirrhosis in trans-Saharan Africa and the United States of America. Cancer 1960;13: 1085–166. 23 Anthony PP. Primary carcinoma of the liver: A study of 282 cases in Ugandan Africans. J Pathol 1973;110:37–48. 24 Chearanai O, Plengvanit U, Asavanich C, et al. Spontaneous rupture of primary hepatoma. Cancer 1983;51:1532–6. 25 Kew MC, Paterson AC. Unusual clinical presentations of hepatocellular carcinoma. Trop Gastroenterol 1985;6:10–22. 26 Kew MC, Hodkinson J. Rupture of hepatocellular carcinoma as a result of blunt abdominal trauma. Am J Gastroenterol 1991;86:1083–5. 27 Kew MC, Dusheiko GM. Paraneoplastic manifestations of hepatocellular Carcinoma. In: Berk PD, Chalmers TC, eds. Frontiers in Liver Disease. New York: Thieme-Stratton Inc, 1981: 305–19. 28 Kew MC. Clinical manifestations and paraneoplastic syndromes of hepatocellular carcinoma. In: Okuda K, Ishak KG, eds. Neoplasms of the Liver. Tokyo: Springer-Verlag, 1987:199– 211. 29 DiBisceglie AM, Hodkinson HJ, Berkowitz I, Kew MC. Pityriasis rotunda – a cutaneous marker of hepatocellular carcinoma in southern African blacks. Arch Dermatol 1986;122:802–4. 30 Berkowitz I, Hodkinson HJ, Kew MC, DiBisceglie AM. Pityriasis rotunda as a cutaneous marker of hepatocellular carcinoma: A comparison with its prevalence in other diseases. Br J Dermatol 1989;120:545–9. 31 Ito M, Tanaka T. Pseudo-ichthyose acquise en taches circulaires. Ann Dermatol et Syphil 1960;87:826–37. 32 Falkson G, Falkson CI. Current approaches in the management of patients with hepatocellular carcinoma. Oncol Res 1989; 4:87–9. 33 Purves LR. Alpha-fetoprotein and the diagnosis of liver cell cancer. In: Cameron HM, Linsell DA, Warwick GP, eds. Liver Cell Cancer. Amsterdam: Elsevier, 1976:61–80. 34 Kew MC. Hepatocellular carcinoma with and without cirrhosis: A comparison in southern African blacks. Gastroenterology 1989;97:136–9. 35 Goldberg RG, Bersohn I, Kew MC. Hypercholesterolemia in primary liver cancer. S Afr Med J 1975;49:1464–6. 36 Kew MC. Tumor markers in HCC. J Gastroenterol Hepatol 1989;4:373–84. 37 Trichopoulos D, Sizaret P, Tabor E, et al. Alpha-fetoprotein levels of liver cancer patients and controls in a European population. Cancer 1980;46:736–40. 38 Kew MC. Detection and treatment of small hepatocellular carcinomas. In: Hollinger FB, Lemon SM, Margolis HS, eds. Viral Hepatitis and Liver Disease. Baltimore: Williams and Wilkins, 1991:535–40. 39 Levy JI, Geddes EW, Kew MC. The chest radiograph in primary liver cancer: An analysis of 449 cases. S Afr Med J 1976;50: 1323–6. 40 Okuda K, Peters RL, Simson IM. Gross anatomic features of hepatocellular carcinoma from 3 disparate geographic areas. Cancer 1984;54:2165–73. 41 Paterson AC, Kew MC, Herman AAB, et al. Liver morphology in southern African blacks with hepatocellular carcinoma: A

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1991;350:429–31. 60 Hsu JC, Metcalf RA, Sun T, et al. Mutational hot spot in p53 gene in human hepatocellular carcinoma. Nature 1991;350: 427–8. 61 Ozturk M, Bressac B, Pusieux A, et al. A p53 mutational hot spot in primary liver cancer is geographically localized to high aflatoxin areas of the world. Lancet 1991;338:1356–9. 62 Kew MC. Synergistic interaction between aflatoxin B1 and hepatitis B virus in hepatocarcinogenesis. Liver Int 2003;23:1–5. 63 Bile K, Aden C, Norder H, et al. Important role of hepatitis C virus infection as a cause of chronic liver disease in Somalia. Scand J Infect Dis 1993;24:559–64. 64 Kew MC. Hepatitis C virus and hepatocellular carcinoma in developing and developed countries. Viral Hepatit Rev 1998;4:259–69. 65 Kew MC. Hepatitis c virus infection in black patients with hepatocellular carcinoma in southern Africa. In: Kobayashi K, Purcell RH, Shimotohno K, Tabor E, eds. Hepatitis C Virus and its Involvement in the Development of Hepatocellular Carcinoma. New Jersey: Princeton Scientific Publishing, 1994:33–40. 66 Kedda M-A, Kew MC, Coppin A. Hepatocarcinogenic potential of genotype 5 of hepatitis C virus. Trop Gastroenterol 1998; 18:153–5. 67 Mohamed AE, Kew MC, Groeneveldt HT. Alcohol consumption as a risk factor for hepatocellular carcinoma in urban southern African blacks. Int J Cancer 1992;51:537–41. 68 Mandishona E, MacPhail AP, Gordeuk VR, et al. Dietary iron overload as a risk factor for hepatocellular carcinoma in black Africans. Hepatology 1998;27:1563–7. 69 Simson IM. Membranous obstruction of the inferior vena cava and hepatocellular carcinoma in South Africa. Gastroenterology 1982;82:171–8. 70 Kew MC, McKnight A, Hodkinson J, et al. The role of membranous obstruction of the inferior vena cava in the etiology of hepatocellular carcinoma in southern African blacks. Hepatology 1989;9:121–5.

Self-assessment answers 1 The reasons are inadequate medical and diagnostic facilities in rural areas, where the majority of cases occur, and a nihilistic attitude toward definitive diagnosis conditioned by the absence of effective treatment and the grave prognosis of symptomatic hepatocellular carcinoma in black Africans. Even in urban areas, the tumor is frequently diagnosed on the basis of a raised serum alpha-fetoprotein concentration or the findings on hepatic imaging without obtaining histologic confirmation. Underdiagnosis is compounded by underreporting. In addition, very few African countries have reliable cancer registries. 2 A sudden unexpected change or deterioration in the condition of these patients may alert the clinician to the

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possibility that hepatocellular carcinoma has supervened in the cirrhotic liver. These changes include the onset of abdominal pain or weight loss, ascites may appear or become blood stained, the liver may suddenly enlarge, a hepatic arterial bruit may be heard, or hepatic failure may supervene.

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3 It is a more useful test in Black African patients. 4 Chronic hepatitis B virus infection and dietary exposure to the fungal toxin, aflatoxin B1. 5 Aflatoxin B1.

43

Anesthetic Management of Liver Surgery Marco P. Zalunardo Institute of Anesthesiology, University Hospital of Zurich, Zurich, Switzerland

In the last two decades orthotopic liver transplantation and hepatic resection have grown into established therapies with improved outcome [1]. In specialized centers performing advanced liver surgery, the anesthesiologist is involved in the preoperative evaluation and perioperative management of patients with severe liver disease and should be able to manage the perioperative care of a patient with end-stage liver disease. This chapter will give a short overview of the anesthetic management for liver surgery, including preoperative evaluation, monitoring and instrumentation, hemodynamic and hemostatic management, perioperative complications, and special considerations, such as coagulation monitoring and transesophageal echocardiography.

Preoperative evaluation Hepatic resection and cryosurgery Not every patient who presents for liver surgery has endstage liver disease. Some are asymptomatic and their pathologic findings are limited to the hepatic tumor itself. The preoperative assessment of these patients is similar to that of otherwise healthy patients scheduled for major abdominal surgery. The recommended preoperative investigations are listed in Table 43.1. Patients with comorbid illness appear to be at increased risk for early postoperative morbidity and mortality after hepatic resection [2]. In patients with HCC and underlying liver disease, the presence of comorbid illness may lead to increased physiologic stress and may exhaust the limited liver reserve following extended hepatic resection. Patients who have significant comorbid illness may not be suitable surgical candidates for extended hepatectomy. Hypoalbuminemia, thrombocytopenia, elevated serum creatinine, major hepatic resection, and transfusion were significant predictors of mortality in a series of 1222 consecutive

patients. Concomitant extrahepatic procedure, thrombocytopenia, and transfusion were predictors of morbidity in this study [3]. Elevated serum creatinine and impaired renal function and hepatorenal syndrome may be present in patients with chronic liver disease, advanced hepatic failure, and portal hypertension. Preoperatively, renal function has to be optimized by maintaining sufficient perfusion pressure rather than by excessive volume loading. Rigorous intraoperative volume restriction and total vascular exclusion may lead to serious renal impairment, especially in cases with pre-existing renal insufficiency. The preoperative evaluation and preparation of the patient scheduled for cryosurgery should anticipate possible intraand post-operative complications, such as bleeding, thrombocytopenia, myoglobinuria, acute renal failure, freeze injuries to lung, and pleural effusion. Therefore, aside from standard evaluation, a special focus on coagulation, and renal and lung function is advantageous (see Table 43.1) [4].

Liver transplantation As a member of the interdisciplinary liver group, the anesthesiologist is involved in the pretransplant evaluation of liver transplantation candidates. The main part of their work is to interpret evaluation results and findings, to complete the evaluation with additional investigations when necessary, and to identify absolute and relative contraindications for anesthesia and surgery. Many patients have acute or chronic liver disease with multiple organ dysfunction. Depending upon the deterioration of organ function, intensive evaluation and perioperative monitoring is needed [5]. Furthermore, with adequate knowledge, the patient’s condition may be optimized significantly prior to transplantation [6].

Hepatic encephalopathy


The clinical manifestations of hepatic encephalopathy range from a slightly altered mental state to coma. Grade 4 encephalopathy may be complicated by the development of cytotoxic or vasogenic cerebral edema and an increase in

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Table 43.1 Preanesthetic investigations before hepatic resection, cryosurgery, and liver transplantation.* Investigation

Hepatic resection

Cryosurgery

Liver transplantation*

Hct, Hb, Lc, Plts Electrolytes, Ca, Mg Liver function tests Amylase, lipase BG, urea, creatinine PT, PTT Urine analysis ECG BGA Chest X-ray Lung function test Echocardiogram Exercise stress tests

x x

x x

x x

x

x

x

x x

x x

x x

x – x – ± x

x x x – x x

x x x x x x

± ±

± ±

x ±

*For other pretransplant evaluation (immunology, serology, gastroenterology, etc) see Chapter 23. Hct, hematocrit; Hb, hemoglobin; Lc, leukocytes; Tc, platelets; Ca, calcium; Mg, magnesium; liver function tests: aspartate aminotransferase, alanine aminotransferase, alcalic phosphatase; bilirubin; gamma-glutamyltransferase, protein; BG, blood glucose; PT, prothrombin time; PTT, partial thromboplastin time; ECG, electrocardiogram; BGA, arterial blood gas analysis; x, examined; –, not examined; ±, decision on a case-by-case basis.

intracranial pressure (ICP), which is a major cause of mortality in patients with fulminant hepatic failure. Invasive ICP monitoring is the most sensitive method for the diagnosis of raised ICP. Although there are no stringent data, the United States Acute Liver Failure Group recommends ICP monitor placement in patients with clinical signs of grade 3 or early grade 4 encephalopathy [7]. ICP monitoring is also recommended when a patient with documented encephalopathy or brain edema is mechanically ventilated [8]. ICP tends to increase during the dissection phase, decrease during the anhepatic phase, and increase again during the reperfusion phase. Complications of ICP monitoring include infection, hemorrhage, technical malfunction, and false interpretation. Bleeding related to the placement of ICP monitors occurs in 10–20% of patients with acute liver failure, but is often mild and of low clinical significance, although fatal outcomes have been described [9]. Therefore, treatment of the bleeding diathesis before insertion is recommended. Intraventricular placement should be avoided. The goals of

520

perioperative ICP management are ICP below 15 mmHg, mean arterial pressure above 80 mmHg, and cerebral perfusion pressure above 65 mmHg. Treatment of intracranial hypertension includes mannitol (0.5–2.0 g/kg/day; serum osmolality is not allowed to exceed 315 mOsm/kg) and a thiopental bolus of 100–200 mg.

Central pontine myelinolysis Central pontine myelinolysis (CPM) is a demyelinating disorder that affects the central portion of the base of the pons cerebri. The clinical manifestation is characterized by irreversible postoperative coma or “locked-in” syndrome after transplantation. In most cases, CPM is a postmortem diagnosis, because the symptoms are obscured by systemic complications. There is a significant relationship between the occurrence of CPM and the increase in sodium concentration during and after liver transplantation [10, 11]. Therefore, liver transplantation in patients with a preoperative sodium concentration below 125 mEq/L is not recommended.

Cardiovascular disease In contrast to earlier studies, recent data show that the prevalence of coronary artery disease (CAD) in patients with end-stage liver disease is equal to or greater than the prevalence rate in the healthy population. Furthermore, the average age of liver transplant candidates has been rising over the years [12]. The morbidity and mortality of patients with CAD who undergo liver transplantation without treatment is very high, making its identification an important consideration. In collaboration with cardiologists, we have established a cardiac evaluation program for liver transplantation candidates at our institution (Table 43.2). Exercise stress echocardiography (ECG) is not a suitable test for most candidates. Ascites, weakness, lethargy, encephalopathy, and drug interactions prevent a successful and convincing test performance. ECG is performed in all candidates for liver transplantation at our institution. ECG is very sensitive for pulmonary hypertension, which is a major perioperative risk factor [13]. In the case series of Krowka et al, patients with a mean pulmonary arterial pressure of 50 mmHg and greater had a mortality of 100%, and patients with a mean pulmonary arterial pressure between 35 and 50 mmHg had a mortality of 50%. No mortality was reported in patients with a mean pulmonary arterial pressure below 35 mmHg [14]. Prior to exclusion of a candidate from the transplantation program, pulmonary hypertension treatment should be established. Prostacycline analogs have been shown to reduce pulmonary pressures significantly and may improve outcome after liver transplantation [15, 16]. ECG is also sensitive for cardiomyopathy in hemochromatosis and dilatative cardiomyopathy in ethylic cirrhosis. Coronary angiography is performed when angina pectoris, a history of myocardial

CHAPTER 43

Table 43.2 Cardiac evaluation of liver transplantation candidates. Examination

Indication

Cardiac history, clinical examination, ECG Screening risk factors for CAD Exercise stress test (ECG)

All patients

Echocardiography Echocardiography control on waiting list

Right heart catheterization Coronary arteriography

Dobutamine stress echocardiography or myocardial perfusion scintigraphy

Anesthetic Management of Liver Surgery

in room air. The inability to achieve a PaO2 of 200 mmHg in an inspired oxygen concentration of 100% may be a contraindication to transplantation [17]. Candidates should stop smoking before transplantation, because pulmonary infection is a major cause of morbidity and mortality after liver transplantation.

All patients

Renal function Inadequate examination for most patients (ascites, lethargy, beta-blockade) All patients All patients every 12 months Patients with pulmonary hypertension (SPAP > 30 mmHg) and/or other pathologic findings in the screening echocardiography Patients with SPAP > 50 mmHg Angina pectoris, history of myocardial infarction, coronary revascularization >5 years ago, congestive heart failure, left bundle block, pacemaker, diabetes mellitus and age >40 years, age >60 years and >2 risk factors for CAD If coronary arteriography is not indicated and one risk factor for CAD or age >60 years

ECG, electrocardiogram; CAD, coronary artery disease; SPAP; systolic pulmonary arterial pressure

infarction, coronary revascularization more than 5 years ago, congestive heart failure, left bundle block, pacemaker, diabetes mellitus and age older than 40 years, age older than 60 years, and more than two risk factors for CAD are present. The sensitivity and specificity of dobutamine stress ECG for CAD is controversial. However, it is a noninvasive investigation with significantly lower mortality and morbidity than coronary angiography. Alternatively, myocardial perfusion scintigraphy, a less invasive screening method with similar sensitivity, may be performed.

Renal function may be impaired in liver transplantation candidates. Hepatorenal syndrome (HRS) is characterized by a reduction of renal blood flow, glomerular filtration rate, urine output, and dilutional hyponatremia in the absence of histologic pathology. Renal function usually recovers after transplantation. Spontaneous recovery without transplantation is very rare. Hemodialysis and hemofiltration can serve as renal support pre-, intra-, and post-operatively [18]. The long-term outcome of patients with cirrhosis and HRS is good, although the presence of HRS is associated with increased morbidity and early mortality. Immediately after transplantation, a further impairment in renal function may be observed. Five percent of patients progress to end-stage renal disease and require long-term hemodialysis.

Coagulopathy Patients with hepatic dysfunction can develop extensive blood-clotting abnormalities. Prothrombin time and partial thromboplastin time may be prolonged. In the liver, vitamin K-dependent clotting factors, specific inhibitors of coagulation, plasminogen, and alpha-2-antiplasmin are synthesized. Malabsorption of vitamin K in patients with chronic liver disease leads to a deficit of coagulation factors II, VII, IX, and X, and the anticoagulant factors protein C and S. Administration of vitamin K may improve hepatic coagulation factor production. Thrombocytopenia is common and is due to bone marrow suppression, chronic disseminated intravascular coagulation, and hypersplenism.

Electrolyte and metabolic disorders Sodium concentration is often low in cirrhotic patients due to renal dysfunction and ascites therapy with diuretics. Deterioration in hepatic function can result in a vast array of metabolic abnormalities, including hypoglycemia, lactic acidosis, hypoproteinemia, clotting factor deficiency, and hyperammonemia. Hypoglycemia can deprive all tissues of energy substrates, most importantly the brain.

Pulmonary function Assessment of the pulmonary condition should include auscultation, chest radiograph, pulmonary function tests, and arterial blood gases. Impaired gas exchange due to ventilation–perfusion mismatch, inadequate hypoxic pulmonary vasoconstriction, atelectasis associated with ascites, and intrapulmonary shunting may result in serious hypoxemia in patients with hepatic failure. Mortality in patients with hepatopulmonary syndrome is associated with lower PaO2

Intraoperative management Hepatic resection Monitoring and instrumentation Aside from standard monitoring, including ECG, pulse oximetry, temperature, and end-tidal gas analysis, invasive arterial blood pressure measurement and central venous

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Table 43.3 Hepatic clearance of perioperative drugs and inhalational agents. (Modified and supplemented from [11, 25, 45, 54].) Flow limited

Flow limited, enzyme limited

Not flow limited, not enzyme limited

Enzyme limited, binding sensitive

Enzyme limited, binding insensitive

Inhalational, low metabolism

Morphine Lidocaine Propranolol Labetalol Nitroglycerine Midazolam Etomidate

Meperidine Metoprolol Alfentanil

Propofola Fentanylb

Diazepam Chlordiazepoxide Warfarin Phenytoin Lorazepam

Ketamine Thiopental Theophylline Succinylcholine

Isoflurane Desfluranec Sevofluranec

a, prolonged recovery; b, with accumulation (repeated doses), enzymatic biotransformation may be limiting for clearance; c, no clinical data for routine use in liver surgery.

access with a multiple lumen catheter are mandatory. Rapid infusion systems, such as Level 1 (SIMS Level 1® Inc, MA), facilitate large volume infusion in a short time, combined with air detection, air removal, and warming. They are standard equipment in cardiac, trauma, and liver transplant surgery. One or more large cannulas for peripheral venous access should be installed. Indications for further instrumentation with pulmonary artery catheter or transesophageal echocardiography depend upon the patient’s cardiovascular risk profile. Installation of thoracic epidural analgesia appears to be advantageous in terms of pain relief, mobility, and postoperative pulmonary complications [19], and is part of the standard procedure at our institution.

Anesthesia induction and maintenance Intravenous as well as inhalational anesthesia, except halothane and nitrous oxide, are appropriate for hepatic resection. However, cirrhotic patients may have prolonged recovery after propofol anesthesia. In summary, drugs with elimination properties independent of liver blood flow or protein binding are preferred (Table 43.3). If thoracic epidural analgesia and general anesthesia are combined, cardiodepressive anesthetics should be titrated cautiously, because systemic vascular resistance is lowered by epidural sympatholysis. To avoid awareness due to insufficient depth of anesthesia, especially in hemodynamically unstable patients with combined anesthesia, bispectral index (BIS) monitoring may be useful. Immediate postoperative extubation is routinely performed, if cardiopulmonary stability, temperature, and recovery of the patient are satisfactory.

Hemodynamic management Bleeding during hepatic resection may be limited by adequate surgical technique, vascular exclusion, and avoidance of venous volume overload (Table 43.4) [20–22]. In over 30

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Table 43.4 Intraoperative measures to reduce bleeding during hepatic resection. • • • • • • • •

Adequate surgical access with sufficient organ exposure Spacious mobilization of the liver Pringle maneuver Hepatic vascular exclusion Controlled dissection of liver parenchyma Ultrasonic dissection Argon-beam coagulation Avoidance of venous volume overload

years of successful hepatic resection, reduction of bleeding and blood product use has paralleled the introduction of advanced surgical techniques and novel auxiliary devices (ultrasonic dissection, argon-beam coagulation). Jones et al [21] and recently Wang et al [23] demonstrated that perioperative blood loss is also correlated with central venous pressures (CVP) above 5 mmHg. In contrast, another prospective study showed that maintaining CVP below 5 mmHg was not associated with a reduction in blood loss [24]. However, there is a direct and undamped anatomic connection between the inferior vena cava (IVC) and the sinusoids. Therefore, fluid overload causes swelling of the liver volume up to 1500 mL and significant increase in blood loss. Accordingly, fluid management should be as restrictive as possible. CVP as the right ventricular filling pressure is not reliably comparable to the filling pressures in the hepatic veins and the IVC, especially when venous return is impaired by surgical mobilization of the liver. Thus, used as sole guidance for fluid management during hepatic resection, absolute “target” values of CVP are insufficient and may be misleading [25]. Heart rate trends, arterial pressure trends, arterial pressure

CHAPTER 43

curve, blood gas analysis, urine output, and CVP trends give more information. Volume overload may be avoided by venous pooling with low-dose 1–3 μg/kg/min nitroglycerine infusion. Arterial hypotension is treated with vasoactive support. Corresponding to the low systemic vascular resistance and the high cardiac output in cirrhotic patients with thoracic epidural sympatholysis, norepinephrine infusion is recommended.

Perioperative complications and adverse events Too aggressive volume restriction may also lead to renal insufficiency. In a retrospective study of 496 patients, 3% experienced a persistent and clinically significant increase in serum creatinine [26]. Most patients with ascites have diuretic therapy, which has to be continued perioperatively. The renal protective effects of low-dose dopamine by increasing renal blood flow is seriously questioned and routine use is not recommended. The following variables are significantly related to postoperative morbidity: age above 55 years, American Society of Anesthesiologists (ASA) physical status II or more, bilirubin greater than 80 μmol/L, alkaline phosphatase activity more than double the reference range, malignant tumors, abnormal liver parenchyma, simultaneous surgical procedures, operative time above 4 h, and perioperative blood transfusion above 600 mL, whereas blood transfusion and simultaneous surgery have the strongest correlation [27].

Cryosurgery and continuous intra-arterial chemotherapy Monitoring and instrumentation for cryosurgery and continuous intra-arterial chemotherapy are similar to those for hepatic resection. Common perioperative complications are hypothermia, thrombocytopenia, fever, and basal pulmonary atelectasis, while the following are less frequent: bleeding, acute renal failure, freeze injuries to skin, lung and other tissues, pleural effusion, disseminated intravascular coagulation, prolonged prothrombin time, and hypoglycemia. Myoglobinemia and myoglobinuria develop usually after cryosurgery and may cause tubular necrosis. Urine output monitoring and aggressive therapy of oliguria and acidosis are mandatory [28].

Liver transplantation The following sections concentrate on clinically relevant issues for the anesthetic management of liver transplantation.


pulmonary artery catheter is mandatory. Despite ECG controls, pulmonary hypertension may be undetected until the day of transplantation [16]. Continuous cardiac output and continuous mixed oxygen saturation measurement (Swan-Ganz CCOmbo SvO2, Edwards Lifesciences Corporation, CA, USA) are optional, but make perioperative data collection much easier and give useful and quick hemodynamic information in most critical situations. Following the practice guidelines of the ASA Task Force on Perioperative Transesophageal Echocardiography (TEE), TEE monitoring in liver transplantation is a recommended indication. TEE is believed to be more accurate in diagnosing the cause of hemodynamic disturbances than is CVP or pulmonary artery catheter monitoring [29]. TEE use in liver transplantation is further discussed below (see Special considerations). The installation of an autotransfusion system may be useful when augmented blood loss is expected due to compromised blood coagulation, massive portal hypertension, or extraordinary abdominal anatomy. Blood coagulation is not altered by blood salvage with cell saver.

Anesthesia induction and maintenance Drugs with elimination properties independent of liver blood flow or protein binding are preferred (see Table 43.3). There is no favourite drug set listed in most reviews on anesthetic management of liver transplantation, but a slight trend for inhalational anesthesia may be seen, especially for isoflurane [30, 31] In animal models flow velocity is enhanced with isoflurane, and hepatic arterial autoregulation and oxygen delivery are effectively maintained [32]. There is little scientific information about sevoflurane or desflurane anesthesia in liver transplantation in humans. Rapid sequence induction is recommended in patients with ascites and a history of food intake 6 h before induction of anesthesia [33]. Muscle relaxation with atracurium is advantageous in patients with known or expected renal impairment [34]. The administration of 4 μg/kg clonidine during induction of liver transplantation significantly reduced the intraoperative requirements for intravenous fluids and blood products without compromising the circulatory stability. Improvement in immediate reperfusion-induced disturbances was also observed [35]. The standard anesthetics for liver transplantation at our institution are: for the induction of anesthesia, midazolam 0.02 mg/kg (except when encephalopathy is present), etomidate 0.15–0.2 mg/kg, fentanyl 1.5–2.5 μg/kg, and succinylcholine 1.5 mg/kg or atracurium 0.6 mg/kg; for anesthesia and relaxation maintenance: atracurium, fentanyl, and isoflurane.

Monitoring and instrumentation Monitoring and instrumentation for liver transplantation significantly exceed the routine standard level for major abdominal surgery and hepatic resection. Aside from invasive arterial blood pressure measurement and central venous access with a multiple lumen catheter, the installation of a

Hemodynamic management Aside from patient-related factors, such as coagulation profile or cardiovascular status, hemodynamic management basically depends on the surgical technique and the use of venovenous bypass. Cross-clamping of the IVC results in a

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marked reduction of venous return and cardiac output. This phenomenon is less pronounced in patients with end-stage liver disease, because left ventricular preload is partially preserved by the inflow through venous collateral vessels. If the piggyback technique of caval anastomosis is used or venovenous bypass is installed prior to cross–clamping, venous return may be significantly improved and cardiac output maintained [5, 31] The decrease in cardiac output during cross-clamping without venovenous bypass may be compensated by fluid administration and vasoactive support. On condition that the function of both ventricles is normal, norepinephrine infusion is recommended to address the low systemic vascular resistance in cirrhotic patients. In case of ventricular failure, dobutamine or epinephrine infusions are indicated. Under these precautions cross-clamping of 40– 60 min duration is usually well tolerated. Dramatic changes in hemodynamic parameters may occur immediately after reperfusion of the transplanted liver and may be characterized by a decrease in arterial blood pressure, bradycardia, supraventricular and ventricular arrhythmias, and occasionally cardiac arrest. The incidence of this postreperfusion syndrome may be up to 30% [36]. Immediately after reperfusion, left ventricular function may be impaired and pulmonary capillary wedge pressure may increase, while TEE monitoring shows a stable or even decreased left ventricular end-diastolic volume. These contrary findings may be due to a period of deteriorating left ventricular compliance or “cardioplegia” on reperfusion [37, 38]. Cautious TEE-guided titration of fluids may then be beneficial.

may question the routine use of aprotinin in all liver transplant recipients [41]. Moreover, the drug has been withdrawn from the worldwide market because of serious adverse events during an ongoing study. As an alternative treatment, tranexamic and epsilon-aminocaproic acids may be used as antifibrinolytic agents during liver transplantation, but their effect on transfusion requirements is controversial [42, 43]. Calcium is an important coenzyme in the coagulation cascade. During the preanhepatic and anhepatic phases of liver transplantation, hypocalcemia may develop, especially when large amounts of fresh frozen plasma have been given. In many transplant centers, continuous calcium infusions are part of standard therapy. Fresh frozen plasma and cryoprecipitate should be indicated restrictively in recipients with a normal coagulation profile. In contrast, in patients with severely prolonged prothrombin time or a corresponding TEG or rotation thromboelastometry (ROTEM) pattern, fresh frozen plasma, cryoprecipitate, and factor concentrates are indicated.

Postoperative complications Major postoperative complications after liver transplantation may be neurologic, infectious, hematologic, renal, metabolic, cardiovascular, pulmonary, and gastrointestinal (Table 43.5). A detailed description of postoperative complications is beyond the scope of this chapter.

Special considerations Coagulation monitoring

Hemostatic management Patients with pre-existing coagulation disorders are common liver transplant recipients. Especially during hepatectomy, blood loss and concomitant hyperfibrinolysis, coagulation factor deficiency, and thrombocytopenia are not always predictable, and transfusion requirements are variable. Without prompt, efficient, and specific volume replacement therapy with blood components, massive bleeding may result. Hemostatic management with advanced monitoring techniques is mandatory for adequate substitution with blood components during liver transplantation. Thromboelastography (TEG) and other useful on-site devices have been rediscovered or developed for coagulation monitoring. They will be discussed later in this chapter. Hyperfibrinolysis contributes to bleeding during orthotopic liver transplantation. Intraoperative use of aprotinin significantly reduces blood transfusion requirements and prophylactic use of aprotinin ameliorates the postreperfusion syndrome in liver transplantation, as reflected by a significant reduction in vasopressor requirements [39, 40]. However, reports on fatal pulmonary thromboembolism

524

The documented benefits of perioperative monitoring of coagulation are reduced consumption of blood and blood products, appropriate volume replacement with blood components, and improved haemostasis management [44].

Thromboelastography TEG was introduced in 1948 by Hellmut Hartert as a research tool [45]. It did not gain widespread usage in clinical practice until Yoogoo Kang and his group used it for coagulation monitoring during liver transplantation in the early 1980s. The TEG principle is simple: a heated cup with whole blood oscillates, while a pin is suspended freely in it from a torsion wire. When the clot starts to form, the fibrin strands increase the elastic shear modulus of the sample. Electromagnetic transduction converts this signal to a TEG tracing. The TEG parameters have specific characteristics. The reaction time, r, depends on the activity of the intrinsic system and increases with factor deficiency. k Measures the speed of clot development and describes thrombin activity and fibrin formation. Alpha is the angle formed by the slope of the tracing from the r to the k value. It indicates the speed of clot strengthening and measures the activity of the intrinsic system and platelet function or count. Maximum amplitude (MA) is the

CHAPTER 43


3500

Table 43.5 Major postoperative complications after liver transplantation.

3000

greatest amplitude of the tracing. It represents the absolute strength of the clot and the maximum dynamic properties of fibrin and platelets. The TEG index is a linear combination of the TEG parameters with specific coefficients. It increases with hypercoagulability, decreases with hypocoagulability, and shows good correlation with bleeding and the coagulation profile [46] Kang and his group demonstrated that hemostasis management with TEG decreases blood transfusion requirements during liver transplantation [47]. To illustrate the clinical impact of TEG, three consecutive TEG tracings from a 60-year-old patient are shown in Figures 43.1–43.3. The patient had chronic C hepatitis, Child class C cirrhosis, and mild renal insufficiency. Initial platelet count was only 44 000/mL and the prothrombin time 76%.

2500 Blood loss (mL)

Neurologic: • Seizures • Encephalopathy • Central pontine myelinolysis • Stroke • Intracranial hemorrhage Infectious Fungal: • Bacterial • Viral • Protozoal • HIV • Hematologic • Coagulopathy • Disseminated intravascular coagulation • Thrombosis (hepatic vessels) • Lymphoproliferative disorders • Bone marrow depression Renal: • Renal tubular necrosis Metabolic: • Protein catabolism Cardiovascular: • Cardiac failure • Hypotension • Shock • Bradycardia Pulmonary: • Pulmonary edema • Acute respiratory distress syndrome Gastrointestinal: • Hemorrhage (esophageal varices, intra-abdominal) • Pancreatitis • Liver failure • Biliary leakage

2000 1500 1000 500

0

2

6 8 10 12 4 Mean caval pressure (mmHg)

14

16

Figure 43.1 Correlation between blood loss and inferior vena caval pressure during liver resection. (Reproduced from Johnson et al. Br J Surg 1998;85:188–90, with permission.)

However, platelets were not substituted at that time because, from a clinical point of view, coagulation was good and TEG showed only a very slight decrease in MA (Figure 43.2). During the anhepatic period, coagulation deteriorated, MA decreased, and reaction time increased (Figure 43.3). In order to increase MA, 12 units of platelets and 10 units of fresh frozen plasma were given to decrease reaction time. After reperfusion, the TEG was normal, the platelet count 66 000/mL, and the prothrombin time 75% (Figure 43.4). It is likely that more units of platelets would have been given without the information from the TEG. In the last few years, the ROTEM TEG analyzer (Pentapharm GmbH, Munich, Germany) has gained widespread acceptance as the perioperative coagulation monitoring tool. The ROTEM creates similar traces to conventional TEG, but offers also the possibility to test specific coagulation components, e.g. fibrinogen concentration and function (Figure 43.5). This new coagulation monitoring method may improve hemostasis management in liver transplantation [48].

On-site prothrombin time and partial thromboplastin time devices The perioperative utility of laboratory hemostasis assays is limited by the delay in obtaining results. The hemostasis management of liver surgery still requires rapid and accurate information about the prevailing coagulation status. Therefore, on-site coagulation monitoring may be beneficial. Furthermore, Despotis et al demonstrated that the use of on-site coagulation assays can reduce the use of blood products, decrease the operating time, and minimize the chest tube drainage in cardiac surgery [49]. The portable

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Plts. 44 000/mL PT 76%

+0.60 TEG index: Normal range: –2.0 to +2.0

10 mm scale

Pt: NR:

SP (mm) R (mm) K (mm) MA (mm) Ang (deg) 5.5 6.0 4.0 66.5 49.5 10–14 3–6 59–68 54–67

LY30 (%) 3.0

LY60 (%) 7.0

Figure 43.2 Thrombelastography (TEG) tracing during hepatectomy in a 60-year-old patient with chronic C hepatitis, Child class C cirrhosis and mild renal insufficiency. MA is slightly decreased, but TEG index and all other parameters are normal. Plts, platelet count; PT, prothrombin time; NR, normal range of TEG parameters.

Plts. 35 000/mL PT 56%

TEG index: –9.27 Normal range: –2.0 to +2.0

10 mm scale

Pt: NR:


LY30 (%) 1.0

LY60 (%) 3.0

Figure 43.3 Thrombelastography (TEG) tracing during the anhepatic phase. MA is decreased and reaction time increased, and the lowered TEG index indicates hypocoagulability. Plts, platelet count; PT, prothrombin time; NR, normal range of TEG parameters.

Plts. 62 000/mL PT 75%

+2.23 TEG index: Normal range: –2.0 to +2.0

10 mm scale

Pt: NR:


LY30 (%) 0.0

LY60 (%) 1.0

Figure 43.4 Thrombelastography (TEG) tracing after reperfusion. After substitution with 12 units of platelets and 10 units of fresh frozen plasma, the TEG tracing and TEG index indicate normal coagulation. Plts, platelet count; PT, prothrombin time; NR, normal range of TEG parameters.

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EXTEM CT: 131 s A10: 34 mm

FIBTEM

INTEM

2007-02-15 13:30 2:

CFT: 219 s A15: 38 mm

α:

53°

A20: 41 mm

CT: 210 s A10: 32 mm


2007-02-15 13:32 2:

CFT: 238 s A15: 38 mm

α:

58°

A20: 42 mm

2007-02-15 13:33 2:

CT: 482 s

CFT:

–s

A10: 3 mm

A15:

3 mm

α:

–°

A20: 3 mm

Figure 43.5 Rotation thromboelastometry (ROTEM) tracing with hypofibrinogenemia. Only FIBTEM (fibrinogen tracing) shows lack of fibrinogen, while the extrinsic (EXTEM) and intrinsic (INTEM) tracings are normal.

coagulation monitor CoaguChek-Plus (Boehringer Mannheim, Germany) has been shown to measure intraoperative on-site prothrombin time and partial thromboplastin time in less than 3 min. However, clinical evaluation under different hemostatic conditions found insufficient correlation with standard laboratory assays. The poor accuracy of the device was found equally for pre-, intra- and postoperative measurements, and for different ranges of prothrombin time [50]. The poor correlation may be caused by the high International Sensitivity Index (ISI) of the thromboplastin used, and more sensitive thromboplastins with lower ISIs should be preferred, because these show a smaller between-laboratory variability. Such new devices with lower ISIs are under investigation. On-site platelet and hemoglobin count (AC.T8 Hemocytometer, Hialeah, USA) is also very useful for hemostasis management during liver transplantation.

has been helpful in the diagnosis of many hemodynamic disturbances. As mentioned earlier in this chapter, filling pressures are not always reflective of preload because of significant fluctuations in ventricular compliance. TEE gives substantial information about preload and may help to identify hemodynamic changes during and after reperfusion of the liver [51]. TEE has also been used in the diagnosis and management of intraoperative complications, such as air embolism and thromboembolism, and in the management of patients with unrelated cardiopulmonary disease, such as CAD, valvular pathology, idiopathic hypertrophic subaortic stenosis, etc [52–54]. TEE has also proven to be an essential monitoring tool in patients with pulmonary hypertension undergoing liver transplantation. Furthermore, TEE allows for the intraoperative evaluation of the major vessels, including suprahepatic IVC anastomosis [55].

Transesophageal echocardiography In the preoperative evaluation, transthoracic echocardiography is used for patients undergoing liver transplantation. It provides information about global cardiac function, valvular function, presence of pericardial effusion, increased right ventricular pressure, and pulmonary hypertension. Due to potential damage to esophageal varices with subsequent severe bleeding, TEE initially was used very reluctantly, but this complication appears to be very uncommon, and if it occurs, it is mild and self-limiting. Today, TEE is used more commonly in patients undergoing liver transplantation, and

Self-assessment questions 1 Which of the following are the major significant predictors of mortality in candidates for extended hepatectomy? (more than one answer is possible) A Fluid overload B Thrombocytopenia C Elevated serum creatinine D Elevated serum bilirubin E Transfusion

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2 Which one of the following explains why fluid overload may be deleterious in hepatic resection? A Arterial hypertension leads to a significant increase in blood loss B Liver volume may increase up to 1500 mL C Concomitant hemodilution leads to deterioration of the coagulation profile D High central venous pressure may lead to distension and failure of the right ventricle E Blood loss is augmented by the elevation of the systemic pressure 3 Pulmonary hypertension is not an absolute contraindication for liver transplantation, because pulmonary arterial pressure between 35 and 50 mmHg has a mortality of 50%. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 4 Preoperative sodium concentration below 125 mEq/L may be fatal, because central pontine myelinolysis is caused by low sodium concentrations. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 5 Echocardiography may be helpful for the risk stratification of liver transplant candidates, because it reveals which one of the following? A Congenital heart disease B Coronary heart disease C Diastolic dysfunction D Pulmonary hypertension E Atrial septum defect 6 Thromboelastography is used in the perioperative setting of liver transplantation, because it is an established test for chronic coagulation disorders. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct

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7 Which of the following are perioperative complications in cryosurgery? (more than one answer is possible) A Hypothermia B Fever C Hyperglycemia D Renal failure E Liver failure 8 In contrast to patients with end-stage liver disease, cross-clamping of the vena cava during liver transplantation results in a marked reduction of venous return and cardiac output in liver transplant recipients without cirrhosis, because left ventricular preload is not preserved by the inflow through venous collateral vessels. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 9 Which one of the following symptoms is not characteristic for the postreperfusion syndrome? A Ventricular fibrillation B Atrial fibrillation C Low output syndrome D Increase of the plasma potassium concentration E Hypothermia (blood flush of the cold liver) 10 Which one of the following is not a complication of intracranial pressure monitoring? A Bleeding B Infection C Malfunction D Misinterpretation E Intracranial hypertension

References 1 Clavien PA, Petrowsky H, DeOliveira ML, Graf R. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med 2007;356:1545–59. 2 Wei AC, Tung-Ping Poon R, Fan ST, Wong J. Risk factors for perioperative morbidity and mortality after extended hepatectomy for hepatocellular carcinoma. Br J Surg 2003;90:33–41. 3 Poon RT, Fan ST, Lo CM, et al. Improving perioperative outcome expands the role of hepatectomy in management of benign and malignant hepatobiliary diseases: analysis of 1222 consecutive patients from a prospective database. Ann Surg 2004;240:698– 708; discussion 708–10. 4 Littlewood K. Anesthetic considerations for hepatic cryotherapy. Semin Surg Oncol 1998;14:116–21.

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5 Merritt WT. An International View of Perioperative Issues in Liver Transplantion, parts 1 and 2, vol 44. Hagerstown: Lippincott Williams and Wilkins, 2006. 6 De Wolf AM. Preoperative optimization of patients with liver disease. Curr Opin Anaesthesiol 2005;18:325–31. 7 Stravitz RT, Kramer AH, Davern T, et al. Intensive care of patients with acute liver failure: Recommendations of the U.S. Acute Liver Failure Study Group. Crit Care Med 2007;35: 2498–508. 8 Bass NM. Monitoring and treatment of intracranial hypertension. Liver Transpl 2000;6:S21–6. 9 Vaquero J, Fontana RJ, Larson AM, et al. Complications and use of intracranial pressure monitoring in patients with acute liver failure and severe encephalopathy. Liver Transpl 2005;11: 1581–9. 10 Yu J, Liang TB, Zheng SS, Shen Y, Wang WL, Ke QH. [The possible causes of central pontine myelinolysis after liver transplantation.] Zhonghua wai ke za zhi 2004;42:1048–51. 11 Heng AE, Vacher P, Aublet-Cuvelier B, et al. Centropontine myelinolysis after correction of hyponatremia: role of associated hypokalemia. Clin Nephrol 2007;67:345–51. 12 Tiukinhoy-Laing SD, Rossi JS, Bayram M, et al. Cardiac hemodynamic and coronary angiographic characteristics of patients being evaluated for liver transplantation. Am J Cardiol 2006;98:178–81. 13 Torregrosa M, Genesca J, Gonzalez A, et al. Role of Doppler echocardiography in the assessment of portopulmonary hypertension in liver transplantation candidates. Transplantation 2001;71:572–4. 14 Krowka MJ, Plevak DJ, Findlay JY, Rosen CB, Wiesner RH, Krom RA. Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation. Liver Transpl 2000;6:443–50. 15 Ashfaq M, Chinnakotla S, Rogers L, et al. The impact of treatment of portopulmonary hypertension on survival following liver transplantation. Am J Transplant 2007;7: 1258–64. 16 Minder S, Fischler M, Muellhaupt B, et al. Intravenous iloprost bridging to orthotopic liver transplantation in portopulmonary hypertension. Eur Respir J 2004;24:703–7. 17 Krowka MJ, Wiseman GA, Burnett OL, et al. Hepatopulmonary syndrome: a prospective study of relationships between severity of liver disease, PaO(2) response to 100% oxygen, and brain uptake after (99 m)Tc MAA lung scanning. Chest 2000;118: 615–24. 18 Cardenas A, Uriz J, Gines P, Arroyo V. Hepatorenal syndrome. Liver Transpl 2000;6:S63–71. 19 Ballantyne JC, Carr DB, deFerranti S, et al. The comparative effects of postoperative analgesic therapies on pulmonary outcome: cumulative meta-analyses of randomized, controlled trials. Anesth Analg 1998;86:598–612. 20 Bechstein WO, Neuhaus P. Bleeding problems in liver surgery and liver transplantation. Chirurg 2000;71:363–8. 21 Jones RM, Moulton CE, Hardy KJ. Central venous pressure and its effect on blood loss during liver resection. Br J Surg 1998;85: 1058–60. 22 Chen H, Merchant NB, Didolkar MS. Hepatic resection using intermittent vascular inflow occlusion and low central venous

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pressure anesthesia improves morbidity and mortality. J Gastrointest Surg 2000;4:162–7. Wang WD, Liang LJ, Huang XQ, Yin XY. Low central venous pressure reduces blood loss in hepatectomy. World J Gastroenterol 2006;12:935–9. Chhibber A, Dziak J, Kolano J, Norton JR, Lustik S. Anesthesia care for adult live donor hepatectomy: our experiences with 100 cases. Liver Transpl 2007;13:537–42. Bhattacharya S, Jackson DJ, Beard CI, Davidson BR. Central venous pressure and its effects on blood loss during liver resection. Br J Surg 1999;86:282–3. Melendez JA, Arslan V, Fischer ME, et al. Perioperative outcomes of major hepatic resections under low central venous pressure anesthesia: blood loss, blood transfusion, and the risk of postoperative renal dysfunction. J Am Coll Surg 1998;187: 620–5. Pol B, Campan P, Hardwigsen J, Botti G, Pons J, Le Treut YP. Morbidity of major hepatic resections: a 100-case prospective study. Eur J Surg 1999;165:446–53. Goodie DB, Horton MD, Morris RW, Nagy LS, Morris DL. Anaesthetic experience with cryotherapy for treatment of hepatic malignancy. Anaesth Intensive Care 1992;20:491–6. Practice guidelines for perioperative transesophageal echocardiography. A report by the American Society of Anesthesiologists and the Society of Cardiovascular Anesthesiologists Task Force on Transesophageal Echocardiography Anesthesiology 1996;84: 986–1006 Park GR, Kang Y. Anesthesia and Intensive Care for Patients with Liver Disease. Boston: Butterworth-Heinemann, 1995. Amand MS, Al-Sofayan M, Ghent G, Wall JW. In: Sharpe MD, Gelb AW, eds. Anesthesia and Transplantation. Boston: Butterworth-Heinemann, 1999:171–200. Grundmann U, Zissis A, Bauer C, Bauer M. In vivo effects of halothane, enflurane, and isoflurane on hepatic sinusoidal microcirculation. Acta Anaesthesiol Scand 1997;41:760–5. Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration: application to healthy patients undergoing elective procedures: a report by the American Society of Anesthesiologist Task Force on Preoperative Fasting. Anesthesiology 1999;90: 896–905. Lawhead RG, Matsumi M, Peters KR, Landers DF, Becker GL, Earl RA. Plasma laudanosine levels in patients given atracurium during liver transplantation Anesth Analg 1993;76:569–73. De Kock M, Laterre PF, Van Obbergh L, Carlier M, Lerut J. The effects of intraoperative intravenous clonidine on fluid requirements, hemodynamic variables, and support during liver transplantation: a prospective, randomized study. Anesth Analg 1998; 86:468–76. Aggarwal S, Kang Y, Freeman JA, Fortunato FL, Pinsky MR. Postreperfusion syndrome: cardiovascular collapse following hepatic reperfusion during liver transplantation. Transplant Proc 1987;19:54–5. De Wolf AM. Does ventricular dysfunction occur during liver transplantation? Transplant Proc 1991;23:1922–3. de la Morena G, Acosta F, Villegas M, et al. Ventricular function during liver reperfusion in hepatic transplantation. A transesophageal echocardiographic study. Transplantation 1994;58: 306–10.

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39 Porte RJ, Molenaar IQ, Begliomini B, et al. Aprotinin and transfusion requirements in orthotopic liver transplantation: a multicentre randomised double-blind study. EMSALT Study Group. Lancet 2000;355:1303–9. 40 Molenaar IQ, Begliomini B, Martinelli G, Putter H, Terpstra OT, Porte RJ. Reduced need for vasopressors in patients receiving aprotinin during orthotopic liver transplantation. Anesthesiology 2001;94:433–8. 41 Fitzsimons MG, Peterfreund RA, Raines DE. Aprotinin administration and pulmonary thromboembolism during orthotopic liver transplantation: report of two cases. Anesth Analg 2001;92:1418–21. 42 Dalmau A, Sabate A, Acosta F, et al. Tranexamic acid reduces red cell transfusion better than epsilon-aminocaproic acid or placebo in liver transplantation Anesth Analg 2000;91:29–34. 43 Kaspar M, Ramsay MA, Nguyen AT, Cogswell M, Hurst G, Ramsay KJ. Continuous small-dose tranexamic acid reduces fibrinolysis but not transfusion requirements during orthotopic liver transplantation. Anesth Analg 1997;85:281–5. 44 Nuttall GA, Oliver WC, Ereth MH, Santrach PJ. Coagulation tests predict bleeding after cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1997;11:815–23. 45 Hartert H. Blutgerinnungsstudien mit der Thrombelastographie, einem neuen Untersuchungsverfahren. Klinische Wochenschrift 1948;26:577–83. 46 Mallett SV, Cox DJ. Thrombelastography. Br J Anaesth 1992;69:307–13. 47 Kang Y. Transfusion based on clinical coagulation monitoring does reduce hemorrhage during liver transplantation. Liver Transpl Surg 1997;3:655–9. 48 Coakley M, Reddy K, Mackie I, Mallett S. Transfusion triggers in orthotopic liver transplantation: a comparison of the thromboelastometry analyzer, the thromboelastogram, and conventional coagulation tests. J Cardiothorac Vasc Anesth 2006;20: 548–53. 49 Despotis GJ, Santoro SA, Spitznagel E, et al. Prospective evaluation and clinical utility of on-site monitoring of coagulation in

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Qualitative and Economic Aspects of Liver Surgery René Vonlanthen1, Ksenija Slankamenac1, and Christian Ernst2 1 Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland 2 Economics and Management of Social Services, University Hohenheim, Stuttgart, Germany

Patients requiring elective surgery are often faced with a choice between a variety of public and private hospitals. They make their choice based on their insurance status and the reputation of the hospital, as well as its vicinity and convenience, and often also for irrational or intuitive reasons. For many procedures, particularly the more complex ones, the patient’s choice of provider/treating physician may have a profound impact on postoperative morbidity or even mortality. To help the patient and/or referring physician to make the right choice of hospital, it is therefore crucial to establish evidence-based outcome measures and quality assessment of the respective procedures. Unfortunately, there is little agreement among health economists on how these data should be used. A much debated issue is whether the publication of such data leads to overall quality improvements. As with most economic choices, such a proposal has benefits as well as possible detrimental effects. A positive effect is that publication of outcome data, such as mortality or complication rates, may lead to a better match between severity of illness and provider capability. A possible negative effect is that such data may affect provider reputation, especially if they are tied to reimbursement, leading to the most capable providers avoiding the most severely-ill patients because there is a high probability that these patients will negatively affect measures of their performance. In one of the best studies to date, Dranove et al [1] showed that for report cards on cardiac surgery, the detrimental effect of patient selection dominated the beneficial effect of a better matching between illness severity and provider experience. Based on this finding, the authors conclude that report cards did in fact reduce both patient welfare and overall welfare for society. This trade-off should be borne in mind in the following discussion, but it does not detract from the general desirability of establishing such objective quality performance measures, because they may help surgeons to improve


performance even if they are not made publicly available. An example of this approach is the use of the data of the “Bundesgeschäftsstelle Qualitätssicherung GmbH” (BQS) in the German healthcare system. These data are not published, but if a provider’s scores are consistently below average, peer visits and a structural dialogue with the reporting institution ensue.

Quality measurement in surgical care Surgical outcomes vary quite considerably with healthcare provider. Debate is ongoing about which parameters should be used to reflect surgical quality. Birkmeyer et al proposed quality measurement in three domains: structure, process, and outcome − adopted from the Donabedian paradigm [2]. Though a very helpful framework, it should be borne in mind that many open questions remain as to the exact relationship between these three dimensions of quality. Structural measures (capabilities) are represented by variables reflecting the setting or system in which surgical care is provided. Procedure volume is the most commonly used surrogate for surgical quality. Other important structural variables are, for example, subspecialty training by the operating surgeon, “closed” intensive care units, high nurse-to-bed ratios, and resource availability. All these parameters seem to be important predictors of surgical outcome. Process measures reflect the care that patients receive and are strongly associated with improved patient outcomes. Examples of process measures associated with surgical outcomes are: venous thromboembolism prophylaxis, early nutritional support in critically ill patients, and procedures related to central venous line management. Another example is the use of institution-specific clinical pathways developed from national or international evidence-based guidelines. At the same time, procedure-specific processes of care, individually and in combination, may sometimes explain apparent associations between structural variables and outcomes. Outcome measures are represented, amongst others, by morbidity and mortality rates, patient satisfaction, and

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functional health. In the face of ever increasing healthcare expenditures, treatment costs have also been suggested as a possible outcome measure from a society perspective. The problem here is that the objective of low treatment costs often conflicts with the other outcome measures (the socalled cost–quality trade-off). The most effective approach to quality measurement is to look at the baseline risk of the procedure and how commonly it is performed at individual hospitals. According to these parameters, recommendations exist for when particular variables should be the focus [2]. There are several scenarios for a given surgical procedure. For example, most procedures in liver surgery carry a high baseline risk for complications. If a hospital has a high caseload for liver surgery, structural and outcome variables are recommended for quality assessment, but if the caseload is low, only structural variables should be applied. This applies particularly for complex liver resections, pancreatic resections, and esophagectomies.

Table 44.1 Clavien–Dindo classification of surgical complication [9, 10]. Grade

Definition

Grade 1

Any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic, and radiological interventions Allowed therapeutic regimens are: drugs as antiemetics, antipyretics, analgesics, diuretics and electrolytes, and physiotherapy. This grade also includes wound infections opened at the bedside

Grade 2

Requiring pharmacological treatment with drugs other than those allowed for grade 1 complications Blood transfusions and total parenteral nutrition are also included

Grade 3

Requiring surgical, endoscopic or radiological intervention Intervention not under general anesthesia Intervention under general anesthesia

Structural and outcome measures in hepatic surgery

Grade 3a Grade 3b

Hospital volume is defined as the average number of surgical procedures per year [3]. Many studies have shown better results for cardiovascular surgery, cancer resections, and other high-risk procedures in high-volume centers [4, 5]. Definitions of what is a low- or high-volume center still lack standardization. The Leapfrog Group [6] has made some efforts to implement a minimum number of operations for a center to qualify as a high-volume center. In visceral surgery, this group suggests a minimum of 11 pancreatic resections and 13 esophagectomies per year, while for liver surgery consensus is still lacking. In Germany, explicit minimum procedure volumes for hepato-pancreatico-biliary (HPB) surgery are: partial liver resections and hepatectomies, 20 per hospital/year; liver transplantations, 20 per hospital/year, and pancreatic procedures, 10 per hospital/ year. Hospitals will only receive a diagnosis-related group (DRG)-reimbursement if these minimum-volume thresholds are met (situation in 2009). Mortality is clearly defined, but the terms complication or morbidity lack standardization. Martin et al showed that complications are routinely reported in the surgical literature [7] and are often used to show improvements over time or to assess the impact of therapeutic changes on patient outcome. However, because of the inconsistency of reporting and the lack of accepted standards in assessment of complications, these data do not qualify as indicators of quality in surgery. Efforts to change this situation were first reported by Clavien et al in 1992 who proposed a new classification. They defined negative outcome by differentiating complications, sequelae, and failures to cure [8]. Using this definition, Dindo et al proposed a five-scale classification based on the therapy needed to correct the complication [9] (Table 44.1). This

Grade 4

532

Grade 4a Grade 4b

Life-threatening complication (including CNS complications*) requiring intermediate care/ intensive care unit management Single organ dysfunction (including dialysis) Multiorgan dysfunction

Grade 5

Death of a patient

Suffix “d”

If the patient suffers from a complication at the time of discharge, the suffix “d” (for “disability”) is added to the respective grade of complication. This label indicates the need for follow-up to fully evaluate the complication

*Brain hemorrhage, ischemic stroke, subarachnoid bleeding, but not transient ischemic attacks

classification system has recently found wide acceptance in the literature. Despite the lack of definitions and widely accepted standards, in 1998 Choti et al [11] in an overview of 606 liver resections conducted in 36 hospitals (data obtained from the Maryland Health Services Cost Review Commission) addressed the question, Does hospital or surgical volume have an impact on mortality and postoperative complications in hepatic surgery?. Of these resections, 43.6% were performed in one high-volume center (average 40.6 cases/ year) and the remaining 56.4% of resections at 35 lowvolume hospitals (average 1.5 cases/year). The mortality rate for all procedures in the low-volume group was 7.9% compared to 1.5% for the high-volume provider (p < 0.01, relative risk = 5.2). This lower mortality rate was seen for all

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types of resection. No overall differences were observed between the low- and high-volume providers in total hospital charges. Improved results at high-volume centers probably have multifactorial explanations: they may reflect the increased surgical and perioperative management (including anesthesia, intensive care management, nursing and other supportive care), expertise that is gained when larger numbers of procedures are performed. These experienced teams may avert adverse events through earlier recognition of problems. Furthermore, a better infrastructure, newer surgical techniques and equipment (intraoperative ultrasonography, argon beam coagulation, ultrasonic dissection, and anatomic resection techniques) may positively influence outcome. A generally accepted but unproven finding was the recognition that liver resections in patients with primary hepatic malignancies (often associated with cirrhosis) were associated with a worse overall outcome than that for those undergoing resection for metastatic disease. Although this study has provided first evidence of the high volume–low complication paradigm, it suffers from several limitations: only a single hospital was included in the high-volume group and only inhospital clinical outcomes were measured [11]. Further publications support the conclusion of Choti et al and emphasize the importance of the centralization of hepatic resections [12–14]. In 1999, Glasgow et al showed an up to four-fold higher mortality rate for low-volume centers in a series of 507 patients undergoing hepatectomy for hepatocellular carcinoma (HCC) [13]. Crude operative mortality rates decreased with increasing hospital volume, from 24.4% in the lowest-volume centers to 6.2% in the highest-volume centers. High-volume centers were found to have shorter average lengths of hospital stay. The lowestvolume providers had a mean length of stay of 14.7 days compared with 10.8 days in the high-volume providers. Overall, high-volume centers required lower resources. Dimick et al compared the mortality and morbidity rates for 569 hepatic resections conducted in high- and low-volume centers [12]. The overall inhospital mortality rate was 4.8%, and this was significantly lower in the high-volume centers (2.8%) than in low-volume centers (10.2%). In the lowvolume centers, increased rates of complications were observed, e.g. significantly higher rates of reintubation (RR, 2.5; 95% CI, 1.8–3.4), pulmonary failure (RR, 2.3; 95% CI, 1.6–3.5), acute renal failure (RR, 2.0; 95% CI, 1.1–3.7), acute myocardial infarction (RR, 2.6; 95% CI, 1.2–5.9), and aspiration (RR, 1.4; 95% CI, 0.9–2.0). The difference in outcome between the low- and high-volume centers seems to rely on a variation and a summation in postoperative complications. A recent study by McKay et al investigated the effects of an individual surgeon’s volume and training on the outcome after hepatic resections [14]. In total, 1107 hepatic resections performed by 72 surgeons were analyzed. The inhospital mortality rate was 6% and the overall complication rate 46%. Statistically significant predictors of

Qualitative and Economic Aspects of Liver Surgery

operative mortality were: urgency of admission, diagnosis of primary hepatic malignancy, extent of resection, and an increasing burden of comorbidities. The surgeon’s training was predictive of postoperative complications, along with patient’s gender, urgency of admission, diagnosis of primary hepatic malignancy, extent of resection, and the number of comorbidities.

Is long-term survival in high-volume centers superior after resection for cancer? The question of whether there is a correlation between the volume and experience of the surgeon, and outcome cannot be answered in general as some of the simpler procedures may be performed well in low-volume hospitals. Each procedure has to be evaluated separately. A series of publications has looked at outcome after oncologic procedures [15–17]. Killeen et al showed that high-volume providers have a significantly better outcome for complex cancer surgery, specifically for pancreatectomy, esophagectomy, gastrectomy, and rectal resections. Absolute differences in 5-year survival rates between low- and high-volume hospitals range from 17% for esophageal cancer resection, 6% for gastric cancer, and 5% for pancreatic cancer resection [15, 16]. Fong et al showed in their study of long-term survival after resection of hepatic malignancies that hospital volume lost its significance with time, indicating that in this group, the major effect of volume was on the perioperative outcome [17].

Summary Hospital volume, surgical experience, and training have an important impact on mortality and morbidity in hepatic surgery. These data underline the importance of centralization of complex hepatic surgery in high-volume centers and a specialized training for HPB surgery. Decreasing morbidity and mortality rates along with improving surgical quality may also have important economic consequences. However, it has to be emphasized that no single quality measurement will be appropriate for all operations. Policy-makers should consider sample size in selecting the best quality measure for specific procedures, particularly when data are used for public reporting. We are convinced that a broad implementation of a standardized classification into the surgical literature may facilitate the evaluation and comparison of surgical outcomes among different surgeons, centers, and therapies. An interesting related question concerns also the “optimal” center size. The German Institute for Quality and Efficiency in the Healthcare System (IQWIG) has shown worsening outcomes (post-surgical mobility of joint) for knee-replacement surgery if the number of cases is increased beyond a certain level [18]. This question has not yet been investigated for liver surgery.

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Economic aspects of hepato-pancreatobiliary surgery Cost-effectiveness analysis can help inform policy-makers on better ways to allocate limited resources. Based on these analyses, a diagnostic test or a treatment may be adopted or excluded. However, up to now interpreting the results of cost-effectiveness analysis remains a challenge. Whereas it is generally possible to compare the results of effectiveness studies between countries, economic evaluations require cost measures which are expressed in monetary terms and these tend to differ considerably internationally. For instance, a therapy that shows prohibitive costs per life year gained for the very expensive United States healthcare system (high drug prices) may nevertheless prove efficient for a healthcare system with price caps on important resources. Additional problems occur because of the low number of published data, a lack of standardization, and publication bias. In the following section we will provide a systematic review of the few cost-effectiveness studies in HPB surgery. To better understand the issues, definitions of frequently used terms are given initially.

Definitions: cost-effectiveness, cost-utility, and cost-benefit analysis The cost-effectiveness (CEA) of a therapeutic or preventive intervention is the ratio of the costs of the intervention to a relevant measure of its effect (costs per measure of effect). A special form of CEA is cost-utility analysis (CUA). The purpose of CUA is to estimate the ratio between costs of a health-related intervention and the benefit. CUA is often given in quality adjusted life-years gained (QALY). Consequently, a QALY takes into account both the quantity and the quality of life generated by healthcare interventions. It is the arithmetic product of life-expectancy and a measure of the quality of the remaining life-years. Using the CUA, it is possible to compare different interventions. To understand the value of CEA and CUA it is essential to appreciate that both methods can only achieve a relative, and not an absolute, ranking of alternatives [19]. The idea is to spend a given budget (usually for a given disease or indication) efficiently, so that only those measures are undertaken that require the least amount of Euros or US dollars expended per life-year gained, or QALY. Two important problems result from this. One is the fact that the often cited threshold levels of US$50 000/QALY (£30 000/QALY in the UK) cannot be endogenously derived from the model. Second, there is a risk that alternatives are compared that are inefficient in absolute terms. To see this, consider a therapy that costs US$ 10 000/QALY (CUA). If individuals attach a monetary value of only US$ 8000 to one QALY gained, the net benefit of the therapy would be “$8000 − $10 000 = − $2000”! Clearly,

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society and individuals would be better off without that therapy but both CEA and CUA fail to show this because no monetary value is attached to the outcome measures. The only evaluation method that can rank alternatives in absolute terms is therefore cost-benefit analysis (CBA), where a monetary value is attached to both the resources used (costs) and the benefits or consequences. Needless to say, this is also the most challenging technique in terms of data input and methodology, and it is not surprising that we have been unable to identify a single cost–benefit analysis for the treatment options considered here. Despite these limitations, below we follow the often suggested practice of considering a CEA ratio below US$50 000 per life-year gained as cost-effective. For some studies we also considered the incremental cost-effectiveness ratio (ICER), defined as the ratio of the change in costs of a therapeutic intervention (compared to the alternative, such as doing nothing or using the best available alternative treatment) to the change in effects of the intervention.

Cost-effectiveness studies in hepato-pancreatobiliary diseases and surgery Surveillance of cirrhosis for hepatocellular carcinoma In a systematic review and economic analysis, Thompson Coon et al showed in a cohort of liver cirrhosis patients with mixed etiology (alcohol, hepatitis B and C) that the most effective surveillance strategy is to screen each patient with an alpha-fetoprotein (AFP) assay and ultrasound imaging on a 6-monthly basis [20]. However, when costs are taken into account it is doubtful whether ultrasound should be routinely offered to those with a blood AFP level of less than 20 ng/mL, as the costs are over US$88 275/QALY gained. At an acceptable threshold of US$50 000, the most costeffective strategy would be an AFP measurement every 6 months (ICER, US$40 600 US/QALY gained). Furthermore, the cost-effectiveness of surveillance for HCC depends on the etiology of cirrhosis. It is much more cost-effective in those with HBV-related cirrhosis than in those with alcoholic liver disease-related cirrhosis.

Cost–effectiveness studies in liver surgery for (colorectal) liver metastases The first cost-effectiveness analysis for hepatic resection for colorectal liver metastases was published by Beard et al in 2000 [21]. They compared the surgical procedure with standard chemotherapeutic treatment. A simple decisionanalysis model based on published and locally derived data was presented. In this study hepatic resection for colorectal liver metastases provides an estimated marginal benefit of 1.6 life-years. Further, surgical resection of the liver for colorectal metastases was highly cost-effective compared with nonsurgical treatment, with a cost per life year gain

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(LYG) of US$2160–13 285. Univariate sensitivity analysis of key model parameters showed the cost per LYG to be consistently less than US$22 000. In this model, hepatic resection appears highly costeffective compared with nonsurgical treatment for colorectal-related liver metastases. However, to unambiguously establish this result with the highest possible evidence level would require a double-blind randomized controlled trial, since the current data only consider the relative economic merits of resection on modeled case series data. However, such a randomized controlled trial of liver resection versus conservative therapy would probably never be approved for ethical reasons, given that conventional nonsurgical treatments show only modest survival benefits for these patients. An indepth analysis of cost-effectiveness is particularly useful for multistage procedures where additional steps might increase cost with limited benefit to the patient. One such study looked at the cost-effectiveness of hepatic resection in patients with metachronous liver metastases from colorectal carcinoma and investigated the impact of operative and follow-up strategies on outcomes, cost, and costeffectiveness [22]. The study considered a treatment strategy comprising resection of up to six metastases and one repeat resection, with computed tomography (CT) follow-up every 6 months. With this approach, a gain of 2.63 QALYs relative to the no-test/no-treat strategy, at an incremental cost of US$18 100/QALY, was achieved. When additional surgical strategies were considered, the ICER (relative to the next least effective strategy) was US$31 700 QALY. More aggressive treatment strategies (i.e. resection of more metastases or resection of recurrent metastases) were superior to less aggressive strategies and had ICERs below US$35 000/ QALY. It was concluded that hepatic resection of metastases appears to be a cost-effective option for selected patients with metachronous colorectal liver metastases limited to the liver. The study provides a first and interesting insight into the economic aspects of complex liver disease, with the caveat that it is based on a heterogeneous patient population and assumptions for the model parameters may have to be re-evaluated. A similar study compared the cost-effectiveness of percutaneous radiofrequency ablation (RFA) versus that of hepatic resection. The authors concluded that RFA is a cost-effective treatment option for patients with colorectal liver metastases [23]. However, in most scenarios, hepatic resection is a more successful therapy than RFA in terms of QALYs gained, and it has an ICER of less than US$35 000/QALY. Colorectal liver metastasis are a very common disease with variable presentation, including in tumor size, and the number and localization of these metastasis. Therefore, several therapeutic options have been developed to best fit the individual patient’s need. Since economic aspects may conflict with pure outcome studies, the latter have


received more attention. In a prospective, nonrandomized pilot study, four different treatment options for colorectal liver metastases were assessed in 40 patients with the goal of identifying the optimal cost-utility ratio. The four options were hepatic resection, RFA, systemic chemotherapy, and symptom control alone. Hepatic surgery appeared to be the most effective approach, with an average benefit of 2.58 QALYs compared with 1.95 QALYs for RFA, 1.18 QALYs for chemotherapy, and 0.82 QALYs for symptom control alone, giving cost-utility ratios of US$7792, US$8056, US$12 571, and US$4788/QALY, respectively [24]. The cost-utility of hepatic resection and RFA are not dissimilar, although with the limited number of cases assessed, it is not clear whether the conclusions drawn can be generalized.

Cost-effectiveness studies comparing partial hepatectomy with orthotopic liver transplantation for the treatment of resectable hepatocellular carcinoma The treatment of patients with compensated liver cirrhosis and small HCCs is still being debated [25–29]. While partial hepatectomy for HCC in cirrhotic liver is widely recommended, another option, orthotopic liver transplantation (OLT), has become more and more attractive [30]. Excellent 5-year patient survivals of greater than 70% after liver transplantation have been reported from many centers using criteria for OLT in patients with HCC similar to or slightly exceeding the Milan criteria (single lesion of ≤5 cm, or two to three lesions of ≤3 cm) [31]. Cost studies in hepatic surgery exist mainly for liver transplantation. Charges for liver transplantation range from US$60 000 to US$200 000 and are higher in the United States than in Europe. As we have already argued above, this difference is explained by the different healthcare systems, in particular the costs of inputs such as drugs and personnel. In general, the risk factors associated with higher costs vary widely for liver transplantation, except for renal insufficiency [32]. In 1997 Sarasin et al showed that there was a substantial survival benefit for patients with HCC treated with OLT compared with liver resection. A minimum of 1 year to a maximum of 4.7 years were gained with OLT, depending on the treatment-related survival rates [33]. However, the magnitude of this benefit depended on the availability of organ donors. Currently, the waiting time for cadaveric organs is long, increasing the risk for tumor growth and dissemination during this time. When this constraint is included in the calculations, the predicted marginal cost-effectiveness ratios of transplantation compared with resection range between US$44 454 and US$183 840/QALY, depending on the time delay before receiving a transplant. Obviously, this range comprises values below and above the often-used US$50 000/ QALY threshold. This documents a need for multiway sen-

535

SECTION 7


sitivity analyses, preferably using probabilistic methods so that a probability distribution can be assigned to the respective extreme possible realizations of the ratio. Ideally this would yield probability assessments such as “the probability that the threshold of $50 000/QALY is exceeded is 10%.”

Cost-utility analysis of living donor living transplantation for hepatocellular carcinoma As the results of cadaveric liver transplantation (CLT) for HCC depend on the waiting time, as shown by Llovet et al [34], a solution to this dilemma can be provided by living donor liver transplantation (LDLT), which allows patients to be transplanted before they develop tumor progression or show metastasis. Sarasin et al showed that LDLT in early HCC offered substantial gain in life-expectancy with acceptable cost-effectiveness ratios [35]. LDLT was cost-effective (10%) and provided gains in life-expectancy of 4.8–6.1 months at an acceptable cost (US$40 000/QALY) for patients waiting for 1 year or more, while for shorter waiting periods it was not cost-effective (US$74 000/QALY). In the same study, the cost-effectiveness of percutaneous treatment, which increases the life-expectancy by 5.2–6.7 months, was shown to be associated with a marginal cost of approximately US$20 000/QALY in all cases and for all waiting periods. These conclusions were confirmed more recently in another institution by Gores et al [37].

Cost-effectiveness of adjuvant therapy strategies after liver resection Adjuvant interferon therapy after surgical resection of hepatitis C-related HCC is a promising therapeutic option. The cost-effectiveness and life-expectancy benefit were investigated in a retrospective analysis by Hoshida et al [38]. They concluded that adjuvant interferon after surgical resection of primary hepatitis C-related HCC improved life-expectancy through suppression of recurrent cancer. The costeffectiveness of US$15 700/QALY compared with no interferon therapy was quite acceptable.

Impact of complications on costs following major hepato-pancreato-biliary surgery The growing demand for quality in healthcare has triggered interest in measuring clinical outcome and costs. Complications have become quantifiable using severity-oriented complication scores. The question remains how complications impact on costs after major HPB surgery. 536

To answer this question our group looked at postoperative outcome and costs (calculated according to the “bottom up” methodology) of 519 consecutive patients undergoing major HPB- surgery in a single interdisciplinary center. Data were prospectively analyzed over a 4-year period (2005–2008) for 404 major liver/bile duct and 115 pancreatic operations. Postoperative complications were evaluated according to a standardized severity-oriented complication score [9], and their impact on inhospital costs was assessed using linear regression models. Cost drivers (independent variables) used for calculation of costs of complications were severity and number of complications, age, Charlson index, American Society of Anesthesiologists (ASA) score, nutrition risk factor, operating time, and hospital stay. Overall mortality was 4.4%, while morbidity was 59.3%. Patients with uneventful courses incurred median costs of US$24 918 (interquartile range (IQR) US$19 598–32 425) per case. Costs increased with the severity of complications and reached US$83 360 (range US$40 794–122 826) for grade 4 complications. For all types of surgery, costs increased with severity of complications. Complications after pancreatic surgery incurred significantly higher costs than liver/bile duct surgery. ASA and type of surgery appeared to be independent risk factors for costs. Additionally, operating time and number of complications correlated with increased cost. This study demonstrates the dramatic impact of severe complications on total inhospital costs, which can increase more than three times. It highlights a relevant savings capacity for HPB procedures, and supports efforts to lower complications, e.g. by treatment in a high-volume centre. Consequently, the severity of complications could be used as an additional cost-determining variable in a DRG system.

Cost comparison of endoscopic stenting versus surgical treatment for unresectable cholangiocarcinoma The limited therapeutic options for unresectable cholangiocarcinomas were analyzed in a retrospective study by Martin et al [39]. They compared the total costs of endoscopic stenting versus surgical therapy in a study including only 20 patients. The median total lifetime costs for surgical therapy was US$60 986 (mean survival 16.5 months) versus US$24 251 (mean survival 19 months) for endoscopic therapy. Consequently, endoscopic therapy is an effective palliative therapy for unresectable cholangiocarcinoma with significantly lower costs and higher life-expectancy compared with surgical treatment.

Summary Only a small number of cost-effectiveness analyses in HPB surgery exist, making recommendations and conclusions difficult. The value of these analyses is very limited mainly because of the study designs (e.g. retrospective analysis,

CHAPTER 44

small case numbers, heterogeneity of patients, lack of standardization, varying country-specific costs, etc). However, results do suggest that both liver resection for colorectal liver metastasis and liver transplantation for HCC are costeffective. Additionally, severe complications dramatically increase costs in liver surgery. Though in countries like the United Kingdom resource allocation is based on QALYs, more consistent empirical evidence is required before this approach can be universally justified. Due to the rising cost of healthcare, economic and cost-effectiveness aspects will probably tend to become more and more important in liver surgery. Ideally, data should be collected prospectively to serve as a base for discussions that may impact on the decision to choose a specific therapeutic option. This discussion may also spawn an ethical debate in view of financial restrictions influencing medical decisions.

Self-assessment questions 1 Quality measurement in surgery, based on the Donabedian paradigm, can be done using which of the following? (more than one answer is possible) A Structure variables B Process variables C Baseline risk of a procedure complication D Outcome variables E Grade of complication 2 Where there is a high baseline risk for a complication for a surgical procedure and a low caseload per hospital, which one of the following variables should be measured? A Process variable B Process and outcome variables C Outcome variables D Structure variables 3 In health economics which one of the following is the only evaluation method that can rank alternatives in absolute terms? A Cost-utility analysis B Cost-benefit analysis C Cost-effectiveness analysis D None of the above 4 What is the often cited threshold level for a QALY? A US$20 000 B US$30 000 C US$40 000 D US$50 000 E US$60 000


References 1 Dranove D, Kessler D, McClellan M, Satterthwaite M. Is more information better? The effects of “report cards” on health care providers. J Political Economy 2003;111:555–86. 2 Birkmeyer JD, Dimick JB, Birkmeyer NJ. Measuring the quality of surgical care: structure, process, or outcomes? J Am Coll Surg 2004;198:626–32. 3 Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume and surgical mortality in the United States. N Engl J Med 2002;346:1128–37. 4 Luft HS, Bunker JP, Enthoven AC. Should operations be regionalized? The empirical relation between surgical volume and mortality. N Engl J Med 1979;301:1364–9. 5 Begg CB, Cramer LD, Hoskins WJ, Brennan MF. Impact of hospital volume on operative mortality for major cancer surgery. JAMA 1998;280:1747–51. 6 The Leapfrog Group. Evidence-based Hospital Referral (EBHR), 2007. Available at: www.Leapfroggroup.org 7 Martin RC 2nd, Brennan MF, Jaques DP. Quality of complication reporting in the surgical literature. Ann Surg 2002;235: 803–13. 8 Clavien PA, Sanabria JR, Strasberg SM. Proposed classification of complications of surgery with examples of utility in cholecystectomy. Surgery 1992;111:518–26. 9 Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien–Dindo Classification of Surgical Complications. Five-Year Experience. Ann Surg 2009;250:187–96. 10 Clavien PA, Strasberg SM. Severity Grading of Surgical Complications. Editorial. Ann Surg 2009;250:197–8. 11 Choti MA, Bowman HM, Pitt HA, et al. Should hepatic resections be performed at high-volume referral centers? J Gastrointest Surg 1998;2:11–20. 12 Dimick JB, Pronovost PJ, Cowan JA Jr, Lipsett PA. Postoperative complication rates after hepatic resection in Maryland hospitals. Arch Surg 2003;138:41–6. 13 Glasgow RE, Showstack JA, Katz PP, Corvera CU, Warren RS, Mulvihill SJ. The relationship between hospital volume and outcomes of hepatic resection for hepatocellular carcinoma. Arch Surg 1999;134:30–5. 14 McKay A, You I, Bigam D, et al. Impact of surgeon training on outcomes after resective hepatic surgery. Ann Surg Oncol 2008;15:1348–55. 15 Killeen SD, O’Sullivan MJ, Coffey JC, Kirwan WO, Redmond HP. Provider volume and outcomes for oncological procedures. Br J Surg 2005;92:389–402. 16 Birkmeyer JD, Sun Y, Goldfaden A, Birkmeyer NJ, Stukel TA. Volume and process of care in high-risk cancer surgery. Cancer 2006;106:2476–81. 17 Fong Y, Gonen M, Rubin D, Radzyner M, Brennan MF. Long-term survival is superior after resection for cancer in high-volume centers. Ann Surg 2005;242:540–4; discussion 4–7. 18 (IQWIG) IfQuWiG. Entwicklung und Anwednungen von Modellen zur Entwicklung von Schwellenwerten für die Knie Total-Endoprothese, Abschlussbericht B05/01a. 2005. 19 Drummond M, Sculpher, M., Torrance, G. Methods for the Economic Evaluation of Health Care Programs, 3rd edn. Oxford: Oxford University Press, 2005. 537

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20 Thompson Coon J, Rogers G, Hewson P, et al. Surveillance of cirrhosis for hepatocellular carcinoma: systematic review and economic analysis. Health Technol Assess 2007;11:1–206. 21 Beard SM, Holmes M, Price C, Majeed AW. Hepatic resection for colorectal liver metastases: A cost-effectiveness analysis. Ann Surg 2000;232:763–76. 22 Gazelle GS, Hunink MG, Kuntz KM, et al. Cost-effectiveness of hepatic metastasectomy in patients with metastatic colorectal carcinoma: a state-transition Monte Carlo decision analysis. Ann Surg 2003;237:544–55. 23 Gazelle GS, McMahon PM, Beinfeld MT, Halpern EF, Weinstein MC. Metastatic colorectal carcinoma: cost-effectiveness of percutaneous radiofrequency ablation versus that of hepatic resection. Radiology 2004;233:729–39. 24 McKay A, Kutnikoff T, Taylor M. A cost-utility analysis of treatments for malignant liver tumours: a pilot project. HPB (Oxford) 2007;9:42–51. 25 Vargas V, Castells L, Balsells J, et al. Hepatic resection or orthotopic liver transplant in cirrhotic patients with small hepatocellular carcinoma. Transplant Proc 1995;27:1243–4. 26 Iwatsuki S, Starzl TE, Sheahan DG, et al. Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg 1991; 214:221–8; discussion 8–9. 27 Bismuth H, Chiche L, Adam R, Castaing D, Diamond T, Dennison A. Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients. Ann Surg 1993;218: 145–51. 28 Moreno P, Jaurrieta E, Figueras J, et al. Orthotopic liver transplantation: treatment of choice in cirrhotic patients with hepatocellular carcinoma? Transplant Proc 1995;27:2296–8. 29 Bruix J. Treatment of hepatocellular carcinoma. Hepatology 1997;25:259–62. 30 McPeake J, Williams R. Liver transplantation for hepatocellular carcinoma. Gut 1995;36:644–6. 31 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;334:693–9.

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32 Sagmeister M, Mullhaupt B. Is living donor liver transplantation cost-effective? J Hepatol 2005;43:27–32. 33 Sarasin FP, Giostra E, Mentha G, Hadengue A. Partial hepatectomy or orthotopic liver transplantation for the treatment of resectable hepatocellular carcinoma? A cost-effectiveness perspective. Hepatology 1998;28:436–42. 34 Llovet JM, Mas X, Aponte JJ, et al. Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation. Gut 2002;50:123–8. 35 Sarasin FP, Majno PE, Llovet JM, Bruix J, Mentha G, Hadengue A. Living donor liver transplantation for early hepatocellular carcinoma: A life-expectancy and cost-effectiveness perspective. Hepatology 2001;33:1073–9. 36 Sagmeister M, Mullhaupt B, Kadry Z, et al. Cost-effectiveness of cadaveric and living-donor liver transplantation. Transplantation 2002;73:616–22. 37 Gores GJ. Hepatocellular carcinoma: gardening strategies and bridges to transplantation. Liver Transpl 2003;9:199–200. 38 Hoshida Y, Shiratori Y, Omata M. Cost-effectiveness of adjuvant interferon therapy after surgical resection of Hepatitis C-related hepatocellular carcinoma. Liver 2002;22:479–85. 39 Martin RC, 2nd, Vitale GC, Reed DN, Larson GM, Edwards MJ, McMasters KM. Cost comparison of endoscopic stenting vs surgical treatment for unresectable cholangiocarcinoma. Surg Endosc 2002;16:667–70.

Self-assessment answers 1 2 3 4

A, B, D D B D

Index

73T strain, Newcastle disease virus 356 “aberrant” arteries 14 abscesses, cryoablation and 228, 235 (Table) “accessory” arteries 14–15, 80 (Fig.) acetic acid ablation 127, 267 clinical results 272 dosage 268 acini 30 acquired immune deficiency syndrome see human immunodeficiency virus infection activated clotting time, isolated hepatic perfusion 164 activated partial thromboplastin time (APTT) on-site monitoring 525–7 for percutaneous ethanol injection 269 acupoints 415 acupuncture 417 acute cholinergic syndrome 107 ACVBP (chemotherapy regimen), post-transplant lymphoproliferative disorders 465 adenoma, hepatic computed tomography 81 magnetic resonance imaging 94 (Fig.) pregnancy 467 transplantation and 285–6 adenovirus 354 (Table), 356–60, 408 adhesions, repeat liver resection 216 adjuvant therapy chemotherapy breast carcinoma metastases 446 cholangiocarcinoma 187 colorectal carcinoma metastases 110–11, 158, 159 (Table), 196, 344–5 see also preoperative chemotherapy HCC 296–303 cost-effectiveness 536 retinoids 297 (Table), 299–300, 387–8 transarterial chemoembolization as 147 see also bridging therapy adoptive transfer, lymphocytes 300 Adriamycin see doxorubicin aflatoxin HCC 54, 489, 515 p53 gene mutations 371, 515 Africa 509–18 afterloading, radionuclide therapy 126 age cholangiocarcinoma incidence 57 colorectal carcinoma metastases 193–4

HCC 52 Africa 509–10 China 510 hepatitis B and C viruses, Africa 510 hepatitis C virus vs hepatitis B virus infections 510, 515 liver resection 310 see also elderly people agenesis of gallbladder 22 AIDS see human immunodeficiency virus infection Akt (protein) 374, 386–7 alcohol cholangiocarcinoma 58, 59, 60, 72 HCC 53–4 Africa 515 Brazil 505 see also ethanol ablation alcoholic steatohepatitis 30–1, 32 algorithms 307 for assessment HCC detection, Japan 490, 491 (Fig.) perioperative cardiac 458–9 for treatment Barcelona Clinic Liver Cancer staging system 319 (Fig.) cholangiocarcinoma 325 (Fig.), 327 (Fig.), 329 (Fig.) colorectal carcinoma metastases 343 (Fig.) gallbladder carcinoma 338–9 Japan 320 (Fig.) HCC 494 (Fig.) liver resection in cirrhosis 309 (Fig.) percutaneous coronary intervention and 459 (Table), 460 (Table) see also clustering algorithms alkali therapy, percutaneous 277 alkaline phosphatase see liver function allocation policies, transplantation for HCC 288–9 alpha-1-antitrypsin deficiency, cholangiocarcinoma 60 fibrolamellar HCC 41 alpha-fetoprotein 43, 69–71 diagnosis 70 HCC 71 Africa 513 Asia 489–90 cost-effectiveness of screening 534 postoperative follow-up 222

hepatoblastoma 477, 481 L3 fraction, HCC surveillance 490 prognosis 127 promoters for gene therapy 354–5, 357 treatment monitoring 70–1 alpha-L-fucosidase 71 alternating current, heating by 244–6 alternative medicine 414–17, 419 altitude, implantable infusion pump flow rates 151 American Joint Committee on Cancer, staging of gallbladder carcinoma 335–6 amplicons, herpes simplex type 1 virus 360–3 amplifications, chromosomal, HCC 370 anatomic resections 181 colorectal carcinoma metastases 194 segment 1 183 anatomy 11–26, 177–8 blood supply 131 see also specific blood vessels historical aspects 4 nomenclature 5, 177–8 pathological distortions 22 regeneration of liver on 216 anesthesia liver surgery 519–30 induction and maintenance 522, 523 percutaneous ethanol injection 268 anesthetic agents, hepatic clearance 522 (Table) angiogenesis 400–4 inhibitors 349, 376–8, 388–9, 400–13 conventional treatment combined with 409 see also specific drugs liver as environment for 402 tumor growth 401–2 angiogenic barrier concept 410 angiogenic switch 400 angiography 93–5, 97 (Fig.) angiosarcoma 439 computed tomography 79–80 internal radiotherapy 132 percutaneous hepatic perfusion 169 selective continuous intra-arterial chemotherapy 152 transarterial embolization 142 angiopoietin-2, HCC 402 angiosarcoma 46, 439–41, 482 chemotherapy 116, 440 transplantation for 291, 440

539

Index angiostatin 407–8 doxorubicin with 409 animal models, molecular targeted therapies 374 anomalies bile ducts 15–16 extrahepatic 23–4 gallbladder carcinoma 333–4 left hemiliver drainage 16 right hemiliver drainage 15–16 cystic artery 23 gallbladder 22 hepatic artery 24, 152 of origin 14 (Fig.) portal vein 18 antennae, microwave thermal ablation 254, 255, 257 anterior approach, liver resection 195 anti-VEGF antibody 404–5 antiangiogenic compounds endogenous 407–8 see also angiogenesis, inhibitors; specific drugs antibody-mediated vascular targeting 409 anticoagulants herbal remedies interacting with 416 isolated hepatic perfusion 164 antineoplastons (Burzynski) 415 antioxidants, dietary 416 antiplatelet therapy 459 antisense oligonucleotides Bcl-2 397 IGF-2 383–4 apoptosis 393–4, 395 (Fig.) induction 393–9 see also TRAIL apoptosis protease activating factor-1 394 appendix, primary neuroendocrine tumors 425 aprotinin 524 arantian plate 21 Aretxabala, Xabier de, on gallbladder carcinoma invasion 504 Argentina metastases 505 colorectal carcinoma 505 transplantation 501, 505 see also River Plate school arginine deiminase 404 (Table) argon, for cryoablation 230 argon beam coagulation, gas embolism 204 Arrow implantable infusion pumps 151, 153 arterialization 33 arteries see blood vessels; named arteries ascites hemorrhagic 97 (Fig.) liver resection planning 179 open vs laparoscopic liver resection 210 Asia 487–99 interferon side-effects 298–9 living donor liver transplantation 492–3 HCC and 288 sorafenib trial 385–6 aspartate, thrombocytopenia 233 atelectasis, cryoablation 233 atracurium, liver transplantation 523 atrophic gastritis, chronic 425

540

autopsy, liver weight, Africa 511 autotransfusion, liver transplantation 523 awareness, anesthesia 522 AXIN1 mutations 388 Ayurveda 414–15 AZD2171 (Recentin) 110, 404 (Table) B4 (bile duct), anomalies 16 bacteria, gallbladder carcinoma 503 Bad (protein), underexpression 396 Bantu visceral siderosis 515 Barcelona Clinic Liver Cancer staging system 139, 140 (Fig.), 317, 318 Japanese guidelines vs 320–1 treatment algorithm 319 (Fig.) bare area 21 bare crease 21 basic fibroblast growth factor, HCC 402 batimastat 408 Bax (protein), underexpression 396 BAY12–9566 (selective MMPI) 408–9 Bcl-2 (protein) antisense oligonucleotides 397 overexpression 396 Beckwith–Wiedemann syndrome 475 Berchtold system, radiofrequency ablation 247 Bernardino needle 268 beta-blockers, perioperative 459 beta-catenin cholangiocarcinoma 61 HCC 388 see also Wnt signaling pathway beta emission, radioconjugates 132 (Table) bevacizumab 404 (Table), 405–6 biliary tract carcinoma 115 breast carcinoma metastases 406 colorectal carcinoma metastases 108–9, 197, 405 neoadjuvant 344 HCC 112, 113, 349, 376, 377 (Table), 388 erlotinib with 376, 389 liver resection and 115, 310, 406 pancreatic endocrine tumors 115 renal cell carcinoma metastases 406 bile duct system (biliary tract) anastomosis, high biliary-enteric 16 anatomy 15–16 extrahepatic 23–4 intrahepatic 11 liver regeneration on 216 anomalies 15–16 extrahepatic 23–4 gallbladder carcinoma 333–4 left hemiliver drainage 16 right hemiliver drainage 15–16 blood supply 24–5 bypass, segment 3 bile duct 16 carcinoma systemic therapy 113–15 see also cholangiocarcinoma; gallbladder, carcinoma caudate lobe 16–17 colorectal carcinoma metastases 48, 111 cystadenocarcinoma 45–6

cysts, cholangiocarcinoma and 57 (Table), 58 excision 337 fibrosis of liver due to diseases of 33 fistula, after cryoablation 235 (Table) preoperative catheterization, cholangiocarcinoma resection 186, 312, 328 radioembolization toxicity 134 strictures gelfoam embolization 142 radiofrequency ablation and 252 see also cholangiography; common bile duct bile salt transporter proteins, cholangiocarcinoma 61 biliary cystadenocarcinoma 45–6 biliary-enteric anastomosis, high 16 biliary fistula, after cryoablation 235 (Table) biliary intraepithelial neoplasia (BilIN) 61 biliary papillomatosis cholangiocarcinoma and 57 (Table), 60 see also intraductal cholangiocarcinoma biliary tract see bile duct system bilirubin, liver resection planning 179 bilomas 23 at cryosites 240 biopsy 474 angiosarcoma 439 fatty liver disease 31 HCC 282 hepatoblastoma 479 hilar cholangiocarcinoma 326 Kaposi sarcoma 462 neuroendocrine tumors 427 post-transplant lymphoproliferative disorders 465 seeding and 282 biotherapy, neuroendocrine tumors 427–8 Bismuth classification, hilar cholangiocarcinoma 326 Bismuth, Henri 6 “blind” instruments, laparoscopic liver transection 206–7 blood loss inferior vena cava pressure 525 (Fig.) resection of liver 180 laparoscopic 208 blood salvage, liver transplantation 523 blood supply 131 bile ducts 24–5 by hepatic artery 11–12 see also vascularity of tumors blood vessels cryotherapy 228 as heat sinks 228, 245–6 sealing system, laparoscopic liver transection 206 see also vascularity of tumors body mass index, HCC mortality 54 body surface area, total liver volume vs 198 boiling carboplatin 275 bone marrow hepatoblastoma 477 radiation dose limitation 134

Index bortezomib 378–9 bracketed technique, microwave thermal ablation 255 Bragg peak 124 Brazil HCC 504–5 liver surgery 501–2 breast carcinoma metastases 48, 443 (Fig.), 445–6 bevacizumab 406 internal radiotherapy 136 MRI contrast agents 95 (Fig.) tumor marker 73 molecular targeted therapies, hazard ratios 379 (Table) breath tests, microsomal hepatic function 310 (Table) breathing motion, external beam radiotherapy 122, 123 bridge of liver tissue (in umbilical fissure), division at hilar cholangiocarcinoma surgery 18 bridging therapy 286–7 chemoembolization, transarterial 286, 287 cost-effectiveness 536 embolization 147 radioembolization 135 radiofrequency ablation 251–2, 286, 287 resection of liver 286–7 cost-effectiveness 536 transarterial chemoembolization 286, 287 Brisbane nomenclature, liver anatomy 5, 11–12, 178, 194 brivanib 404 (Table) Broelsch, Christoph E., split liver transplantation 6 bubbles, after transarterial embolization 143 Budd–Chiari syndrome 489 bystander effect, suicide gene prodrug therapy 353 c-MET/hepatocyte growth factor signaling pathway 350, 384 CA 15-3 (tumor marker) 73 CA 19-9 (tumor marker) 72 colorectal carcinoma metastases 192 gallbladder carcinoma 503 CA 27-29 (tumor marker) 73 “cage” configuration, microwave thermal ablation 255, 257 calcification patterns, gallbladder carcinoma 49 (Fig.), 334 calcineurin inhibitors 287 calcium infusion, liver transplantation 524 Calne, Sir Roy (surgeon) 6 Cancell (biologic remedy) 415 Cancer of the Liver Italian Program score 317, 318 (Table) Cantlie, James, Rex–Cantlie line 4 capabilities see structural measures capecitabine colorectal carcinoma metastases 108 mitomycin with, biliary carcinoma 114 capillarization, sinusoids 33

CAPIRI regimen, colorectal carcinoma metastases 108 CAPOX regimen, colorectal carcinoma metastases 108 bevacizumab with 109 capsule of liver 21–2 11 C-ethanol, dynamic PET 267 11 C-labeled 3,4-dihydroxyphenylalanine PET, neuroendocrine tumors 427 carbon dioxide pneumoperitoneum 204, 504 carboplatin, boiling 275 carcinoembryonic antigen 42, 72 colorectal carcinoma metastases 192, 342 postoperative follow-up 219 cryoablation follow-up 232, 239 gallbladder carcinoma 503 carcinogenesis, cholangiocarcinoma 60–1 carcinogens 59, 60 carcinoid syndrome heart 427, 429 interferon 115–16 carcinoid tumors 424–5 imaging 428 (Fig.) systemic therapy 115–16 tumor markers 73 cardiac assessment, perioperative 458–9 see also electrocardiography cardiac output, liver transplantation 523 cardiac risk 456–60 liver transplantation 520–1 surgery-specific 457–8 cardiotrophin-1 314 Carell, Alexis (surgeon) 6 Caroli syndrome, cholangiocarcinoma and 57 (Table), 58 carriers, hepatitis B virus 488, 514 caseloads, quality assessment methods and 532 caspases 393–4, 395 (Fig.) downregulation in tumors 396 catheter(s) biliary, cholangiocarcinoma resection 186 radionuclides, radiotherapy 126 catheter-assisted angiography 93–5, 97 (Fig.) catheter-assisted arterial portography, CT with 95–6 catheterization pulmonary artery 523 right heart 521 (Table) caudate lobe 12 biliary drainage 16–17 systemic venous drainage 19 caudate veins 12 division 21 cautery, saline-linked 195, 246 cavernous hemangioma 481 Cavitron ultrasonic surgical aspiration (CUSA) 180 CD gene 357 CD34 antigen, angiosarcoma 46 celecoxib 388 cell death temperature 244 see also apoptosis; necrosis Celon system, radiofrequency ablation 247

central fibrosis 33 central pontine myelinolysis 520 central venous pressure, hemostasis and 195, 522 ceramides, apoptosis 394, 397 cerebral edema 519, 520 cetuximab as antiangiogenic agent 404 (Table) biliary tract carcinoma 115 colorectal carcinoma metastases 109, 157, 160, 197, 376, 406–7 HCC 377 (Table), 383 models 373 charged particle radiotherapy 124–5 charring 245 chemical shift imaging, MRI 85 chemicals, industrial 60 chemoembolic therapy 93–4, 127 as control arm for clinical trials 375 neuroendocrine tumors 433–5 see also transarterial chemoembolization chemotherapy 105, 107–21 alpha-fetoprotein 71 angiosarcoma 116, 440 bevacizumab with 405 carcinoembryonic antigen 72 colorectal carcinoma metastases 107–12 adjuvant 110–11, 158, 159, 196, 344–5 cost-effectiveness 535 palliation 112–13 repeat resection vs 218 selective continuous intra-arterial 155–8 gallbladder carcinoma 188, 335, 337, 504 HCC, Africa 514 hepatoblastoma 116, 480 internal radiotherapy with 136 intralesional 275, 276 (Fig.) Kaposi sarcoma 463 liver changes 36, 216, 310 neuroendocrine tumors 432–3 non-Hodgkin lymphoma 463 parenchymal friability 216 post-transplant lymphoproliferative disorders 465 resection of liver, safety after 197 selective continuous intra-arterial 151–63, 523 selective portal vein occlusion and 312 transplantation for cholangiocarcinoma 289–90 see also adjuvant therapy, chemotherapy; FOLFOX; neoadjuvant chemotherapy; preoperative chemotherapy; regional chemotherapy; transarterial chemotherapy chemotherapy-associated steatohepatitis, portal hypertension, radioembolization toxicity 134 chest infections, cryoablation 235 (Table) chest X-ray, raised hemidiaphragm 513 chi (life force) 415 Chiba needle 267–8 chicken-wire fibrosis 32 children 475–86 HCC 481 Africa 510 metastases 482, 496–7 transplantation, Argentina 501

541

Index Children’s Oncology Group (USA), hepatoblastoma staging 478 Chile gallbladder carcinoma 502, 504 HCC 505 liver surgery 502 China HCC 487–8 mean age 510 microwave thermal ablation equipment 253, 254 percutaneous chemical ablation vs liver resection 492 Chinese medicine, traditional 415 Chinese University Prognostic Index 317, 318 (Table) chitosan 134 cholangiocarcinoma 56–63, 324–32 Asia 494–6 computed tomography 81–2 cost comparisons of treatment 536 epidemiology 56–7 etiology 57–60 immunohistochemistry 42 (Table) internal radiotherapy 136 liver changes 35–6 magnetic resonance cholangiopancreatography 98 magnetic resonance imaging and 92 natural history 60–1 pathology 44–5 portal vein anatomy at surgery 17–18 positron emission tomography 84–5, 86 (Fig.) post-transplant 466–7 regional chemotherapy 158–60 resection 175, 186–7 biliary drainage before 312, 328 elderly people 461 staging 43 (Table) intrahepatic 44 perihilar 45, 328 systemic treatment 113–15 transplantation 187, 289–90 hilar tumor 289–90, 328 recurrence after 466–7 tumor markers 72 cholangiography 96–8 CT with, hilar cholangiocarcinoma 82 see also magnetic resonance cholangiopancreatography cholecystectomy gallbladder carcinoma 187, 334, 336, 338–9 prophylactic 503 stopping surgery 339 pregnancy 468 at selective continuous intra-arterial chemotherapy 152 choledochal cysts, cholangiocarcinoma and 57 (Table), 58 cholelithiasis, gallbladder carcinoma 187, 333, 502–3 cholesterol see hypercholesterolemia cholinergic syndrome, acute 107

542

CHOP regimen, post-transplant lymphoproliferative disorders 465 chromogranin, neuroendocrine tumor metastases 48 chromosomes, HCC 369–70 chronic atrophic gastritis 425 CI-1042 (genetically engineered adenovirus) 357–60 cirrhosis 33 abdominal drainage and 181 alpha-fetoprotein 70 cost-effectiveness of screening 534 angiogenesis 388 cholangiocarcinoma 36, 59–60 HCC 53, 281–2 Africa 510, 512–13, 513–14, 515 repeat resection and 222 transplantation 282 nonalcoholic steatohepatitis 454, 455 portal hypertension, radioembolization toxicity 134–5 Pringle’s maneuver and 180 resection of liver 210, 308 algorithms 309 (Fig.) sorafenib and 385 transplantation 282, 284, 285 cisplatin, cholangiocarcinoma 114, 187 cisplatin/epinephrine injectable gel 275, 276 (Fig.) clamp crushing, parenchymal transection 180 clamping inferior vena cava 501, 523–4 laparoscopic liver resection 205 portal triad, intermittent 314 Clavien–Dindo classification of complications 532 clear cell adenocarcinoma, gallbladder 49 clearance (hepatic) drugs 522 (Table) tests 310 (Table) indocyanine green 179, 310–11 clearance (total body), regional drug delivery and 154–5 CLF regimen, biliary tract carcinoma 114 clinical target volume (CTV), radiotherapy 122 clinical trials chemotherapy 110 guidelines 350 molecular targeted therapies 375 CLIP (Cancer of the Liver Italian Program) score 317, 318 (Table) clonidine, liver transplantation 523 Clonorchis sinensis, cholangiocarcinoma and 58, 495 clopidogrel 459 clustering algorithms, genomics 371 CNHK500 (dual-regulated oncolytic adenovirus) 357 CoaguChek-Plus 527 coagulating current 245 coagulation (blood), monitoring 524–7 isolated hepatic perfusion 164 percutaneous ethanol injection 269

coagulopathy cryoablation 235 (Table) see also thrombocytopenia liver transplantation 521 coils, embolization with 142 coils (MRI), high-density surface coils 85–6 cold preservation, donor livers 6 colectomy, open vs laparoscopic, COST trial 207 collagen(s) 30 acetic acid on 267 collagen XVIII 408 Collins formula 154, 155 collision tumors, mixed hepatocellular/ cholangiocarcinoma 45 Colombia, transplantation 502 colorectal carcinoma, ceramide deficiency 397 colorectal carcinoma metastases 64–8, 128, 342–6 bevacizumab 108–9, 197, 405 neoadjuvant 344 bile ducts 48 cetuximab 109, 157, 160, 197, 376, 406–7 chemotherapy 107–12 adjuvant 110–11, 158, 159, 196, 344–5 cost-effectiveness 535 palliation 112–13 repeat resection vs 218 selective continuous intra-arterial 155–8 computed tomography and PET/CT 85 cost-effectiveness of treatments compared 535 cryoablation 236–9 liver resection and 219–20, 228, 236, 238 (Table) synchronous with primary resection 228 detection 65 epidemiology 64–5 epidermal growth factor inhibitors 406–7 extrahepatic 193, 219, 342 G207 virus 362 isolated hepatic perfusion 166–7 Japan 496 laparoscopic resection 212 laser thermal ablation 259–61 microvessel density 403 molecular targeted therapies, hazard ratios 379 (Table) MRI 92 (Fig.) natural history 65–7 number of 193 radioembolization 136 radiofrequency ablation see radiofrequency ablation (RFA), colorectal carcinoma metastases recurrence see recurrence, colorectal carcinoma resection see resections of liver, colorectal carcinoma metastases selective continuous intra-arterial chemotherapy 155–8 South America 505 treatment 128, 342–5 tumor markers 72–3 see also hereditary nonpolyposis colorectal carcinoma syndrome colorectal neuroendocrine tumors 425

Index common bile duct 23 blood supply 24 diameter 23 excision 337 strictures 329 common hepatic artery 13 common hepatic duct 23 blood supply 24 confluence with cystic duct 22, 23 (Fig.) comorbid illness, liver surgery 519 compensated cirrhosis, transplantation and 284, 285 complementary medicine 414, 417–18, 419 information sources 415 (Table) complications effect of staff training 533 impact on costs 536 quality of care and 532 see also specific procedures computed tomographic angiography 79–80 computed tomography 78–85 absent left portal vein 18 angiosarcomas 439 catheter-assisted arterial portography with 95–6 catheter-assisted arteriography with 95–6 colorectal carcinoma metastases 192, 219 contrast agents 98 after cryoablation 232 for cryoablation 230 epithelioid hemangioendothelioma 441 gallbladder carcinoma 334 HCC detection 490 hepatoblastoma 477 left portal vein, absent 18 lipiodol 271 percutaneous ethanol injection 268, 270 positron emission tomography with 83–5, 219 cholangiocarcinoma 86 (Fig.) radiotherapy planning 122 remnant liver volume assessment 311 TACE patients, assessment 143 without contrast agent 80–1 see also multidetector computed tomography concentrations, regional delivery 154–5 conditionally replicative adenovirus (CRAd), immunomodulation 357 conductive heating 245 conformal radiotherapy, fluorodeoxyuridine with 128 conformal treatment planning four-dimensional 123 three-dimensional 122–3, 124 (Fig.), 125 (Fig.) dose–volume histograms 126 (Fig.) Consensus Conference on CLM, statement 198–9 continuous intra-arterial chemotherapy, selective 151–63, 523 contraceptives (oral), hepatic adenoma 467 contrast agents computed tomography 78, 98 HCC detection, Japan 490 MDCT 78 MRI 89–90, 93 (Fig.) adenoma 94 (Fig.)

breast carcinoma metastases 95 (Fig.) double-contrast 90–1 focal nodular hyperplasia 92 gadolinium 88–9 liver-specific 89–90, 93 (Fig.) sonographic 77 contrast-enhanced ultrasound (CEUS) 77 clinical role 78 control arms, clinical trials 375 convective heat loss 245–6 conversion rates, laparoscopic to open liver resection 208 cooling probes for microwave thermal ablation 253, 255 radiofrequency electrodes 246 coronary angiography, for liver transplantation 520–1 coronary artery disease liver transplantation 520 see also cardiac risk coronary ligament 21 coronary revascularization, preoperative 459–60 cost(s) as outcome measures 532 percutaneous ablation therapies 275–6 see also economics cost-benefit analysis 534 cost-effectiveness 534–7 cost–quality trade-off 532 COST trial, open vs laparoscopic colectomy 207 cost-utility analysis 534 living donor liver transplantation, HCC 536 Couinaud, Claude 4, 5 (Fig.) segments of liver 4, 11, 14 (Fig.), 177–8 counter attack against T cells 396 counterstaining, segment 5 segmentectomy 182 cracking of ice ball, cryoablation 233, 235 (Table) Crown needle 267–8 crushing with clamp, parenchymal transection 180 cryoablation 227–43 colorectal carcinoma metastases 236–9 liver resection and 219–20, 228, 236, 238 (Table) synchronous with primary resection 228 complications 523 neuroendocrine tumors 431 postoperative follow-up 232, 233 (Fig.) preanesthetic investigations 520 (Table) preoperative preparation 519 prognostic factors 239–40 cryoassisted wedge excision 217 cryoprecipitate, liver transplantation 524 cryoshock 233, 234 (Table) cryptogenic cirrhosis 455 crystallization of water 227 CTL102 (adenovirus) 360 CTNNB1 gene 371, 388 cure cryoablation with liver resection 240 fibrolamellar HCC 127 repeat resection of colorectal carcinoma metastases 218

cyclooxygenase-2, cholangiocarcinoma 61 cyclophosphamide, activation by P450 2B1 transgene 362 cyclosporine A, historical aspects 6 cyst(s) choledochal, cholangiocarcinoma and 57 (Table), 58 computed tomography 81 cystadenocarcinoma, biliary 45–6 cystadenoma, biliary 46 cystic artery 23 cystic duct anatomy 22, 23 (Fig.) common bile duct mistaken for 24 cystic plate 21, 23 cystic veins 23 cytochrome c, prevention of release 396 cytochrome P450 enzymes cholangiocarcinoma 61 milk thistle and 416 cytokeratins intrahepatic cholangiocarcinoma vs metastases 45 tumor immunohistochemistry 42 (Table) cytokine genes, immunomodulation 356 cytokines, liver regeneration 311 cytology, intraoperative, gallbladder 503 cytoplasm, HCC 40 cytoreductive surgery (debulking) neuroendocrine tumors 424, 428–9, 435 see also downstaging cytosine deaminase gene, suicide gene prodrug therapy 353 cytosolic hepatic function, tests 310 (Table) dacarbazine, neuroendocrine tumors 115 DcR3 (decoy receptor) 396 de Aretxabala, Xabier, on gallbladder carcinoma invasion 504 de novo recurrences HCC 296 after liver transplantation 464, 465–6, 467 death ligands 396 death receptors 393 debulking see cytoreductive surgery decompensated cirrhosis, transplantation and 284, 285 decoy receptors 396 defective infection single-cycle HSVs (DISCs) 360, 361 des-γ-carboxy prothrombin (DCP) 71, 490 desiccation 245 “detoxification” (alternative therapy) 416 dexamethasone, selective continuous intraarterial chemotherapy with 156 (Table), 157 diabetes mellitus cholangiocarcinoma 60 nonalcoholic steatohepatitis 455 steatosis 32 dialysis patients, hepatitis C virus 465 diet alternative therapies 415 iron overload 515 for steatosis 309

543

Index differentiation, as criterion for transplantation 284 diffuse HCC 40 diffusers, laser thermal ablation 259 direct cholangiography 97, 98 (Fig.) computed tomography with, hilar cholangiocarcinoma 82 DISCs (defective infection single-cycle HSVs) 360, 361 Disse, space of 30, 31 (Fig.) disseminated intravascular coagulation, adenoviruses 360 dissemination see seeding of tumor distal cholangiocarcinoma 324, 328–30 distal intrahepatic selective embolization, hepatic artery, neuroendocrine tumors 433 dl1520 (genetically engineered adenovirus) 357–60 dlsptk (HSV mutant), oncolytic therapy 361 DNA, hepatitis B virus, HCC 53 dobutamine stress electrocardiography, for liver transplantation 521 donor livers preservation 6 steatosis 7 donor-origin post-transplant lymphoproliferative disorders 465 DOPA, 11C-labeled, PET, neuroendocrine tumors 427 dopamine, low-dose 523 Doppler ultrasound 76 dorsal resection 183, 184 (Fig.) dorsal sector of liver 177 dosage acetic acid ablation 268 isolated hepatic perfusion, maximum tolerated 165 dose calculation internal radiotherapy 133 see also radiation dose limitations dose–response curves, cytotoxic drugs 155 dose–volume histograms (DVH) 123, 126 (Fig.) safe doses 128 double-contrast MRI 90–1 double gallbladder 22 double-stranded protein kinase, oncolytic therapy 355 doubling times colorectal carcinoma metastases 65–6 HCC 54 Africa 512 downstaging 285 colorectal carcinoma metastases 111–12 see also under transplantation doxorubicin (Adriamycin) angiostatin with 409 HCC 112, 377 (Table) cetuximab with 383 isolated hepatic perfusion 167 sorafenib with 386 neuroendocrine tumors, chemoembolic therapy 434 pancreatic endocrine tumors, streptozocin with 115 RAD001 with 387

544

drainage (surgical) bile duct system, cholangiocarcinoma resection 186, 312, 328 liver resection 181, 186 dropout, transplantation waiting lists 286 see also bridging therapy drug-eluting beads (DEB) 146 drugs hepatic clearance 522 (Table) interactions with herbal remedies 416 prodrugs, suicide gene prodrug therapy 353 dual loop probes, microwave thermal ablation 255 dual-regulated oncolytic adenovirus CNHK500 357 “ducts of Luschka” 23 duodenum, primary neuroendocrine tumors 425 duration of freezing 227 dye injection, selective continuous intra-arterial chemotherapy 152 dynamic positron emission tomography, ethanol in tumors 267 dysplasia–carcinoma sequence, cholangiocarcinoma 61, 62 (Fig.) dysplastic nodules 41 e antigen negativity, hepatitis B virus 515 E1A gene, oncolytic therapy 357 E1B-55K-encoding gene 357 Eastern Cooperative Oncology Group (ECOG), performance status 132 ECF regimen, biliary tract carcinoma 114 echinococcosis, computed tomography 80–1 echocardiography 521 (Table) transesophageal 523, 527 economics 534–7 edges see margins elderly people, resection of liver 460–1 electrical heating 244 electrical stimulation, for pruritus 417 electrocardiography 456–7 liver transplantation 520 dobutamine stress 521 electrodes microwave thermal ablation 254 radiofrequency ablation 245, 246, 247, 248 ELF regimen, biliary tract carcinoma 114 embolization 127 hepatic artery colorectal carcinoma metastases, after liver resection 219–20 neuroendocrine tumors vs chemoembolic therapy 434–5 distal intrahepatic selective 433 recurrent HCC 223 for internal radiotherapy 132 radioconjugates 132 (Table) portal veins 198, 311, 312, 314, 328 after chemotherapy 344 historical aspects 487 see also chemoembolic therapy; internal radiotherapy; postembolization syndrome; transarterial chemoembolization embryonal pattern, hepatoblastoma 43 embryonal rhabdomyosarcoma 47, 482

embryonal sarcoma 47 encephalopathy 519–20 endocrine tumors see neuroendocrine tumors endogenous antiangiogenic compounds 407–8 endogenous opioids, acupuncture and 417 endoscopic stenting, cholangiocarcinoma, costs 536 endoscopic ultrasound gallbladder carcinoma 334 hilar cholangiocarcinoma 326 endostatin 408 endothelial cells 400 antibody-mediated vascular targeting 409 HCC 402 sinusoidal 404 VEGF as survival factor 405 endpoints, clinical trials 375 energy requirements, cardiovascular status 457 (Table) eosinophilic globules, embryonal sarcoma 47 epicholedochal plexus 24 epidemiology 29 cholangiocarcinoma 56–7 colorectal carcinoma metastases 64–5 HCC 52 epidermal growth factor inhibitors 406–7 epidermal growth factor receptor (EGFR) 349, 373, 376, 382–3 cetuximab on 109, 376 panitumumab and 109–10 transforming growth factor α on 374 epidural analgesia, thoracic 522 epinephrine, intralesional chemotherapy 275 epirubicin, pancreatic endocrine tumors 115 epithelial hepatoblastoma 43–4 epithelioid hemangioendothelioma 46–7, 441–2 chemotherapy 116 transplantation for 291, 442 epsilon-aminocaproic acid, liver transplantation 524 Epstein–Barr virus non-Hodgkin lymphoma 463 post-transplant lymphoproliferative disorders 464 p-ERK (MAPK pathway activation marker) 383 erlotinib as antiangiogenic agent 404 (Table) colorectal carcinoma metastases 110 HCC 113, 373, 376, 377 (Table), 383 bevacizumab with 376, 389 sorafenib with 386 Escherichia coli, lacZ gene mutation, gene therapy 362 Essiac (herbal remedy) 416 estimated total liver volume 198 ethanol ablation 127, 266–72 clinical results 271–2 colorectal carcinoma metastases, recurrence after liver resection 220 in combination therapies 274–5 complications 269–70 HCC 251, 321 recurrent 223 metastases 220, 275 in multiablation therapy 275

Index neuroendocrine tumors 432 radiofrequency ablation vs 273–4, 277, 286 costs 276 HCC 251, 321 recurrent HCC 223 technique 268–9 transportal, TACE with 274 etiology cholangiocarcinoma 57–60 HCC 52–4 genetics 52–3, 368–74 etomidate, liver transplantation 523 Europe, treatment guidelines, HCC 318 everolimus 287, 376 evidence, gallbladder carcinoma 333–5 evidence-based guidelines, HCC, Japan 493, 494 (Fig.) examination (physical), cardiovascular status 456 exenteration, transplantation for neuroendocrine tumors with 432 exercise stress testing 520, 521 (Table) experience, value of 533 expression dysregulation, genes 371–2 extended resection, gallbladder carcinoma 336, 337 external beam radiotherapy 122–30 extracellular matrix 30 angiogenesis 400 fibrosis 32–3 extracorporeal circuit isolated hepatic perfusion 164, 165 (Fig.) percutaneous hepatic perfusion 169 extraction of specimen, laparoscopic liver resection 207 incisions 210 extraction ratio, hepatic 155 extrahepatic arteries 24 extrahepatic bile ducts 23–4 extrahepatic cholangiocarcinoma 45, 56 epidemiology 56, 57 survival rates 61 extrahepatic metastases colorectal carcinoma 193, 219, 342 epithelioid hemangioendothelioma 442 exclusion for cryoablation 230 HCC 83 hepatoblastoma 480 extrinsic pathway, apoptosis 393–4, 395 (Fig.) eye melanoma, metastases from, isolated hepatic perfusion 166–7 factor VIII-related antigen, angiosarcoma 46 FADD activation, apoptosis 393 falciform ligament 22 familial adenomatous polyposis 475–6 Fas (protein) decreased in HCC 396 signaling pathway for apoptosis 393 fat, chemical shift imaging, MRI 85 fat-storing cells see hepatic stellate cells fatty liver see nonalcoholic fatty liver disease; steatosis FCU1 gene, suicide gene prodrug therapy 355–6 FELV regimen, biliary tract carcinoma 114 fentanyl, liver transplantation 523

ferumoxides see superparamagnetic iron oxide fetal pattern, hepatoblastoma 43 fever HCC, Africa 512 percutaneous ethanol injection 269 postembolization syndrome 143 fibrinogen fibrolamellar HCC 41 ROTEM TEG analysis 527 (Fig.) fibrinolysis see hyperfibrinolysis fibrolamellar HCC 35, 41, 481 curability 127 epidemiology 513 systemic therapy 113 transplantation and 285, 286 (Table) tumor markers 72 fibrosis 32–4 steatohepatitis 32 nonalcoholic 455 fiducial markers 123 finger fracture technique 487 fish, liver flukes 58 5–5 rule, liver transplantation 493 5-hydroxytryptamine, PET, neuroendocrine tumors 427 floxuridine (FUDR; fluorodeoxyuridine) 151, 154, 427 conformal radiotherapy with 128 cryoablation and 240 G207 virus with 362–3 hyperfractionated radiotherapy with 127 isolated hepatic perfusion 167 pharmacokinetics 155 transarterial chemotherapy 312 fluid management, liver surgery 522 fluorescein injection, selective continuous intraarterial chemotherapy 152, 154 (Fig.) 18 F-fluorodeoxyglucose PET 83 colorectal carcinoma metastases 192 assessment of response to radioembolization 136 computed tomography integrated with 83 cryoablation follow-up 232 neuroendocrine tumors 426, 427 radiofrequency ablation follow-up 252 on role of intraoperative ultrasound 78 see also positron emission tomography fluorodeoxyuridine see floxuridine 5-fluorouracil apoptosis and 397 cholangiocarcinoma 114, 187 colorectal carcinoma metastases 107, 111, 157, 158, 344 neuroendocrine tumors, streptozocin with 115 pharmacokinetics 155 prodrugs tegafur 110 see also capecitabine suicide gene prodrug therapy 353, 355 focal nodular hyperplasia imaging 81, 91 (Fig.) pregnancy 467 FOLFIRI regimen, colorectal carcinoma metastases 107, 108 (Table), 111 cetuximab with 109

FOLFOX regimens, colorectal carcinoma metastases 107, 108 (Table), 157, 158, 218, 220 bevacizumab with 109, 405 cetuximab with 109 neoadjuvant 344 resection with 110–11 FOLFOXIRI, colorectal carcinoma metastases 111 folinic acid 5-fluorouracil with, colorectal carcinoma metastases 107 FUDR with, isolated hepatic perfusion 167 foot massage 418 four-dimensional conformal treatment planning 123 freeze–thaw cycle, repetition 228, 231 frequency (Hz) 245 fresh frozen plasma, liver transplantation 524 friable parenchyma 216 Frizzled (transmembrane receptor) 372 FUDR see floxuridine functional capacity, cardiovascular status 456, 457 (Table) future liver remnant volume, colorectal carcinoma metastases workup 192, 193, 197–8, 199 (Fig.) G207 (multimutated virus) 362–3 gadolinium (contrast agent) lipophilic variants 90 use in MRI 88–9 galactose elimination capacity test 310 (Table) galactosyl human serum albumin, 99mTc-labeled, uptake test 310 (Table) Galen (130–200 AD) 3 gallbladder anatomy 22 anomalies 22 carcinoma 48–9, 333–41 adjuvant transarterial chemotherapy 344 Chile 502, 504 diagnosis 335 epidemiology 57 follow-up 345 PET/CT 85 prognosis 335 resection 187–8 South America 502–4 staging 49, 187, 335–6, 337–8 systemic treatment 113–15 treatment guidelines 333–41 right hepatic duct joining infundibulum 24 68 Ga-octreotide PET, neuroendocrine tumors 427 gallstones cholangiocarcinoma 57 (Table), 59, 495 gallbladder carcinoma 187, 333, 502–3 gamma emission, radioconjugates for internal radiotherapy 132 (Table) gamma probes, neuroendocrine tumors 426 ganciclovir (GCV), suicide gene prodrug therapy 353 gas embolism, laparoscopic liver resection 203–4, 208 gases, for cryoablation 230 gastrinomas 425–6

545

Index gastritis, chronic atrophic 425 gastroduodenal artery, selective continuous intraarterial chemotherapy 152 gastroenteropancreatic NETs, chemotherapy 116 gastrointestinal tract complications of radioembolization 135 post-transplant lymphoproliferative disorders 464 primary neuroendocrine tumors 424–5 gefinitib 376 gelfoam 142 hemostasis, cryoablation 231 gemcitabine cholangiocarcinoma 114 adjuvant chemotherapy 187 mitomycin with 114 gallbladder carcinoma 188 HCC, oxaliplatin with 112–13, 376, 377 (Table) pancreatic endocrine tumors and 115 gender cholangiocarcinoma incidence 57 gallbladder carcinoma 333, 502 HCC incidence 52, 488 Africa 509 gene expression dysregulation 371–2 gene expression profiling, selection criterion for transplantation 284 gene therapy HCC, adjuvant 297 (Table), 300 viral-based 352–67 angiostatin 408 generators microwave thermal ablation 254 radiofrequency ablation 245, 246 genetics cholangiocarcinoma 60–1 colorectal carcinoma metastases 67 HCC, etiology 52–3, 368–74 genomic analyses 349–50 clustering algorithms 371 see also microarray technologies geography HCC 52, 487–8 hepatitis C virus 514 Germany minimum procedure volumes 532 quality measurements 531 gestational immunosuppression 468 gimeracil 110 Gli (protein), Hedgehog pathway signaling on 372 Glisson, Francis (17th century) 3 glucagonomas 426 chemotherapy 433 glycoprotein(s), as tumor markers 72–3 glycoprotein H, cell line for DISC-HSV culture 361 gold seeds (fiducial markers) 123 Goldman cardiac risk index, revised 457 gradient recalled echo sequences, MRI adenoma 94 (Fig.) volumetric 87–8 grading, HCC (WHO) 40

546

granulocyte–macrophage colony-stimulating factor (GM-CSF), gene therapy 361, 363 gross tumor volume (GTV) 122 grounding pads, radiofrequency ablation 247–8 growth factors, liver regeneration 311 growth rates see doubling times Guangxi, China, HCC 487–8 guided imagery 418 guidelines 307 cholangiocarcinoma 325, 327 (Fig.) clinical trials 350 gallbladder carcinoma 333–41 HCC 317–23 Japan 319–21, 493, 494 (Fig.) neuroendocrine tumors 435 (Table) perioperative cardiac assessment 458–9 H2-receptor blockers 428 Haberer, Hans von (surgeon) 4 Habib Laparoscopic Sealer 4XL® 206 half-lives alpha-fetoprotein 70 18 F-fluorodeoxyglucose 83 radioconjugates for internal radiotherapy 132 (Table) hamartoma, mesenchymal 47 hand-assisted laparoscopic liver resection 204, 205 (Fig.), 206, 208, 210 “hanging maneuver,” right hepatectomy 19, 181, 195 harmonic imaging, ultrasound 76–7 harmonic scalpels 206 hazard ratios, molecular targeted therapies 378–9 HB signature see “hepatoblast signature, HB” HCC Healey, John E. 4 nomenclature 177–8 heart carcinoid syndrome 427, 429 catheterization, liver transplantation 521 (Table) HCC invasion 512 toxicity, sorafenib and doxorubicin 386 see also cardiac assessment; cardiac risk heat sinks, blood vessels as 228, 245–6 heating by alternating current 244–6 by microwave energy 253 heavy-ion radiotherapy 125 Hedgehog signaling pathway 372 helical computed tomography see spiral computed tomography hemangioendothelioma infantile 481–2 see also epithelioid hemangioendothelioma hemangioma angiosarcoma vs 439 cavernous 481 computed tomography 81 contrast-enhanced ultrasound 77 pregnancy 467–8 hemidiaphragm, raised on chest X-ray 513 hemihepatectomy 12, 181 see also hepatectomy

hemihypertrophy (overgrowth syndrome) 475 hemilivers 177 biliary drainage anomalies 15–16 inflow occlusion 180 hemochromatosis, HCC 54 hemodynamics contrast-enhanced ultrasound 77 management liver surgery 522–3 liver transplantation 523–4 hemoperitoneum, ruptured HCC 140 hemorrhage biopsy, Kaposi sarcoma 462 hemangioma 467 intracranial pressure monitor placement 520 hemorrhagic ascites 97 (Fig.) hemostasis cryoablation 231, 235 (Table), 240 liver resection 180–1, 522–3 historical aspects 4 laparoscopic 206, 208 two-surgeon technique 195, 196 (Fig.) liver transplantation 524 hepatectomy 12 cost-effectiveness 535 elderly people 461 laparoscopic, transplantation after 212 left hepatic veins 20 laparoscopic 211 (Table) right 19–20, 177 laparoscopic 205–6, 210, 211 (Table) two-stage, metastases 194–5, 312, 313 (Fig.), 342 virtual 80 see also resections of liver hepatic arteries anatomy 11–12 surgical 13–15 see also angiography anomalies 24, 152 of origin 14 (Fig.) chemoembolization (HACE) neuroendocrine tumors 433–5 see also transarterial chemoembolization (TACE) CT angiography 80 (Fig.) distal intrahepatic selective embolization, neuroendocrine tumors 433 infusion (HAI) 105 see also regional chemotherapy; entries beginning transarterial . . . ligation 140 neuroendocrine tumors 433 supply to tumors 131 surgical anatomy 13–15 see also embolization hepatic ducts anomalies 15–16 right, anomalies 23–4 see also common hepatic duct hepatic encephalopathy 519–20 hepatic stellate cells 30, 31 (Fig.) liver fibrosis 33, 34 (Fig.)

Index hepatic veins 178 (Fig.), 183 (Fig.), 184 (Fig.) HCC involvement 512 hemihepatectomy 181 hepatoblastoma involvement 478 liver resection 18–20 hemostasis 195 middle hepatic vein 18–20, 181 (Fig.) hepatico-jejunostomy, bile duct transection 24 hepatico-pancreatico-biliary centers 7 hepatitis, fibrosis 33 hepatitis B virus Africa 514–15 age 510 angiogenesis in infection 388 on apoptosis 395–6 cholangiocarcinoma 59 HCC 52, 53 adjuvant immunotherapy 296–9 Asia 488, 489 children 481 incidence 34–5 radiation-induced liver disease 128 on Raf/MEK/ERK signaling pathway 385 hepatitis C virus Africa 515 age 510 angiogenesis in infection 388 Asia 488–9 Chile 505 cholangiocarcinoma 59 cirrhosis 455 dialysis patients 465 geography 514 HCC 52, 53 adjuvant immunotherapy 296–9 incidence 34 HIV co-infection 463 on Raf/MEK/ERK signaling pathway 385 “hepatoblast signature, HB” HCC 372 hepatoblastoma 43–4, 475–81 Asia 495 (Table) chemotherapy 116, 480 Japan 496 hepatocellular adenoma see adenoma hepatocellular carcinoma adjuvant therapy 296–303 cost-effectiveness 536 retinoids 297 (Table), 299–300, 387–8 Africa 509–18 angiogenesis 402–3 Asia 487–94, 495 (Table) children 481 Africa 510 cirrhosis 53, 281–2 Africa 510, 513–14, 515 repeat resection and 222 transplantation 282 clinical trial design 375 computed tomography 81 contrast-enhanced ultrasound 77 cryoablation 233–4, 236 (Table) diagnosis 282 endogenous antiangiogenic compounds 407–8

epidemiology 52 etiology 52–4 genetics 52–3, 368–74 external beam radiotherapy 126–8 guidelines for treatment 317–23 HIV/AIDS patients 463–4 immunohistochemistry 42–3 isolated hepatic perfusion 167 Japan detection 489–90, 491 (Fig.) evidence-based guidelines 493, 494 (Fig.) resection 490 treatment guidelines 319–21 laparoscopic resection of liver 211–12 liver changes 34–5 microwave thermal ablation 254–5, 257 Milan criteria 135, 283 molecular targeted therapies, hazard ratios 379 (Table) multicentric 220–1 natural history 54 nonalcoholic steatohepatitis 455–6 pathology 40–3 percutaneous ethanol injection 271–2 PET/CT 83–4 post-transplant 465 pregnancy 468 PTEN/MMAC mutations 387 radioembolization 135–6 radiofrequency ablation 251–2, 257 ethanol ablation vs 251, 321 recurrent 223 receptor tyrosine kinases 382–4 see also tyrosine kinase inhibitors recurrence see recurrence, HCC regional chemotherapy 158–60 resection of liver laparoscopic 211–12 see also resections of liver, HCC sarcomatoid 47 screening 54, 71, 184, 463, 465 Asia 489–90 cost-effectiveness 534 signaling pathways 368–81 softness 266 South America 504–5 staging 43, 317, 318 (Table) systemic therapy unresectable tumor 112–13 see also specific drugs transarterial embolization 139–50 as adjuvant therapy 147 efficacy 143–6 transplantation see transplantation of liver, for HCC tumor markers 69–72 vascularity 139, 266 hepatocellular/cholangiocarcinoma, mixed 45 hepatocystic triangle 22 hepatocyte growth factor 350, 374, 384 hepatocytes 30 elderly people 460 mass, tests 310 (Table) preconditioning 180

hepatolithiasis, cholangiocarcinoma 57 (Table), 59, 495 hepatomegaly, Africa 512 hepatoprotection, liver resection 308–16 hepatorenal syndrome gadolinium contrast agents and 89 liver transplantation 521 hepatotoxicity herbal remedies 416 irinotecan 197, 310 HepPar-1 (antibody) 42 Her2/neu (receptor) 373 herbal remedies 416 Chinese medicine 415 hereditary nonpolyposis colorectal carcinoma syndrome 60 Herophilus (330–280 BC) 3 herpes simplex type 1 virus (HSV-1) 360–3 see also thymidine kinase gene (HSV-tk) herpesviruses 359 (Table) multimutated, rRp450 362 safety 363 see also human herpes simplex virus 8 high biliary-enteric anastomosis 16 high-density surface coils, MRI 85–6 high dorsal resection 183, 184 (Fig.) high-dose chemotherapy 155 high-frequency alternating currents 245 high-volume vs low-volume centers 532–3 highly active antiretroviral therapy 462 hilar cholangiocarcinoma 45, 56, 324, 326–8 computed tomography 81–2 resection 175 biliary drainage before 312, 328 with chemotherapy 187 portal vein anatomy 17–18 transplantation 289–90, 328 treatment guidelines 327 (Fig.) hilar communicating artery 24 hilar plate 21 hilar plexus 24 histology HCC 40 liver 467–76 tumor markers 69 historical aspects 3–10, 177 Asia 487, 488 (Table) cryotherapy 227 HCC stage at diagnosis 369 (Fig.) internal radiotherapy 131 microwave thermal ablation 253 radiofrequency ablation 244 South America 500–2 viral therapy 352 history-taking, cardiovascular risk 456 Hjorstjo, Carl-Herman 4 Hjorstjo’s crook 16 holmium-166 132 (Table), 134 Hong Kong liver resection 487, 490 viral hepatitis 488, 489 Honjo, Ichio, liver resection 5 hospital volume 532 hot carboplatin 275

547

Index hot saline injection 272–3 hrR3 (HSV mutant), oncolytic therapy 361–2 human herpes simplex virus 8, 466 human immunodeficiency virus infection cholangiocarcinoma 60 liver tumors associated 462–4 steatosis 32 human macrophage elastase 407–8 human telomerase reverse transcriptase promoter (hTERT), oncolytic therapy 357 hydatid disease, Chile 502 hydrochloric acid, percutaneous injection therapy 277 5-hydroxytryptamine, PET, neuroendocrine tumors 427 hypercalcemia, sclerosing HCC and 42 hypercholesterolemia, paraneoplastic 513 hyperfibrinolysis 524 hyperfractionated radiotherapy 127 hyperthermia 244 hot carboplatin 275 hot saline injection 272–3 isolated hepatic perfusion 164 melanoma metastases 166 hypnotherapy 418 hypocalcemia, liver transplantation 524 hypoglycemia, insulinomas 426 hypotension, liver surgery 523 hypothermia, cryoablation 233 hypoxia-inducible VEGF receptor, gene therapy 361 hypoxia response promoter, oncolytic therapy 357 ice crystallization 227 ICG-001 (molecular agent), on Wnt signaling pathway 378 ICP6 region deletion, rRp450 (multimutated herpesvirus) 362 ideal tumor marker 69, 70 (Table) IFL chemotherapy regimen, colorectal carcinoma metastases 107 ileum, primary neuroendocrine tumors 425 image-guided radiotherapy 123–4 imagery, guided 418 imaging 76–102 carcinoid tumors 428 (Fig.) cryoablation 232 gallbladder carcinoma suspected 339 HCC detection 490 hepatoblastoma 477 neuroendocrine tumors 426–7 percutaneous ethanol injection 268 follow-up 270–1 pretransplant 283 radiofrequency ablation 247 follow-up 252 see also specific modalities imatinib, HCC 376, 377 (Table) immunohistochemistry angiosarcoma 46 embryonal sarcoma 47 liver fibrosis 33, 34 (Fig.) malignant liver tumors 42–3

548

metastases 42 (Table), 48 intrahepatic cholangiocarcinoma vs 45 neuroendocrine tumors 48, 427 immunomodulation adenovirus 357–60 gene therapy 353 retroviruses 355 vaccinia virus 356 HSV amplicons 360–1 Newcastle disease virus 356 immunosuppression 461–7 extrahepatic metastases, epithelioid hemangioendothelioma 442 gestational 468 HCC recurrence 283, 287 historical aspects 6 for viral therapy 352 immunotherapy 300 colorectal carcinoma metastases 108–10 HCC 113 interferon 296–9 see also immunomodulation impedance 245, 246–7 implantable infusion pumps 151–63, 523 failure rates 152–3 incidental discovery, gallbladder carcinoma 338–9 incidental HCC 286 incisions cryoablation 230–1 laparoscopic liver resection hand-assisted 205 (Fig.) specimen extraction 210 open liver resection 210 selective continuous intra-arterial chemotherapy 152 incremental cost-effectiveness ratio (ICER) 534 resection of colorectal carcinoma metastases 535 India, HCC 489 indirect cholangiography 97–8 111 In-octreotide scintigraphy, neuroendocrine tumors 426, 427 111 In-somatostatin analog radiotherapy, neuroendocrine tumors 433 indocyanine green clearance test 179, 310–11 industrial chemicals 60 infantile hemangioendothelioma 481–2 infections chest, cryoablation 235 (Table) drainage tubes 181 implantable pump pockets 154 see also specific viruses infectious mononucleosis 464 inferior vena cava clamping 501, 523–4 drainage of caudate veins 12 HCC involvement 512 hepatoblastoma involvement 478 resection 479, 480 isolation at hepatic resection 20 membranous obstruction 515 pressure, blood loss at surgery 525 (Fig.) venography, percutaneous hepatic perfusion 169

“inferior vena caval ligament” 19 inflammation colorectal carcinoma metastases 67 HCC 53 inflammatory bowel disease, cholangiocarcinoma 60 inflow occlusion 180, 314 by cryotherapy 227 for cryotherapy 228 laser thermal ablation with 261 for radiofrequency ablation 246, 248 see also Pringle’s maneuver infusion pumps see implantable infusion pumps inhalational anesthetic agents hepatic clearance 522 (Table) liver transplantation 523 inhibitor of apoptosis proteins (IAPs) 397 insulin-like growth factor, signaling 374, 383–4 insulin-like growth factor-1 receptor, humanized antibodies 384 insulin-like growth factor-2 and receptor 383–4 insulin-like growth factor receptor-1, signaling pathway 350 insulinomas 426 111 In-octreotide scintigraphy 426 integrative oncology 414–20 intensity-modulated radiotherapy (IMRT) 123 intention-to-treat analyses, transplantation 284–5 interferon adjuvant to liver resection 296–9 cost-effectiveness 536 carcinoid syndrome 115–16 Kaposi sarcoma 463 neuroendocrine tumors 427–8 interleukin-2 HSV amplicon 360 immunomodulation 357 interleukin-6, cholangiocarcinoma 60–1 interleukin-12 HSV amplicon 360 multimutated virus NV1042 363 interleukin-18, immunomodulation 357 intermittent clamping of portal triad 314 intermittent hepatic artery occlusion, neuroendocrine tumors 433 internal radiotherapy 105, 131–8 complications 134–5 gallbladder carcinoma, salvage 345 131 I-lipiodol, adjuvant therapy, HCC 297 (Table), 299 neuroendocrine tumors 433, 435 post-treatment assessment 133 pretreatment assessment 132 technique 133 internal target volume (ITV), radiotherapy 123 International Hepatobiliary Pancreatic Association (IHBPA), Brisbane nomenclature 5, 11–12, 178, 194 international normalized ratio (INR), for percutaneous ethanol injection 269

Index intersectional planes 11, 13 (Fig.) intersegmental planes 11 interstitial electrodes 245 interventional oncology see embolization; internal radiotherapy intra-arterial chemotherapy, selective continuous 151–63, 523 intra-arterial therapy percutaneous, ethanol 274 see also entries beginning transarterial . . . intracellular signaling pathways 384–8 intracranial pressure, liver transplantation 520 intraductal cholangiocarcinoma 324 intraductal papillary neoplasia of bile duct 61 intrahepatic cholangiocarcinoma 44–5, 56, 324–5 Asia 494–6 choledochal cysts 58 epidemiology 56–7 hepatolithiasis 59 internal radiotherapy 136 regional chemotherapy 158–60 resection 186–7 elderly people 461 survival rates 61 transplantation 289 treatment guidelines 325 intrahepatic selective embolization, hepatic artery, neuroendocrine tumors 433 intralesional chemotherapy 275, 276 (Fig.) intraoperative cytology, gallbladder 503 intraoperative management 521–4 intraoperative staging laparoscopy, colorectal carcinoma metastases 192 intraoperative ultrasound 78, 490 cryoablation 230, 232 historical aspects 487 liver resection planning 180, 181 neuroendocrine tumors 426 for radiofrequency ablation 247, 248 (Fig.) intraoperative use of gamma probes, neuroendocrine tumors 426 intravenous access liver surgery 522 liver transplantation 523 intravital microscopy 404 intrinsic pathway, apoptosis 394 invasion cholangiocarcinoma 324 intrahepatic 44 gallbladder carcinoma 337–8, 504 portal veins HCC 222, 283, 490 hepatoblastoma 478 see also vascular invasion 131 I-lipiodol 132 (Table), 133 adjuvant therapy, HCC 297 (Table), 299 131 I-meta-iodobenzylguanidine scintigraphy, neuroendocrine tumors 426–7 ionic friction 244 irinotecan colorectal carcinoma metastases 107, 111, 196 capecitabine with 108 cetuximab with 109

neoadjuvant 344 regional chemotherapy with 158 friable parenchyma 216 liver toxicity 197, 310 iron overload disorders, HCC 54 Africa 515 iron oxide see superparamagnetic iron oxide Iscador (herbal remedy) 416 ischemia, inflow occlusion 180, 314 islet cell tumors 425–6 chemotherapy 432–3 isoflurane, liver transplantation 523 isolated hepatic perfusion (IHP) 105, 164–8, 170 isolated limb perfusion 409 IsoMed implantable infusion pumps 151, 152 (Fig.), 153 Ito cells see hepatic stellate cells Japan colorectal carcinoma metastases 496 HCC detection 489–90, 491 (Fig.) evidence-based guidelines 493, 494 (Fig.) resection 490 treatment guidelines 319–21 hepatitis C virus infection 59 hepatoblastoma 496 liver resection 487 liver weight at necropsy 511 living donor liver transplantation 487, 492–3 microwave thermal ablation, equipment 253 tumor incidence by type 495 (Table) Japan Integrated Staging score 317, 318 (Table) jaundice, gallbladder carcinoma suspected 339 K-ras mutation colorectal carcinoma metastases, on therapy response 160 on EGFR blockade 109 Kaposi sarcoma 462–3, 466 Kasabach–Merritt phenomenon 467 Keen, William W. (surgeon) 3 Klatskin tumor see hilar cholangiocarcinoma Kupffer cells 30 L3 fraction of alpha-fetoprotein, HCC surveillance 490 lacZ gene mutation (Escherichia coli), gene therapy 362 Langenbuch, Carl, surgery, historical aspects 3, 4 (Fig.) “laparoscopic segments” 207, 210 laparoscopy ablative therapies 229 cryoablation 231 ethanol injection therapy 269 neuroendocrine tumors 431 radiofrequency ablation 247, 431 gallbladder carcinoma 334, 336, 339, 504 hilar cholangiocarcinoma, staging 328 intraoperative staging, colorectal carcinoma metastases 192 resection of liver by 203–15 colorectal carcinoma metastases 212

HCC 211–12 open resection vs 208–10 outcomes 207–12 laparotomy, for isolated hepatic perfusion 164 lapatinib 376, 383 large cell change, dysplastic nodules 41 large regenerative nodules 40–1 laser thermal ablation 257–61 late recurrences see de novo recurrences lateral decubitus position, laparoscopic liver resection 203 left hepatectomy hepatic veins 20 laparoscopic 211 (Table) left hepatic duct 16 left hepatic vein 18–20 left lateral decubitus position, laparoscopic liver resection 203 left lateral sectionectomy, laparoscopic 205, 206 (Fig.), 210 left portal vein 17 absence 18 umbilical portion 17, 22 left ventricular dysfunction, sorafenib and doxorubicin 386 leucovorin see folinic acid ligamentum teres 22 ligamentum venosum 17, 22 ligation of hepatic arteries 140 neuroendocrine tumors 433 limited resections see nonanatomic resections Lindbergh, Charles A. 6 linear accelerators, image-guided radiotherapy 123 lipiodol follow-up imaging and 271 188 Re HDD-lipiodol 132 (Table), 134 transarterial chemotherapy 141 see also 131I-lipiodol lipocytes see hepatic stellate cells lipophilic gadolinium variants 90 liquid nitrogen 230 lithiasis cholangiocarcinoma 57 (Table), 59, 495 gallbladder carcinoma 187, 333, 502–3 liver flukes, cholangiocarcinoma and 58–9, 495 liver function colorectal carcinoma metastases workup 192 after cryoablation 233 HCC 221, 222 after preconditioning therapy 314 protection strategies 312–14 radiation-induced liver disease 134 sorafenib on 385 tests before surgery 310–11 see also decompensated cirrhosis “liver kampo” (Chinese botanical) 416–17 liver toxicity herbal remedies 416 irinotecan 197, 310 liver transplantation see transplantation of liver and also bridging therapy; living donor liver transplantation liver tumors of unknown origin 447–9

549

Index living donor liver transplantation 6, 186 Asia 492–3 HCC and 288 hepatocellular carcinoma 287–8 cost-utility analysis 536 historical aspects 487 laparoscopic liver procurement 210–11 Pringle’s maneuver 180 South America 500 lobules 30, 31 (Fig.) loop antennae, microwave thermal ablation 254, 255, 257 Lortat-Jacob, Jean-Louis, liver resection 5 loss of heterozygosity, colorectal carcinoma 73 low birthweight, hepatoblastoma 477 low-concentration alkali therapy, percutaneous 277 low-dose dopamine 523 low-dose nitroglycerine infusion 523 low-volume vs high-volume centers 532–3 lung colorectal carcinoma metastases 110, 193, 219, 342 injury from cryoablation 233 radiation dose limitation 134, 135 lung cancer, molecular targeted therapies, hazard ratios 379 (Table) lung shunt fraction (LSF), internal radiotherapy 132 177 Lu-somatostatin analogs, neuroendocrine tumors 433 lymph nodes aspiration 328 colorectal carcinoma metastases 342 gallbladder carcinoma involvement 337 pedicle, colorectal carcinoma 193 lymphocytes, adoptive transfer 300 lymphoma AIDS 463 liver transplantation for 291–2 post-transplant 464–5 primary hepatic 47, 443–4 Lynch syndrome 60 macroaggregated albumin, 99mTc-labeled, scanning for internal radiotherapy 132 macrobiotic diet 415 macroregenerative nodules 40–1 macrosteatosis, liver resection 308–9 macrotrabecular pattern, hepatoblastoma 43–4 macrovesicular steatosis 31 magnetic field strength, MRI 86–7 magnetic resonance cholangiopancreatography, cholangiocarcinoma 98 magnetic resonance imaging and 92 magnetic resonance imaging 85–93 adenoma 94 (Fig.) clinical role 90–3 contraindications 90 cryoablation 232 gallbladder carcinoma 334 hepatoblastoma 477 hilar cholangiocarcinoma resectability 326

550

laser thermal ablation guidance 259 percutaneous ethanol injection 270 for radiofrequency ablation 247 remnant liver volume assessment 311 magnetic resonance spectrometry, nonalcoholic steatohepatitis prevalence 454 Makuuchi, M., developments in liver tumor management 487 Makuuchi’s criteria 179 Makuuchi’s maneuver 180 Makuuchi’s segmentectomy 181, 182 (Fig.) malignant melanoma see melanoma Mallory bodies 31 (Fig.), 32 mammalian target of rapamycin (mTOR) 374 inhibitors 287, 376 sorafenib with 386 signaling pathway see PI3K/Akt/mTOR signaling pathway mangafodipir trisodium 90 MAPK signaling pathway, HCC 113, 385–6 margins cryotherapy 240 resection of colorectal carcinoma metastases 195–6, 249 marimastat 408 markers see tumor markers mass-forming intrahepatic cholangiocarcinoma 324–5, 496 massage therapy 418 massive HCC 40 mathematics, number of overlapping ablations 248–9 matrix metalloproteinase inhibitors, Kaposi sarcoma 463 matrix metalloproteinases, cholangiocarcinoma 61 maximum intensity projection, MDCT 80 (Fig.) maximum tolerated dose, isolated hepatic perfusion 165 Mayo Clinic protocol, hilar cholangiocarcinoma 328 Medline searches, gallbladder carcinoma 333 Medtronic implantable infusion pumps 151, 152 (Fig.) melanoma, metastases 446–7, 448 (Table) immunohistochemistry of 48 isolated hepatic perfusion 166–7 percutaneous hepatic perfusion 170 MELD score see model for end-stage liver disease (MELD), score melphalan isolated hepatic perfusion 165–7, 168 percutaneous hepatic perfusion 169 membranous obstruction of inferior vena cava 515 Memorial Sloan-Kettering Cancer Center, adjuvant chemotherapy trials 158, 159 (Table) mental imagery see guided imagery meridians (Chinese medicine) 415 mesenchymal hamartoma 47 MET (protein) 384 c-MET/hepatocyte growth factor signaling pathway 350, 384

metabolic syndrome 31 metabolic therapies (alternative medicine) 416 metachronous metastases, colorectal carcinoma 65 metachronous primaries, HCC 221 metallic coils 142 metalloproteinase inhibitors 408–9 metastases Africa, hepatomegaly 512 angiogenesis 403–4 Asia 496–7 bevacizumab 405–6 breast carcinoma see breast carcinoma, metastases children 482, 496–7 cholangiocarcinoma vs 44–5 colorectal carcinoma see colorectal carcinoma metastases computed tomography 82–3 cryoablation 239 HCC, genetics 371 hepatoblastoma 478 immunohistochemistry 42 (Table), 48 intrahepatic cholangiocarcinoma vs 45 intrahepatic cholangiocarcinoma vs 44–5 laser thermal ablation 259–61 liver changes 36 magnetic resonance imaging 92–3 neuroendocrine tumors see neuroendocrine tumors, metastases noncolorectal non-neuroendocrine 444–9 pathology 48 percutaneous ethanol injection 275 radioembolization 136–7 selective portal vein occlusion and 312 South America 505 transplantation for 292 tumor markers 72–3 two-stage hepatectomy 194–5, 312, 313 (Fig.), 342 ultrasound, contrast-enhanced 77 see also extrahepatic metastases metastatic mixed neoplasia, radioembolization 136–7 METAVIR scoring system, liver fibrosis 33, 34 (Fig.) methylation of tumor suppressor genes, cholangiocarcinoma 61 MIBG scintigraphy, neuroendocrine tumors 426–7 microarray technologies angiogenic factors in blood 403 gene expression dysregulation 371 microbubble contrast agents 77 microsatellite instability, colorectal carcinoma 73 microsomal hepatic function, tests 310 (Table) microspheres starch 142 yttrium-90 131–3 microvesicular steatosis 31, 32 microvessel density (MVD) HCC 402–3 metastases 403

Index microwave thermal ablation 253–7 in multiablation therapy 275 radiofrequency ablation vs 255–7, 258 (Table) mid-plane of liver 11, 12 (Fig.) midazolam, liver transplantation 523 middle cholangiocarcinoma 328–9 middle hepatic vein 18–20, 181 (Fig.) Milan criteria HCC 135, 283 liver transplantation 492, 493 Milican (radioconjugate) 132 (Table), 134 milk thistle 416 mind–body therapies 418 see also traditional alternative medical systems mindfulness-based stress reduction (MBSR) 418 minimum procedure volumes 532 Mirizzi, Pablo 500 Mirizzi syndrome, right hepatic duct anomaly 24 Mirizzi technique 500 mitochondrial membrane proteins apoptosis regulation 394 overexpression 396 mitogen-activated protein kinase signaling pathway, HCC 113, 385–6 mitomycin, biliary carcinoma capecitabine with 114 gemcitabine with 114 mixed epithelial/mesenchymal hepatoblastoma 44 mixed hepatocellular/cholangiocarcinoma 45 mixed metastatic neoplasia, radioembolization 136–7 MOC-31 (antibody) 42–3 model for end-stage liver disease (MELD), score 179, 288 HCC 288 Argentina 505 modified vaccinia virus (MVA) 355–6 molecular pathogenesis HCC 368–74 see also signaling pathways molecular targeted therapies 374–9 monoclonal antibodies colorectal carcinoma metastases 196 see also specific drugs mortality cholangiocarcinoma extrahepatic 57 intrahepatic 57 colorectal carcinoma 64 HCC body mass index 54 from treatment 368 high-volume vs low-volume centers 532–3 mosaic vessels 409 Mozambique, HCC 510 age distribution 510 MTH68 strain, Newcastle disease virus 356 mTOR see mammalian target of rapamycin; PI3K/ Akt/mTOR signaling pathway mucins, intrahepatic cholangiocarcinoma 44

multiablation therapy 275 multicentric HCC 220–1 multidetector computed tomography (MDCT) 78–9 gallbladder carcinoma 334 hilar cholangiocarcinoma resectability 326 magnetic resonance imaging compared with 90 multikinase inhibitors see sorafenib; sunitinib multimutated herpesviruses 362–3 multiple endocrine neoplasia type 1, pancreatic neuroendocrine tumors 426 multiple repeat liver resections colorectal carcinoma metastases 219 HCC 222 multistage procedures, colorectal carcinoma metastases, cost-effectiveness 535 multivisceral transplantation, neuroendocrine tumors 432 muscularis propria, gallbladder carcinoma invasion 337 music therapy 417–18 mutations hepatitis B virus 515 see also specific mutations myelinolysis, central pontine 520 myoglobin release, cryoablation 233, 235 (Table) National Comprehensive Cancer Network Guidelines Panel for HCC 318–19 natural history cholangiocarcinoma 60–1 colorectal carcinoma metastases 65–7 HCC 54 nausea acupuncture 417 mind–body therapies 418 necropsy, liver weight, Africa 511 necrosis apoptosis vs 394, 395 effect of ethanol 267 radiofrequency ablation 245 transarterial embolization response 143 needle guidance, cryoablation 231 needles percutaneous ethanol injection 267–8 see also biopsy neoadjuvant chemotherapy colorectal carcinoma metastases 110–11, 112, 344 HCC, children 481 primary lymphoma 444 transplantation for cholangiocarcinoma 289–90 see also preoperative chemotherapy neodymium:YAG laser 259 nephrogenic systemic sclerosis 89 neuroendocrine tumors computed tomography 82 (Fig.) metastases 48, 424–38 cryoablation 230, 234–6 isolated hepatic perfusion 167, 168 (Fig.) percutaneous hepatic perfusion 169–70 radioembolization 136

radiofrequency ablation 249 transplantation for 290–1 systemic therapy 115–16 neurofibromatosis, schwannomas 442–3 neuropathy, oxaliplatin 108 neurotensin, fibrolamellar HCC 72 Newcastle disease virus 354 (Table), 356, 358 (Table) NHANES III (survey), nonalcoholic steatohepatitis 454 nitric oxide, cholangiocarcinoma 61 nitrogen, liquid 230 nitroglycerine, low-dose infusion 523 nitrosoamines, cholangiocarcinoma 59 “no-touch technique,” hilar cholangiocarcinoma resection 328 nodular HCC 40 nodules, precursor lesions of HCC 40–1 nolatrexed, HCC 377 (Table) nomenclature 11–26 liver anatomy 5, 177–8 Brisbane nomenclature 5, 11–12, 178, 194 neuroendocrine tumors 424 non-Hodgkin lymphoma, AIDS 463 nonalcoholic fatty liver disease 454–5 HCC 35 nonalcoholic steatohepatitis 31, 32, 310, 454–6 HCC 455–6 nonanatomic resections 181, 183 colorectal carcinoma metastases 194 noncolorectal non-neuroendocrine metastases 444–9 nonsmall cell lung cancer, molecular targeted therapies, hazard ratios 379 (Table) norepinephrine infusion, liver surgery 523, 524 North American staging, children 476 (Table) nuclear medicine imaging hepatoblastoma 477 for internal radiotherapy 132 neuroendocrine tumors 426–7 see also positron emission tomography 99m Tc-galactosyl HSA uptake test 310 (Table) see also internal radiotherapy NV1020, NV1034, NV1042 (multimutated viruses) 363 obesity gallbladder carcinoma 333 HCC 54 nonalcoholic steatohepatitis 454, 455 steatosis 31 occlusion, vascular see inflow occlusion octreotide 427–8 68 Ga-labeled, PET, neuroendocrine tumors 427 HCC 112 adjuvant therapy 297 (Table), 300 111 In-labeled, scintigraphy of neuroendocrine tumors 426, 427 ocular melanoma metastases, isolated hepatic perfusion 166–7 Okuda staging system 317, 318 (Table) omega-3 fatty acids, for steatosis 309 oncogenes, cholangiocarcinoma 61

551

Index oncolytic therapy 353–4 adenovirus 357–60 hrR3 (HSV mutant) 361–2 HSV-1 361 Newcastle disease virus 356 reovirus 355 ribonucleotide reductase 361–2 Onyx-015 see dl1520 (genetically engineered adenovirus) open colectomy, vs laparoscopic 207 open liver resection incisions 210 vs laparoscopic 208–10 conversion rates 208 open surgery, radiofrequency ablation 247 opioids, endogenous, acupuncture and 417 Opisthorchis viverrini, cholangiocarcinoma and 58–9, 495 optimal center size 533 oral contraceptives, hepatic adenoma 467 osteopontin 372 oteracil 110 outcome measures, quality of care 531–2 oval cells, hepatitis C virus infection 59 overlapping ablations, number of 248–9 oxaliplatin in biliary tract carcinoma regimens 114 colorectal carcinoma metastases 107–8, 111, 157, 196–7 neoadjuvant 344 regional therapy 158 friable parenchyma 216 HCC, gemcitabine with 112–13, 376, 377 (Table) isolated hepatic perfusion 170 liver toxicity 197, 310 oxygen saturation measurement, liver transplantation 521, 523 p-ERK (MAPK pathway activation marker) 383 p53 (protein), apoptosis 394 p53 gene mutations 370–1, 396, 515 replacement 353 P450 2B1 transgene, rRp450 (multimutated herpesvirus) 362 packaging genes 354 pain HCC, Africa 510–11 music therapy 417 percutaneous ethanol injection 269 “pale bodies,” fibrolamellar HCC 41 palliation chemotherapy, colorectal carcinoma metastases 112–13 gallbladder carcinoma 337 neuroendocrine tumor metastases, resection 429, 430, 435 percutaneous ethanol injection 267 see also complementary medicine pancreas distal cholangiocarcinoma 324, 328–30 endocrine tumors 425–6 systemic therapy 115, 116

552

pancreaticobiliary duct anomalies, gallbladder carcinoma 333–4 pancreaticoduodenectomy, distal cholangiocarcinoma 330 panitumumab, colorectal carcinoma metastases 109–10 papillomatosis, biliary cholangiocarcinoma and 57 (Table), 60 see also intraductal cholangiocarcinoma parallel imaging, MRI 87 paraneoplastic phenomena 512, 513 parenchyma friable 216 transection 180–1 laparoscopic 205–7 parenteral nutrition, steatosis 32 partial thromboplastin time see activated partial thromboplastin time particle size, radioconjugates for internal radiotherapy 132 (Table) Patched (receptor) 372 pathology liver 467–76 malignant liver tumors 40–51 pathway addiction 373 pazopanib 404 (Table) pedicle lymph nodes, colorectal carcinoma 193 pedicles, portal 21 clamping in laparoscopic liver resection 205 division 21 see also inflow occlusion; Pringle’s maneuver pedicular cholangiocarcinoma 328–9 pentoxifylline 314 percutaneous chemical ablation 127, 266–80 China 492 clinical results 271–2 colorectal carcinoma metastases 219–20 in combination therapies 274–5 complications 269–70 guidelines, West vs East 321 HCC radiofrequency ablation vs 251 recurrent 223 metastases 275 in multiablation therapy 275 neuroendocrine tumors 432 technique 268–9 percutaneous coronary intervention 459–60 percutaneous cryoablation 231 percutaneous hepatic perfusion (PHP) 168–70 percutaneous hot water injection see hot saline injection percutaneous radiofrequency ablation 247 perfusion isolated hepatic (IHP) 105, 164–8, 170 isolated limb 409 percutaneous hepatic (PHP) 168–70 tests 310 (Table) see also implantable infusion pumps periductal infiltrating intrahepatic cholangiocarcinoma 324–5 perihilar cholangiocarcinoma see hilar cholangiocarcinoma

perioperative cardiac assessment 458–9 see also electrocardiography peripheral cholangiocarcinoma see intrahepatic cholangiocarcinoma peritoneal carcinomatosis 193 see also seeding of tumor Peru HCC 505 liver surgery 502 pharmacokinetics, selective continuous intraarterial chemotherapy 154–5 pheochromocytoma, duodenal neuroendocrine tumors and 425 phosphatidylinositol-3-kinase pathway 349, 374, 386–7 phospholipase C-gamma 382 32 P-GMS 132 (Table), 134 physical examination, cardiovascular status 456 physical signs, HCC, Africa 511–12 PI3K/Akt/mTOR signaling pathway 349, 374, 386–7 PIAF regimen, HCC 112 Pichlmayr, Rudolf, split graft transplantation 6 PIP3 phosphatases 387 pityriasis rotunda 512 PIVKA-II (protein induced by vitamin K absence; des-γ-carboxyprothrombin), HCC surveillance 71, 490 PKI116 (epidermal growth factor inhibitor) 406 planning target volume (PTV), radiotherapy 123 plasminogen 402 plate/sheath system 20–1 platelet counts hepatoblastoma 477 for percutaneous ethanol injection 269 see also thrombocytopenia pleural effusions, cryoablation 233, 235 (Table) PLUTO (Pediatric Liver Unresectable Tumor Observatory) 480 pneumonitis, radiation-induced 135 pneumoperitoneum 203–4, 504 polyprenoic acid 300, 387–8 polyps, gallbladder, malignancy 334 polyvinyl alcohol 142, 144–5 pontine myelinolysis, central 520 populations, for clinical trials 375 port sites laparoscopic liver resection 204 resection of 337 portal fibrosis 33 portal hypertension liver resection and 221 radioembolization toxicity 134–5 portal pedicles 21 clamping in laparoscopic liver resection 205 division 21 see also inflow occlusion; Pringle’s maneuver portal veins anatomy 17–18, 178 liver regeneration on 216 catheter-assisted arterial portography, CT with 95–6

Index embolization 198, 311, 312, 314, 328 after chemotherapy 344 historical aspects 487 ethanol injection TACE with 274 thrombolysis 267 invasion HCC 222, 283, 490 hepatoblastoma 478 MDCT venography 80 selective occlusion 311–12, 313 (Fig.) thrombosis (PVT) 142 internal radiotherapy suitability 135 see also left portal vein portography, catheter-assisted arterial, CT with 95–6 positioning of patient, laparoscopic liver resection 203 positron emission tomography cholangiocarcinoma 84–5, 86 (Fig.) colorectal carcinoma metastases 342 computed tomography with 83–5, 219 cholangiocarcinoma 86 (Fig.) dynamic, ethanol in tumors 267 extrahepatic disease 230 gallbladder carcinoma 334 neuroendocrine tumors 427 before radiofrequency ablation 249 see also 18F-fluorodeoxyglucose PET postembolization syndrome 134, 143 postoperative complications impact on costs 536 liver transplantation 524, 524 (Table) postoperative morbidity, factors 523 postreperfusion syndrome 524 power Doppler ultrasound 76 pravastatin, HCC 297 (Table), 300 preclinical models, molecular targeted therapies 374 precocious puberty 477 preconditioning inflow occlusion 180, 314 pharmacologic 314 precursor lesions, HCC 40–1 pregnancy alpha-fetoprotein 70 gallbladder carcinoma 502 liver tumors 467–8 magnetic resonance imaging and 90 preload, transesophageal echocardiography 527 preoperative assessment 519–21 pregnancy 468 see also electrocardiography; perioperative cardiac assessment preoperative catheterization of biliary tract, cholangiocarcinoma resection 186, 312, 328 preoperative chemotherapy breast carcinoma metastases 446 colorectal carcinoma metastases 196–7 Consensus Conference on 198–9 hepatoblastoma 480 see also neoadjuvant chemotherapy preoperative coronary revascularization 459–60

preoperative observation period, repeat resection of colorectal carcinoma metastases 219 presentation, gallbladder carcinoma, basis for therapeutic algorithm 338–9 PRETEXT system, staging in children 476, 477–8, 479 (Table) pretransplant imaging 283 primary colorectal carcinoma, resection 342 primary sclerosing cholangitis cholangiocarcinoma 57 (Table), 58 perihilar 45 tumor markers and 72 transplantation 289 Pringle’s maneuver 180, 195, 314 laser thermal ablation with 261 radiofrequency ablation 248 see also inflow occlusion prioritization, transplantation for HCC 288–9 probes cryoablation 230, 231 gamma-emitting, neuroendocrine tumors 426 intraoperative ultrasound 78 radiofrequency ablation 246, 248 process measures, quality of care 531 prodrugs, suicide gene prodrug therapy 353 proliferation index, neuroendocrine tumor metastases 290 Prometheus 3, 4 (Fig.) promoter hypermethylation, cholangiocarcinoma 61 proper hepatic artery 13, 131 left hepatic artery mistaken for 15 (Fig.) prophylactic cholecystectomy, gallbladder carcinoma 503 propofol 522 prostacycline analogs, pulmonary hypertension 520 prostate specific antigen, metastases 48 protease inhibitors 408–9 proteasome activation, drugs inhibiting 378–9 protective techniques, liver resection 308–16 protein kinase(s) 384–5 double-stranded, oncolytic therapy 355 protein kinase C 382 prothrombin induced by vitamin K absence or antagonist-11 (PIVKA-11) 71, 490 prothrombin time, on-site monitoring 525–7 proton magnetic resonance spectrometry, nonalcoholic steatohepatitis prevalence 454 proton pump inhibitors 428 proton radiotherapy 125 pruritus acupuncture 417 gallbladder carcinoma 337 PTEN/MMAC mutations, HCC 387 PTEN mutation 374 publication of quality measurements 531 pulmonary artery catheterization, liver transplantation 523 pulmonary function, liver transplantation 521 pulmonary hypertension 520 pulse diagnosis (Chinese medicine) 415 pulsed current, radiofrequency ablation 246 pumps see implantable infusion pumps

quality adjusted life years 534 quality of care, measurement 531–3 Quattlebaum, Julian K., liver resection 5 R7020 (multimutated virus) 363 RAD001, doxorubicin with 387 radiation dose limitations lung 135 188 Re HDD-lipiodol 134 radiation exposure liver tolerance 122, 127–8 reduction technology, MDCT 80 radiation-induced liver disease (RILD) 127, 128, 134 radiation pneumonitis 135 radiation therapy see radiotherapy radioembolization see internal radiotherapy radiofrequency ablation (RFA) 127, 244–53, 490–1 clinical studies 249–52 colorectal carcinoma metastases 249–51 cost-effectiveness 535 after liver resection 220 liver resection vs 251 synchronous with primary resection 228 compensated cirrhosis 284 complications 252 cryoablation vs 229, 240 ethanol ablation vs 273–4, 277, 286 costs 276 HCC 251, 321 HCC ethanol ablation vs 251, 321 recurrent 223 liver resection vs 185 metastases 275 microwave thermal ablation vs 255–7, 258 (Table) in multiablation therapy 275 neuroendocrine tumors 431–2, 435 transplantation, bridging therapy 251–2, 286, 287 radiofrequency-assisted hepatic resection 206 Radionics/Valleylab system, radiofrequency ablation 247 radionuclides radiotherapy 126 neuroendocrine tumors 433 transarterial therapy (TART), 188Re HDD-lipiodol 134 see also nuclear medicine radiosurgery see stereotactic body radiotherapy Radiotherapeutics system, radiofrequency ablation 246–7 radiotherapy 105 colorectal carcinoma metastases 128 external beam 122–30 gallbladder carcinoma 504 HCC 126–8 hepatoblastoma 480 planning 122–6 transplantation for cholangiocarcinoma 289–90 see also internal radiotherapy

553

Index Raf/MEK/ERK signaling pathway, HCC 113, 385–6 randomized clinical trials 375 rapamycin (sirolimus) 374, 376 Kaposi sarcoma 466 transplantation for epithelioid hemangioendothelioma 291 rapid infusion systems 522 rapid sequence induction of anesthesia 523 Ras signaling pathway 387–8 oncolytic therapy 355 see also K-ras mutation real-time tumor tracking, radiotherapy 123 receptor tyrosine kinases, HCC 382–4 see also tyrosine kinase inhibitors rectum carcinoma 116 primary neuroendocrine tumors 425 recurrence cholangiocarcinoma, post-transplant 466 colorectal carcinoma 158 after cryoablation 239 CT and PET/CT 85 detection 219 prevention 220 radiofrequency ablation vs resection 251 HCC 175, 185 de novo 296 prediction by molecular studies 372 after resection 220–1, 222–3, 252, 296–303 after transplantation 283, 287, 465–6 after liver transplantation 464, 465–6, 467 after microwave thermal ablation 257 after percutaneous ethanol injection 271 see also repeat resection, liver reflexology 418 regeneration of liver 3, 5, 311 bevacizumab on 197 elderly people 460 friable parenchyma 216 portal vein embolization 198 see also macroregenerative nodules regenerative nodular hyperplasia, chemotherapy 36 regional chemotherapy 105, 158–60 colorectal carcinoma metastases 158, 159 (Table) cryoablation with 238 (Table) see also transarterial chemoembolization (TACE); transarterial chemotherapy regional delivery, concentrations 154–5 remnant liver volume assessment 311 see also future liver remnant volume renal cell carcinoma bevacizumab for metastases 406 clear cell adenocarcinoma vs, gallbladder 49 renal failure cryoablation and 233 gadolinium contrast agents and 89 liver surgery 523 renal function, liver surgery 519, 521 renal transplantation HCC 465 transarterial chemoembolization and 466

554

reovirus 355 repeat resection gallbladder carcinoma 334–5 liver 185, 216–26 repeat transplantation for HCC 466 reperfusion liver transplants 524 thromboelastography 526 (Fig.) preconditioning 314 “replaced” arteries 13–14, 14–15 replication, liver cells 311 resectability colorectal carcinoma metastases 65, 111–12, 175, 193–4, 344 vs chemotherapy response 156 factors precluding 67 gallbladder carcinoma (de Aretxabala) 504 HCC Africa 514 children 481 hepatoblastoma 479 hilar cholangiocarcinoma 326 resection of port sites 337 resection of wounds, gallbladder carcinoma surgery 503 resections of liver 175, 177–91 anatomy 13–15, 177–8 Asia 487, 490, 492 bevacizumab and 115, 310, 406 Brazil 501 breast carcinoma metastases 445–6 as bridging therapy for transplantation 286–7 cost-effectiveness 536 Chile 502 cholangiocarcinoma hilar 326 intrahepatic 495–6 colorectal carcinoma metastases 110–11, 175, 192–202, 342–4 cost-effectiveness 534–5 cryoablation and 219–20, 228, 236, 238 (Table) margin status 195–6, 249 radiofrequency ablation previously 220 radiofrequency ablation vs 251 repeat 217–20 compensated cirrhosis 284 contraindications 179 cryoablation and 236, 238 (Table), 240 elderly people 460–1 gallbladder carcinoma 335, 336, 337 HCC 175, 183–6, 490 cost-effectiveness 535 elderly people 461 HIV/AIDS patients 464 post-transplant 466 radiofrequency ablation vs 251 recurrence 220–1, 222–3, 252, 296–303 repeat surgery 220–3 hemihepatectomy 12, 181 hepatic veins 18–20 hemostasis 195 hepatoblastoma 479, 480

historical aspects 3–5 inferior vena cava isolation 20 intraoperative management 521–3 melanoma metastases 446–7 neuroendocrine tumors 428–31, 435 Peru 502 portal veins 17–18 preanesthetic investigations 520 (Table) preoperative biliary drainage 312, 328 protective techniques 308–16 repeat 216–26 gallbladder carcinoma 334–5 HCC 185 River Plate school 500–1 safety after chemotherapy 197 steatosis 308–10, 456 surgical anatomy 13–15, 177–8 terminology 12, 13 (Fig.), 14 (Fig.) two-stage hepatectomy, metastases 194–5, 312, 313 (Fig.), 342 virtual 80 see also cardiac risk; hepatectomy; laparoscopy, resection of liver by resistance (electrical) 245 resistive heating 244 respiratory motion, external beam radiotherapy 122, 123 response rates, as clinical trial endpoints 375 retinoids, HCC, adjuvant therapy 297 (Table), 299–300, 387–8 retroviruses 358 (Table) gene therapy 354–5 Rex–Cantlie line 4 RFA see radiofrequency ablation rhabdomyosarcoma, embryonal 47, 482 188 Re HDD-lipiodol 132 (Table), 134 ribonucleotide reductase, oncolytic therapy 361–2 right heart catheterization, liver transplantation 521 (Table) right hemiliver drainage, biliary anomalies 15–16 right hepatectomy 19–20, 177 laparoscopic 205–6, 210, 211 (Table) right hepatic artery accessory 80 (Fig.) anomaly 24 right hepatic ducts, anomalies 23–4 right hepatic veins 19 right portal vein, absence 18 RILD (radiation-induced liver disease) 127, 128, 134 RITA system, radiofrequency ablation 246, 248 rituximab, post-transplant lymphoproliferative disorders 465 River Plate school 500–1 RNA encapsidation signal, hepatitis B virus 514–15 Rokitansky Aschoff sinuses, gallbladder carcinoma invasion 337 “rolloff,” radiofrequency ablation programs 247 ROTEM TEG analyzer 525, 527 (Fig.) rRp450 (multimutated herpesvirus) 362

Index rupture adenoma 467 HCC Africa 511 hemoperitoneum 140 hemangioma 467 S-1 (fluoropyrimidine) 110 safety adenoviruses 360 herpesviruses 363 liver resection after chemotherapy 197 protective techniques 308–16 saline, hot 272–3 saline-linked cautery 195, 246 Salmonella spp., gallbladder carcinoma 503 salvage chemotherapy, gallbladder carcinoma 345 salvage of blood, liver transplantation 523 salvage transplantation, HCC 222, 285 sarcomas Asia 495 (Table) post-transplant 466 primary hepatic 46–7, 439–41 undifferentiated 47, 440–1, 482 sarcomatoid HCC 47 Saudi Arabia, viral hepatitis 489 schwannoma, hepatic 442–3 scintigraphy see nuclear medicine sclerosing cholangitis see primary sclerosing cholangitis sclerosing HCC 42 scoring systems liver fibrosis 33, 34 (Fig.) tumor marker grading 69 see also model for end-stage liver disease; staging screening, HCC 54, 71, 184, 463, 465 Asia 489–90 cost-effectiveness 534 second primaries, HCC 221 sectional arteries, hepatic 11 sectional bile ducts, anomalies 16 sectionectomies 12, 13 (Fig.), 194 laparoscopic 205, 206 (Fig.), 210 sectors, liver 177 sedation, percutaneous ethanol injection 268 seeding of tumor biopsy 282 gallbladder carcinoma 334, 337, 504 radiofrequency ablation and 252, 286 see also peritoneal carcinomatosis SEER Registry, cholangiocarcinoma 56 segment 3 bile duct, biliary bypass 16 segmental arteries 11 segmentectomies 12, 177, 181–3, 194 segment 1 183, 184 (Fig.) segment 4, 3 and 2 183 segment 5 182–3 segment 6 183 segment 7 183 segment 8 181–2 segments (Couinaud) 4, 11, 14 (Fig.), 177–8 segments (Healey) 177–8

segments (‘laparoscopic’) 207, 210 selection effect, publication of quality measurements 531 selective continuous intra-arterial chemotherapy 151–63, 523 selective embolization via hepatic artery, neuroendocrine tumors 433 selective internal radiotherapy see internal radiotherapy sepsis, cholangiocarcinoma 61 septa, in tumors 267 seroma, implantable pump pocket 153–4 serotonin acupuncture and 417 liver regeneration 311 see also carcinoid syndrome 73T strain, Newcastle disease virus 356 sevoflurane 314 shaft antennae, microwave thermal ablation 253, 255 shape of liver 22 shark cartilage 415 SHARP trial, sorafenib 113, 378 (Fig.) sheaths, plate/sheath system 20–1 Sho-Saiko-To (Chinese botanical) 416–17 “shrunken” gallbladder 22 sialic acid, as tumor marker 72–3 signaling pathways 349–50 for apoptosis 393 HCC 368–81 Raf/MEK/ERK 113, 385–6 Ras 387–8 oncolytic therapy 355 see also K-ras mutation targeted therapies 376–8, 382–92 Wnt 61, 350, 371, 372 drugs targeting 378–9, 388 signs, HCC, Africa 511–12 simulation, external beam radiotherapy 122 Singapore, HCC prevention 489 single photon emission computed tomography, neuroendocrine tumors 426 sinusoids 30 endothelial cells 404 liver fibrosis 33 obstruction, cytotoxic drugs 197, 310 SIOPEL/PRETEXT system, staging in children 476, 477–8, 479 (Table) SIR-Spheres® (radioconjugate) 132 dose calculation 133 sirolimus (rapamycin) 287, 289 Kaposi sarcoma 466 transplantation for epithelioid hemangioendothelioma 291 skin, cetuximab toxicity 109 slice thickness, MDCT 78–9 small cell change, dysplastic nodules 41 small cell undifferentiated pattern, hepatoblastoma 44 small intestine, primary neuroendocrine tumors 425 smoking cholangiocarcinoma 58 hepatoblastoma 477

Smoothened (receptor) 372 sodium, central pontine myelinolysis 520 sodium hydroxide, percutaneous 277 softness, HCC 266 somatostatin HCC 112 neuroendocrine tumors 427 somatostatin analogs 427–8 radiolabeled, radiotherapy with 433 see also octreotide somatostatinomas 426 sorafenib 404 (Table) on angiogenesis 389 control arm for clinical trials 375 HCC 113, 135, 140, 287, 349, 377 (Table), 378, 385–6, 407 adjuvant therapy 300 adverse events 113 unresectable 287 South America 500–8 space of Disse 30, 31 (Fig.) specimen extraction, laparoscopic liver resection 207 incisions 210 sphere, volume of 268 spherical ablations 246 maximum size 248 sphingomyelin transport molecules 397 Spiegelian lobe 11 spiral computed tomography 78, 83 see also multidetector computed tomography splenic artery, selective continuous intra-arterial chemotherapy 152 split liver transplantation 6 Src (non-receptor tyrosine kinase) 383 staging 127 children 475, 476 PRETEXT system 476, 477–8, 479 (Table) cholangiocarcinoma 43 (Table) intrahepatic 44 perihilar 45, 328 colorectal carcinoma metastases, intraoperative laparoscopy 192 gallbladder carcinoma 49, 187, 335–6, 337–8 HCC 43, 317, 318 (Table) hepatoblastoma 44, 477–8 Kaposi sarcoma 462 liver fibrosis 33 malignant liver tumors 43 see also Barcelona Clinic Liver Cancer staging system staining, segmentectomy 182 standardized future liver remnant volume 198 stapler hepatectomy 206 starch microspheres 142 Starzl, Thomas E., liver transplant 5 statins, perioperative 459 steatosis 30–2 chemical shift imaging, MRI 85 cytotoxic agents causing 197, 344 donors for transplantation 7 liver resection 308–10, 456 see also nonalcoholic fatty liver disease

555

Index stellate cells, hepatic 30, 31 (Fig.) liver fibrosis 33, 34 (Fig.) stents cholangiocarcinoma, costs 536 gallbladder carcinoma 335, 337 stereotactic body radiotherapy (SBRT) 123, 124 (Fig.), 125 (Fig.) dose–volume histogram 126 (Fig.) stomach carcinoma, metastases from 447, 448 (Table) primary neuroendocrine tumors 425 streptozocin, neuroendocrine tumors 115 structural measures, quality of care 531, 532–3 subserosa, gallbladder carcinoma invasion 337–8 succinylcholine, liver transplantation 523 suicide gene prodrug therapy 352–3 adenovirus 356–60 retroviruses 354 vaccinia virus 355–6 sunitinib 404 (Table) HCC 113, 376–8, 388–9 superior mesenteric artery, catheter-assisted arterial portography 95 superparamagnetic iron oxide (SPIO) 90 MRI 93 (Fig.), 96 (Fig.) double-contrast 90–1 supine position, laparoscopic liver resection 203 surface tumors, percutaneous ethanol injection contraindicated 267 surgery historical aspects 3–5 pregnancy 468 surgery-specific cardiac risk 457–8 survivin 397 Swedish massage 418 symptoms, HCC, Africa 510–11 SynchroMed EL implantable infusion pumps 153 (Table) synchronous metastases, colorectal carcinoma 64–5 synergism G207 virus 362–3 HSV amplicons 360 systemic therapy 107–21 preoperative, colorectal carcinoma metastases 196–7 regional chemotherapy with 157 T-cell lymphoma, primary hepatic 47 T1-weighted images, MRI 85 cryoablation 232 T2-weighted images, MRI 85 TACE see chemoembolic therapy; hepatic arteries, chemoembolization (HACE); transarterial chemoembolization (TACE) Taiwan finger fracture technique 487 HCC 489 resection 490 hepatitis B virus vaccination 481 tamoxifen, HCC 112 tape, “hanging maneuver,” right hepatectomy 195

556

tattooing, segmentectomy 182 taxanes, pancreatic endocrine tumors and 115 99m Tc-galactosyl HSA, uptake test 310 (Table) 99m Tc-macroaggregated albumin, scanning for internal radiotherapy 132 TEG (thromboelastography) 524–5, 526 (Fig.), 527 (Fig.) tegafur 110 telomerase reverse transcriptase (TERT) immunization 379 see also human telomerase reverse transcriptase promoter (hTERT) temozolomide, pancreatic endocrine tumors 115 temperature (body), infusion pump flow rates 151–2 temperature (tissues) cell death 244 cryotherapy 227 temsirolimus 376 termination of pregnancy, HCC 468 terminology see nomenclature testosterone, HCC and 52 tetracycline, VEGF inhibition 405 Thailand, cholangiocarcinoma 56, 58–9 thalassemia, HCC 54 thalidomide 404 (Table), 408 pancreatic endocrine tumors 115 thawing, cryotherapy 227–8, 231 TheraSphere® (radioconjugate) 132 dose calculation 133 thermal ablation 244–65 see also microwave thermal ablation; radiofrequency ablation thermocouples cryoablation monitoring 232 laser ablation monitoring 259 thin slices, MDCT 78–9 thoracic epidural analgesia 522 thoracic route, percutaneous ethanol injection 268 thoracoscopy, hand-assisted laparoscopic liver resection with 210 Thorotrast 59 angiosarcoma 46 cholangiocarcinoma 57 (Table) three-dimensional conformal treatment planning 122–3, 124 (Fig.), 125 (Fig.) dose–volume histograms 126 (Fig.) three-dimensional images MDCT 78 volumetric MRI 87–8 threshold levels, quality adjusted life years 534 thrombocytopenia 521 cryoablation 233 see also coagulopathy thromboelastography 524–5, 526 (Fig.), 527 (Fig.) thrombolysis, percutaneous ethanol injection 267 thromboplastins coagulation monitoring 527 see also activated partial thromboplastin time thrombosis, portal veins (PVT) 142 internal radiotherapy suitability 135

thymidine kinase gene (HSV-tk) oncolytic therapy 361 suicide gene prodrug therapy 353, 354, 356–60 thyroid gland, 131I-lipiodol and 133 Tibetan yoga 418 ticlodipine 459 Tijuana, Mexico, metabolic therapies 416 time to progression as clinical trial endpoint 375 sorafenib on 385 tines, radiofrequency ablation 246 TMUGS (Tumor Marker Utility Grading Scheme) 69 worksheet 70 (Fig.) total body clearance, regional drug delivery and 154–5 total liver volume 197–8 total vascular exclusion 180 toxicity heart, sorafenib and doxorubicin 386 herbal remedies 416 irinotecan 197, 310 radioembolization 134–5 skin, cetuximab 109 TRADD activation, apoptosis 393 traditional alternative medical systems 414–15 TRAIL (TNF-related apoptosis-inducing ligand), immunomodulation 357 training of staff effect on complications 533 laparoscopic liver resection 212 tranexamic acid, liver transplantation 524 transabdominal ultrasound 76–8 transaminases see liver function transarterial chemoembolization (TACE) 105, 127, 139–40, 141, 492 as adjuvant therapy 147 efficacy 143–6 follow-up imaging 271 HCC before cryoablation 234 recurrent tumor 223 hepatoblastoma 480 131 I-lipiodol therapy vs 133 laser thermal ablation after 261 percutaneous ethanol injection with 274 portal vein occlusion with 312 radiotherapy with 128 renal transplant patients 466 transplantation of liver, bridging therapy 286, 287 see also chemoembolic therapy transarterial chemotherapy cryoablation with 240 gallbladder carcinoma, adjuvant 344 lipiodol as carrier 141 selective portal vein occlusion with 312 see also selective continuous intra-arterial chemotherapy transarterial embolization (TAE) HCC 139–50 as adjuvant therapy 147 efficacy 143–6

Index laser thermal ablation after 261 percutaneous ethanol injection with 266, 274 transarterial radionuclide therapy (TART), 188Re HDD-lipiodol 134 transcatheter arterial embolization see transarterial embolization transcatheter radioembolization see internal radiotherapy transducers, intraoperative ultrasound 78 transection bile ducts, hepatico-jejunostomy 24 parenchymal 180–1 laparoscopic 205–7 transection line, intraoperative ultrasound 180 transesophageal echocardiography, liver transplantation 523, 527 transforming growth factor α, HCC models 373–4 transforming growth factor β hepatitis C virus, HCC 53 after portal vein embolization 198 radiation-induced liver disease 127 transforming growth factor β1 71 type II receptor gene mutation 73 transhepatic tumoral intubation (Praderi) 500 transition tumors, mixed hepatocellular/ cholangiocarcinoma 45 transplantation of kidney HCC 465 transarterial chemoembolization and 466 transplantation of liver 175, 281–95, 492 anesthesiology 519–21, 523–4 for angiosarcoma 291, 440 Argentina 501, 505 Brazil 501–2 for breast carcinoma metastases 446 children 481 Chile 502 for cholangiocarcinoma 187, 289–90 hilar 289–90, 328 Colombia 502 cryptogenic cirrhosis 455 for epithelioid hemangioendothelioma 291, 442 guidelines, West vs East 321 for HCC 167, 185–6, 281–9, 292 children 481 cost-effectiveness 535 HIV/AIDS patients 464 noncirrhotic patients 285–6 recurrence after 283, 287, 465–6 repeat 466 “salvage” 222, 285 for hepatoblastoma 479–80 historical aspects 5–7 after laparoscopic hepatectomy 212 for neuroendocrine tumors 432 Peru 502 preanesthetic investigations 520 (Table) South America 500, 501–2, 505 steatosis and 32 thromboelastography 525, 526 (Fig.) transesophageal echocardiography 523, 527 tumors developing after 464–7

see also bridging therapy; living donor liver transplantation transportal ethanol injection, TACE with 274 transthoracic route, percutaneous ethanol injection 268 transverse portion, left portal vein 17 trastuzumab 373, 376 trauma, rupture of HCC, Africa 511 triple loop antenna, microwave thermal ablation 255 trisectionectomy 12 trocars, laparoscopic liver resection 204 TroVax (MVA virus carrying tumor antigen 5T4 gene) 356 tumor-associated markers 69 tumor growth angiogenesis 401–2 selective portal vein occlusion 312 tumor markers 69–75 gallbladder carcinoma 503 neuroendocrine tumors 427 see also CA 19–9 tumor necrosis factor (TNF), isolated hepatic perfusion 166–7 tumor necrosis factor alpha signaling pathway for apoptosis 393 as therapy 397 tumor-specific markers 69 tumor suppressor genes cholangiocarcinoma 61 replacement 353 adenovirus 357 retroviruses 354–5 tumorectomies see nonanatomic resections two-dimensional treatment planning, external beam radiotherapy 122 two-stage hepatectomy, metastases 194–5, 312, 313 (Fig.), 342 two-surgeon techniques, liver resection hemostasis 195, 196 (Fig.) laparoscopic 212 tyrosine kinase inhibitors 376, 407 see also receptor tyrosine kinases ulcers, gastrointestinal, after radioembolization 135 Ulex europaeus, angiosarcoma 46 Ulster strain, Newcastle disease virus 356 ultrasonic dissectors 195 Cavitron ultrasonic surgical aspiration 180 laparoscopic surgery 206 ultrasonic scalpels, laparoscopic surgery 206 ultrasound 76–8 gallbladder carcinoma 334, 503 hepatoblastoma 477 laparoscopic 205 liver resection planning 180 nonalcoholic steatohepatitis prevalence 454 percutaneous ethanol injection 268, 270 postoperative follow-up 219 see also echocardiography; endoscopic ultrasound; intraoperative ultrasound umbilical plate 21 umbilical portion, left portal vein 17, 22

“umbilical vein” 18 United States of America Children’s Oncology Group, hepatoblastoma staging 478 microwave thermal ablation 253, 254, 255 treatment guidelines, HCC 318 University of California, San Francisco-expanded criteria for liver transplantation 283, 493 University of Wisconsin solution 6 unknown origin, liver tumors of 447–9 unsaturated vitamin B12-binding capacity, fibrolamellar HCC 72 upper abdominal exenteration, transplantation for neuroendocrine tumors with 432 urokinase-type plasminogen activator 71 Uruguay, River Plate school 500–1 vaccination, hepatitis B virus 53, 481, 489 vaccinia virus 354 (Table), 355–6, 358 (Table) vandetanib 404 (Table) variants see anomalies vascular endothelial growth factor 376 blood levels 403 factor A (VEGF-A) 349 HCC 402 hypoxia-inducible receptor, gene therapy 361 inhibition 404–6 metastases 403–4 receptor binding AZD2171 110 bevacizumab 108–9 vascular exclusion, total 180 vascular injury, radioembolization 135 vascular invasion HCC 283 portal veins HCC 222, 283, 490 hepatoblastoma 478 vascular occlusion see inflow occlusion vascular status of tumors 409 vascular targeting 409 vascularity of tumors contrast-enhanced ultrasound 77 HCC 139, 266 vessels supplying 131 see also blood vessels vasoactive intestinal peptide 426 VEGF factor A (VEGF-A) 349 vena cava see inferior vena cava venography inferior vena cava, percutaneous hepatic perfusion 169 portal veins (by MDCT) 80 venous access liver surgery 522 liver transplantation 523 venovenous bypass isolated hepatic perfusion 164 liver transplantation 524 total vascular exclusion of liver 180 Verner–Morrison syndrome 426 very low birthweight, hepatoblastoma 477 vessel sealing system, laparoscopic liver transection 206

557

Index VIPomas 426 viral-based gene therapy 352–67 angiostatin 408 virilization 477 virtual hepatectomy 80 visualization (guided imagery) 418 vitamin A derivatives, HCC, adjuvant therapy 297 (Table), 299–300, 387–8 vitamin B12-binding capacity, fibrolamellar HCC 72 vitamin K 521 Vivant Medical system, microwave thermal ablation 255 volume of liver 80, 197–8 remnant 198, 311 volume of sphere 268 volume of tumor, gross (GTV) 122 volume overload, liver surgery 523 volume-rendered MDCT 80 (Fig.) volumetric MRI 87–8 von Recklinghausen disease, schwannomas 442–3

558

waiting lists for transplantation 288 on cost-effectiveness 535 dropout 286 see also bridging therapy watersheds blood supply to bile ducts 24 hepatic blood supply 11 wave distortion, ultrasound 76–7 WDHA syndrome (Verner–Morrison syndrome) 426 websites complementary and alternative medicine 415 (Table) guidelines on HCC 318, 319 wedge resections 194 repeat 216–17 see also nonanatomic resections Weibel-Palade bodies 46 Wendell, Walter, liver resections 4 Wnt signaling pathway 61, 350, 371, 372 drugs targeting 378–9, 388 World Health Organization, grading of HCC 40

wound resection, gallbladder carcinoma surgery 503 XELIRI regimen, colorectal carcinoma metastases 108 cetuximab with 109 XELOX regimen, colorectal carcinoma metastases 108 cetuximab with 109 xenografts, drug evaluation 374 yoga 418 yttrium-90 historical aspects 131 microspheres 131–3 90 Y-somatostatin analogs, neuroendocrine tumors 433 ZD 6126 (vascular targeting agent) 409 Zollinger–Ellison syndrome 425, 428 zone of necrosis, radiofrequency ablation 245

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